Clinical trial NCT03189563
Conditions: Parkinson's Disease
Sponsor: Dong-A ST Co., Ltd.
Start date: 2018-02-06; Completion date: 2019-04-10
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase IIa, first in human, randomized, double-blind, multicenter study to evaluate the safety, tolerability and efficacy of DA-9805 at 45mg, 90mg versus placebo in subjects diagnosed with early Parkinson's disease.

Detailed description:
Parkinson's disease (PD) is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies.

Parkinson's disease affects an estimated 1.5 million persons in the United States, with over ten million affected worldwide, and these estimates are expected to increase substantially in the next few decades. Despite the increasing prevalence, the approved agents for the early management of Parkinson's disease have changed little in the past decade; however, there have been advances in drug delivery, dosing, and the use of combination therapy in an attempt to reduce adverse events. The most important, unmet medical need in targeting Parkinson's disease is developing agents with neuroprotective potential. So far, no drug has been shown to reduce or slow down the progression of PD.

DA-9805 is a botanical drug product composed of three main raw herbal materials. It is expected that DA-9805 will help treat PD by prevention of dopaminergic neurodegeneration via recovery of mitochondrial dysfunction, anti-inflammatory effect and relief from Endoplasmic reticulum (ER) stress and oxidative stress.

Arms: arm 1: placebo, tid arm 2: DA-9805 45mg arm 3: DA-9805 90mg
Interventions: intervention 1: DA-9805 45mg intervention 2: DA-9805 90mg intervention 3: Placebo
Intervention descriptions: intervention 1: DA-9805 15mg tid intervention 2: DA-9805 30mg tid intervention 3: Placebo, tid

Protocol documents:
Prot_000.pdf: 
 
Protocol # DA-9805-PD-001 
Version 3.0 
Date: 12 Jul2017  
 
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Page 1 of 110 
 
A 
PHASE 
IIA, 
RANDOMIZED, 
MULTICENTER, 
DOUBLE-BLIND, 
PLACEBO-
CONTROLLED STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND EFFICACY 
OF DA-9805 IN SUBJECTS WITH PARKINSON’S DISEASE 
 
 
Protocol Number: 
DA-9805-PD-001 
Version Number: 
Version 3.0 
Version Date 
12 Jul2017 
Development Phase: 
Phase IIa 
Investigational Compound: 
DA-9805 
Control: 
Placebo 
 
 
Sponsor: 
Dong-A ST Co., Ltd. 
Protocol Prepared By: 
Amarex Clinical Research, LLC 
20201 Century Blvd, 4th Floor 
Germantown, MD  20874 
USA 
 
Confidentiality Statement 
 
This protocol is provided for conducting a clinical research study. The information contained in this 
document is confidential and, except to the extent necessary to obtain informed consent or IEC/IRB 
approval, cannot be disclosed unless required by governmental regulation. Persons to whom any 
portion of the contents of this document is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
 
 
 


 
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PROTOCOL APPROVAL PAGE 
 
 
 
 
Protocol Number:  
DA-9805-PD-001 
 
Version: 
 
Version 3.0 
 
Date: 
 
12 Jul2017 
We, the undersigned, have reviewed this protocol and agree that it contains all relevant information 
required to meet FDA, GCP and all applicable regulatory guidelines and statutes. 
PROTOCOL APPROVAL FOR USE 
 
 
 
 
 
 
Anandkrishnan 
Balasubramanian; 
B.Pharm 
(Hons); Amarex Clinical Research, LLC 
Project Manager 
 
 
Date 
 
 
 
 
  
 
Shide Badri, MD; Amarex Clinical Research, 
LLC.  
Medical Monitor 
 
Date 
 
 
 
 
  
 
Hana 
Mekonnen, 
MA; 
Amarex 
Clinical 
Research, LLC.  
Biometrics 
 
 
 
 
 
Date 
 
Jin Seok Jeong; Dong-A ST Co., Ltd. 
Research Scientist, Strategic Project Team 
  Date 
 
 
 


 
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INVESTIGATOR’S SIGNATURE PAGE 
 
 
 
Protocol Number:  
DA-9805-PD-001 
 
Version: 
 
Version 3.0 
 
Date: 
 
12 Jul2017 
 
I have read the protocol specified above and agree to participate in and comply with the procedures, as 
outlined herein for the conduct of this clinical trial. I also agree to comply with US Food and Drug 
Administration (FDA) regulations and Investigational Review Board/Institutional Ethics (IRB/IEC) 
requirements for testing on human subjects. I agree to ensure that the requirements for obtaining 
informed consent are met.  
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
Date 
Print Name 
 
 
 
 
 
 
Site Number 
 
 
 
 
 
 
 


 
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STUDY SPONSOR INFORMATION 
Dong-A ST Co., Ltd. 
Primary Contact: 
Dong-A ST Co., Ltd. 
 
64, Cheonho-daero  
 
Dongdaemun-gu 
 
Seoul, Korea 
 
 
E-mail: 
treadwheel@donga.co.kr 
 
 
 
CLINICAL RESEARCH ORGANIZATION INFORMATION 
 
Amarex Clinical Research, LLC (Amarex) 
 
Amarex Office: 
Amarex Clinical Research, LLC. 
 
20201 Century Boulevard, 4th Floor 
 
Germantown, MD 20878 USA 
 
Project Manager: 
Anandkrishnan Balasubramanian 
Telephone number: 
+1 (301) 956-2531 
Fax number: 
+1 (301) 528-2300 
E-mail: 
anandb@amarexcro.com  
 
Medical Monitor: 
Shide Badri, MD 
 
Telephone number:  
+1 (240) 454-6844 
Fax number: 
+1 (240) 454-6602 
E-mail: 
saereporting@amarexcro.com 
 
 
 


 
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LIST OF ABBREVIATIONS 
TERM 
DEFINITION 
% 
Percent 
ADR 
Angelica dahurica root 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
Amarex 
Amarex Clinical Research, LLC. 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
BCRP 
Breast Cancer Resistance Protein 
BMI 
Body Mass Index 
BF 
Bupleurum Root 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COX-2 
Cyclooxygenase-2 
CRF 
Case Report Form 
CFR 
Code of Federal Regulations 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology criteria for Adverse events 
CV 
Curriculum vitae 
DAT 
Dopamine Transporter 
DSMC 
Data Safety and Monitoring Committee 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorder-Version 5 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
ER 
Endoplasmic reticulum 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
g/dL 
grams/deciliter 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practices 
HDL 
High Density Lipoprotein 
HEENT 
Head, Ears, Eyes, Nose, and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 


 
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TERM 
DEFINITION 
H&Y 
Hoehn and Yahr 
IA 
Interim Analysis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-B 
Interleukin-1b 
iNOS 
Inducible Nitric Oxide Synthase 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intra Uterine Device 
IWRS 
Interactive Web Based Response System 
Kg 
Kilograms 
LDH 
Lactate Dehydrogenase 
LPS 
Lipopolysaccharides 
MAO-B 
MonoAmine Oxidase type B inhibitors 
MAPK 
Mitogen-activated protein serine/threonine kinase 
MC 
Moutan Root Bark 
MCV 
Mean corpuscular volume 
MDS-UPDRS Movement Disorder Society - Unified Parkinson Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFDS 
Ministry of Food and Drug Safety 
Mg 
Milligrams 
mg/dL 
Milligram/deciliter 
mmol/L 
Millimole/Liter 
MMRM 
Mixed Model Repeated Measures  
MMSE 
Mini-Mental State Examination 
MPP+ 
1-methyl-4 phenylpyridinium 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
Msec 
Milliseconds 
MC 
Moutan Root Bark 
NF-κB 
Nuclear Factor Kappa B 
OAT 
Organic Anion Transporter 
OATP 
Organic Anion Transporter Polypeptide 
OCT 
Organic Cation Transporter 
OECD 
Organization for Economic Co-operation and Development 
OHDA 
Neurotoxin 6-hydroxydopamine 
PD 
Parkinson’s Disease 
PDE 
Phosphodiesterase 
PDQ 
Parkinson's Disease Questionnaire 
PP 
Per Protocol 
RBC 
Red Blood Cells 


 
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TERM 
DEFINITION 
RR 
Respiration Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard Deviation 
SOP 
Standard Operating Procedures 
SN 
Substantia Nigra 
SNpc 
Substantia Nigra pars compacta 
ST 
Striatum 
S&E 
Schwab and England 
TEAE 
Treatment Emergent Adverse Event 
TH 
Tyrosine Hydroxylase 
TID 
ter in die (Three times daily) 
TNF 
Tumor Necrosis Factor 
TV 
Treatment Visit 
U/L 
Units/Liter 
UGT 
Uridine 5'-diphospho-Glucuronosyltransferase 
USA 
United States of America 
WBC 
White Blood Cells 
WHO 
World Health Organization 
μL 
Microliter 
 
 
 
 


 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  
Dong-A ST Co. Ltd 
Name of Study Product: DA-9805 tablet 
Comparator Product: Placebo tablet 
Protocol Number:  
DA-9805-PD-001 
Indication:  
Parkinson’s Disease 
Title of Study: 
A Phase IIa, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability and Efficacy of DA-9805 in Subjects With Parkinson’s Disease. 
Study Center: Up to 10 research sites in USA 
Planned Number of Subjects:  
60 Subjects (20 subjects per arm) 
Study Development Phase:  
IIa 
Indication for Use: Parkinson’s Disease 
Objectives:  
Primary Objective: 
To evaluate the safety and tolerability of DA-9805 at 45mg, 90mg compared to Placebo (0 mg) in 
subjects with Parkinson’s Disease. 
 
Secondary Objective: 
To evaluate DA-9805 at 45mg, 90mg compared to Placebo (0 mg), in terms of efficacy in subjects 
with Parkinson’s Disease. 
Study Outcomes: 
Primary Outcome Measure: 
 Change in motor MDS-Unified Parkinson Disease Rating Scale (MDS-UPDRS) total score 
from baseline at week 12. 
Secondary Outcome Measures: 
 Change in total MDS- UPDRS total score from baseline at week 12. 
 Change in MDS-UPDRS subscale scores from baseline at week 12. 
 Change in Schwab and England (S&E) Scale total score from baseline at week 12. 
 Change in Parkinson's Disease Questionnaire (PDQ-39) total score from baseline at week 12.  
 Change in Hoehn and Yahr (H&Y) scale total score from baseline at week 12.  
 Change in Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-


 
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Name of Sponsor/Company:  
Dong-A ST Co. Ltd 
Name of Study Product: DA-9805 tablet 
Comparator Product: Placebo tablet 
Protocol Number:  
DA-9805-PD-001 
Indication:  
Parkinson’s Disease 
Improvement (CGI-I) scale score from baseline at week 12. 
 
Safety Assessments: 
 Incidence of Treatment-Emergent Adverse Events (AEs). 
 Incidence of withdrawals due to AEs. 
 Change/shifts in laboratory values. 
 Change in vital signs. 
 Change in Electrocardiogram (ECG) parameters. 
 Change in Columbia-Suicide Severity Rating Scale (C-SSRS) from baseline at week 12.  
 
Trial Design:  
This is a phase IIa, first in human, randomized, double-blind, multicenter study to evaluate the safety, 
tolerability and efficacy of DA-9805 at 45mg, 90mg versus placebo in subjects diagnosed with early 
Parkinson’s disease. 
The study will include three parts: a 2-week Screening part, a 12-week Double-Blind Treatment part, 
and a 4-week Follow-up part. The Schedule of Events is provided in Table 4-1. 
Screening part (Day -14 to Day -1), up to 14 days: 
Screening part is designed to determine subject’s eligibility to proceed to Randomization and the 
Treatment Phase of the study. During this part, a series of assessments will be performed to determine 
subject eligibility as per inclusion and exclusion criteria (Refer to Section 3.1.2 and Section 3.1.3). 
At the Screening Visit, prior to any study-related procedures, a written informed consent will be 
obtained from the subject by the Investigator or suitable qualified personnel. Screening procedures will 
be conducted per the study schedule of events. All screening information will be documented in the 
case report forms. 
Subjects who meet eligibility criteria, but have some abnormal laboratory values, based on PI review a 
repeat laboratory sample may be collected. The repeat laboratory reports should be reviewed by the PI 
to confirm eligibility prior to randomization. 
Subjects who fail to meet eligibility criteria during the Screening part will be considered screen 
failures and will be exited from the study. Subjects who meet the eligibility criteria will be scheduled 
for randomization visit.  
Double-Blind Treatment Part (12 weeks): 
Subjects who have successfully completed the Screening part will enter the Double-Blind treatment 


 
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Name of Sponsor/Company:  
Dong-A ST Co. Ltd 
Name of Study Product: DA-9805 tablet 
Comparator Product: Placebo tablet 
Protocol Number:  
DA-9805-PD-001 
Indication:  
Parkinson’s Disease 
part of the study. Treatment part followed by randomization will last for 12 weeks. Subjects will take 
the assigned randomized treatment, DA-9805 at 45mg, 90mg or placebo for 12 weeks. DA-9805 and 
matching placebo are oral tablets that will be taken three times daily during this study.  
 
Randomization/Treatment Visit 0 (TV0): On Day 0 prior to randomization, the subject’s continued 
eligibility will be evaluated (Refer to Section 3.1.2 and Section 3.1.3). Subjects who continue to be 
eligible will be randomized in a 1:1:1 ratio to one of the following treatment groups and assigned the 
study treatment kit: 
 Group 1: DA-9805 45mg tablet 
 Group 2: DA-9805 90mg tablet 
 Group 3: placebo tablet (0 mg DA-9805) 
 
Treatment Visits 1 (TV1) through 3 (TV3): 
Clinic treatment visits TV1 through TV3 will be conducted every four (4) week (± window periods).  
During each of these visits, study evaluations will be conducted per the study schedule of events (Refer 
to Section 4.1.3), and sufficient supply of DA-9805 or placebo till the next treatment visit will be 
dispensed.  
Treatment Visit 3 (TV3) will be the end of treatment (EOT) clinic visit. Study evaluations, review of 
the adverse events, concomitant medications and final study treatment accountability will be 
conducted.  
Follow-up Part (4 weeks ± 3 days) 
The follow-up part will consist of a follow-up visit at the end of the Double-Blind Treatment part. The 
detailed study schedule and assessments in each visit are provided in Section 4.1 of the protocol. 


 
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Name of Sponsor/Company:  
Dong-A ST Co. Ltd 
Name of Study Product: DA-9805 tablet 
Comparator Product: Placebo tablet 
Protocol Number:  
DA-9805-PD-001 
Indication:  
Parkinson’s Disease 
Duration of Screening Part: 2 weeks 
Duration of Double-Blind Treatment Part: 12 weeks 
Duration of follow-up Part: 4 weeks 
Total Study Duration: 18 weeks  
Inclusion Criteria:  
Subjects will be eligible for enrollment in the study only if they meet ALL of the following criteria: 
1. Male or female subjects who are between 30 and 79 years old inclusive  with a clinical diagnosis 
of Parkinson’s disease as per UK Brain Bank Criteria for two (2) years or less at screening. 
2. Hoehn and Yahr I or II at screening. 
3. Subjects who are newly diagnosed & currently not on any Parkinson’s disease medication (or) 
subjects who are on stable doses for at least 4 weeks prior to screening on Amantadine or 
anticholinergics for treatment of Parkinson’s disease 
(1) Note: Subjects that had anti-parkinsonian medication (including levodopa, dopamine 
agonists, entacapone and monoamine oxidase-B inhibitors) discontinued at least 60 
days prior to screening, e.g., for intolerance, may be considered eligible if all other 
eligibility requirements are met. 
4. Women of child-bearing potential should use reliable contraception. Acceptable methods of 
contraception include: surgical sterilization (e.g. bilateral tubal ligation), hormonal contraception 
(implantable, patch, and oral), and double-barrier methods (condom, diaphragm and spermicide 
are each considered a barrier). Women of child-bearing potential are defined as women 
physiologically capable of becoming pregnant, UNLESS they meet the following criteria: 
(1) Post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of 
spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels > 
40mIU/m, OR;  
(2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy 
5. If a male and heterosexually active with a female of childbearing potential, the subject must agree 
to use a double barrier method of birth control (or must have been surgically sterilized) and to not 
donate sperm during the study. 
6. Without clinically significant abnormalities in physical exam, neurological exam and laboratory 
assessments (urine/blood routine, biochemical tests and ECG) which would exclude the subject 
from the study in the opinion of the Investigator. For Aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) and alkaline phosphatase (ALP) the screening levels should be ≤ 2 times 


 
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Name of Sponsor/Company:  
Dong-A ST Co. Ltd 
Name of Study Product: DA-9805 tablet 
Comparator Product: Placebo tablet 
Protocol Number:  
DA-9805-PD-001 
Indication:  
Parkinson’s Disease 
upper limit normal. 
7. Subject is capable of providing informed consent and is willing to sign the ICF prior to study 
Screening and agrees to comply with the study protocol requirements. 
Exclusion Criteria: 
Subjects will be eligible for enrollment in the study only if they meet NONE of the following criteria: 
1. Subject has an atypical parkinsonian syndrome or secondary parkinsonism (e.g., due to drugs, 
metabolic neurogenetic disorders, encephalitis, cerebrovascular disease or degenerative disease). 
2. Subjects with history of neurosurgical intervention for Parkinson’s disease. 
3. Subjects who meet the DSM-V criteria at screening for bipolar disorder, major depressive 
disorder, psychotic disorders, or any other comorbid mental disorders that in the opinion of the 
Investigator may interfere with study conduct and results interpretation. 
4. Subjects with clinical diagnosis of dementia (MMSE score <24) as determined by the investigator 
using Mini–Mental State Examination (MMSE). 
5. Female subjects who are pregnant or breast feeding. 
6. Initiation of any anti-parkinsonian medication (including levodopa, dopamine agonists, 
entacapone and monoamine oxidase-B inhibitors) for the duration of the trial.  
7. Initiation of Amantadine or anticholinergics for newly diagnosed subjects or change in the dosage 
of Amantadine or anticholinergics during the trial for subjects who were on stable doses for 4 
weeks prior to screening. 
8. Subjects who used investigational drugs or devices within 60 days prior to screening or 
investigational biologics within the last 6 months prior to screening. 
9. Subjects with a clinically significant medical or surgical condition, including major surgeries 
within 28 days prior to enrollment. 
Statistical Considerations:   
Sample Size Determination and Rationale 
The sample size of 60 subjects (20 subjects per group) will be used in this trial. Early Parkinson’s 
disease subjects will be randomized in this trial. This sample size is selected on the basis of clinical 
judgment and not based on statistical power calculation; it is deemed adequate to provide clinically 
meaningful descriptive results consistent with the study objectives. 
Interim Analysis 
There is no interim analysis planned for this study.  


 
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Name of Sponsor/Company:  
Dong-A ST Co. Ltd 
Name of Study Product: DA-9805 tablet 
Comparator Product: Placebo tablet 
Protocol Number:  
DA-9805-PD-001 
Indication:  
Parkinson’s Disease 
Analysis Populations 
Intent-to-Treat (ITT) population 
The Intent-to-Treat (ITT) population is defined as all randomized subjects who have received at least 
one dose of study treatment and undergone at least one post-randomization efficacy assessment.  
Per Protocol (PP) Population 
The Per Protocol (PP) population is defined as the set of subjects who meet the ITT population 
requirements, and were not associated with a major protocol violation. This population will be 
identified before the database lock, and before the treatment assignments are revealed.   
Safety Population 
The Safety population is defined as all subjects receiving at least one dose of the treatment after 
randomization.  
Analysis Methods:  
The primary analysis of the primary and secondary endpoints will be conducted using the PP 
population.  
Efficacy Analysis:  
For analysis of the primary and secondary endpoints the following will be considered:  
 For endpoints that are continuous in nature 
o Number of observations, mean, median, minimum and maximum, and standard deviation 
(SD) values will be presented as descriptive summary.  
o For inferential statistics: 
 If the Normality assumption is met, t-test or ANCOVA using the baseline value as a 
covariate will be used.  
 If the Normality assumption is not met, a rank –ANCOVA analysis i.e., an ANCOVA 
analysis on rank-transformed data or other non-parametric methods will be used.  
 For endpoints that are categorical in nature: 
o Frequency counts and percentages will be presented as descriptive summary.  
o Chi-square test or Logit model will be used for inferential statistics. 
To assess the consistency of the Primary Analysis results, a supportive analysis will be conducted 
using the ITT population. Statistical methodology for the supportive analyses will be the same as that 
of the primary analysis, with the exception of the analysis population.  


 
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Name of Sponsor/Company:  
Dong-A ST Co. Ltd 
Name of Study Product: DA-9805 tablet 
Comparator Product: Placebo tablet 
Protocol Number:  
DA-9805-PD-001 
Indication:  
Parkinson’s Disease 
 
Safety Analysis: 
The Safety population will be used for the analysis of all safety parameters or measurements.  
Adverse events will be coded using the most recent version of MedDRA. Treatment-Emergent AEs 
(TEAE) are defined as events with an onset on or after the first randomized treatment. TEAEs will be 
summarized by treatment group, System Organ Class, and preferred term. 
Summary statistics of raw data and change from baseline values for each laboratory parameter will be 
presented by treatment group and time point. Data will be summarized as appropriate to the variable 
type (i.e. continuous or categorical variables).  
Individual subject changes will be identified through shift tables. Shift tables will be presented for each 
laboratory parameter with counts and percentages of subjects, by treatment group and time point, for 
shift from baseline, using the normal ranges. 
In addition, all the data from physical examination, 12 Lead ECG and vital signs will also be 
descriptively summarized.  
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS................................................................................................................... 5
PROTOCOL SYNOPSIS ......................................................................................................................... 8
TABLE OF CONTENTS ....................................................................................................................... 15
LIST OF TABLES .................................................................................................................................. 19
LIST OF FIGURES ................................................................................................................................ 19
1 INTRODUCTION ............................................................................................................................ 20
1.1
Statement of Intent ....................................................................................................................... 20
1.2
Background .................................................................................................................................. 20
1.3
DA-9805 ....................................................................................................................................... 21
1.4
Summary of Prior Pre-Clinical Studies ........................................................................................ 21
1.5
Study Design Rationale ................................................................................................................ 25
1.6
Risks and Benefits ........................................................................................................................ 25
2 STUDY OBJECTIVES .................................................................................................................... 26
3 STUDY DESIGN ............................................................................................................................. 27
3.1
Study Population .......................................................................................................................... 30 
3.1.1 
Number of Subjects .................................................................................................... 30 
3.1.2 
Inclusion Criteria ........................................................................................................ 31 
3.1.3 
Exclusion Criteria ....................................................................................................... 31
4 STUDY SCHEDULE ....................................................................................................................... 32
4.1 
Screening and Randomization ...................................................................................................... 35
4.1.1
Screening Visit (Day -14to Day -1), up to 14 Days ................................................... 35
4.1.2
Treatment Visit 0 (TV0): Randomization/Baseline Visit (Day 0) ............................. 35
4.1.3
Treatment Visit 1 (TV1) (Week 4: Day 28±3), Treatment Visit 2 (TV2) (Week 8: 
Day 56±3), Treatment Visit 3 (TV3) (Week 12: Day 84±3) ..................................... 36
4.2
Follow-Up .................................................................................................................................... 36 
4.2.1 
Visit  Phone Call (Follow-Up Visit, Week 16: Day 112±3) ...................................... 36
4.3
Unscheduled Visits ....................................................................................................................... 37
4.4
Missed Visits ................................................................................................................................ 37
5 SUBJECT COMPLETION AND WITHDRAWAL ........................................................................ 38
5.1
Subject Completion ...................................................................................................................... 38
5.2
Subject Premature Withdrawal from the Study ........................................................................... 38
5.3
Screen Failures ............................................................................................................................. 39
6 STUDY TREATMENTS.................................................................................................................. 40
6.1
Method for Assigning Eligible Subjects to Treatment ................................................................. 40
6.2
Test Treatment ............................................................................................................................. 40
6.3
Control Treatment ........................................................................................................................ 40


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6.4
Study Treatment Labeling and Packaging ................................................................................... 41
6.5
Study Treatment Storage .............................................................................................................. 41
6.6
Study Treatment Administration .................................................................................................. 41
6.7
Study Treatment Dispensation ..................................................................................................... 41
6.8
Study Treatment Accountability .................................................................................................. 42
6.9
Study Drug Compliance ............................................................................................................... 42
7 CONCOMITANT AND PROHIBITED MEDICATIONS .............................................................. 43
7.1
Prohibited Medication .................................................................................................................. 43
8 DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES ................................... 44
8.1
Informed Consent ......................................................................................................................... 44
8.2
Eligibility Assessment .................................................................................................................. 44
8.3
Subject Demographics ................................................................................................................. 44
8.4
Medical History ............................................................................................................................ 44
8.5
Vital Signs .................................................................................................................................... 45
8.6
Height, Weight And BMI ............................................................................................................. 45
8.7
Physical Exam .............................................................................................................................. 45
8.8
Laboratory Assessments ............................................................................................................... 46
8.9
Electrocardiogram (ECG) ............................................................................................................ 47
8.10 Urine Pregnancy Test ................................................................................................................... 47
8.11 MDS- Unified Parkinson Disease Rating Scale (MDS-UPDRS) ................................................ 47
8.12 Hoehn and Yahr Stage ................................................................................................................. 48
8.13 Parkinson’s Disease Questionnaire (PDQ 39) ............................................................................. 48
8.14 Clinical Global Impression .......................................................................................................... 48
8.15 Schwab and England Activities of Daily Living Scale ................................................................ 49
8.16 Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................................... 49
8.17 Mini-Mental State Examination ................................................................................................... 49
9 STATISTICAL CONSIDERATIONS ............................................................................................. 51
9.1 
Treatment Groups ......................................................................................................................... 51
9.2 
Description of Study Endpoints ................................................................................................... 51
9.2.1
Safety Outcome Measures .......................................................................................... 51
9.2.2
Primary Efficacy Outcome Measure .......................................................................... 51
9.2.3
Secondary Efficacy Outcome Measures .................................................................... 51
9.3
Sample Size Determination .......................................................................................................... 51
9.4
Randomization ............................................................................................................................. 52
9.5
Blinding and prevention of Bias .................................................................................................. 52
9.6
Interim Analysis (IA) ................................................................................................................... 52
9.7
General Statistical Considerations ............................................................................................... 52
9.8
Analysis Populations .................................................................................................................... 52


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9.8.1
Intent-to-Treat (ITT) population ................................................................................ 52
9.8.2
Per Protocol (PP) Population ..................................................................................... 52
9.8.3
Safety Population ....................................................................................................... 53
9.9 
Statistical Methods ....................................................................................................................... 53
9.9.1
Subject Disposition .................................................................................................... 53
9.9.2
Demographics and baseline characteristics analysis .................................................. 53
9.9.3
Concomitant Medications/Therapies ......................................................................... 53
9.9.4
Medical history ........................................................................................................... 53
9.9.5
Study Treatment Compliance ..................................................................................... 53
9.10 Safety Outcome Analyses ............................................................................................................ 53
9.10.1
Adverse Events ........................................................................................................... 53
9.10.2
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 53
9.10.3
Clinical Laboratory Data ............................................................................................ 54
9.10.4
Vital Sign and Weight ................................................................................................ 54
9.10.5
ECG ............................................................................................................................ 54
9.10.6
Physical Examination ................................................................................................. 54
9.11 Efficacy Outcome Analyses ......................................................................................................... 54
10 ADVERSE EVENTS (DEFINITIONS AND REPORTING) .......................................................... 54
10.1 Adverse Event .............................................................................................................................. 55
10.2 Reporting of Adverse Events ....................................................................................................... 55
10.2.1
Impact on Study Treatment ........................................................................................ 55
10.2.2
CTCAE Grade (Intensity) Assessment ...................................................................... 55
10.2.3
Causality Assessment ................................................................................................. 56
10.2.4
Treatment Given as a Result of the Event .................................................................. 56
10.2.5
Outcome Assessment ................................................................................................. 56
10.3 Expected / Anticipated Adverse Events ....................................................................................... 57
10.4 Serious Adverse Events ................................................................................................................ 57
10.5 Reporting of Serious Adverse Events (SAE) ............................................................................... 57
10.6 SAE Follow-Up ............................................................................................................................ 58
11 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION .................................................... 59
12 DATA SAFETY MONITORING COMMITTEE (DSMC) ............................................................. 60
13 QUALITY CONTROL AND QUALITY ASSURANCE ............................................................... 61
13.1 Monitoring Requirements ............................................................................................................ 61
13.2 Acceptability of Case Report Forms ............................................................................................ 61
13.3 Modification Of Protocol ............................................................................................................. 61
13.4 Reporting Protocol Deviations ..................................................................................................... 62
14 ETHICS AND REGULATORY REQUIREMENTS ....................................................................... 63
14.1 Institutional Review Board/Independent Ethics Committee ........................................................ 63


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14.2 Investigator’s Responsibilities ..................................................................................................... 63
14.3 Subject Informed Consent Requirements ..................................................................................... 63
15 DATA HANDLING AND RECORD KEEPING ............................................................................ 65
15.1 Recording and Collection of Data ................................................................................................ 65
15.2 Clinical Data Management ........................................................................................................... 65
15.3 Archiving ...................................................................................................................................... 65
16 PUBLICATION PLAN .................................................................................................................... 67
17 REFERENCES ................................................................................................................................. 68
18 APPENDICES .................................................................................................................................. 70
18.1 Appendix 1: MDS-UPDRS,  Hoehn & Yahr Scale ...................................................................... 70
18.2 Appendix 2: Schwab & England Activities of Daily Living Scale ............................................ 102
18.3 Appendix 3: Parkinson’s Disease Questionnaire (PDQ-39) ...................................................... 103
18.4 Appendix 4: Clinical Global Impression .................................................................................... 106
18.5 Appendix 5: Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................. 107


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List of Tables 
Table 4-1:
Study Schedule of Events ................................................................................................. 33
Table 6-1:
Study Treatment Ingredients ............................................................................................ 40
Table 10-1:
CTCAE v4.03 General Guidelines ................................................................................... 55
List of Figures 
Figure 3-1:
Study Flow Diagram ........................................................................................................ 29
Figure 8-1:
C-SSRS (Lifetime/Recent) ............................................................................................. 107
Figure 8-2:
C-SSRS (Since Last Visit) ............................................................................................. 109


 
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1 
INTRODUCTION 
1.1 
STATEMENT OF INTENT 
The design, conduct and reporting of this trial will be in compliance with the protocol, International 
Conference on Harmonization (ICH)/Good Clinical Practice (GCP) and all appropriate regulatory 
requirements. The protocol will follow 21 Code of Federal Regulations (CFR) 50, subpart D and will 
provide all the necessary safeguards for study subjects. All of the Investigators will have documented 
training in GCP. Independent monitoring of the trial will be accomplished by utilizing Amarex Clinical 
Research as the Contract Research Organization (CRO). 
1.2 
BACKGROUND  
Parkinson’s disease (PD) is recognized as one of the most common neurologic disorders, affecting 
approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings:  
 the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) and 
 the presence of Lewy bodies.  
 
Most cases of Parkinson’s disease are hypothesized to be due to a combination of genetic and 
environmental factors. However, no environmental cause of Parkinson’s disease has yet been proven. 
A known genetic cause can be identified in approximately 10% of cases, and these are more common 
in younger-onset patients.  
 
The classic motor features of Parkinson’s disease typically start insidiously and emerge slowly over 
weeks or months, with tremor being the most common initial symptom. The 3 cardinal signs of 
Parkinson’s disease are resting tremor, rigidity, and bradykinesia. Postural instability (balance 
impairment) is sometimes listed as the fourth cardinal feature. However, balance impairment in 
Parkinson’s disease is a late phenomenon.  
 
Parkinson's disease affects an estimated 1.5 million persons in the United States, with over ten million 
affected worldwide, and these estimates are expected to increase substantially in the next few decades. 
Despite the increasing prevalence, the approved agents for the early management of Parkinson's 
disease have changed little in the past decade; however, there have been advances in drug delivery, 
dosing, and the use of combination therapy in an attempt to reduce adverse events. The available 
treatments continue to focus on the dopaminergic system and include primarily carbidopa/levodopa, 
monoamine oxidase type B (MAO-B) inhibitors, and dopamine agonists. Current research on the early 
management of Parkinson's disease focuses on improved and more consistent drug delivery systems, 
targeting alternate neurotransmitter systems and the identification of neuroprotective therapies for 
Parkinson's disease. There has also been an increased interest in earlier intervention with various forms 
of exercise in addition to pharmacological treatments. 
 
The most important, unmet medical need in targeting Parkinson’s disease is developing agents with 
neuroprotective potential. So far, no drug has been shown to reduce or slow down the progression of 
PD. 
 


 
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1.3 
DA-9805 
DA-9805 is a botanical drug product composed of three main raw herbal materials; Moutan Root Bark 
[MC], Bupleurum Root [BF] and Angelica dahurica root [ADR]. The main active ingredients are 
Paeonol, Saikosaponin A and Imperatorin respectively. All the three herbal raw materials are listed in 
the Japanese, Korean and Chinese Pharmacopoeias. DA-9805 reduces neuronal loss by: 
1. Protection of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced nigrostriatal 
dopamine neuron degeneration. 
2. Restoration of 6-OHDA (neurotoxin 6-hydroxydopamine) induced nigrostriatal dopamine 
neuron degeneration. 
3. Inhibition of Rotenone induced α-synuclein accumulation in substantial niagra (SN). 
4. Inhibition of LPS induced microglial/astrocyte activation in substantial niagra/striatum(ST).     
It is expected that DA-9805 will help treat PD by prevention of dopaminergic neurodegeneration via 
recovery of mitochondrial dysfunction, anti-inflammatory effect and relief from Endoplasmic 
reticulum (ER) stress and oxidative stress.  
1.4 
SUMMARY OF PRIOR PRE-CLINICAL STUDIES 
The botanical components of DA-9805 (Moutan Root Bark [MC], Bupleurum Root [BF] and Angelica 
dahurica root [ADR]) have a long history of human use and have been tested individually and in 
various combinations in animal models. Based on available published information, MC has been 
attributed anti-depression, prevention of dementia, improvement of cognitive functions, and anti-
inflammatory, neuroregenerative, anti-oxidant, anti-cancer and hypoglycemic effects. Similarly, BF is 
attributed therapeutic effects in brain damage and depression, and has also shown neuroprotective, 
neuroregenerative, anti-cancer, anti-allergy effects. Based on published literature, ADR is attributed 
anti-depression, prevention of dementia, improvement of cognitive function and anti-inflammatory, 
antioxidant and anti-asthmatic effects. 
 
All three botanicals listed in KP, Chinese Pharmacopoeia (CP) and Japanese Pharmacopoeia (JP) as 
well as other pre-existing oriental medicine books as over-the-counter (OTC) medicines and approved 
drugs in Korea, China and Japan. However, none of these consist of individual components of DA-
9805 alone, but rather a various combinations with other botanicals. DA-9805 will be the first 
botanical mixture comprising of all three botanical ingredients.  
 
In addition to Korea, China and Japan, MC, BF and/or ADR containing products can also be found in 
US, Canada, Australia, Taiwan, Europe and Southeast Asia. These products are not only available as 
prescription drugs, but also as herbal OTC medicinal products and dietary/food supplements. MC 
containing products have been used in central nervous system disorders, indigestion, cough, dental 
care, anemia, and constipation, among other indications. BF containing products have been used in 
headache, cold, insomnia, enterogastritis, constipation, neurosis and other indications. Finally, ADR 
containing products are used in fever, headache, antiemetic, cold, insect bites, rhinitis and other 
indications. 
 
The current market status on products that contain MC, BF and ADR, individually or in combination, 
in various countries is briefly summarized below.  


 
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 In Korea, there are hundreds of products containing MC (115), BF (162) or ADR (67), which 
are all approved and released as medicinal products by MFDS. MC, BF or ADR are prohibited 
as raw materials for food in Korea.  
 In China, MC, BF or ADR are approved as raw materials for health food and they are found in 
many of the nutritional products that are approved by the China Food and Drug Administration. 
The Chinese Pharmacopoeia has listed 29, 22 and 47 regulated products of Traditional Patent 
Medicine containing MC, BF and ADR, respectively.  
 In Japan, out of the 233 common herbal prescriptions and 148 medicinal herbal prescriptions 
approved by the government, MC is found in 18 products, BF is found in 38 products and ADR 
is found in 18 products.  
 In Taiwan, out of the 200 Chinese medicinal prescriptions listed in the Taiwan Herbal 
Pharmacopoeia, 12 products contained MC, 25 products contained BF and 14 products 
contained ADR. 
 In US, there are some dietary supplements that contain MC, BF or ADR but they have not been 
registered or regulated. 
 In Canada, MC, BF and ADR are listed as acceptable traditional Chinese medicine ingredients 
for natural health products in Canada. Traditional Chinese medicine (TCM) products 
containing MC, BF or ADR are registered marketed as dietary supplements in Canada by 
various Chinese pharmaceutical companies. 
 In Australia, traditional Chinese medicine (TCM) products containing MC, BF or ADR are 
registered and marketed as complementary medicine by various Chinese pharmaceutical 
companies. 
 In Southeast Asia, countries such as Vietnam, Malaysia, Singapore and Indonesia allow 
imports of TCM products containing MC, BF or ADR from China.  
 In Hong Kong, there are some traditional medicinal products and foods containing MC, BF and 
ADR. 
 In Europe, a few traditional Chinese patent medicines containing MC and ADR are marketed in 
England and Belgium as dietary supplements. 
 
Dong-A conducted a number of nonclinical studies with DA-9805 and its individual botanical 
components, as well as with proposed purified active ingredients. Dong-A DA-9805 nonclinical 
studies were conducted in compliance with the Ministry of Food and Drug Safety (MFDS) 
(Notification No. 2013-232 ‘The Standards of Pharmacology Study for Medicinal Products’ [Oct 30, 
2013] and  Notification No. 2014-67 ‘Good Laboratory Practice [GLP]’ [Feb 12, 2014]) and 
Organization for Economic Co-operation and Development (OECD) GLP requirements and also 
comply with the current International Conference on Harmonization (ICH) guidelines, including ICH 
guideline S7A ‘Safety Pharmacology Studies for Human Pharmaceuticals’ (Nov 08, 2000). 
 
DA-9805 has not undergone any clinical testing in the US or anywhere else in the world; the study 
proposed under this IND is the first-in-human study. Non-clinical study data summarized below 
provides safety data for conducting the first DA-9805 in-human study. The NOAEL of DA-9805 in 
rats was determined at 2000 mg/kg in males and 1000 mg/kg in females with stomach being the 
affected organ. Based on the FDA guidance on Estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers (2005), the human equivalent dose (HED) can 
be estimated from animal NOAEL using conversion factors based on body surface area, in which the 


 
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maximum recommended starting dose (MRSD) is then derived from by applying a safety factor. 1000 
mg/kg NOAEL rat dose is equivalent to HED 161 mg/kg, or 9677 mg for a 60 kg adult. The proposed 
starting doses selected for the first in human clinical trial are 45 mg/day and 90 mg/day; highest 
selected dose, 90 mg/day, is not expected to result in safety issues based on the animal data and the 
applied safety factor of 100. 
 
Primary Pharmacology studies evaluated the effects of individual extracts of botanical components 
of DA-9805, various ratios of botanicals in the final drug substance mixture as well as the DA-9805 
final formulation. MC extract was shown to have neuroprotective effect, including increased 
dopamine availability, promoted dopaminergic neuron survival and recovery, and inhibition of 
mitochondrial dysfunction and mitochondria-mediated apoptosis after MPTP and MPP+ - induced 
damage in cell culture and in mice. BF extract effects, as well as effects of individual isolated BF 
components (saikosaponins B3, B4 and D) were studied in LPS-induced inflammatory dopaminergic 
neurodegeneration mouse model. BF extract and its individual saikosaponins components showed the 
potential to inhibit the apoptosis of dopamine neurons in microglial cells through inhibiting the NF-кB-
mediated inflammatory pathway. ADR extract effects were studied in multiple models. In spinal cord 
injury model in vitro (LPS-activation of microglial cell culture) and in vivo, ADR decreased the levels 
of pro-inflammatory factors such as tumor necrosis factor-a (TNF-α), interleukin (IL)-1b, IL-6, 
inducible nitric oxide synthase (iNOS), ROS and cyclooxygenase-2 (COX-2), and subsequently 
alleviated oxidative stress. In endoplasmic reticulum (ER) stress model, pre-treatment with ADR in 
human neuroblastoma cell line was found to partially protect cells from thapsigargin and tunicamycin 
cytotoxicity, reduce intracellular ATP levels, and decrease mRNA levels of markers of ER stress 
suggesting potential to decrease neuronal damage by inhibiting ER stress. In MPTP-induced PD mouse 
model, ADR alleviated behavioral impairments and protected against MPTP effect on tyrosine 
hydroxylase (TH), a rate-limiting enzyme in brain catecholamine biosynthesis. Various MC, BF and 
ADR ratios were screened in vitro (MPP+-induced mitochondrial dysfunction model in human 
neuroblastoma cells) and in vivo (MPTP-induced mouse PD model). 1:1:1 ratio was selected for the 
DA-9805 composition as the one with the optimal pharmacological effect. Proposed active 
ingredients of botanicals MC, BF and ADR (paeonol, saikosaponin A and imperatorin) were shown to 
improve levels of TH in Substantia Nigra pars compacta (SNpc) of MPTP-induced mice at doses 
corresponding to 10 mg/kg DA-9805. Based on the results from the above studies, it was concluded 
that all three selected botanical components of DA-9805 contributed to the neuroprotective effect of 
DA-9805 and the optimal ratio of the botanicals was 1:1:1.   
 
DA-9805 pharmacological effect was investigated in multiple in vitro and in vivo models of PD as well 
as compared to effects of individual components in order to confirm synergistic effects. In in vitro 
studies, pre-treatment of DA-9805 was found to alleviate MPP+-induced mitochondrial dysfunctions, 
decrease endogenous indicators of ER stress induced by Tunicamycin or Thapsigargin as well as 
attenuate NO production and NF-kB activation induced by LPS. DA-9805 was also shown to inhibit 
PDE enzymatic activities and subsequently convey protective properties against dopaminergic 
neuronal cell lose and α-synuclein accumulation by autophagy activation. In vitro binding and 
inhibition profile showed that DA-9805 inhibited COX-2, MAO-B, PDE1, JNK1 and DAT - enzymes 
and receptors known to be involved in the pathogenesis of PD and targeted by current PD therapies. 
Based on additional studies, the inhibitory effect of DA-9805 on MAO-B can at least in part be 
attributed to paeonol from MC; the inhibitory effects on MAO-B, PDE1, and DAT can at least in part 
be attributed to imperatorin from ADR. 


 
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In in vivo studies, DA-9805 provided significant protection against MPTP-induced PD motor 
symptoms and exhibited a positive effect on TH levels in DA neurons in the SNpc. Both effects were 
stronger than those of individual botanical extracts alone confirming synergistic effect. 
Neuroprotective effect of DA-9805 was further confirmed in 6-OHDA-lesion mouse model of PD, in 
rotenone PD rat model, LPS-induced neuroinflammatory PD mouse model. Neuroprotective effects 
were shown to be stronger than those of rasagiline. Optimal DA-9805 dose from MPTP-induced PD 
mouse study was established to be 10 and 20 mg/kg.  
 
Safety Pharmacology studies evaluated the effects of DA-9805 on body temperature and general 
behavior in mice and respiration rate and volume in rats after single oral administration. NOAEL for 
both studies was concluded to be the highest tested dose, 1000 mg/kg. A dog telemetry study showed 
that single oral administration of DA-9805 up to 250 mg/kg (highest tested dose) did not affect the 
blood pressure, heart rate and electrocardiogram parameters in male beagle dogs. Additional safety 
pharmacology study, effects of DA-9805 on the cardiovascular hERG in CHO cells, is currently 
ongoing and results will be provided to the IND when available.  
 
Pharmacokinetic studies investigated the effect of DA-9805 on metabolizing enzymes in liver 
microsomes and human hepatocyte culture showed that DA-9805 co-administration is not expected to 
result in clinically significant drug interactions with CYP2C8, CYP2C9, CYP2E1, UGT1A1, 
UGT1A4, UGT1A9, UGT2B7, and SULT2A1 substrates. Higher doses of DA-9805 (5 and 10 µg/mL) 
suggested possible interactions with CYP3A4, CYP1A2 and CYP2B6 substrates in the in vitro studies. 
Inhibitory activity was shown to be attributed to imperatorin and paeonol. Drug-drug interactions were 
further investigated in vivo and no significant inhibitory effects on the enzymatic activities of 
CYP1A2, CYP2B6, and CYP3A were observed in SD rats that were administered single or multiple 
oral doses of DA-9805 (60 mg/kg/day).  DA-9805 is not expected to cause drug interactions due to 
inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A9, and UGT2B7 enzyme activities. 
 
DA-9805 effect was further evaluated on uptake and influx hepatic transporters. DA-9805 inhibited the 
transport activity of OCT1, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 with IC50 values of 74.8, 
70.1, 24.6, 9.5, 40.1, and 45.3 µg/mL, respectively. DA-9805 did not inhibit the efflux of digoxin via 
P-gp upto 200 µg/mL in LLC-PK1-MDR1 cells, but DA-9805 inhibited the transport activity of BCRP 
with IC50 value of 20.6 µg/mL in LLC-PK1-BCRP cells. These results suggest that DA-9805 has a 
potential for drug interactions through inhibition of the transport activity of OAT1, OAT3, and BCRP. 
 
Toxicology studies with DA-9805 showed an overall favorable profile. Acute oral toxicity in rats at 
2000 mg/kg dose showed transient symptoms such as salivation, decrease in locomotor activity, 
incomplete eyelid opening, crouching position, panting and decreased respiration rate in most of the 
animals. Those symptoms were resolved within 3 hours of drug administration. The Approximate 
Lethal Dose of DA-9805 is considered to be higher than 2000 mg/kg for both sexes. Repeat dose 
toxicity study for 13 weeks in rats concluded NOAEL of DA-9805 to be 2000 mg/kg/day in males and 
1000 mg/kg/day in females, with stomach being the target organ in females. The only toxicologically 
significant changes were erosion/ulceration in glandular and non-glandular stomach revealed in 
histopathological examination in female rats in the 2000 mg/kg/day group. Other histopathological 
changes were normalized after completion of dosing and were not considered toxicologically 


 
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significant. Repeat dose toxicity was further evaluated in a 4-week dog study to determine dosages for 
chronic toxicity studies and 750 mg/kg/day was selected.  
 
Chronic oral toxicity for 26 weeks in rats at doses ≥ 500 mg/kg/day showed salivation right after 
dosing. Transient microscopic changes that are related to DA-9805 but not considered adverse were 
observed in the liver and thyroids in both sexes at ≥ 500 mg/kg/day, stomach and duodenum in both 
sexes at 1000 and/or 2000 mg/kg/day, and bone marrow in both sexes at 2000 mg/kg/day. The NOAEL 
of this study was considered to be the highest dose at 2000 mg/kg/day in box sexes in rats. The 39-
week chronic oral toxicity study in dogs showed decrease in body weight and food consumption after 
dosing in both sexes at the highest dose of 720 mg/kg/day. These observations were considered 
adverse. Microscopic examination showed changes in the liver of females at 720 mg/kg/day with 
increased liver weight, which were considered not adverse and symptoms were reversed after recovery. 
The NOAEL of this study was considered to be 240 mg/kg/day for both sexes in dogs. 
 
Genotoxicity of DA-9805 was evaluated in Ames test, Chromosome Aberration Test and Mouse Bone 
Marrow Micronucleus Assay. Neither of the studies showed any signs of the genetic toxicity.  
1.5 
STUDY DESIGN RATIONALE 
This Phase IIa study is designed to establish the safety and tolerability of DA-9805 compared to 
placebo in subjects with PD. This study will also seek to determine the effectiveness of DA-9805 in 
subjects with PD, which will provide information for subsequent clinical trials with DA-9805. 
 
1.6 
RISKS AND BENEFITS  
The safety monitoring practices employed by this protocol are adequate to protect the subjects’ safety 
and should detect all Treatment Emergent Adverse Events (TEAEs). The approximate volume of blood 
(~ 60-75 mL) planned for collection from each subject over the course of the entire study presents no 
undue risk to the participants. An indirect health benefit to the subjects enrolled in this trial is the free 
medical tests received at screening and during the study. 
 
 
 


 
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2 
STUDY OBJECTIVES 
 To evaluate the safety and tolerability of DA-9805 at 45mg, 90mg compared to Placebo (0 mg) 
in subjects with Parkinson’s disease.  
 To evaluate DA-9805 at 45mg, 90mg compared to Placebo (0 mg), in terms of efficacy in 
subjects with Parkinson’s disease. 
 
 
 


 
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3 
STUDY DESIGN  
This is a phase IIa, first in human, randomized, double-blind, multicenter study to evaluate the safety, 
tolerability and efficacy of DA-9805 at 45mg, 90mg versus placebo in subjects with early diagnosed Parkinson’s 
disease. 
The study will include three parts: a 2-week Screening part, a 12-week Double-Blind Treatment part, and a 4-
week Follow-up part. The Schedule of Events is provided in Table 4-1. 
 
Study Visits:  
 
 Screening Visit (Day -14 to Day -1), up to 14 days:  
 
Screening part is designed to determine subject’s eligibility to proceed to Randomization and the 
Treatment Phase of the study. During this part, a series of assessments will be performed to determine 
subject eligibility as per inclusion and exclusion criteria. 
 
At the Screening Visit, prior to any study-related procedures, a written informed consent will be 
obtained from the subject by the Investigator or suitable qualified personnel. Screening procedures will 
be conducted per the study schedule of events (Refer to section 4.1.1). All screening information will 
be documented in the case report forms. 
 
Subjects who meet eligibility criteria, but have some abnormal laboratory values, based on PI review a 
repeat laboratory sample may be collected. The repeat laboratory reports should be reviewed by the PI 
to confirm eligibility prior to randomization. 
 
Subjects who fail to meet eligibility criteria during the Screening part will be considered screen 
failures and will be exited from the study. Subjects who have successfully completed the Screening 
part will enter the Double-Blind treatment part of the study. Treatment part followed by randomization 
will last for 12 weeks. Subjects will take the randomized treatment, DA-9805 at 45mg, 90mg or 
placebo for 12 weeks. 
 
 Visit 0: Randomization/Baseline Visit (Day 0) (TV0): On Day 0 prior to randomization, the 
subject’s continued eligibility will be evaluated (Refer to section 4.1.2). Subjects who continue to 
be eligible will be randomized in a 1:1:1 ratio to one of the following treatment groups and 
assigned the study treatment kit: 
 
o Group 1: DA-9805 45mg tablet 
o Group 2: DA-9805 90mg tablet 
o Group 3: placebo (0 mg DA-9805) tablet 
 
DA-9805 and matching placebo are oral tablets that will be taken three times daily during this study.  
 


 
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 Treatment Visits 1 (TV1) through Treatment Visit 3 (TV3):  
Clinic treatment visits TV1 through TV3 will be conducted every four (4) week (± 3 days).  During 
each of these visits, study evaluations will be conducted per the study schedule of events (Refer to 
section 4.1.3), and sufficient supply of DA-9805 or placebo till the next treatment visit will be 
dispensed.  
 
Treatment Visit 3 (TV3) will be considered the end of treatment (EOT) clinic visit. Study evaluations, 
review of the adverse events and concomitant medications and final study treatment accountability will 
be conducted. 
 Follow-up Part (4 weeks ± 3 days) 
The follow-up part will consist of a follow-up visit at the end of the Double-Blind Treatment part.  
 
The detailed study schedule and assessments in each visit are provided in Section 4.1 of the protocol. 
 


 
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Figure 3-1: 
Study Flow Diagram 
Screening Part
SCREENING PHASE
14-day 
Screening
Period of 
Medication 
Washout
RANDOMIZATION/TREATMENT PHASE
Confirmation of 
Continued Eligibility
Is Subject 
Still Eligible for 
Randomization?
Randomization &
Treatment 
Administration
TV0
Treatment Visits
TV0 to TV3
End of Study
FOLLOW UP PHASE
No
Yes
End of Study
Yes
Yes
 
No
No
Does 
Subject Meet 
Inclusion/Exclusion 
Criteria?
Screen 
Failure
Screen 
Failure
Criteria Met for Withdrawal
Follow Up Part
 (Week 4)
Informed 
Consent
Did Subject complete
TV3?
Continue treatment 
(Max. 12 weeks per 
subjects)
Yes
 


 
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3.1 
STUDY POPULATION 
3.1.1 NUMBER OF SUBJECTS 
A total of 60 subjects will be randomized to this study from up to 10 Centers within the USA.  


 
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3.1.2 INCLUSION CRITERIA 
Subjects will be eligible for enrollment in the study only if they meet ALL of the following criteria: 
1. Male or female subjects who are between 30 and 79 years old inclusive  with a clinical diagnosis of 
Parkinson’s disease as per UK Brain Bank Criteria for two (2) years or less at screening. 
2. Hoehn and Yahr I or II at screening. 
3. Subjects who are newly diagnosed & currently not on any Parkinson’s disease medication (or) 
subjects who are on stable doses for at least 4 weeks prior to screening on Amantadine or 
anticholinergics for treatment of Parkinson’s disease. 
1. Note: Subjects that had anti-parkinsonian medication (including levodopa, dopamine 
agonists, entacapone and monoamine oxidase-B inhibitors) discontinued at least 60 days 
prior to screening, e.g., for intolerance, may be considered eligible if all other eligibility 
requirements are met. 
4. Women of child-bearing potential should use reliable contraception. Acceptable methods of 
contraception include: surgical sterilization (e.g. bilateral tubal ligation), hormonal contraception 
(implantable, patch, and oral), and double-barrier methods (condom, diaphragm and spermicide are 
each considered a barrier). Women of child-bearing potential are defined as women physiologically 
capable of becoming pregnant, UNLESS they meet the following criteria: 
1. Post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of 
spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels > 
40mIU/m, OR;  
2. 6 weeks post surgical bilateral oophorectomy with or without hysterectomy 
5. If a male and heterosexually active with a female of childbearing potential, the subject must agree 
to use a double barrier method of birth control (or must have been surgically sterilized) and to not 
donate sperm during the study. 
6. Without clinically significant abnormalities in physical exam, neurological exam and laboratory 
assessments (urine/blood routine, biochemical tests and ECG) which would exclude the subject 
from the study in the opinion of the Investigator. For Aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) and alkaline phosphatase (ALP) the screening levels should be ≤ 2 times 
upper limit normal. 
7. Subject is capable of providing informed consent and is willing to sign the ICF prior to study 
Screening and agrees to comply with the study protocol requirements. 
3.1.3 EXCLUSION CRITERIA 
Subjects will be eligible for enrollment in the study only if they meet NONE of the following criteria: 
1. Subject has an atypical parkinsonian syndrome or secondary parkinsonism (e.g., due to drugs, 
metabolic neurogenetic disorders, encephalitis, cerebrovascular disease or degenerative disease). 
2. Subjects with history of neurosurgical intervention for Parkinson’s disease. 
3. Subjects who meet the DSM-V criteria at screening for bipolar disorder, major depressive 
disorder, psychotic disorders, or any other comorbid mental disorders that in the opinion of the 
Investigator may interfere with study conduct and results interpretation. 
4. Subjects with clinical diagnosis of dementia (MMSE score <24) as determined by the investigator 
using Mini–Mental State Examination (MMSE). 
5. Female subjects who are pregnant or breast feeding. 


 
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6. Initiation of any anti-parkinsonian medication (including levodopa, dopamine agonists, 
entacapone and monoamine oxidase-B inhibitors) for the duration of the trial.  
7. Initiation of Amantadine or anticholinergics for newly diagnosed subjects or change in the dosage 
of Amantadine or anticholinergics during the trial for subjects who were on stable doses for 4 
weeks prior to screening. 
8. Subjects who used investigational drugs or devices within 60 days prior to screening or 
investigational biologics within the last 6 months prior to screening. 
9. Subjects with a clinically significant medical or surgical condition, including major surgeries 
within 28 days prior to enrollment. 
 
4 
STUDY SCHEDULE 
The schedules for the protocol-specified assessments and procedures for this study are detailed in this 
section. Day 0 is used as the day of Randomization/baseline and first randomized study treatment 
administration. See Table 4-1. 
 
 
 


 
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Table 4-1: 
Study Schedule of Events 
Study Parts 
                                      
Screening Part 
(2 weeks) 
Double-Blind Treatment Part 
(12 weeks) 
Follow-up Part 
 Follow-up Visit(4 
weeks) 
Treatment Visits 
 
TV0 
Randomization 
TV1 
TV2 
TV3  
FUV  
Weeks from Randomization Date 
(window period: ± days)              
- 2 
 
Day 0 
+ 4 
(± 3) 
+ 8 
 (± 3) 
+ 12 
 (± 3) 
+ 16 
(± 3) 
Pre- 
Post- 
Written Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Schedule Randomization Day 
X 
 
 
 
 
 
 
Continued Eligibility 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
Height1 and Weight 
X 
X 
 
 
 
X 
 
ECG 
X 
X 
 
X 
 
X 
 
Serum Hematology2  
X 
 
 
X 
X 
X 
 
Serum Chemistry2 
X 
 
 
X 
X 
X 
 
Urine Analysis2 
X 
 
 
X 
X 
X 
 
Urine Pregnancy Test3 
X 
X 
 
 
 
X 
 
MDS-UPDRS 
 
X 
 
X 
X 
X 
 
H & Y 
X 
X 
 
X 
X 
X 
 
S & E 
 
X 
 
X 
X 
X 
 
PDQ-39 
 
X 
 
X 
X 
X 
 
CGI-S and CGI-I4 
X 
X 
 
X 
X 
X 
 
C-SSRS 
X 
X 
 
X 
X 
X 
 
MMSE 
X 
X 
 
 
 
 
 
Dispense the DA-9805 or placebo5 
 
 
X 
X 
X 
 
 
DA-9805 
or 
Placebo 
first 
dose 
administration 
 
 
X 
 
 
 
 
Study treatment accountability 
 
 
 
X 
X 
X 
 


 
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Study Parts 
                                      
Screening Part 
(2 weeks) 
Double-Blind Treatment Part 
(12 weeks) 
Follow-up Part 
 Follow-up Visit(4 
weeks) 
Treatment Visits 
 
TV0 
Randomization 
TV1 
TV2 
TV3  
FUV  
Weeks from Randomization Date 
(window period: ± days)              
- 2 
 
Day 0 
+ 4 
(± 3) 
+ 8 
 (± 3) 
+ 12 
 (± 3) 
+ 16 
(± 3) 
Pre- 
Post- 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
 
X 
X 
X 
X 
 
1 Height only at Screening. 
2 Subjects who meet eligibility criteria, but have some abnormal laboratory values, based on PI review a repeat laboratory sample may be collected. The repeat laboratory reports 
should be reviewed by the PI to confirm eligibility prior to randomization. 
3 Only for female subjects of childbearing potential. 
4 CGI-I will be done only at Treatment Visit 1 to Treatment Visit 3 
5 Dispense the DA-9805 or placebo at each of the clinic treatment visit, except TV3 which is the End of Treatment visit (EOT). 
 
 
 
 
 


 
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4.1 
SCREENING AND RANDOMIZATION 
4.1.1 SCREENING VISIT (DAY -14TO DAY -1), UP TO 14 DAYS 
The subject will sign and date the ICF, and Health Insurance Portability and Accountability Act 
(HIPAA) authorization (according to site practices) prior to any study-related procedures. A subject 
number will be assigned to each subject in successive order of consent signing at each center, 
beginning with 001 at each site. Each study site will receive a unique numeric designation, and will 
precede the subject number (e.g. at study center 01 the first two consented subjects would be 01-001 
and 01-002; at study center 02 the first two consented subjects would be 02-001 and 02-002).  
 
Screening Visit procedures are per below: 
 
 Informed Consent will be obtained prior to any study-related procedures. (Refer to Section 8.1) 
 Eligibility assessment per the inclusion and exclusion criteria and diagnosis confirmation (Refer to 
Section 3.1.2 and Section 3.1.3). 
 Subject demographics  (Refer to Section 8.3) 
 Medical history (Refer to Section 8.4) 
 Vital signs (Refer to Section 8.5) 
 Height, Weight and BMI (Refer to Section 8.6) 
 Physical examination (Refer to Section 8.7) 
 List concomitant medications (Refer to Section 7) 
 Laboratory assessments (hematology, biochemistry and urine analysis) (Refer to Section 8.8) 
 Electrocardiogram (Refer to Section 8.9) 
 Urine pregnancy test (Refer to Section 8.10) 
 Hoehn and Yahr (H&Y) Scale (Refer to Section 8.12) 
 Columbia-Suicide Severity Rating Scale (C-SSRS) (Refer to Section 8.16) 
 Clinical Global Impression-Severity (CGI-S) scale (Refer to Section 8.14) 
 Mini-Mental State Examination (MMSE) (Refer to Section 8.17) 
 Schedule randomization visit 
 
4.1.2 TREATMENT VISIT 0 (TV0): RANDOMIZATION/BASELINE VISIT (DAY 0) 
If continued to be eligible for the study at TV0, the subject will proceed to be randomized. All entrance 
criteria must be met prior to randomization of a subject into the protocol. The following assessments 
will be performed: 
 
Treatment Visit 0 (TV0) – Prior to Randomization: Perform the following baseline assessments 
 
 Assessment of continued eligibility (Refer to Section 3.1.2 and Section 3.1.3) 
 Medical history (Refer to Section 8.4) 
 Vital signs (Refer to Section 8.5) 
 Body Weight (Refer to Section 8.6) 
 Physical Examination (Refer to Section 8.7) 
 Electrocardiogram (Refer to Section 8.9) 
 Urine pregnancy test (Refer to Section 8.10) 


 
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 MDS-UPDRS Scale (Refer to Section 8.11) 
 Hoehn and Yahr (H&Y) Scale (Refer to Section 8.12) 
 Schwab and England (S&E) Scale (Refer to Section 8.15) 
 Parkinson's Disease Questionnaire (PDQ-39) total score (Refer to Section 8.13) 
 Clinical Global Impression-Severity (CGI-S) scale (Refer to Section 8.14) 
 List concomitant medications (Refer to Section 7) 
 Columbia-Suicide Severity Rating Scale (C-SSRS) (Refer to Section 8.16) 
 Mini-Mental State Examination (MMSE) (Refer to Section 8.17) 
 Randomization (Refer to Section 9.4) 
 
Treatment Visit 0 (TV0) – Post Randomization: Perform the following assessments 
 Vital signs (Refer to Section 8.5) 
 Study treatment dispensation (Refer to Section 6.7) 
 Study treatment first dose administration (Refer to Section 6.7) 
 Adverse events evaluation after first dose (Refer to Section 10) 
 
4.1.3 TREATMENT VISIT 1 (TV1) (WEEK 4: DAY 28±3), TREATMENT VISIT 2 (TV2) (WEEK 8: DAY 
56±3), TREATMENT VISIT 3 (TV3) (WEEK 12: DAY 84±3) 
The following assessments will be performed: 
 
 Vital signs (Refer to Section 8.5) 
 Weight and BMI (Refer to Section 8.6)  (Only at TV3) 
 Physical examination (Refer to Section 8.7)  
 Laboratory assessments (hematology, biochemistry and urine analysis) (Refer to Section 8.8)  
 Electrocardiogram (Refer to Section 8.9) (This is done ONLY at TV1 and TV3) 
 Urine pregnancy test (Refer to Section 8.10) (This is done ONLY at TV3) 
 MDS-UPDRS Scale (Refer to Section 8.11) 
 Hoehn and Yahr (H&Y) Scale (Refer to Section 8.12) 
 Schwab and England (S&E) Scale (Refer to Section8.15) 
 Parkinson's Disease Questionnaire (PDQ-39) total score (Refer to Section 8.13) 
 Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) 
scale (Refer to Section 8.16) 
 List concomitant medications (Refer to Section 7) 
 Columbia-Suicide Severity Rating Scale (C-SSRS) (Refer to Section 8.16) 
 Adverse events evaluation (Refer to Section 10) 
 Study treatment dispensation (This is done ONLY at TV1 and TV2) (Refer to Section 6.7) 
 Study treatment accountability (Refer to Section 6.9) 
4.2 
FOLLOW-UP 
4.2.1 FOLLOW-UP VISIT (WEEK 16: DAY 112±3) 
The following assessments will be performed: 
 
 List concomitant medications (Refer to Section 7) 
 Adverse events evaluation (Refer to Section 10) 


 
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4.3 
UNSCHEDULED VISITS 
Unscheduled visits may be required in addition to the scheduled visits per the Investigator’s discretion. 
The details of these unscheduled visits with subjects will be recorded in the medical records and on the 
Case Report Form (CRF). 
4.4 
MISSED VISITS 
If a subject misses a visit, the site is to make every effort to have the subject return as soon as possible 
to make up the visit. Once the subject is seen, he/she is to return to his/her original visit schedule.  
 
 


 
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5 
SUBJECT COMPLETION AND WITHDRAWAL 
5.1 
SUBJECT COMPLETION 
A subject who completes TV3 will be considered to have completed the study.  
5.2 
SUBJECT PREMATURE WITHDRAWAL FROM THE STUDY 
A subject who is randomized into the study, but who does not complete the study will be considered 
prematurely discontinued.  
 
All subjects have the right to withdraw at any point during the study without prejudice. It will be 
documented whether or not each subject completed the clinical study. If for any subject, study 
treatment or observations were discontinued, the reason(s) will be recorded and the Sponsor should be 
notified promptly. All efforts must be made to collect data and report records and tests as completely 
as possible. Reasons for subject withdrawal/discontinuation may constitute one of the following: 
 
 Subject withdrew consent 
 Subject chooses to withdraw  
 Subject is withdrawn due to an AE 
 Pregnancy 
 Lost to follow-up  
 Subject is treated with or takes a prohibited medication 
 The Investigator determines that it is in the subject’s best interest 
 Excessive protocol deviations, as determined by the Investigator or the Sponsor 
 Discontinuation of study by the Sponsor 
 
For subjects who withdraw/are discontinued prematurely, TV3 assessments will be performed as the 
end of study evaluations. For all withdrawn/discontinued subjects the Follow-up visit will happen 4 
weeks ±3 days after the end of study Visit evaluations.   
 
Important Notes: 
1. Subjects may drop out or be withdrawn at their own request. Although subjects do not need to give 
a reason for requesting withdrawal from the trial, the Investigator should make a reasonable effort 
to ascertain the reason(s), while fully respecting the subject's rights. 
2. Any subjects reporting Serious Adverse Events (SAEs) that have not resolved by their last study 
visit will be followed to resolution or until 30 days after the subject completes the study. 
3. Every attempt should be made to collect follow-up information. The reason for withdrawal from 
the study (if known) will be recorded in the source documents and on the appropriate page of the 
CRF. 
4. Before a subject is identified as lost-to-follow-up, the site should make all reasonable efforts to 
contact the subject. These attempts must be documented and should include at a minimum one 
phone call and one follow-up certified letter.  


 
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5.3 
SCREEN FAILURES 
A subject who has signed the consent form but is not randomized is classified as a screen failure. 
Subject number, demographic information, and reason for screen failure will be collected.  
 
 
 


 
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6 
STUDY TREATMENTS 
6.1 
METHOD FOR ASSIGNING ELIGIBLE SUBJECTS TO TREATMENT 
Study eligible subjects will be randomized based on a randomization schedule prepared by Amarex 
Clinical Research, as the contracted CRO. Details of the randomization and assignment of the subject 
number are provided in Section 4.1 and Section 9.4. 
 
At Baseline/Randomization visit (Treatment Visit 0, Day 0), all eligible subjects will be randomized 
1:1:1 to receive DA-9805 at 45mg, 90mg or Placebo for 12 weeks.  
 
After a subject has been determined to be eligible for the treatment in the study, a randomization 
number will be assigned. Once the randomization number is assigned, it cannot be re-assigned even if 
the subject is subsequently deemed ineligible or withdraws consent.  
 
A subject who is randomized to study treatment becomes part of the Intent-to-Treat (ITT) population. 
Once a subject is randomized to study treatment, the subject must either complete the protocol or 
withdraw from the protocol (with reason specified). Randomized subjects may not be considered 
screen failures.  
6.2 
TEST TREATMENT  
Test treatment for this trial is defined as DA-9805 45mg or 90mg. DA-9805 is an oral tablet that will 
be taken three times daily during this study.  
 Group 1: DA-9805 45mg tablet (15 mg TID) 
 Group 2: DA-9805 90mg tablet (30 mg TID) 
 Group 3: placebo tablet (0 mg DA-9805 TID) 
The ingredients in each DA-9805 tablet are included in Table 6-1 below. 
6.3 
CONTROL TREATMENT  
The control treatment is Placebo, which will look, and will be packaged and maintained exactly the 
same way as the test treatment. The ingredients in each placebo tablet are included in Table 6-1. 
 
Table 6-1: 
Study Treatment Ingredients 
 
Ingredient(mg/tablet) 
DA-9805 
45mg (15mg TID) 
DA-9805 
90mg (30 mg TID) 
Placebo 
0mg (0mg TID) 
 
Moutan Root Bark 
ㆍBupleurum RootㆍAngelica 
Dahurica Root (1:1:1) 
90% Ethanol Soft Extract 
15 
30 
0 
 
Copovidone 
2.5 
2.5 
2.5 
 
Magnesium 
Aluminometasilicate 
20 
40 
20 


 
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Lactose Hydrate 
39 
21.5 
39 
 
Microcrystalline Cellulose 
39 
21.5 
54 
 
Croscarmellose Sodium 
7.5 
7.5 
7.5 
 
Magnesium Stearate 
2 
2 
2 
 
Opadry White 
3.75 
3.75 
3.75 
 
Opadry Pink 
5 
5 
5 
 
Carnauba Wax 
0.05 
0.05 
0.05 
Total weight 
133.8mg 
133.8mg 
133.8mg 
 
6.4 
STUDY TREATMENT LABELING AND PACKAGING  
Both DA-9805 and placebo tablets will be provided under appropriate investigational product labeling. 
For the Double-Blind phase of the study, investigational product will be provided as blister packs. 
Each blister pack will contain 10 tablets of DA-9805 or placebo.  
6.5 
STUDY TREATMENT STORAGE 
All study treatments will be stored at temperatures up to 25℃ and protected from direct light (Storage: 
Up to 25℃ ). Access to study treatment will be restricted to authorized personnel only.  
6.6 
STUDY TREATMENT ADMINISTRATION  
All subjects, after signing the Informed Consent Form (ICF), will be assessed during the screening 
phase. Eligible subjects who have completed the screening phase will proceed with randomization and 
the double-blind treatment phase of the study. 
 Subjects randomized to the active treatment groups (45mg or 90mg) will take one tablet three times 
daily with water.  
 Subjects randomized to the Placebo treatment group will take one Placebo tablet three times daily 
with water. 
 
Placebo tablets, as described in Section 6.3will be identical in appearance to the DA-9805 tablets.  
6.7 
STUDY TREATMENT DISPENSATION 
At Treatment Visits 0, 1 and 2 of the study, sufficient randomized study treatments will be dispensed 
to each randomized subject for the period of time between the current clinic visit and the next clinic 
visit. Investigational products will be provided as blister packs. Each blister pack will contain 10 
tablets of DA-9805 or placebo. For the active treatment group, 11 blister packs of active tablets (DA-
9805 45mg or DA-9805 90mg as per treatment assignment) will be dispensed at each of these visits. 
For the placebo group, 11 blister packs of placebo tablets will be dispensed at each of these visits.  


 
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6.8 
STUDY TREATMENT ACCOUNTABILITY 
The Investigator or designee will verify the contents of each shipment against the shipping documents. 
Verification of study treatment receipt will be documented according to the Sponsor’s requirements.  
 
A study treatment accountability log will be provided to the site for use by the Investigator to maintain 
current and accurate inventory records (batch, expiry, and quantity) covering the receipt, dispensing 
and the destruction of all the study treatments.  
 
At the conclusion of the study, or other situations as applicable (ex. site closure, IP expiry, etc.) the 
Investigator must agree to return or destroy all study materials as instructed by the Sponsor.  
6.9 
STUDY DRUG COMPLIANCE  
Subjects will be instructed to bring used/unused study treatment blister packs. At each of these visits, 
tablet counts of returned study treatments will be conducted to determine if the subject has taken the 
study treatment per the protocol. If the number of dispensed tablets minus the number of remaining 
tablets (<80%) indicates that the subject is not taking their study treatment according to the study 
protocol, this will be recorded as a study drug non-compliance and the subject will be re-instructed on 
proper dosing. If the subject continues to be non-compliant with the dosing regimen the subject might 
be withdrawn from the study per the PI and/or the Sponsor’s discretion. During Visits 1 to 3 subjects 
are required to report the date and time for the last daily dose of study treatment taken since the last 
visit. 
 
 


 
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7 
CONCOMITANT AND PROHIBITED MEDICATIONS  
Initiation of any new Parkinson’s treatment during the study is prohibited.   
 
Subjects must be questioned at each study visit concerning any new medications or changes in current 
medications including over-the-counter medication and topical medication. All medications and 
therapies administered or taken by the subject beginning 30 days prior to signing the ICF and 
throughout the study will be recorded in the source documents and on the appropriate page of the CRF.  
 
For each medication and non-study treatment, the following will be documented: 
 
 Medication/treatment name (generic name may be used if trade name is unknown) 
 Dose, unit, and frequency of dosing (individual dosages, not total daily dose). Note: Each new dose 
of medication should be recorded as a separate entry, with the exception of medications that are 
given on a sliding scale. For these, it is acceptable to enter the range of the dosage, including the 
start and stop dates for which the specified dosage range was used. 
 Route of dosing 
 Indication for use 
 The start date  
 The stop date (if medication/therapy is not ongoing) 
 
7.1 
PROHIBITED MEDICATION 
The following treatments and medications are prohibited throughout the study 
1. Initiation of any anti-parkinsonian medication (including levodopa, dopamine agonists, 
entacapone and monoamine oxidase-B inhibitors) for the duration of the trial.  
2. Initiation of Amantadine or anticholinergics for newly diagnosed subjects or change in the 
dosage of Amantadine or anticholinergics during the trial for subjects who were on stable doses 
for 4 weeks prior to screening. 
 
 
 
 


 
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8 
DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES 
8.1 
INFORMED CONSENT 
Written informed consent will be obtained for this study by the Investigator or suitably qualified 
designee from all subjects before the performance of any protocol-specific procedure. This study will 
be conducted in accordance with the provisions of the Declaration of Helsinki.  
 
In obtaining and documenting informed consent, the Investigator must comply with applicable 
regulatory requirements and must adhere to GCP. The Investigator, or designee, must fully inform 
subjects of all pertinent aspects of the study. Before informed consent may be obtained, the 
Investigator, or a person designated by the Investigator, must provide the subject ample time and 
opportunity to inquire about details of the study and to decide whether or not to participate in the trial. 
All questions about the trial must be answered to the satisfaction of the subject. Prior to the subject’s 
participation in the trial, the written informed consent must be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  
8.2 
ELIGIBILITY ASSESSMENT 
The eligibility assessment will be done as per inclusion and exclusion criteria of this Protocol as 
described in Section 3.1.2 and Section 3.1.3. 
8.3 
SUBJECT DEMOGRAPHICS  
For the purposes of this study, demographic information will include: 
 
 Date of birth 
 Gender 
 Race (American Indian/Alaskan Native, Asian, Black/African American, Native Hawaiian/Pacific 
Islander, Caucasian, or other) 
 Ethnicity (Hispanic/Latino or Not Hispanic/Latino) 
8.4 
MEDICAL HISTORY 
All ongoing and any prior medical conditions that have resolved in the past year will be recorded at the 
Screening Visit. 
 
Events that are reported prior to the first randomized dose administration at Treatment Visit 0 (TV0) 
will be recorded as part of the medical history and not as AEs. Aside from being used to determine 
subject eligibility, this information will permit the Investigator to record the nature, duration and 
severity of any ongoing baseline medical conditions prior to receiving study treatment.  
 
Medical histories will be recorded using the body system categories outlined below: 
 


 
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 Psychiatric 
 Neurological  
 HEENT  
 Respiratory  
 Cardiovascular 
 Gastrointestinal 
 Genitourinary 
 Musculoskeletal 
 Endocrine  
 Substance Abuse 
 Integumentary 
 Other 
 
For each relevant history, the following will be documented:  
 
 Disease/disorder/condition 
 Date of onset/diagnosis 
 History status (resolved or ongoing) 
 Date of resolution, if applicable 
8.5 
VITAL SIGNS 
The following vital signs will be collected in the CRF and should be in the subject’s medical records:  
 
 Blood Pressure (systolic and diastolic)* 
 Heart Rate (HR) 
 Respiration Rate (RR) 
 Temperature 
 
*Note: Blood Pressure will be assessed in “Sitting Position” after 5 minutes’ rest. 
8.6 
HEIGHT, WEIGHT AND BMI 
Measurements will be taken in street clothing with jacket/coat and shoes removed. Body mass index 
(BMI) will be calculated from the height and weight measurements using the following formulas: 
 
 Metric: BMI = Weight (kg) / [Height (m)]2 
 
Or, 
 
 Imperial: BMI= Weight (lb) / [Height (in)]2 x 703 
8.7 
PHYSICAL EXAM 
The physical examination will include routine examinations, not including rectal or genitourinary 
examinations. All clinically significant abnormalities will be recorded in subject’s medical record and 
on the physical exam CRF page. Any abnormality that, in the opinion of the Investigator, is relevant to 
the safety of the subject or could impact safety or efficacy results for the subject will be considered as 
“clinically significant”. After administration of the first dose of study treatment, each physical exam 
abnormality that is clinically significant will be recorded as an AE. 


 
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8.8 
LABORATORY ASSESSMENTS 
The subjects are not required to be fasting. The following lab measurements will be obtained (as part 
of the subject’s medical record) and recorded: 
 
 Biochemistry: 
 
 AST (U/L)  
 ALT (U/L)  
 ALP (U/L) 
 Bilirubin, direct and total (mg/dL)  
 LDH (U/L)  
 BUN (mg/dL)  
 GGT (U/L) 
 Serum creatinine (mg/dL)  
 Uric acid (mg/dL)  
 Sodium (mmol/L)  
 Potassium (mmol/L) 
 Chloride (mmol/L) 
 Serum triglycerides (mg/dL) 
 HDL (mg/dL) 
 Blood glucose (mg/dL) 
 Hematology: 
 Red blood cell (RBC) count (millions/μL)  
 White blood cell (WBC) count (thousands/μL)  
 Platelet count (thousands/μL)  
 Hemoglobin (g/dL)  
 Hematocrit (%)  
 Mean Corpuscular Volume (MCV) (fL) 
 WBC differential including percentages of total WBC and absolute counts: 
o Neutrophils (i.e., segmented neutrophils) 
o Immature neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
 Urine analysis: 
 Color  
 Specific gravity  
 pH 
 Semi-quantitative (dipstick) assessments for: 
o Blood  
o Glucose (mg/dL) 
o Protein (mg/dL) 


 
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o If abnormality is detected, microscopic assessment:  
 RBC (number per High Power Field [HPF]) 
 WBC (number per HPF) 
 Epithelial cells (number per HPF) 
 Cast (number per HPF) 
 Crystals (number per HPF) 
8.9 
ELECTROCARDIOGRAM (ECG) 
ECG will be performed per the site standard procedures. The following parameters will be recorded (as 
part of the subject’s medical record) and recorded on the appropriate page of the CRF: ventricular rate 
(beats per minute), PR interval (msec), QRS interval (msec), QT interval (msec), and QTc interval 
(msec). Additionally, the Investigator will record the overall results of the ECG reading as either 
normal or abnormal, and if abnormal, as either “not clinically significant” or “clinically significant.” If 
abnormalities are observed, each will be recorded. Each treatment-emergent abnormality that is 
clinically significant will be recorded as an AE. Each ECG should be signed by a physician. 
8.10 URINE PREGNANCY TEST 
The result must be documented on the source documents and in the CRF. Subjects who are found to be 
pregnant during the screening period will be considered a screen failure. If pregnancy occurs during 
the course of the study, the subject will be withdrawn from the study and the pregnancy will be 
followed up to term for safety purposes. Relevant safety information collected after the study has 
completed will be reported as supplemental information. 
8.11 MDS- UNIFIED PARKINSON DISEASE RATING SCALE (MDS-UPDRS) 
The MDS-UPDRS is a multimodal scale assessing both impairment and disability and is separated into 
4 subscales (Parts I-IV). The MDS-UPDRS includes components assessed by the study investigator as 
well as sections completed by the subject. Every effort should be made to have the same investigator 
perform the ratings for an individual subject throughout the course of the study. 
 
 Part I: This assesses non-motor experiences of daily living and is comprised of two 
components: 
o Part IA contains 6 questions that are assessed by the Investigator and focuses on 
complex behaviors. 
o Part IB contains 7 questions that are part of the Patient Questionnaire completed by the 
subject. 
 Part II: This assesses motor experiences of daily living. There are an additional 13 questions 
that are also part of the Patient Questionnaire completed by the subject. 
 Part III: This assesses the motor signs of PD and is administered by the Investigator. 
 Part IV: This assesses motor complications, dyskinesias and motor fluctuations using historical 
and objective information. The Investigator will complete this assessment at each visit once a 
subject has started PD medication. 


 
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8.12 HOEHN AND YAHR STAGE 
The Hoehn and Yahr is a commonly used system for describing how the symptoms of Parkinson’s 
disease progress. The scale allocates stages from 0 to 5 to indicate the relative level of disability. This 
scale is included within the MDS-UPDRS and will be completed for all subjects. 
 Stage zero: No symptoms. 
 Stage one: Symptoms on one side of the body only. 
 Stage two: Symptoms on both sides of the body. No impairment of balance. 
 Stage three: Balance impairment. Mild to moderate disease. Physically independent. 
 Stage four: Severe disability, but still able to walk or stand unassisted. 
 Stage five: Wheelchair-bound or bedridden unless assisted. 
8.13 PARKINSON’S DISEASE QUESTIONNAIRE (PDQ 39) 
Parkinson’s disease questionnaire (PDQ-39) is the most widely used patient reported rating scale in 
Parkinson’s disease. PDQ 39 has questions relating to mobility, activities of daily living, emotional 
well-being, social support, cognition, communication and bodily discomfort. Subjects will be asked to 
answer the questions related to the last month. 
8.14 CLINICAL GLOBAL IMPRESSION 
The CGI measures global severity of illness at a given point in time, and the improvement from 
baseline at visits following the initial baseline visit. At the screening and baseline visit, the investigator 
will assess the severity on a seven-point scale. At subsequent visits, the investigator will assess the 
subject’s severity and improvement relative to baseline.  
 
Severity of Illness (CGI-S) 
 
Rating should account for severity of the patient’s illness. 
 
0 =  
Not assessed 
1 =  
Normal, not at all ill 
2 =  
Borderline ill 
3 =  
Mildly ill 
4 =  
Moderately ill 
5 =  
Markedly ill 
6 =  
Severely ill 
7 =  
Extremely ill 
 
Global Improvement (CGI-I) 
 
Compared to the patient’s condition at the baseline of this study, how much has the patient's illness 
improved or worsened?  (Circle one) 
 
Rating should account for severity of the patient’s illness. 


 
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0 =  
Not assessed 
1 =  
Very much improved 
2 =  
Much improved 
3 =  
Minimally improved 
4 =  
No change 
5 =  
Minimally  worse 
6 =  
Much worse 
7 =  
Very much worse 
 
8.15 SCHWAB AND ENGLAND ACTIVITIES OF DAILY LIVING SCALE 
The Schwab & England Activities of Daily Living (ADL) scale reflects the speed, ease, and 
independence with which an individual performs daily activities, or personal chores, such as eating, 
toileting, and dressing. This scale uses a rating scale from 0% to 100%, with 100% representing 
complete independence in performing daily activities and 0% representing a vegetative, bedridden 
state. 
8.16 COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a widely used suicidal ideation/suicidal 
behavior assessment tool (Posner, 2011). The C-SSRS assesses both suicidal ideation and suicidal 
behavior using questions in eleven (11) categories: five (5) for suicidal ideation, five (5) for suicidal 
behavior, and one (1) for self-injurious behavior without suicidal intent. There is a binary response 
(yes/no) for each question. For the purpose of this study, the “Lifetime/Recent” version of the C-SSRS, 
including questions spanning subjects’ lifetime as well as the one (1) month prior to screening will be 
used as the baseline evaluation. On the following visits the “Since Last Visit” version of the C-SSRS 
will be used to assess the treatment-emergent suicidal ideation/behavior under study treatment. 
Suicidal ideation or behavior is defined as a “yes” answer to any one of the 10 suicidal ideation or 
behavior questions on the C-SSRS. All ratings will be done by a trained interviewer and ideally by the 
same individual at each study site. Examples for both versions of the C-SSRS to be used are depicted 
in the text Figure 18-1 and text Figure 18-2. 
 
8.17 MINI-MENTAL STATE EXAMINATION 
The MMSE is a commonly used tool to evaluate cognition (Folstein et al., 1975). It comprises of 11 
items within different categories (orientation, registration, attention and calculation, recall, language 
and complex commands). The total score can range between 0 and 30. The example scoring of the tool 
is presented in text 
 
Example Mini-Mental State Exam (MMSE) 
Maximum 
Score 
 
5 
 
What is the (year) (season) (date) (day) (month)? 


 
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5 
 
Where are we (state) (country) (town) (hospital) (floor)? 
3 
 
Name 3 objects: 1 second to say each. Then ask the patient all 3 after 
you have said them. Give 1 point for each correct answer. Then 
repeat them until he/she learns all 3. Count trials and record. 
5 
 
Serial 7’s. 1 point for each correct answer. Stop after 5 answers. 
Alternatively spell “world” backward. 
3 
 
Ask for the 3 objects repeated above. Give 1 point for each correct 
answer. 
2 
 
Name a pencil and watch 
1 
 
Repeat the following “No ifs, ands, or buts” 
3 
 
Follow a 3-stage command: “Take a paper in your hand, fold it in 
half, and put it on the floor.” 
1 
 
Read and obey the following: CLOSE YOUR EYES 
1 
 
Write a sentence. 
1 
 
Copy the design shown. 
 
 
 
 
 
 


 
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9 
STATISTICAL CONSIDERATIONS  
This section presents general information about statistical considerations and concepts such as 
randomization, covariates, sample size, and a brief discussion on analysis methodology, as well as 
some data conventions. Detailed descriptions of the statistical analysis methods and data conventions 
will be included in a separate document; i.e., the Statistical Analysis Plan (SAP). 
 
9.1 
TREATMENT GROUPS  
The following treatment groups will be assessed:  
Group 
Description 
1 
DA-9805  (45 mg/day – 15mg TID) for 12 weeks 
2 
DA-9805  (90 mg/day – 30mg TID) for 12 weeks  
3 
Placebo (0 mg/day) for 12 weeks  
9.2 
DESCRIPTION OF STUDY ENDPOINTS  
9.2.1 SAFETY OUTCOME MEASURES 
 Incidence of Treatment-Emergent Adverse Events (AEs). 
 Incidence of withdrawals due to AEs. 
 Change/shifts in laboratory values. 
 Change in vital signs. 
 Change in Electrocardiogram (ECG) parameters. 
 Change in Columbia- Suicide Severity Rating Scale from baseline at week 12. 
9.2.2 PRIMARY EFFICACY OUTCOME MEASURE 
 Change in motor MDS-Unified Parkinson Disease Rating Scale (MDS-UPDRS) total score 
from baseline at week 12. 
9.2.3 SECONDARY EFFICACY OUTCOME MEASURES 
 Change in total MDS- UPDRS total score from baseline at week 12. 
 Change in MDS-UPDRS subscale scores from baseline at week 12. 
 Change in Schwab and England (S&E) Scale total score from baseline at week 12. 
 Change in Parkinson's Disease Questionnaire (PDQ-39) total score from baseline at week 12.  
 Change in Hoehn and Yahr (H&Y) scale total score from baseline at week 12.  
 Change in Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-
Improvement (CGI-I) scale score from baseline at week 12. 
 
9.3 
SAMPLE SIZE DETERMINATION  
It is planned to randomize a total of 60 subjects (20 subjects per group) with early Parkinson’s disease 
in this trial. This sample size is selected on the basis of clinical judgment and not based on statistical 


 
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power calculation; it is deemed adequate to provide clinically meaningful descriptive results consistent 
with the study objectives. 
9.4 
RANDOMIZATION 
Treatment assignment will be based on randomization schedule. An individual, independent of the 
clinical trial team, will develop the randomization schedules. The actual randomization assignment will 
be made through an Interactive Web Based Response System (IWRS) called WebView®. Subjects who 
have provided written informed consent and have met all the inclusion criteria and none of the 
exclusion criteria will be randomized to one of the treatment groups. 
The randomization in this multi-center study will be applied centrally across the sites and will use a 
mixed block size of 3 and 6 with a 1:1:1 ratio of DA-9805 (45mg/day), DA-9805 (90mg/day) and 
Placebo Treatment groups.  
9.5 
BLINDING AND PREVENTION OF BIAS 
The subjects, Investigators and their staff, and all Sponsor/CRO personnel involved in the 
management, and data collection in this study will be blinded to the treatment assignments.  
 
Treatment un-blinding for the study will occur after all clinical data have been received, data 
inconsistencies have been resolved, and the database is locked, except for safety reasons on a case-by-
case basis (i.e., emergency unblinding).  
 
9.6 
INTERIM ANALYSIS (IA) 
There is no interim analysis planned for this study. 
 
9.7 
GENERAL STATISTICAL CONSIDERATIONS  
All collected study data will be presented in subject data listings. Statistical analyses will be performed 
using SAS® for Windows, version 9.3 or later.  
 
9.8 
ANALYSIS POPULATIONS  
The details of the analysis population to be used for the study are described below: 
9.8.1 INTENT-TO-TREAT (ITT) POPULATION 
The Intent-to-Treat (ITT) population is defined as all randomized subjects who have received at least 
one dose of study treatment and undergone at least one post-randomization efficacy assessment.   
9.8.2 PER PROTOCOL (PP) POPULATION  
The Per Protocol (PP) population is defined as the set of subjects who meet the ITT population 
requirements, and were not associated with a major protocol violation. This population will be 
identified before the database lock, and before the treatment assignments are revealed.    


 
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9.8.3 SAFETY POPULATION 
The Safety population is defined as all subjects receiving at least one dose of the treatment after 
randomization.   
9.9 
STATISTICAL METHODS  
A Statistical Analysis Plan (SAP) will be developed and approved before the database is locked. The 
SAP will present the detailed statistical methodology to be used in analyzing the efficacy and 
tabulating the safety data from this trial. All inferential statistical analyses will be based on a two-sided 
test with a Type I error rate of 0.05. 
9.9.1 
  SUBJECT DISPOSITION  
The disposition of all subjects who sign an ICF will be provided. The numbers of subjects screened, 
randomized, completed, and discontinued during the study, as well as the reasons for all post-
randomization discontinuations will be summarized by treatment group. Disposition and reason for 
study discontinuation will also be provided as a by-subject listing.   
9.9.2 
  DEMOGRAPHICS AND BASELINE CHARACTERISTICS ANALYSIS  
Demographics and baseline characteristics will be summarized by treatment group using appropriate 
descriptive statistics. 
9.9.3 
  CONCOMITANT MEDICATIONS/THERAPIES 
Concomitant medications/therapies will be summarized separately for the Safety population. All prior 
and concomitant medications recorded in the case report form will be coded to all matching Anatomic 
Therapeutic Classification codes using the most recent version of WHO Drug. Descriptive summaries, 
by treatment group and stage of the study, will be prepared using the coded term. All concomitant 
medications/therapies recorded in the case report form will be listed.   
9.9.4 
  MEDICAL HISTORY 
The medical history will be summarized and/or listed descriptively. 
9.9.5 
 STUDY TREATMENT COMPLIANCE 
The study treatment compliance data will be summarized and/or listed descriptively. 
 
9.10 SAFETY OUTCOME ANALYSES 
Analyses of safety outcomes will be conducted using the safety population.  
9.10.1   ADVERSE EVENTS  
Adverse events will be coded using MedDRA. Treatment Emergent AE’s (TEAE) are defined as 
events with an onset on or after the first randomized treatment. TEAEs will be summarized by 
treatment group and by stage of the study, System Organ Class, and preferred term. The following 
TEAE summaries will be provided: 
 TEAEs by severity grade 
 TEAEs by relationship to study treatment. 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 
9.10.2 COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
All the data from C-SSRS will be listed and descriptive summaries will be presented for each of the 
subscales (i.e. Suicidal Ideation and Suicidal Behavior). 


 
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9.10.3 CLINICAL LABORATORY DATA 
All laboratory values will be listed. Laboratory measurements will also be summarized and presented 
by treatment group and time point.  
9.10.4 VITAL SIGN AND WEIGHT  
All changes in vital signs and weight will be listed and summarized over time. 
9.10.5 ECG 
All changes in ECG will be listed and summarized over time. 
9.10.6 PHYSICAL EXAMINATION 
All results for physical examination will be listed and summarized. 
 
9.11 EFFICACY OUTCOME ANALYSES 
The primary analysis of the primary and secondary endpoints will be conducted using the PP 
population. 
 
For the efficacy endpoints the data will be summarized and compared according to the variable type.   
Continuous data summaries will include:  
o Descriptive summary of number of observations, mean, standard deviation, median, and minimum 
and maximum values.   
o Inferential statistics include: 
 t-test or ANCOVA using the baseline value as a covariate , if the Normality assumption is met 
 rank –ANCOVA analysis i.e., an ANCOVA analysis on rank-transformed data or other non-
parametric methods, if the Normality assumption is not met. 
 
Categorical data summaries will include: 
 Frequency counts and percentages.  
 Logit model for inferential statistics. 
 If the Normality assumption is met, t-test or ANCOVA using the baseline value as a covariate 
will be used.  
 If the Normality assumption is not met, a rank –ANCOVA analysis i.e., an ANCOVA analysis 
on rank-transformed data or other non-parametric methods will be used.  
 
10 ADVERSE EVENTS (DEFINITIONS AND REPORTING) 
The Investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE, as provided in this protocol. During the study when there is a safety 
evaluation, the Investigator or site staff will be responsible for detecting, documenting, and reporting 
AEs and SAEs as detailed in this section of the protocol.  


 
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10.1 ADVERSE EVENT 
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease that 
occurs or is reported by the subject to have occurred, or a worsening of a pre-existing condition. An 
AE may or may not be related to the study treatment.  
 
AEs will be elicited through direct questioning and subject reports. Any abnormalities in visit 
evaluations, physical examination findings or laboratory results that the Investigator believes are 
clinically significant to the research subject and that occurred after initiation of the first study treatment 
will be reported as AEs. Abnormal findings that are NOT clinically significant should not be recorded 
as an AE. 
10.2 REPORTING OF ADVERSE EVENTS 
Report initiation for all AEs and SAEs will begin at the time of the first randomized treatment and 
continue up until the final study visit. All events will be followed to resolution or until 30 days after 
the subject completes the study. A final assessment of outcome will be made at that time. 
 
All AEs must be recorded in the subject’s medical records and on the CRF. AEs will be reported using 
customary medical terminology along with the following information: the onset and end dates, whether 
the event is considered to be an SAE (see Section 10.4), the impact the event had on study treatment 
(see Section 10.2.1), the CTCAE grade (intensity) of the event (see Section 10.2.2), the causality of the 
event (see Section 10.2.3), whether treatment was given as a result of the event (see Section 10.2.4), 
and the outcome of the event (see Section 10.2.5). 
10.2.1 IMPACT ON STUDY TREATMENT 
The impact the event had on the study treatment will be assessed as either: none, study treatment 
interrupted, study treatment discontinued, or not applicable. The “not applicable” assessment will be 
used only when the subject is no longer in the treatment phase of the protocol, or if the outcome of the 
event was “death”. 
10.2.2  CTCAE GRADE (INTENSITY) ASSESSMENT 
The guidelines outlined in CTCAE v4.03 will be used for assessing the intensity of the event. The 
general guidelines for assessing the AE grade appear below. Full guidelines may be obtained at 
http://evs.nci.nih.gov/ftp1/CTCAE. 
Table 10-1: 
CTCAE v4.03 General Guidelines 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self care ADL†. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
†Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 
-Common Terminology Criteria for Adverse Events (CTCAE), v4.03: June 14, 2010 


 
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10.2.3 CAUSALITY ASSESSMENT 
Adverse events will be assigned a relationship (causality) to the study treatment. The Principal 
Investigator must review each AE and make the determination of relationship of the event to the study 
treatment. Relationship of AEs to study treatment will be classified as follows: 
 
1. Definitely related: This category applies to those AEs that the Investigator feels are 
incontrovertibly related to the study treatment. An AE may be assigned an attribution of 
definitely related if or when it meets all of the following criteria: (1) it follows a reasonable 
temporal sequence from administration of the study treatment; (2) it could not be reasonably 
explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it follows a known response 
pattern to treatment with the study treatment. 
2. Probably related: This category applies to those AEs which, after careful medical 
consideration at the time they are evaluated, are felt with a high degree of certainty to be related 
to the study treatment. An AE may be considered probable if or when (must have three): (1) it 
follows a reasonable temporal sequence from administration of the study treatment. (2) It could 
not readily have been produced by subject’s clinical state, environmental or toxic factors, or 
other therapies administered to the subject. (3) Disappears or is decreased upon discontinuation 
of the study treatment. (4) It follows a known response pattern to treatment with the study 
treatment.  
3. Possibly related: This category applies to those AEs which, after careful medical consideration 
at the time they are evaluated, are judged unlikely but cannot be ruled out with certainty to the 
study treatment. An AE may be considered possible if or when (must have two): (1) it follows a 
reasonable temporal sequence from administration of the study treatment. (2) It could not 
readily have been produced by subject’s clinical state, environmental or toxic factors, or other 
therapies administered to the subject. (3) Disappears or is decreased upon discontinuation of the 
study treatment. (4) It follows a known response pattern to treatment with the study treatment.  
4. Remotely related: In general this category can be considered applicable to those AEs which, 
after careful medical consideration at the time they are evaluated, are judged likely to be 
unrelated to the study treatment. An AE may be considered unlikely if or when (must have 
two): (1) it does not follow a reasonable temporal sequence from administration of the study 
treatment. (2) It could not readily have been produced by subject’s clinical state, environmental 
or toxic factors, or other therapies administered to the subject. (3) Disappears or is decreased 
upon discontinuation of the study treatment. (4) It does not follow a known response pattern to 
treatment with the study treatment.  
5. Unrelated: This category applies to those AEs which, after careful consideration at the time 
they are evaluated, are clearly and incontrovertibly due to extraneous causes (disease, 
environment, etc.) and determined with certainty to have no relationship to the study treatment.  
10.2.4 TREATMENT GIVEN AS A RESULT OF THE EVENT 
The event impact in terms of treatment provided will be as either: none, medication administered, non-
medication therapy administered, surgery, or other (with a specification). 
10.2.5 OUTCOME ASSESSMENT 
The outcome of the event will be assessed as either: resolved, resolved with sequelae, ongoing, or 
death. Only one AE per subject is allowed to have an outcome assessment as “death.” If there are 


 
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multiple causes of death for a given subject, only the primary cause of death will have an outcome of 
death.   
10.3 EXPECTED / ANTICIPATED ADVERSE EVENTS 
There are no expected AEs associated with participation in this study. 
10.4 SERIOUS ADVERSE EVENTS 
A SAE is defined as any AE that: 
 
 Results in death 
 Is life threatening (the subject is at immediate risk of dying from the AE) 
 Requires subject hospitalization or prolongs existing hospitalization 
 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered  serious when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. 
10.5   REPORTING OF SERIOUS ADVERSE EVENTS (SAE)  
The Investigator is required to report all SAEs that occur during the time period specified in 
Section 10.2. Once the Investigator becomes aware of an SAE, he/she must report the SAE to Amarex 
Safety Department within 24 hours: 
 
CRO Medical Monitor 
Attn: Shide Badri, MD 
Amarex LLC 
20201 Century Boulevard, Suite 450 
Germantown, MD 20874 
Email: saereporting@amarexcro.com 
Phone: +1 (240) 454-6844 
Fax: +1 (240) 454-6602 
 
A written report, including a full description of the event as described in Section 10.2, must follow 
within 24 hours from the time the Investigator first learned of the event. The Amarex Medical Monitor 
may request additional supporting documentation as it becomes available, such as lab reports, ECG 
reports, discharge summary, hospital notes, etc.   
The Investigator is also responsible for reporting all SAEs to the appropriate Institutional Review 
Board (IRB) in accordance with local laws and regulations. The Investigator is responsible for 
maintaining documentation in the study file that indicates the IRB has been properly notified.  


 
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10.6   SAE FOLLOW-UP 
All subjects experiencing an SAE, including the discontinued subjects, must be closely followed until 
sufficient information is obtained to indicate a return to normal status or until the event stabilizes at a 
level acceptable to the investigator (i.e., recovery, return to baseline status, no further improvement 
expected, or death). 
 
For each SAE indicated as an unresolved event on the initial report, regardless of whether the subject 
completed the study or withdrew, the site should submit a follow-up report with updated information. 
 
 
 


 
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11 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Subjects will be identified on CRFs by a unique subject identification number and on source 
documents by name and date of birth. No personal identifier will be used in any publication or 
communication used to support this research study. The subject identification number will be used if it 
becomes necessary to identify data specific to a single subject.  
 
The monitors, auditors, personnel authorized by the Sponsor, the local IRB, and the FDA are eligible 
to review medical and research records related to this study as a part of their responsibility to protect 
human subjects in clinical research and will be given direct access to source data and documentation 
(e.g., medical charts/records, printouts etc.) for source data verification, provided that subject 
confidentiality is maintained in accordance with local requirements. Access to electronic medical 
records may be governed by institution policy and each site will be required to ensure access while 
remaining compliant with institutional requirements. 
 
 
 


 
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12 DATA SAFETY MONITORING COMMITTEE (DSMC) 
A Data Safety and Monitoring Committee (DSMC), independent of the study operations will be 
established to consider safety data generated during the study. The details of the DSMC 
responsibilities will be included in the DSMC charter. The DSMC charter will be developed and 
operated in adherence to the current FDA guidance on DSMC (Establishment and Operation of 
Clinical Trial Data Safety Monitoring Committees [March 2006]). The DSMC meetings will take place 
at least once and at other time-points as determined by the DSMC charter. In addition to the pre-
specified time-points, the DSMC may also decide to schedule a meeting whenever they decide a 
review of emergent safety data is warranted. The charter will detail the roles and responsibilities of the 
DSMC members once they have been appointed. The study data will be provided to the Committee 
members in the form of a data report. Meetings to discuss the data will be held in person or by 
teleconference, based on the DSMC Chair’s decision. The meetings will be in two stages: an “open 
stage” which will involve discussion on general aspects of the trial, and a “closed stage” between the 
DSMC members only. The remit of the DSMC will be primarily to assess the safety aspects of the 
trial. 
 
 
 


 
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13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 MONITORING REQUIREMENTS 
In an effort to fulfill the obligations outlined in 21 CFR Part 312 and ICH guidelines which require the 
Sponsor to maintain current personal knowledge of the progress of a study, the Sponsor's designated 
monitor will visit the center(s) during the study as well as maintain frequent telephone and written 
communication. The Investigator will permit the Sponsor to monitor the study as frequently as is 
deemed necessary and provide access to medical records to ensure that data are being recorded 
adequately, that data are verifiable and that protocol adherence is satisfactory.  
 
The Investigator will permit representatives of the Sponsor and/or designated CRO to inspect all CRFs 
and corresponding study subject original medical records (source documents) at regular intervals 
throughout the study. Subject original medical records and other relevant data must be available to 
support all data recorded in the CRF. In addition to the original medical records, these data may 
include but are not limited to, study, laboratory and diagnostic reports, wound images and tracings, etc.  
 
Site inspections serve to verify strict adherence to the protocol and the accuracy of the data being 
entered on the CRFs, in accordance with federal regulations. A Monitoring Log will be maintained at 
each study site that the monitor will sign, date, and state the type of visit.  
 
The Investigator should be aware that the study site and subject records may be inspected by the 
Sponsor and or representatives of the designated CRO, FDA, or other regional regulatory authority. 
 
The final statistical analysis of data will be performed after all clinical monitoring has been completed, 
all data queries have been resolved, and all data have been verified (Quality Control checked) prior to 
formal database lock. The Sponsor will authorize the final database lock. 
13.2 ACCEPTABILITY OF CASE REPORT FORMS  
All CRFs will be completed as soon as possible after the subject's visit. Corrections to data on the 
CRFs will be made according to standard data correction procedures. The Investigator will review 
CRFs to indicate that, to his/her knowledge, they are complete and accurate. CRFs will be reviewed by 
the Sponsor’s or designated CRO’s monitor, who will make a decision as to their acceptability.   
13.3 MODIFICATION OF PROTOCOL 
The Investigator will not modify or alter this protocol without first obtaining the concurrence of the 
Sponsor. Approval by the Investigator’s IRB must also be obtained prior to implementation of the 
change, with two exceptions: 
 
1. When necessary to eliminate apparent immediate hazard to the subject; or 
2. When the modification does not involve the subject’s participation in the trial. 
 
An amendment may also require modification of the ICF. The Investigator will provide an approval 
letter for the amendment and revised ICF, if applicable, to the Sponsor. An amendment must be in 


 
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writing and it must be dated by both the Sponsor and the Investigator. If necessary, the Sponsor will 
submit protocol amendments to FDA and other appropriate regulatory authorities and notify other 
Investigators using this protocol. 
13.4 REPORTING PROTOCOL DEVIATIONS 
The Investigator is obligated to follow the protocol without departure from the requirements written in 
the protocol. If the Investigator deviates from the protocol requirements, the Sponsor will make the 
determination as to whether the subject will continue in the study. The Sponsor also has the right to 
discontinue the subject for protocol violations. The IRB may also have to be contacted if safety to the 
subject or if the scientific soundness of the study is involved. All protocol deviations must be 
documented in the CRFs. 
 
 
 


 
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14 ETHICS AND REGULATORY REQUIREMENTS 
This study is to be conducted in accordance with the specifications of this protocol and in accordance 
with principles consistent with the Declaration of Helsinki, GCP, 21 CFR 312, ICH E6, HIPAA 
regulations in 45 CFR Part 164, and the Belmont Principles of respect for persons, beneficence, and 
justice. No protocol changes will be implemented without the prior review and approval of the IRB, 
except where it may be necessary to eliminate an immediate hazard to a research subject. In such a 
case, the change will be reported to the IRB as soon as possible, according to IRB regulations. 
Additionally, all study products used in this study are manufactured, handled and stored in accordance 
with applicable Good Manufacturing Practices (GMP) and the products provided for this study will be 
used only in accordance with this protocol. 
14.1 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The Principal Investigator will provide the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) with all appropriate materials as required by their IRB/IEC, including but not limited to the 
clinical study protocol, ICFs, and any advertising materials. The study will not be initiated until the 
IRB/IEC provides written approval of the aforementioned documents and until approval documents 
have been obtained by the Principal Investigator and Sponsor or Sponsor designee. The Investigator 
will not participate in the decision. If the Investigator is an IRB or IEC member, documentation must 
be provided indicating recusal from the approval process. Appropriate reports on the progress of this 
study by the Principal Investigator will be made to the IRB/IEC as required by local and applicable 
government regulations and in agreement with policy established by the Sponsor. The Investigator is 
required to maintain an accurate and complete record of all written correspondence to and received 
from the IRB/IEC, and must agree to share all such documents and reports with the Sponsor. 
 
No changes from the final approved protocol will be initiated without the IRB/IEC’s prior written 
approval or favorable opinion of a written amendment, except when necessary to eliminate immediate 
hazards to the subjects or when the change involves only logistics or administration.   
14.2 INVESTIGATOR’S RESPONSIBILITIES 
The Investigators are responsible for performing the study in full accordance with the protocol and the 
current revision of the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guideline, 
approved by the ICH, and any applicable national and local laws and regulations. Information 
regarding any study centers participating in this study that cannot comply with these standards will be 
documented. 
14.3 SUBJECT INFORMED CONSENT REQUIREMENTS 
Written and oral information about the study in a language understandable by the subject will be given 
to all subjects by the Principal Investigator and/or designee. Written informed consent will be obtained 
from each subject accordingly before any procedures or assessments that would not otherwise be 
required for the care of the subject are done and after the aims, methods, anticipated benefits, potential 
hazards, and insurance arrangements in force are explained and the subject has been given sufficient 
time to ask questions and consider participation in the study. It will also be explained to the subjects 


 
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that they are free to refuse entry into the study and free to withdraw from the study at any time without 
prejudice to future treatment. The written ICF is to be in compliance with CFR 21 Part 50.27, 45 Part 
46 and GCP guidelines. The Sponsor and/or designated CRO will approve the ICF and all amendments 
to the ICF prior to submission to the IRB/IEC. A copy of the ICF to be used will be submitted by the 
Investigator to the IRB/IEC for review and approval prior to the start of the study. Each study site must 
provide the Sponsor with an unsigned copy of IRB/IEC-approved ICF along with applicable 
documentation to support this approval. The original signed ICF is retained in the subject's study 
records, and a copy is provided to the subject. A second copy may be filed in the subject’s medical 
record, if allowed by institutional policy.  
 
 
 


 
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15 DATA HANDLING AND RECORD KEEPING 
15.1 RECORDING AND COLLECTION OF DATA 
The primary source document for this study will be the subject's medical records. If separate research 
records are maintained by the Investigator(s), the medical records and the research records will be 
considered the source documents for the purposes of auditing the study.  
 
Applicable source data will be manually transcribed to the approved CRFs. The Investigator is 
ultimately responsible for the accuracy of the data transcribed on the forms. All source documents and 
CRFs will be completed as soon as possible after the subject's visit. 
 
The Investigator will review CRFs to indicate that, to his/her knowledge, they are complete and 
accurate. If further changes are made after this, the Investigator will need to again sign the Investigator 
signature page. Designated source documents will be signed and dated by the appropriate study 
personnel. The Investigator must agree to complete and maintain source documents and CRFs for each 
subject participating in the study. The Investigator will maintain a confidential list of study subjects 
that will include each subject’s study number, name, date of birth and unique hospital identification 
number if applicable. This list will be kept by the Investigator and will not be collected by the Sponsor. 
A notation will be made in the subject’s case history/medical chart that he/she is participating in a 
clinical study and that the subject has provided a signed and dated ICF accordingly as well as the 
required site HIPAA authorization (if separate from the ICF). The Investigator must also maintain a 
separate screening log of all the subjects screened for participation in the study; it should include 
gender; age; eligibility status; reason for ineligibility, if applicable; and study allocated subject 
number, if applicable.  
15.2 CLINICAL DATA MANAGEMENT 
The Sponsor and/or designated CRO will be responsible for the processing and quality control of the 
data. Data management will be carried out as described in the Sponsor’s or CRO’s standard operating 
procedures (SOPs) for clinical studies. 
 
The handling of data, including data quality control, will comply with regulatory guidelines (e.g., ICH 
E6 GCP, and local regulations where applicable) and the Sponsor’s or the CRO’s SOPs as well as 
provisions of the study-specific Data Management Plan. All research data will be entered, either 
electronically or manually, into a computerized database, designed in accordance with 21 CFR Part 11 
and based on protocol requirements defined by the Sponsor in association with clinical data manager, 
including double-data entry, where applicable. The data will be reviewed, manually and/or 
electronically, and queries will be prepared for any data discrepancies. 
15.3 ARCHIVING 
All study documentation at the Investigator site and Sponsor site will be archived in accordance with 
ICH GCP E6 and the Sponsor’s quality standards and SOPs. 
 


 
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In accordance with CFR 21 Part 312, study records must be retained by the Investigator for at least two 
years (or longer per the state/local regulations) after all investigational use of the product is 
discontinued and the FDA is notified or until two years after the last approval of a marketing 
application. Study records should not be destroyed without prior written agreement between the 
Sponsor and the study Investigator. At the completion of the study, details of the archival process must 
be provided to the Sponsor. Study records are subject to inspection by applicable health and regulatory 
agencies at any time.   
 
Records to be retained by the Investigator include, but are not restricted to: 
 
 Case Report Forms and the source data and the primary records upon which they are based (e.g., 
subject’s progress notes, AE data, test results, and any other diagnostic procedures required to 
evaluate the progress of the study). 
 Signed protocols and protocol amendments 
 Laboratory ranges and certifications  
 Product accountability records 
 Study personnel signature log 
 Monitoring logs 
 Correspondence to and from the Sponsor, designee and IRB 
 Investigator and sub-Investigator CVs 
 Signed informed consent and HIPAA forms 
 Subject screening and randomization log 
 Serious adverse event reports 
 Institutional Review Board approval and re-approval letters 
 Other documents pertaining to the conduct of the study 
 
These documents must be maintained and kept on file by the Investigator so that the conduct of the 
study can be fully documented and monitored. 
 
 
 


 
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16 PUBLICATION PLAN 
The Investigator will refer to the Investigator agreement and clinical trial agreement for the publication 
and disclosure policy.  
 
 
 


 
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17 REFERENCES 
1. Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Goetz, 
C. G., Tilley, B. C., Shaftman, S. R., Stebbins, G. T., Fahn, S., Martinez-Martin, P., Poewe, W., 
Sampaio, C., Stern, M. B., Dodel, R., Dubois, B., Holloway, R., Jankovic, J., Kulisevsky, J., 
Lang, A. E., Lees, A., Leurgans, S., LeWitt, P. A., Nyenhuis, D., Olanow, C. W., Rascol, O., 
Schrag, A., Teresi, J. A., van Hilten, J. J. and LaPelle, N. (2008), Movement Disorder Society-
sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale 
presentation and clinimetric testing results. Mov. Disord., 23: 2129-2170. 
2. Fahn S, Elton RL, and members of the UPDRS committee. Unified Parkinson's Disease Rating 
Scale. In: Fahn S, Marsden CD, Goldstein M, Calne DB, eds. Recent developments in 
Parkinson's Disease. New Jersey: McMillan Health Care, 1987:153-163. 
3. Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 
1967;17:427-442. 
4. Peto V, Jenkinson C, Fitzpatrick R, Greenhall R. The development and validation of a short 
measure of functioning and well-being for individuals with Parkinson' disease. Qual Life Res 
1995; 4: 241-248 
5. Fearnley, J. M. & Lees, A. J. Ageing and Parkinson's disease: substantia nigra regional 
selectivity. Brain 114 ( Pt 5), 2283-2301 (1991). 
6. Halliday, G., Lees, A. & Stern, M. Milestones in Parkinson's disease--clinical and pathologic 
features. Movement disorders : official journal of the Movement Disorder Society 26, 1015-
1021, doi:10.1002/mds.23669 (2011). 
7. Przuntek, H., Muller, T. & Riederer, P. Diagnostic staging of Parkinson's disease: conceptual 
aspects. J Neural Transm 111, 201-216, doi:10.1007/s00702-003-0102-y (2004). 
8. Halliday, G., Lees, A. & Stern, M. Milestones in Parkinson's disease--clinical and pathologic 
features. Movement disorders : official journal of the Movement Disorder Society 26, 1015-
1021, doi:10.1002/mds.23669 (2011). 
9. Emre, M. et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. 
Movement disorders : official journal of the Movement Disorder Society 22, 1689-1707; quiz 
1837, doi:10.1002/mds.21507 (2007). 
10. Olanow CW. The scientific basis for the current treatment of Parkinson’s disease. Annu Rev 
Med 2004;55:41-60. 
11. Schapira AHV, Olanow CW. Neuroprotection in Parkinson’s disease: myths, mysteries, and 
misconceptions. JAMA 2004;291:358-64. 
12. Olanow CW, Kieburtz K, Schapira AH. Why have we failed to achieve neuroprotection in 
Parkinson’s disease? Ann Neurol 2008; 64 (suppl 2): S101–10. 
13. Hart RG, Pearce LA, Ravina BM, Yaltho TC, Marler JR. Neuroprotection trials in Parkinson’s 
disease: systematic review. Mov Disord 2009; 24: 647–54. 
14. Fox SH, Katzenschlager R, Lim SY, et al. The Movement Disorder Society evidence-based 
medicine review update: treatments for the motor symptoms of Parkinson’s disease. Mov 
Disord 2011; 26 (suppl 3): S2–41. 
15. National Institute of Mental Health (NIMH). Early clinical drug evaluation unit (ECDEU). 
Clinical 
global 
impressions. 
In: 
Guy 
W, 
ed. 
ECDEU 
assessment 
manual 
for 
psychopharmacology, revised edition. Rockville, MD: NIMH USA; 1976: 216–22. 


 
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16. Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for 
reappraisal? Ann Neurol 2006; 59: 559–62. 
17. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N 
Engl J Med 2004; 351: 2498–508. 
18. McRae C, Diem G, Vo A, et al. Schwab & England: standardization of administration. Mov 
Disord 2000; 15:335–6. 
19. Schwab RS, England Jr AC. Projection technique for evaluating surgery in Parkinson’s disease. 
In: Gilingham FJ, Donaldson IML, eds. Third symposium on Parkinson’s disease. Edinburgh: E 
& S Livingstone, 1969:152–7. 
20. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM225130.pdf 
21. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ.  The Columbia–Suicide Severity Rating Scale: Initial 
Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and 
Adults. Am J Psychiatry. 2011 Dec;168(12):1266-77 
22. Forkmann T, Scherer A, Boecker M, Pawelzik M, Jostes R, Gauggel S. The clinical global 
impression scale and the inﬂuence of patient or staff perspective on outcome. BMC Psychiatry 
2011; 11:83. 
23. Martinez-Martin P, Forjaz MJ, Cubo E, Frades B, de Pedro Cuesta J, The ELEP project 
members. Global versus factor-related impression of severity in Parkinson's disease: a new 
clinimetric index (CISI-PD). Mov Disord 2006; 21:208-14. 
24. Kim HG, Park G, Piao Y, Kang MS, Pak YK, Hong SP, Oh MS. Effects of the root bark of 
Paeonia suffruticosa on mitochondria-mediated neuroprotection in an MPTP-induced model of 
Parkinson's disease. Food Chem Toxicol. 2014;65:293-300. 
25. Park WH, Kang S, Piao Y, Pak CJ, Oh MS, Kim J, Kang MS, Pak YK. Ethanol extract of 
Bupleurum falcatum and saikosaponins inhibit neuroinflammation via inhibition of NF-κB. J 
Ethnopharmacol. 2015;174:37-44. 
26. Moon YJ, Lee JY, Oh MS, Pak YK, Park KS, Oh TH, Yune TY. Inhibition of inflammation 
and oxidative stress by Angelica dahuricae radix extract decreases apoptotic cell death and 
improves functional recovery after spinal cord injury. J Neurosci Res. 2012; 90(1):243-56. 
27. The Korean Pharmacopoeia 10th edition. (The KFDA Notification No. 2012–129. 2012. Dec 
27th. Korea Food & Drug Administration.) 
28. The Japanese Pharmacopoeia 16th Edition (English edition). (March 24, 2011 The MHLW 
Ministerial Notification No. 65). 
29. Chinese Pharmacopoeia 2010. (June 17, 2010 The CFDA Notification No. 2010-43). 
 
 
 
 
 
 
 
 
 
 
 


 
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18 APPENDICES 
18.1 APPENDIX 1: MDS-UPDRS,  HOEHN & YAHR SCALE 
 
 
 


 
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MDS-UPDRS 
The Movement Disorder Society (MDS)-sponsored new version of the UPDRS is founded on the critique 
that was formulated by the Task Force for Rating Scales in Parkinson's disease (Mov Disord 2003;18 738-750). 
Thereafter, the MOS recruited a Chairperson to organize a program to provide the Movement Disorder 
community with a new version of the UPDRS that would maintain the overall format of the original UPDRS, but 
address issues identified in the critique as weaknesses and ambiguities. The Chairperson identified 
subcommittees with chairs and members. Each part was written by the appropriate subcommittee members 
and then reviewed and ratified by the entire group. These members are listed below. 
The MDS-UPDRS has four parts: Part I (non-motor experiences of daily living), Part II (motor 
experiences of daily living, Part Ill (motor examination) and Part IV (motor complications). Part I has two 
components: IA concerns a number of behaviors that are assessed by the investigator with all pertinent 
information from patients and caregivers, and IB is completed by the patient with or without the aid of the 
caregiver, but independently of the investigator. These sections can, however, be reviewed by the rater to 
ensure that all questions are answered clearly and the rater can help explain any perceived ambiguities. Part II 
is designed to be a self-administered questionnaire like Part IB, but can be reviewed by the 
investigator to ensure completeness and clarity. Of note, the official versions of Part IA, Part IB and Part II of 
the MDS-UPDRS do not have separate on or off ratings. However, for individual programs or protocols the same 
questions can be used separately for on and off. Part Ill has instructions for the rater to give or demonstrate 
to the patient; it is completed by the rater. Part IV has instructions for the rater and also instructions to be read 
to the patient. This part integrates patient-derived information with the rater's clinical observations and judgments 
and is completed by the rater 
The authors of this new version are: 
Chairperson: Christopher G. Goetz 
Part I: Werner Poewe (chair), Bruno Dubois, Anette Schrag 
Part II: Matthew B. Stern (chair), Anthony E. Lang, Peter A LeWitt 
Part Ill : Stanley Fahn (chair), Joseph Jankovic, C. Warren Olanow 
Part IV Pablo Martinez-Martin (chair), Andrew Lees, Olivier Rascal, Bob van Hillen 
Development Standards: Glenn T. Stebbins (chair), Robert Holloway, David Nyenhuis 
Appendices Cristina Sampaia (chair), Richard Dodel, Jaime Kulisevsky 
Statistical Testing Barbara Tilley (chair), Sue Leurgans, Jean Teresi, 
Consultant: Stephanie Shaftman, Nancy LaPelle 
Contact person: Christopher G. Goetz, MD 
Rush University Medical Center 
1725 W. Harrison Street, Suite 755 
Chicago, IL USA 60612 
Telephone 312-942-8016 
Email: cgoetz@rush.edu 
July 1, 2008 
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Part I: Non-Motor Aspects of Experiences of Daily Living (nM-EDL) 
Overview: This portion of the scale assesses the non-motor impact of Parkinson's disease (PD) on patients' 
experiences of daily living. There are 13 questions. Part 1A is administered by the rater (six questions) and focuses 
on complex behaviors. Part 1 Bis a component of the self-administered Patient Questionnaire that covers seven 
questions on non-motor experiences of daily living. 
Part 1 A: 
In administering Part IA, the examiner should use the following guidelines: 
1. Mark at the top of the form the primary data source as patient, caregiver, or patient and caregiver in equal 
proportion. 
2. The response to each item should refer to a period encompassing the prior week including the day on which the 
information is collected. 
3. 
All items must have an integer rating (no half points, no missing scores). In the event that an item does not 
apply or cannot be rated (e.g., amputee who cannot walk), the item is marked UR for Unable to Rate. 
4. The answers should reflect the usual level of function and words such as "usually", "generally", "most of the time" 
can be used with patients. 
5. Each question has a text for you to read (Instructions to patients/caregiver). After that statement, you can 
elaborate and probe based on the target symptoms outlined in the Instructions to examiner. You should NOT 
READ the RATING OPTIONS to the patient/caregiver, because these are written in medical terminology. From 
the interview and probing, you will use your medical judgment to arrive at the best response. 
6. Patients may have co-morbidities and other medical conditions that can affect their function. You and the patient 
must rate the problem as it exists and do not attempt to separate elements due to Parkinson's disease from other 
conditions. 
EXAMPLE OF NAVIGATING THROUGH THE RESPONSE OPTIONS FOR PART 1A 
Suggested strategies for obtaining the most accurate answer: 
After reading the instructions to the patient, you will need to probe the entire domain under discussion to determine 
Normal vs. problematic: If your questions do not identify any problem in this domain, record O and move on to the 
next question. 
If your questions identify a problem in this domain, you should work next with a reference anchor at the mid-range 
(option 2 or Mild) to find out if the patient functions at this level, better or worse. You will not be reading the choices of 
resr2onses to the r2atient as the resr2onses use clinical terminology:. You will be asking enough r2robing questions to 
determine the resr2onse that should be coded. 
Work up and down the options with the patient to identify the most accurate response, giving a final check by 
excluding the options above and below the selected response. 
I 
I 
'Yes'. 
I 
Mark (0) Normal. 
I 
Is this item normal for you? 
I 
· 1 
'No, I have problems.i 
I 
Consider mild (2) as a reference point I 
'Yes, slight is closest'. 
I 
Confirm and mark (1) Slight. I 
and then compare with slight (1). 
I 
· 1 
If mild is closer than slight.! 
I 
Consider moderate (3) to see if this 
I 'No, moderate is too severe~.I 
Confirm and mark (2) Mild. 
I 
answer fits better. 
I 
· 1 
If moderate is closer than mild! 
I 
I 
Consider severe (4) to see if this 
'No, severe is too severe'.~ : Confirm and mark (3) Moderate. I 
answer fits better. 
I 
i 
I 
'Yes, severe is closest.' 
I 
I Confirm and mark (4) Severe. I 
I 
I 
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,m ooNG-AST 
-
------
(mm-dd-yyyy) 
Patient Name or Subject ID 
Site ID 
Assessment Date 
Investigator's Initials 
MDS UPDRS 
Part I: Non-Motor Aspects of Experiences of Daily Living (nM-EDL) 
Part 1A: Complex behaviors: [completed by rater) 
Primary source of information: 
D Patient 
D Caregiver 
D Patient and Caregiver in Equal Proportion 
To be read to the patient: I am going to ask you six questions about behaviors that you may or may not experience. 
Some questions concern common problems and some concern uncommon ones. If you have a problem in one of the 
areas, please choose the best response that describes how you have felt MOST OF THE TIME during the PAST 
WEEK. If you are not bothered by a problem, you can simply respond NO I am trying to be thorough, so I may ask 
questions that have nothing to do with you. 
1.1 COGNITIVE IMPAIRMENT 
Instructions to examiner Consider all types of altered level of cognitive function including cognitive slowing, 
impaired reasoning, memory loss, deficits in attention and orientation. Rate their impact on activities of 
daily living as perceived by the patient and/or caregiver. 
Instructions to patients [and caregiver]: Over the past week have you had problems remembering things, 
following conversations, paying attention, thinking clearly, or finding your way around the house or in town? 
[If yes, examiner asks patient or caregiver to elaborate and probes for information] 
D: Normal: 
1: Slight: 
No cognitive impairment 
Impairment appreciated by patient or caregiver with no concrete interference with the 
patient's ability to carry out normal activities and social interactions. 
2: Mild: 
Clinically evident cognitive dysfunction, but only minimal interference with the 
patient's ability to carry out normal activities and social interactions. 
3 Moderate: 
Cognitive deficits interfere with but do not preclude the patient's ability to carry out 
normal activities and social interactions. 
4: Severe: 
Cognitive dysfunction precludes the patient's ability to carry out normal activities and 
social interactions. 
SCORE 
D 
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1.2 HALLUCINATIONS AND PSYCHOSIS 
Instructions to examiner: Consider both illusions (misinterpretations of real stimuli) and 
hallucinations (spontaneous false sensations). Consider all major sensory domains (visual, 
auditory, tactile, olfactory and gustatory). Determine presence of unformed (for example sense of 
presence or fleeting false impressions) as well as formed (fully developed and detailed) 
sensations. Rate the patients insight into hallucinations and identify delusions and psychotic 
thinking. 
Instructions to patients {and caregiverl' Over the past week have you seen, heard, smelled or felt 
things that were not really there? [If yes, examiner asks patient or caregiver to elaborate and 
probes for information] 
O: Normal: 
1: Slight: 
No hallucinations or psychotic behaviour. 
Illusions or non-formed hallucinations, but patient recognizes them without 
loss of insight. 
2: Mild: 
Formed hallucinations independent of environmental stimuli. No loss of 
insight. 
3: Moderate: 
Formed hallucinations with loss of insight. 
4: Severe: 
Patient has delusions or paranoia. 
1.3 DEPRESSED MOOD 
Instructions to examiner: Consider low mood, sadness, hopelessness, feelings of emptiness or 
loss of enjoyment. Determine their presence and duration over the past week and rate their 
interference with the patient's ability to carry out daily routines and engage in social interactions. 
Instruction to the patient (and caregiver): Over the past week have you felt low, sad, hopeless or 
unable to enjoy things? If yes, was this feeling for longer than one day at a time? Did it make it 
difficult for you carry out your usual activities or to be with people? If yes, examiner asks patient or 
caregiver to elaborate and probes for information] 
O: Normal: 
1: Slight: 
2 Mild 
No depressed mood. 
Episodes of depressed mood that are not sustained for more than one day 
at a time. No interference with patient's ability to carry out normal activities 
and social interactions. 
Depressed mood that is sustained over days, but without interference with 
normal activities and social interactions. 
3: Moderate: 
Depressed mood that interferes with, but does not preclude, the patient's 
ability to carry out normal activities and social interactions. 
4: Severe: 
Depressed mood precludes patient's ability to carry out normal activities and 
social interactions. 
SCORE 
D 
D 
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1.4 ANXIOUS MOOD 
Instructions to examiner: Determine nervous, tense, worried or anxious feelings (including panic attacks) 
over the past week and rate their duration and interference with the patient's ability to carry out daily 
routines and engage in social interactions. 
Instructions to patients [and caregiverr Over the past week have you felt nervous, worried or tense? If 
yes, was this feeling for longer than one day at a time? Did it make it difficult for you to follow your usual 
activities or to be with other people? [If yes, examiner asks patient or caregiver to elaborate and probes 
for information.] 
0: Normal: 
No anxious feelings. 
1: Slight 
2: Mild: 
Anxious feelings present but not sustained for more than one day at a time. No 
interference with patient's ability to carry out normal activities and social interactions. 
Anxious feelings are sustained over more than one day at a time, but without 
interference with patient's ability to carry out normal activities and social interactions. 
3: Moderate: Anxious feelings interfere with, but do not preclude, the patient's ability to carry out 
normal activities and social interactions. 
4: Severe: 
Anxious feelings preclude patient's ability to carry out normal activities and social 
interactions. 
1.5 APATHY 
Instructions to examiner: Consider level of spontaneous activity, assertiveness, motivation and initiative 
and rate the impact of reduced levels on performance of daily routines and social interactions. Here the 
examiner should attempt to distinguish between apathy and similar symptoms that are best explained by 
depression. 
Instructions to patients (and caregiver). Over the past week, have you felt indifferent to doing activities 
or being with people? If yes, examiner asks patient or caregiver to elaborate and probes for information.] 
O: Normal: 
1: Slight 
2: Mild: 
No apathy. 
Apathy appreciated by patient and/or caregiver, but no interference with daily 
activities and social interactions. 
Apathy interferes with isolated activities and social interactions. 
3: Moderate: Apathy interferes with most activities and social interactions. 
4: Severe: 
Passive and withdrawn, complete loss of initiative. 
SCORE 
D 
D 
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1.6 FEATURES OF DOPAMINE DYSREGULATION SYNDROME 
Instructions to examiner: Consider involvement in a variety of activities including atypical or 
excessive gambling (e.g. casinos or lottery tickets), atypical or excessive sexual drive or 
interests (e.g., unusual interest in pornography, masturbation, sexual demands on partner), 
other repetitive activities (e.g. hobbies, dismantling objects, sorting or organizing), or taking 
extra non-prescribed medication for non-physical reasons (i.e., addictive behavior). Rate the 
impact of such abnormal activities/behaviors on the patient's personal life and on his family and 
social relations (including need to borrow money or other financial difficulties like withdrawal of 
credit cards, major family conflicts, lost time from work, or missed meals or sleep because of the 
activity). 
Instructions to patients {and caregiver/: Over the past week, have you had unusually strong 
urges that are hard to control? Do you feel driven to do or think about something and find it 
hard to stop? (Give patient examples such as gambling, cleaning, using the computer, taking 
extra medicine, obsessing about food or sex, all depending on the patients. 
O: Normal: 
1: Slight: 
No problems present. 
Problems are present but usually do not cause any difficulties for the patient or 
family/caregiver. 
2: Mild: 
Problems are present and usually cause a few difficulties in the patient's personal 
and family life. 
3: Moderate: 
Problems are present and usually cause a lot of difficulties in the patient's personal 
and family life. 
4: Severe: 
Problems are present and preclude the patient's ability to carry out normal 
activities or social interactions or to maintain previous standards in personal and 
family life 
SCORE 
D 
The remaining questions in Part I (Non-motor Experiences of Daily Living) [Sleep, Daytime Sleepiness, Pain and 
Other Sensation, Urinary Problems, Constipation Problems, Lightheadedness on Standing, and Fatigue] are in the 
Patient Questionnaire along with all questions in Part 11 (Motor Experiences of Daily Living]. 
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Patient Questionnaire: 
Instructions: 
This questionnaire will ask you about your experiences of daily living. 
There are 20 questions. We are trying to be thorough, and some of these questions may 
therefore not apply to you now or ever. If you do not have the problem, simply mark O for NO. 
Please read each one carefully and read all answers before selecting the one that best 
applies to you. 
We are interested in your average or usual function over the past week including today. Some 
patients can do things better at one time of the day than at others. However, only one answer 
is allowed for each question, so please mark the answer that best describes what you can do 
most of the time. 
You may have other medical conditions besides Parkinson's disease. Do not worry about 
separating Parkinson's disease from other conditions. Just answer the question with your 
best response . 
Use only 0, 1, 2, 3, 4 for answers, nothing else. Do not leave any blanks. 
Your doctor or nurse can review the questions with you, but this questionnaire is for patients 
to complete , either alone or with their caregivers. 
Who is filling out this questionnaire (check the best answer): 
D Patient 
D Caregiver 
D Patient and Caregiver in Equal Proportion 
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Part I: Non-Motor Aspects of Experiences of Daily Living (nM-EDL) 
1.7 SLEEP PROBLEMS 
Over the past week, have you had trouble going to sleep at night or staying asleep 
through the night? Consider how rested you felt after waking up in the morning. 
0: Normal: 
1: Slight: 
2: Mild: 
No problems. 
Sleep problems are present but usually do not cause trouble 
getting a full night of sleep. 
Sleep problems usually cause some difficulties getting a full night 
of sleep. 
3: Moderate: 
Sleep problems cause a lot of difficulties getting a full night of 
sleep, but I still usually sleep for more than half the night. 
4: Severe: 
I usually do not sleep for most of the night. 
1.8 DAYTIME SLEEPINESS 
Over the past week, have you had trouble staying awake during the daytime? 
0: Normal: 
1: Slight: 
No daytime sleepiness. 
Daytime sleepiness occurs but I can resist and I stay awake. 
2: Mild: 
Sometimes I fall asleep when alone and relaxing . For example, 
while reading or watching TV. 
3: Moderate: 
I sometimes fall asleep when I should not. For example, while 
4: Severe: 
eating or talking with other people. 
I often fall asleep when I should not. For example, while eating or 
talking with other people. 
SCORE 
D 
D 
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SCORE 
1.9 PAIN AND OTHER SENSATIONS 
Over the past week, have you had uncomfortable feelings in your body like pain, aches 
tingling or cramps? 
0: Normal: 
No uncomfortable feelings. 
1 : Slight: 
I have these feelings. However, I can do things and be with other 
people without difficulty. 
2: Mild: 
These feelings cause some problems when I do things or am with D 
other people. 
3: Moderate : 
These feelings cause a lot of problems, but they do not stop me 
from doing things or being with other people. 
4: Severe: 
These feelings stop me from doing things or being with other 
people. 
1.10 URINARY PROBLEMS 
Over the past week, have you had trouble with urine control? For example, an urgent 
need to urinate, a need to urinate too often, or urine accidents? 
0: Normal: 
No urine control problems. 
1 : Slight: 
I need to urinate often or urgently. However, these problems do 
not cause difficulties with my daily activities. 
2: Mild: 
Urine problems cause some difficulties with my daily activities. 
However, I do not have urine accidents. 
D 
3: Moderate: 
Urine problems cause a lot of difficulties with my daily activities, 
including urine accidents. 
4: Severe: 
I cannot control my urine and use a protective garment or have a 
bladder tube. 
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SCORE 
1.11 CONSTIPATION PROBLEMS 
Over the past week have you had constipation troubles that cause you difficulty 
moving your bowels? 
O: Normal: 
No constipation. 
1 : Slight: 
I have been constipated. I use extra effort to move my bowels. 
However, this problem does not disturb my activities or my being 
comfortable. 
2: Mild: 
Constipation causes me to have some troubles doing things or D 
being comfortable. 
3: Moderate: 
Constipation causes me to have a lot of trouble doing things or 
being comfortable. However, it does not stop me from doing 
anything. 
4: Severe : 
I usually need physical help from someone else to empty my 
bowels. 
1.12 LIGHT HEADEDNESS ON STANDING 
Over the past week, have you felt faint, dizzy or foggy when you stand up after sitting 
or lying down? 
O: Normal: 
No dizzy or foggy feelings. 
1 : Slight: 
Dizzy or foggy feelings occur. However, they do not cause me 
troubles doing things. 
2: Mild: 
Dizzy or foggy feelings cause me to hold on to something , but I do D 
not need to sit or lie back down. 
3: Moderate: 
Dizzy or foggy feelings cause me to sit or lie down to avoid 
fainting or falling. 
4: Severe: 
Dizzy or foggy feelings cause me to fall or faint. 
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1.13 FATIGUE 
Over the past week, have you usually felt fatigued? This feeling is not part of being 
sleepy or sad 
0: Normal: 
1: Slight: 
No fatigue. 
Fatigue occurs. However it does not cause me troubles doing 
things or being with people. 
2: Mild: 
Fatigue causes me some troubles doing things or being with 
people. 
3: Moderate : 
Fatigue causes me a lot of troubles doing things or being with 
people. However, it does not stop me from doing anything. 
4: Severe : 
Fatigue stops me from doing things or being with people. 
Part II: Motor Aspects of Experiences of Daily Living (M-EDL) 
2.1 SPEECH 
Over the past week, have you had problems with your speech? 
0: Normal: 
1: Slight: 
Not at all (no problems). 
My speech is soft, slurred or uneven, but it does not cause others 
to ask me to repeat myself. 
2: Mild: 
My speech causes people to ask me to occasionally repeat 
myself, but not everyday. 
3: Moderate: 
My speech is unclear enough that others ask me to repeat myself 
every day even though most of my speech is understood. 
4: Severe: 
Most or all of my speech cannot be understood. 
SCORE 
D 
D 
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SCORE 
2.2 SALIVA & DROOLING 
Over the past week, have you usually had too much saliva during when you are awake 
or when you sleep? 
O: Normal: 
Not at all (no problems). 
1 : Slight: 
I have too much saliva, but do not drool. 
2: Mild: 
I have some drooling during sleep, but none when I am awake. 
3: Moderate: 
I have some drooling when I am awake, but I usually do not need D 
tissues or a handkerchief. 
4: Severe: 
I have so much drooling that I regularly need to use tissues or a 
handkerchief to protect my clothes. 
2.3 CHEWING AND SWALLOWING 
Over the past week, have you usually had problems swallowing pills or eating meals? 
Do you need your pills cut or crushed or your meals to be made soft, chopped or 
blended to avoid choking? 
O: Normal: 
No problems. 
1 : Slight: 
I am aware of slowness in my chewing or increased effort at 
swallowing, but I do not choke or need to have my food specially 
prepared. 
2: Mild: 
I need to have my pills cut or my food specially prepared because D 
of chewing or swallowing problems, but I have not choked over 
the past week. 
3: Moderate. 
I choked at least once in the past week. 
4: Severe: 
Because of chewing and swallowing problems, I need a feeding 
tube. 
July 1, 2008 
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SCORE 
2.4 EATING TASKS 
Over the past week, have you usually had troubles handling your food and using 
eating utensils? For example, do you have trouble handling finger foods or using 
forks, knifes, spoons, chopsticks? 
O: Normal: 
Not at all (No problems). 
1 : Slight: 
I am slow, but I do not need any help handling my food and have 
not had food spills while eating. 
2: Mild: 
I am slow with my eating and have occasional food spills. I may D 
need help with a few tasks such as cutting meat. 
3: Moderate: 
I need help with many eating tasks but can manage some alone. 
4: Severe: 
I need help for most or all eating tasks. 
2.5 DRESSING 
Over the past week, have you usually had problems dressing? For example, are you 
slow or do you need help with buttoning, using zippers, putting on or taking off your 
clothes or jewelry? 
O: Normal: 
Not at all (no problems). 
1 : Slight: 
I am slow but I do not need help. 
2: Mild: 
I am slow and need help for a few dressing tasks (buttons, 
bracelets). 
D 
3: Moderate: 
I need help for many dressing tasks. 
4: Severe: 
I need help for most or all dressing tasks. 
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SCORE 
2.6 HYGIENE 
Over the past week, have you usually been slow or do you need help with washing , 
bathing, shaving, brushing teeth, combing your hair or with other personal hygiene? 
0: Normal: 
Not at all (no problems). 
1 : Slight: 
I am slow but I do not need any help. 
D 
2: Mild: 
I need someone else to help me with some hygiene tasks. 
3: Moderate: 
I need help for many hygiene tasks. 
4: Severe: 
I need help for most or all of my hygiene tasks. 
2.7 HANDWRITING 
Over the past week, have people usually had trouble reading your handwriting? 
O: Normal: 
Not at all (no problems). 
1 : Slight: 
My writing is slow, clumsy or uneven, but all words are clear. 
D 
2: Mild: 
Some words are unclear and difficult to read. 
3: Moderate: 
Many words are unclear and difficult to read . 
4: Severe: 
Most or all words cannot be read. 
2.8 DOING HOBBIES AND OTHER ACTIVITIES 
Over the past week, have you usually had trouble doing your hobbies or other things 
that you like to do? 
0: Normal: 
Not at all (no problems). 
1 : Slight: 
I am a bit slow but do these activities easily. 
D 
2: Mild: 
I have some difficulty doing these activities. 
3: Moderate: 
I have major problems doing these activities, but still do most. 
4: Severe : 
I am unable to do most or all of these activities. 
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SCORE 
2.9 TURNING IN BED 
Over the past week, do you usually have trouble turning over in bed? 
O: Normal: 
Not at all (no problems). 
1 : Slight: 
I have a bit of trouble turning, but I do not need any help. 
D 
2: Mild 
I have a lot of trouble turning and need occasional help from 
someone else. 
3: Moderate: 
To turn over I often need help from someone else. 
4: Severe: 
I am unable to turn over without help from someone else. 
2.10 TREMOR 
Over the past week, have you usually had shaking or tremor? 
O: Normal: 
Not at all. I have no shaking or tremor. 
1 : Slight: 
Shaking or tremor occurs but does not cause problems with any D 
activities. 
2: Mild: 
Shaking or tremor causes problems with only a few activities. 
3: Moderate: Shaking or tremor causes problems with many of my daily 
activities. 
4: Severe: 
Shaking or tremor causes problems with most or all activities. 
2.11 GETTING OUT OF BED, A CAR, OR A DEEP CHAIR 
Over the past week, have you usually had trouble getting out of bed, a car seat, or a 
deep chair? 
O: Normal: 
Not at all (no problems). 
1 : Slight: 
I am slow or awkward, but I usually can do it on my first try. 
D 
2: Mild: 
I need more than one try to get up or need occasional help. 
3: Moderate: 
I sometimes need help to get up, but most times I can still do it on 
my own. 
4: Severe: 
I need help most or all of the time . 
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2.12 WALKING AND BALANCE 
Over the past week, have you usually had problems with balance and walking? 
O: Normal: 
1: Slight: 
2: Mild: 
Not at all (no problems). 
I am slightly slow or may drag a leg. I never use a walking aid. 
I occasionally use a walking aid, but I do not need any help from 
another person. 
3: Moderate: 
I usually use a walking aid (cane, walker) to walk safely without 
falling. However, I do not usually need the support of another 
person. 
4: Severe: 
2.13 FREEZING 
I usually use the support of another persons to walk safely without 
falling. 
Over the past week, on your usual day when walking, do you suddenly stop or freeze 
as if your feet are stuck to the floor. 
O: Normal: 
1: Slight: 
2: Mild: 
Not at all (no problems). 
I briefly freeze but I can easily start walking again. I do not need 
help from someone else or a walking aid (cane or walker) because 
of freezing. 
I freeze and have trouble starting to walk again, but I do not need 
someone's help or a walking aid (cane or walker) because of 
freezing. 
3: Moderate: 
When I freeze I have a lot of trouble starting to walk again and, 
because of freezing , I sometimes need to use a walking aid or 
need someone else's help. 
4: Severe: 
Because of freezing, most or all of the time, I need to use a 
walking aid or someone's help. 
SCORE 
D 
D 
This completes the questionnaire. We may have asked about problems you do not even have, 
and may have mentioned problems that you may never develop at all. Not all patients develop all 
these problems, but because they can occur, it is important to ask all the questions to every 
patient. Thank you for your time and attention in completing this questionnaire . 
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Part Ill: Motor Examination 
Overview: This portion of the scale assesses the motor signs of PD. In administering Part Ill of the MDS-UPDRS 
the examiner should comply with the following guidelines: 
At the top of the form, mark whether the patient is on medication for treating the symptoms of Parkinson's disease 
and, if on levodopa, the time since the last dose. 
Also, if the patient is receiving medication for treating the symptoms of Parkinson's Disease, mark the patient's 
clinical state using the following definitions 
ON is the typical functional state when patients are receiving medication and have a good response. 
OFF is the typical functional state when patients have a poor response in spite of taking medications. 
The investigator should "rate what you see". Admittedly, concurrent medical problems such as stroke, paralysis, 
arthritis, contracture, and orthopedic problems such as hip or knee replacement and scoliosis may interfere with 
individual items in the motor examination. In situations where it is absolutely impossible to test (e.g., amputations, 
plegia, limb in a cast), use the notation "UR" for Unable to Rate. Otherwise, rate the performance of each task as the 
patient performs in the context of co-morbidities. 
All items must have an integer rating (no half points, no missing ratings). 
Specific instructions are provided for the testing of each item. These should be followed in all instances. The 
investigator demonstrates while describing tasks the patient is to perform and rates function immediately thereafter. 
For Global Spontaneous Movement and Rest Tremor items (3.14 and 3.17), these items have been placed 
purposefully at the end of the scale because clinical information pertinent to the score will be obtained throughout the 
entire examination. 
At the end of the rating, indicate if dyskinesia (chorea or dystonia) was present at the time of the examination, and if 
so, whether these movements interfered with the motor examination. 
3a Is the patient on medication for treating the symptoms of Parkinson's Disease? 
D No 
D
Yes 
3b 
If the patient is receiving medication for treating the symptoms of Parkinson's Disease, 
mark the patient's clinical state using the following definitions: 
D ON: On is the typical functional state when patients are receiving medication and have a good response. 
D OFF: Off is the typical functional state when patients have a poor response in spite of taking medications. 
3c Is the patient on Levodopa ? 
D No D Yes 
3.C1 If yes, minutes since last levodopa dose: 
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3.1 SPEECH 
Instructions to examiner: Listen to the patient's free-flowing speech and engage in conversation if 
necessary. Suggested topics: ask about the patient's work, hobbies, exercise, or how he got to the 
doctor's office. Evaluate volume, modulation (prosody) and clarity, including slurring, palilalia (repetition 
of syllables) and tachyphemia (rapid speech, running syllables together). 
O: Normal: 
1: Slight: 
2 Mild 
No speech problems. 
Loss of modulation, diction or volume, but still all words easy to understand. 
Loss of modulation, diction, or volume, with a few words unclear, but the overall 
sentences easy to follow 
3: Moderate: Speech is difficult to understand to the point that some, but not most, sentences are 
poorly understood. 
4: Severe: 
Most speech is difficult to understand or unintelligible. 
3.2 FACIAL EXPRESSION 
Instructions to examiner: Observe the patient sitting at rest for 10 seconds, without talking and also 
while talking. Observe eye-blink frequency, masked facies or loss of facial expression, spontaneous 
smiling and parting of lips. 
O: Normal: 
1: Slight: 
2: Mild: 
Normal facial expression. 
Minimal masked facies manifested only by decreased frequency of blinking. 
In addition to decreased eye-blink frequency, Masked facies present in the lower 
face as well, namely fewer movements around the mouth, such as less 
spontaneous smiling, but lips not parted. 
3: Moderate: Masked facies with lips parted some of the time when the mouth is at rest. 
4: Severe: 
Masked facies with lips parted most of the time when the mouth is at rest. 
SCORE 
D 
D 
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3.3 RIGIDITY 
Instructions to examiner: Rigidity is judged on slow passive movement of major joints with the patient in 
a relaxed position and the examiner manipulating the limbs and neck. First, test without an activation 
maneuver. Test and rate neck and each limb separately. For arms, test the wrist and elbow joints 
simultaneously. For legs, test the hip and knee Joints simultaneously. If no rigidity is detected, use an 
activation maneuver such as tapping fingers, fist opening/closing, or heel tapping in a limb not being 
tested. Explain to the patient to go as limp as possible as you test for rigidity. 
O: Normal: 
1: Slight: 
2 Mild 
No rigidity. 
Rigidity only detected with activation maneuver. 
Rigidity detected without the activation maneuver, but full range of motion is easily 
achieved. 
3: Moderate: Rigidity detected without the activation maneuver; full range of motion is achieved 
with effort 
4: Severe: 
Rigidity detected without the activation maneuver and full range of motion not 
achieved. 
3.4 FINGER TAPPING 
Instructions to examiner: Each hand is tested separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to tap the index finger on the 
thumb 10 times as quickly AND as big as possible. Rate each side separately, evaluating speed, 
amplitude, hesitations, halts and decrementing amplitude. 
0: Normal: 
1: Slight: 
2: Mild: 
No problems. 
Any of the following : a) the regular rhythm is broken with one or two interruptions or 
hesitations of the tapping movement; b) slight slowing; c) the amplitude decrements 
near the end of the 10 taps. 
Any of the following : a) 3 to 5 interruptions during tapping; b) mild slowing; c) the 
amplitude decrements midway in the 10-tap sequence. 
3: Moderate 
Any of the following a) more than 5 interruptions during tapping or at least one 
longer arrest (freeze) in ongoing movement; b) moderate slowing; c) the amplitude 
decrements starting after the 1st tap. 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
SCORE 
D 
Neck 
D 
RUE 
D 
LUE 
D 
RLE 
D 
LLE 
D 
R 
D 
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3.5 HAND MOVEMENTS 
Instructions to examiner: Test each hand separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to make a tight fist with the arm 
bent at the elbow so that the palm faces the examiner. Have the patient open the hand 10 times as fully 
AND as quickly as possible. If the patient fails to make a tight fist or to open the hand fully, remind him/ 
her to do so. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude. 
O: Normal: 
1: Slight: 
2: Mild: 
No problem. 
Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the movement; b) slight slowing; c) the amplitude decrements near 
the end of the task. 
Any of the following: a) 3 to 5 interruptions during the movements; b) mild slowing; 
c) the amplitude decrements midway in the task. 
3: Moderate 
Any of the following : a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing; c) the 
amplitude decrements starting after the 1st open-and-close sequence. 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
3.6 PRONATION-SUPINATION MOVEMENTS OF HANDS 
Instructions to examiner Test each hand separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to extend the arm out in front of 
his/her body with the palms down; then to turn the palm up and down alternately 1 O times as fast and as 
fully as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude. 
O: Normal: 
1: Slight: 
2: Mild 
No problems. 
Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the movement; b) slight slowing; c) the amplitude decrements near 
the end of the sequence. 
Any of the following: a) 3 to 5 interruptions during the movements; b) mild slowing; 
c) the amplitude decrements midway in the sequence. 
3: Moderate: Any of the following: a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing c) the 
amplitude decrements starting after the 1st supination-pronation sequence. 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
SCORE 
D 
R 
D 
D 
R 
D 
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SCORE 
3.7 TOE TAPPING 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms, both feet on the floor. 
Test each foot separately. Demonstrate the task, but do not continue to perform the task while the 
patient is being tested. Instruct the patient to place the heel on the ground in a comfortable position and 
then tap the toes 1 D times as big and as fast as possible. Rate each side separately, evaluating speed, 
amplitude, hesitations, halts and decrementing amplitude. 
D: Normal: 
No problem. 
D 
1: Slight: 
Any of the fo llowing: a) the regular rhythm is broken with one or two interruptions 
or hesitations of the tapping movement; b) slight slowing; c) amplitude 
decrements near the end of the ten taps. 
R 
2: Mild: 
Any of the following : a) 3 to 5 interruptions during the tapping movements; b) mild 
slowing; c) amplitude decrements midway in the task. 
D 
3: Moderate: 
Any of the following : a) more than 5 interruptions during the tapping movements 
or at least one longer arrest (freeze) in ongoing movement; b) moderate slowing; 
c) amplitude decrements after the first tap. 
L 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
3.8 LEG AGILITY 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms. The patient should 
have both feet comfortably on the floor. Test each leg separately. Demonstrate the task, but do not 
continue to perform the task while the patient is being tested. Instruct the patient to place the foot on the 
ground in a comfortable position and then raise and stomp the foot on the ground 1 D times as high and 
as fast as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude. 
D: Normal: 
No problems. 
D 
1: Slight 
Any of the fo llowing a) the regular rhythm is broken with one or two interruptions 
or hesitations of the movement; b) slight slowing; c) amplitude decrements near 
the end of the task. 
R 
2: Mild: 
Any of the following a) 3 to 5 interruptions during the movements; b) mild 
slowness; c) amplitude decrements midway in the task. 
D 
3: Moderate: 
Any of the following: a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing in speed; c) 
amplitude decrements after the first tap. 
L 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
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3.9 ARISING FROM CHAIR 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms, with both feet on the 
floor and sitting back 1n the chair (if the patient is not too short). Ask the patient to cross his/her arms 
across the chest and then to stand up. If the patient is not successful, repeat this attempt a maximum 
up to two more times. If still unsuccessful, allow the patient to move forward in the chair to arise with 
arms folded across the chest. Allow only one attempt in this situation. If unsuccessful, allow the patient 
to push off using his/her hands on the arms of the chair. Allow a maximum of three trials of pushing off. 
If still not successful, assist the patient to arise. After the patient stands up, observe the posture for item 
3.13 
O: Normal: 
1: Slight 
2: Mild: 
3: Moderate: 
4: Severe: 
3.10 GAIT 
No problems. Able to arise quickly without hesitation. 
Arising is slower than normal; or may need more than one attempt; or may 
need to move forward in the chair to arise. No need to use the arms of the 
chair. 
Pushes self up from arms of chair without difficulty. 
Needs to push off, but tends to fall back; or may have to try more than one time 
using arms of chair, but can get up without help. 
Unable to arise without help. 
Instructions to examiner: Testing gait is best performed by having the patient walking away from and 
towards the examiner so that both right and left sides of the body can be easily observed 
simultaneously. The patient should walk at least 10 meters (30 feet), then turn around and return to the 
examiner. This item measures multiple behaviors: stride amplitude, stride speed, height of foot lift, heel 
strike during walking, turning, and arm swing, but not freezing. Assess also for "freezing of gait" (next 
item 3. 11 ) while patient is walking. Observe posture for item 3. 13 
O: Normal: 
1: Slight 
2: Mild 
3: Moderate: 
4: Severe: 
No problems. 
Independent walking with minor gait impairment. 
Independent walking but with substantial gait impairment. 
Requires an assistance device for safe walking (walking stick, walker) but not a 
person. 
Cannot walk at all or only with another person's assistance. 
SCORE 
D 
D 
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3.11 FREEZING OF GAIT 
Instructions to examiner: While assessing gait, also assess for the presence of any gait freezing 
episodes. Observe for start hesitation and stuttering movements especially when turning and reaching 
the end of the task. To the extent that safety permits, patients may NOT use sensory tricks during the 
assessment. 
O: Normal: 
1: Slight: 
2 Mild 
3: Moderate: 
4: Severe: 
No freezing. 
Freezes on starting, turning or walking through doorway with a single halt during 
any of these events, but then continues smoothly without freezing during straight 
walking. 
Freezes on starting, turning or walking through doorway with more than one halt 
during any of these activities, but continues smoothly without freezing during 
straight walking. 
Freezes once during straight walking. 
Freezes multiple times during straight walking. 
3.12 POSTURAL STABILITY 
Instructions to examiner: The test examines the response to sudden body displacement produced by a 
quick, forceful pull on the shoulders while the patient is standing erect with eyes open and feet 
comfortably apart and parallel to each other. Test retropulsion. Stand behind the patient and instruct 
the patient on what is about to happen. Explain that s/he is allowed to take a step backwards to avoid 
falling. There should be a solid wall behind the examiner. at least 1-2 meters away to allow for the 
observation of the number of retropulsive steps. The first pull is an instructional demonstration and is 
purposely milder and not rated. The second time the shoulders are pulled briskly and forcefully towards 
the examiner with enough force to displace the center of gravity so that patient MUST take a step 
backwards. The examiner needs to be ready to catch the patient, but must stand sufficiently back so as 
to allow enough room for the patient to take several steps to recover independently. Do not allow the 
patient to flex the body abnormally forward in anticipation of the pull. Observe for the number of steps 
backwards or falling. Up to and including two steps for recovery is considered normal, so abnormal 
ratings begin with three steps. If the patient fails to understand the test, the examiner can repeat the 
test so that the rating is based on an assessment that the examiner feels reflects the patient's limitations 
rather than misunderstanding or lack of preparedness. Observe standing posture for item 3.13 
0: Normal: 
1: Slight: 
2: Mild: 
3: Moderate: 
4: Severe: 
No problems: Recovers with one or two steps. 
3-5 steps. but subject recovers unaided. 
More than 5 steps, but subject recovers unaided. 
Stands safely, but with absence of postural response ; falls if not caught by 
examiner. 
Very unstable. tends to lose balance spcntaneously or with just a gentle pull on 
the shoulders. 
SCORE 
D 
D 
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3.13 POSTURE 
Instructions to examiner Posture is assessed with the patient standing erect after arising from a chair, 
during walking, and while being tested for postural reflexes If you notice poor posture, te ll the patient 
to stand up straight and see if the posture improves (see option 2 below). Rate the worst posture seen 
in these three observation points. Observe for flexion and side-to-side leaning. 
0 Normal 
No problems. 
1: Slight: 
Not quite erect, but posture could be normal for older person. 
2: Mild 
Definite flexion, scoliosis or leaning to one side, but patient can correct posture to 
normal posture when asked to do so. 
3: Moderate: 
Stooped posture, scoliosis or leaning to one side that cannot be corrected 
volitionally to a normal posture by the patient. 
4: Severe: 
Flexion, scoliosis or leaning with extreme abnormality of posture. 
3.14 GLOBAL SPONTANEITY OF MOVEMENT (BODY BRADYKINESIA) 
Instructions to examiner: This global rating combines all observations on slowness, hesitancy, and 
small amplitude and poverty of movement in general, including a reduction of gesturing and of crossing 
the legs. This assessment is based on the examiner's global impression after observing for 
spontaneous gestures while sitting, and the nature of arising and walking. 
0 Normal: 
No problems. 
1: Slight 
Slight global slowness and poverty of spontaneous movements. 
2: Mild: 
Mild global slowness and poverty of spontaneous movements. 
3 Moderate: 
Moderate global slowness and poverty of spontaneous movements. 
4: Severe: 
Severe global slowness and poverty of spontaneous movements. 
3.15 POSTURAL TREMOR OF THE HANDS 
_Instructions to examiner: All tremor, including re-emergent rest tremor, that is present in this posture is 
to be included in this rating. Rate each hand separately. Rate the highest amplitude seen. Instruct the 
patient to stretch the arms out in front of the body with palms down. The wrist should be straight and 
the fingers comfortably separated so that they do not touch each other. Observe this posture for 10 
seconds. 
0 Normal: 
No tremor. 
1 Slight: 
Tremor is present but less than 1 cm in amplitude. 
2 Mild: 
Tremor is at least 1 but less than 3 cm in amplitude. 
3 Moderate: 
Tremor is at least 3 but less than 10 cm in amplitude. 
4: Severe: 
Tremor is at least 10 cm in amplitude. 
SCORE 
D 
D 
D 
R 
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SCORE 
3.16 KINETIC TREMOR OF THE HANDS 
Instructions to examiner: This is tested by the finger-to-nose maneuver. With the arm starting from the 
outstretched position, have the patient perform at least three finger-to-nose maneuvers with each hand 
reaching as far as possible to touch the examiner's finger. The finger-to-nose maneuver should be 
performed slowly enough not to hide any tremor that could occur with very fast arm movements. Repeat 
with the other hand, rating each hand separately. The tremor can be present throughout the movement D 
or as the tremor reaches either target (nose or finger). Rate the highest amplitude seen. 
0: Normal: 
No tremor 
1: Slight 
Tremor is present but less than 1 cm in amplitude. 
R 
2: Mild 
Tremor is at least 1 but less than 3 cm in amplitude. 
3: Moderate: 
Tremor is at least 3 but less than 10 cm in amplitude. 
D 
4: Severe: 
Tremor is at least 10 cm in amplitude. 
L 
3.17 REST TREMOR AMPLITUDE 
Instructions to examiner: This and the next item have been placed purposefully at the end of the 
D 
examination to allow the rater to gather observations on rest tremor that may appear at any time during 
the exam, including when quietly sitting, during walking and during activities when some body parts are 
moving but others are at rest Score the maximum amplitude that is seen at any time as the final score. 
Rate only the amplitude and not the persistence or the intermittency of the tremor. 
As part of this rating, the patient should sit quietly in a chair with the hands placed on the arms of the 
RUE 
chair (not in the lap) and the feet comfortably supported on the floor for 10 seconds with no other 
directives. Rest tremor is assessed separately for all four limbs and also for the lip/jaw. Rate only the 
maximum amplitude that is seen at any time as the final rating. 
D 
Extremity ratings 
O: Normal: 
No tremor. 
LUE 
1: Slight : 
~ 1 cm in maximal amplitude. 
2: Mild: 
> 1 cm but < 3 cm in maximal amplitude. 
D 
3: Moderate 
3 - 10 cm in maximal amplitude. 
RLE 
4: Severe: 
> 10 cm in maximal amplitude. 
Lip/Jaw ratings 
D 
O: Normal: 
No tremor. 
LLE 
1: Slight 
~ 1 cm in maximal amplitude. 
D 
2: Mild: 
> 1 cm but~ 2 cm in maximal amplitude. 
3: Moderate: 
> 2 cm but~ 3 cm in maximal amplitude. 
Lip/Jaw 
4: Severe: 
> 3 cm in maximal amplitude. 
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3.18 CONSTANCY OF REST TREMOR 
Instructions to examiner: This item receives one rating for all rest tremor and focuses on the constancy 
of rest tremor during the examination period when different body parts are variously at rest. It is rated 
purposefully at the end of the examination so that several minutes of information can be coalesced into 
the rating. 
O: Normal: 
No tremor. 
1: Slight 
Tremor at rest is present ~ 25% of the entire examination period. 
2: Mild: 
Tremor at rest is present 26-50% of the entire examination period. 
3: Moderate: 
Tremor at rest is present 51-75% of the entire examination period. 
4: Severe: 
Tremor at rest is present > 75% of the entire examination period. 
DYSKINESIA IMPACT ON PART Ill RATINGS 
A Were dyskinesias (chorea or dystonia) present during examination? 
B. If yes, did these movements interfere with your ratings? 
HOEHN AND YAHR STAGE 
0: Asymptomatic. 
1: Unilateral involvement only. 
2: Bilateral involvement without impairment of balance. 
D No D Yes 
D No D Yes 
3: Mile to moderate involvement; some postural instability but physically independent; needs 
assistance to recover from pull test. 
4: Severe disability; still able to walk or stand unassisted. 
5: Wheelchair bound or bedridden unless aided. 
SCORE 
D 
D 
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Part IV: Motor Complications 
Overview and Instructions: In this section, the rater uses historical and objective information to assess two motor 
complications, dyskinesias and motor fluctuations that include OFF-state dystonia. Use all information from patient, 
caregiver, and the examination to answer the six questions that summarize function over the past week including 
today. As in the other sections, rate using only integers (no half points allowed) and leave no missing ratings. If the 
item cannot be rated, place UR for Unable to Rate. You wi ll need to choose some answers based on percentages, 
and therefore you will need to establish how many hours generally are awake hours and use this figure as the 
denominator for "OFF" time and Dyskinesias. For "OFF dystonia", the total "Off' time will be the denominator. 
Operational definitions for examiner's use. 
Dyskinesias: Involuntary random movements 
Words that patients often recognize for dyskinesias include "irregular jerking", "wiggling", "twitching" It is essential to 
stress to the patient the difference between dyskinesias and tremor a common error when patients are assessing 
dyskinesias. 
Dystonia: contorted posture, often with a twisting component: 
Words that patients often recognize for dystonia include "spasms", "cramps", "posture". 
Motor fluctuation: Variable response to medication: 
Words that patients often recognize for motor fluctuation include "wearing out', "wearing off', "roller-coaster effect", 
"on-off", "uneven medication effects". 
OFF: Typical functional state when patients have a poor response in spite of taking mediation or the typical functional 
response when patients are on NO treatment for parkinsonism. Words that patients often recognize include "low 
time", "bad time", "shaking time", "slow time", "time when my medications don't work. " 
ON: Typical functional state when patients are receiving medication and have a good response 
Words that patients often recognize include "good time", "walking time", "time when my medications work." 
A . DYSKINESIAS [exclusive of OFF-state dystonia] 
4.1 TIME SPENT WITH DYSKINESIAS 
Instructions to examiner: Determine the hours in the usual waking day and then the hours of 
dyskinesias. Calculate the percentage. If the patient has dyskinesias in the office, you can point them 
out as a reference to ensure that patients and caregivers understand what they are rating. You may also 
use your own acting skills to enact the dyskinetic movements you have seen in the patient before or 
show them dyskinetic movements typical of other patients. Exclude from this question early morning 
and nighttime painful dystonia. 
Instructions to patient [and caregiver]. Over the past week, how many hours do you usually sleep on a 
daily basis, including nighttime sleep and daytime napping? Alright, if you sleep_ hrs, you are awake 
__ hrs. Out of those awake hours, how many hours in total do you have wiggling, twitching or Jerking 
movements? Do not count the times when you have tremor, which is a regular back and forth shaking 
or times when you have painful foot cramps or spasms in the early morning or at nighttime. I will ask 
about those later. Concentrate only on these types of w1gglmg, 1erkmg and irregular movements. Add 
up all me flme during the waking day when these usually occur. How many hours __ (use this 
number for your calculation). 
0: Normal: 
No dyskinesias. 
1: Slight: 
~ 25% of waking day. 
2: Mild: 
26 - 50% of waking day. 
1. Total Hours Awake : 
--
3: Moderate: 
51 - 75% of waking day. 
2. Total Hours with Dyskinesia: --
4: Severe: 
> 75% of waking day. 
3. % Dyskinesia = ((2/1)*100) 
--
SCORE 
D 
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4.2 FUNCTIONAL IMPACT OF DYSKINESIAS 
Instructions to examiner: Determine the degree to which dyskinesias impact on the patient's daily 
function in terms of activities and social interactions. Use the patient's and caregiver's response to your 
question and your own observations during the office visit to arrive at the best answer. 
Instructions to patient [and caregiver]: Over the past week, did you usually have trouble doing things or 
being with people when these jerking movements occurred? Did they stop you from doing things or 
from being with people? 
O: Normal: 
1: Slight 
2: Mild: 
3: Moderate: 
4: Severe: 
No dyskinesias or no impact by dyskinesias on activities or social interactions. 
Dyskinesias impact on a few activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods. 
Dyskinesias impact on many activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods. 
Dyskinesias impact on activities to the point that the patient usually does not 
perform some activities or does not usually participate in some social activities 
during dyskinetic episodes. 
Dyskinesias impact on function to the point that the patient usually does not 
perform most activities or participate in most social interactions during 
dyskinetic episodes. 
B. MOTOR FLUCTUATIONS 
4.3 TIME SPENT IN THE OFF STATE 
Instructions to examiner: Use the number of waking hours derived from 4.1 and determine the hours 
spent in the "OFF" state. Calculate the percentage. If the patient has an OFF period in the office, you 
can point to this state as a reference. You may also use your knowledge of the patient to describe a 
typical OFF period. Additiona lly you may use your own acting skills to enact an OFF period you have 
seen in the patient before or show them OFF function typical of other patients. Mark down the typical 
number of OFF hours, because you will need this number for completing 4.6 
Instructions to patient [and caregiver]: 
Some patients with Parkinson's disease have a good effect 
rom their medications throughout their awake hours and we call that "ON" time. Other patients take 
their medications but still have some hours of low time, bad time, slow time or shaking time. Doctors 
call these low periods "OFF" time. Over the past week, you told me before that you are generally awake 
_ 
hrs each day Out of these awake hours, how many hours in total do you usually have this type of 
'ow level or OFF function __ (Use this number for your calculations). 
0: Normal: 
No OFF time. 
1: Slight 
s 25% of waking day. 
2 Mild: 
26 - 50% of waking day. 
3: Moderate: 
51 - 75% of waking day. 
1 Total Hours Awake: --
4: Severe: 
> 75% of waking day. 
2. Total Hours OFF: 
--
3. % OFF= ((2/1)*100) --
SCORE 
D 
D 
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4.4 FUNCTIONAL IMPACT OF FLUCTUATIONS 
Instructions to examiner: Determine the degree to which motor fluctuations impact on the patient's daily 
function in terms of activities and social interactions. This question concentrates on the difference 
between the ON state and the OFF state. If the patient has no OFF time, the rating must be 0, but if 
patients have very mild fluctuations, it is still possible to be rated O on this item if no impact on activities 
occurs. Use the patient's and caregiver's response to your question and your own observations during 
the office visit to arrive at the best answer. 
Instructions to patient {and caregiver/: Think about when those low or "OFF" periods have occurred over 
the past week. Do you usually have more problems doing things or being with people than compared to 
the rest of the day when you feel your medications working? Are there some things you usually do 
during a good period that you have trouble with or stop doing during a low period? 
O: Normal: 
1: Slight: 
2: Mild: 
3: Moderate: 
4: Severe: 
No fluctuations or No impact by fluctuations on performance of activities or 
social interactions. 
Fluctuations impact on a few activities, but during OFF, the patient usually 
performs all activities and participates in all social interactions that typically 
occur during the ON state. 
Fluctuations impact many activities, but during OFF, the patient still usually 
performs all activities and participates in all social interactions that typically 
occur during the ON state. 
Fluctuations impact on the performance of activities during OFF to the point that 
the patient usually does not perform some activities or participate in some 
social interactions that are performed during ON periods. 
Fluctuations impact on function to the point that, during OFF, the patient usually 
does not perform most activities or participate in most social interactions that 
are performed during ON periods. 
4.5 COMPLEXITY OF MOTOR FLUCTUATIONS 
Instructions to examiner: Determine the usual predictability of OFF function whether due to dose, time 
of day, food intake or other factors. Use the information provided by the patients and caregiver and 
supplement with your own observations. You will ask if the patient can count on them always coming at 
a special time, mostly coming at a special time (in which case you will probe further to separate slight 
from mild), only sometimes coming at a special time or are they totally unpredictable? Narrowing down 
the percentage will allow you to find the correct answer. 
Instructions to patient {and caregiver/: For some patients, the low or "OFF" periods happen at certain 
times during day or when they do activities like eating or exercising. Over the past week, do you usually 
know when your low periods will occur? In other words, do your low periods always come at a certain 
time? Do they mostly come at a certain time? Do they only sometimes come at a certain time? Are 
your low periods totally unpredictable? " 
O: Normal: 
No motor fluctuations. 
1: Slight: 
OFF times are predictable all or almost all of the time(> 75%). 
2: Mild: 
OFF times are predictable most of the time (51-75%). 
3: Moderate: 
OFF times are predictable some of the time (26-50%). 
4: Severe: 
OFF episodes are rarely predictable. (~ 25%). 
SCORE 
D 
D 
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C. "OFF" DYSTONIA 
4.6 PAINFUL OFF-STATE DYSTONIA 
Instructions to examiner: For patients who have motor fluctuations, determine what proportion of the 
OFF episodes usually includes painful dystonia? You have already determined the number of hours of 
"OFF" time (4.3). Of these hours, determine how many are associated with dystonia and calculate the 
percentage. If there is no OFF time, mark 0. 
Instructions to patient [and caregiver/: 
In one of the questions I asked earlier, you said you generally 
have_ hours of low or "OFF" time when your Parkinson's disease is under poor control. During these 
low or "OFF" periods, do you usually have painful cramps or spasms? Out of the total __ hrs of this 
low time, if you add up all the time in a day when these painful cramps come, how many hours would 
this make? 
O: Normal: 
No dystonia OR NO OFF TIME. 
1: Slight: 
~ 25% of time in OFF state. 
2: Mild: 
26-50% of time in OFF state. 
3: Moderate: 
51-75% of time in OFF state. 
4: Severe: 
> 75% of time in OFF state. 
1. Total Hours Off: 
2. Total Off Hours w/Dystonia : 
3. % Off Dystonia = ((2/1)*100) 
Summary statement to patient: READ TO PATIENT 
D 
This completes my rating of your Parkinson's disease. I know the questions and tasks have taken several minutes, but 
I wanted to be complete and cover all possibilities. In doing so, I may have asked about problems you do not even 
have, and I may have mentioned problems that you may never develop at all. Not all patients develop all these 
problems, but because they can occur, it is important to ask all the questions to every patient. Thank you for your time 
and attention in completing this scale with me. 
July 1, 2008 
Copyright © 2008 Movement Disorder Society All rights reserved 
Page 30 
This chart may ,wt be copied, distributed or othenvise used in whole or in part without prior written consent of the Movement Disorder Society 


 
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,m ooNG-AST 
-
-
------
--- ---
------
(mm-dd-yyyy) 
Patient Name or Subject ID 
Site ID 
Assessment Date 
Investigator's Initials 
MDS UPDRS Score Sheet 
LJ Patient 
3.3b 
Rigidity- RUE 
1.A 
Source of information 
D Caregiver 
lJ Patient+ Careaiver 
3.3c 
Rigidrty- LUE 
Part I 
3.3d 
Rigidity- RLE 
1.1 
Cognitive impairment 
3.3e 
Rigidity- LLE 
1.2 
Hallucinations and psychosis 
3.4a 
Finger tapping- Right hand 
1.3 
Depressed mood 
3.4b 
Finger tapping- Left hand 
1.4 
Anxious mood 
3.5a 
Hand movements- Right hand 
1.5 
Apathy 
3.5b 
Hand movements- Left hand 
1.6 
Features of DDS 
3.6a 
Pronation- supination movements- Right hand 
lJ P~tif:'!,nt 
3.6b 
Pronation- supination movements- Left hand 
1.6a 
Who is filling out questionnaire 
D Caregiver 
D Patient+ Caregiver 
3.7a 
Toe tapping-Right foot 
1.7 
Sleep problems 
3.7b 
Toe tapping- Left foot 
1.8 
Daytime sleepiness 
3.8a 
Leg agility- Right leg 
1.9 
Pain and other sensations 
3.8b 
Leg agility- Left I eg 
1.10 
Urinary problems 
3.9 
Arising from chair 
1.11 
Constipation problems 
3. 10 
Gait 
1.12 
Light headedness on standing 
3.11 
Freezing of gait 
1.13 
Fatigue 
3.12 
Postural stability 
Part II 
3. 13 
Posture 
2.1 
Speech 
3.14 
Global spontaneity of movement 
2.2 
Saliva and drooling 
3.15a 
Postural tremor- Right hand 
2.3 
Chewing and swallowing 
3.15b 
Postural tremor- Left hand 
2.4 
Eating tasks 
3.16a 
Kinetic tremor- Right hand 
2.5 
Dressing 
3.16b 
Kinetic tremor- Left hand 
2.6 
Hygiene 
3.17a 
Rest tremor amplitude- RUE 
2.7 
Handwriting 
3.17b 
Rest tremor amplitude- LUE 
2.8 
Doing hobbies and other activities 
3.17c 
Rest tremor amplitude- RLE 
2.9 
Turning in bed 
3.17d 
Rest tremor amplitude- LLE 
2.10 
Tremor 
3.17e 
Rest tremor amplitude- Lip~aw 
2.11 
Getting out of bed 
3.18 
Constancy of rest 
2.12 
Walking and balance 
Were dyskinesias present? 
0
No 0
Yes 
2.13 
Freezing 
Did these movements interfere with ratings? 
0
No 0
Yes 
3a 
Is the patient on medication? 
DNo 
n
Yes 
Hoehn and Yah r Stage 
3b 
Patient's clinical state 
n
off 
n
on 
!Part IV 
3c 
Is the patient on Levodopa? 
0No 
oYes 
4.1 
Time spent with dyskinesias 
3.C1 
If yes, minutes since last dose: 
4.2 
Functional impact of dyskinesias 
Part III 
4.3 
Time spent in the OFF state 
3.1 
Speech 
4.4 
Functional impact of fluctuations 
3.2 
Facial expression 
4.5 
Complexity of motor fluctuations 
3.3a 
Rigidity- Neck 
4.6 
Painful OFF-state dystonia 
July 1, 2008 
Copy11ght © 2 008 Movement Disorder Society. All rights reserved 
This chart may not be copied, distributed or otherwise used in whole or in part without prior written consent of the Movement Disorder Society 


 
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18.2 APPENDIX 2: SCHWAB & ENGLAND ACTIVITIES OF DAILY LIVING SCALE 
 
100% 
Completely independent. Able to do all chores w/o slowness, 
difficulty, or impairment. Essentially normal. Unaware of any 
difficulty. 
 
90% 
Completely independent. Able to do all chores with some degree of 
slowness, difficulty and impairment. May take twice as long. 
Beginning to be aware of difficulty. 
 
80% 
Completely independent in most chores. Takes twice as long. 
Conscious of difficulty and slowing. 
 
70% 
Not completely independent. More difficulty with some chores. X 3-
4 as long  in some. May spend a large part of the day with chores. 
 
60% 
Some dependency. Can do most chores, but exceedingly slowly and 
with much effort. Errors, some impossible. 
 
50% 
More dependent. Help with 1/2 of chores. Difficulty with 
everything. 
 
40% 
Very dependant. Can assist with all chores but few alone. 
 
30% 
With effort, now and then does a few chores alone or begins alone. 
Much help needed. 
 
20% 
Nothing alone. Can do some slight help with some chores. Severe 
invalid. 
 
10% 
Totally dependent, helpless. Complete invalid. 
 
0% 
Vegetative functions such as swallowing, bladder and bowel 
function are not functioning. Bedridden. 
 
 
 
 
 
 
 


 
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18.3 APPENDIX 3: PARKINSON’S DISEASE QUESTIONNAIRE (PDQ-39) 
PDQ-39 Questionnaire 
Please complete the following 
S. 
No 
Due to having Parkinson’s disease, 
how often during the last month 
have you…… 
Please tick one box of each question 
Never Occasionally Sometimes Often Always 
1. 
How difficult doing the leisure 
activities which you would like to 
do? 
 
 
 
 
 
 
 
 
 
 
2.  
Had difficulty looking after your 
home, 
e.g. 
DIY, 
housework, 
cooking? 
 
 
 
 
 
 
 
 
 
 
3.  
Had difficulty carrying bags of 
shopping? 
 
 
 
 
 
 
 
 
 
 
4.  
Had problems walking half a mile? 
 
 
 
 
 
5.  
Had problems walking 100 yards? 
 
 
 
 
 
6. 
Had problems getting around the 
house as easily as you would like? 
 
 
 
 
 
 
 
 
 
 
7. 
Had difficulty getting around in 
public? 
 
 
 
 
 
 
 
 
 
 
8. 
Needed 
someone 
else 
to 
accompany you when you went 
out? 
 
 
 
 
 
 
 
 
 
 
9. 
Felt frightened or worried about 
falling over in public? 
 
 
 
 
 
 
 
 
 
 
10. 
Been confined to the house more 
than you would like? 
 
 
 
 
 
 
 
 
 
 
11. 
Had difficulty washing yourself? 
 
 
 
 
 
12. 
Had difficulty dressing yourself? 
 
 
 
 
 


 
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13. 
Had problems doing up your shoe 
laces? 
 
 
 
 
 
 
 
 
 
 
14. 
Had problems writing clearly? 
 
 
 
 
 
15. 
Had difficulty cutting up your 
food? 
 
 
 
 
 
 
 
 
 
 
16. 
Had difficulty holding a drink 
without spilling it? 
 
 
 
 
 
 
 
 
 
 
17. 
Felt depressed? 
 
 
 
 
 
18. 
Felt isolated and lonely? 
 
 
 
 
 
19. 
Felt weepy or tearful? 
 
 
 
 
 
20. 
Felt angry or bitter? 
 
 
 
 
 
21. 
Felt anxious? 
 
 
 
 
 
22. 
Felt worried about your future? 
 
 
 
 
 
23. 
Felt you had to conceal your 
Parkinson’s from people? 
 
 
 
 
 
 
 
 
 
 
24. 
Avoided situations which involve 
eating or drinking in public? 
 
 
 
 
 
 
 
 
 
 
25. 
Felt embarrassed in public due to 
having Parkinson’s disease? 
 
 
 
 
 
 
 
 
 
 
26. 
Felt worried by other people’s 
reaction to you? 
 
 
 
 
 
 
 
 
 
 
27. 
Had problems with your close 
personal relationships? 
 
 
 
 
 
 
 
 
 
 
28. 
Lacked support in the ways you 
need from your spouse or partner? 
 
 
 
 
 
 
 
 
 
 


 
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If you do not have a spouse or 
partner, tick here 
 
 
 
 
 
 
 
 
 
 
29. 
Lacked support in the ways you 
need from your family or closed 
friends? 
 
 
 
 
 
 
 
 
 
 
30. 
Unexpectedly fallen asleep during 
the day? 
 
 
 
 
 
 
 
 
 
 
31. 
Had 
problems 
with 
your 
concentration, e.g. when reading or 
watching TV? 
 
 
 
 
 
 
 
 
 
 
32. 
Felt your memory was bad? 
 
 
 
 
 
33. 
Had 
distressing 
dreams 
or 
hallucinations? 
 
 
 
 
 
 
 
 
 
 
34. 
Had difficulty with your speech? 
 
 
 
 
 
35. 
Felt unable to communication with 
people properly? 
 
 
 
 
 
36. 
Felt ignored by people? 
 
 
 
 
 
37. 
Had painful muscle cramps or 
spasms? 
 
 
 
 
 
 
 
 
 
 
38. 
Had aches or pains in your joints or 
body? 
 
 
 
 
 
 
 
 
 
 
39. 
Felt unpleasantly hot or cold? 
 
 
 
 
 
 
 
 
 
 
 
Thank you for completing the PDQ-39 Questionnaire! 
 
 
 
 
 
 


 
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18.4 APPENDIX 4: CLINICAL GLOBAL IMPRESSION 
Severity of Illness (CGI-S) 
 
Rating should account for severity of the patient’s illness. 
 
0 =  
Not assessed 
1 =  
Normal, not at all ill 
2 =  
Borderline ill 
3 =  
Mildly ill 
4 =  
Moderately ill 
5 =  
Markedly ill 
6 =  
Severely ill 
7 =  
Extremely ill 
 
Global Improvement (CGI-I) 
 
Compared to the patient’s condition at the baseline of this study, how much has the patient's illness 
improved or worsened?  (Circle one) 
 
Rating should account for severity of the patient’s illness. 
 
0 =  
Not assessed 
1 =  
Very much improved 
2 =  
Much improved 
3 =  
Minimally improved 
4 =  
No change 
5 =  
Minimally  worse 
6 =  
Much worse 
7 =  
Very much worse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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18.5 APPENDIX 5: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
Figure 18-1: C-SSRS (Lifetime/Recent) 
 
 
 
 


 
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Figure 18-2: C-SSRS (Since Last Visit) 
 
 
 
 
 


 
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SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
FOR PROTOCOL DA-9805-PD-001 
 
  
Sponsor: 
 
 
Dong-A ST Co., Ltd 
64, Cheonho-daero  
Dongdaemun-gu 
Seoul, Korea 
 
E-mail: 
treadwheel@donga.co.kr 
 
 
 
Protocol Number: 
DA-9805-PD-001 
 
 
Protocol Title: 
A PHASE IIa, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO EVALUATE THE SAFETY, TOLERABILITY AND 
EFFICACY OF DA-9805 IN SUBJECTS WITH 
PARKINSON’S DISEASE 
 
 
 
Protocol Date / Version: 
Version 3.0 / 12 July 2017 
 
 
 
 
 
 
SAP Author: 
Amarex, Clinical Research 
20201 Century Boulevard 
Germantown, MD   20874 
USA 
Telephone:   1-866-AMAREX-1 
 
 
1-301-528-7000 
 
Facsimile: 
1-301-528-2300 
 
 
Plan Version: 
SAP –Version 1.0 
 
 
Plan Date: 
27 April 2018 
 
 
 
 
 
 
 
--- confidential---  




Protocol: DA-9805-PD-001 
Statistical Analysis Plan 
Dong-A ST Co., Ltd. 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
Section   
Page 
LIST OF ABBREVIATIONS ................................................................................................. 5 
1. 
INTRODUCTION ............................................................................................................... 7 
2. 
PROTOCOL DESIGN AND OBJECTIVES ........................................................................ 7 
2.1 
Study Objectives ...................................................................................................... 7 
2.2 
Design Overview ...................................................................................................... 8 
2.3 
Study Treatments and treatment assignments ............................................................ 11 
2.3.1 
Treatment Groups ...................................................................................... 11 
2.3.2 
Method of Treatment Assignment, Randomization Ratio, and Stratification ... 11 
2.4 
Blinding ................................................................................................................. 12 
3. 
STUDY ASSESSMENTS/ OUTCOME .............................................................................. 12 
3.1 
Efficacy Assessments .............................................................................................. 12 
3.1.1 
Primary Efficacy Outcome Measure ............................................................ 12 
3.1.2 
Secondary Efficacy Outcome Measures: ...................................................... 12 
3.2 
Safety Assessments ................................................................................................. 13 
4. 
SAMPLE SIZE DETERMINATION AND RATIONALE .................................................. 13 
5. 
INTERIM ANALYSIS ....................................................................................................... 13 
6. 
ANALYSIS POPULATIONS ............................................................................................. 13 
6.1 
Intent-to-Treat (ITT) population ............................................................................... 13 
6.2 
Per Protocol (PP) Population ................................................................................... 13 
6.3 
Safety Population ................................................................................................... 14 
7. 
DATA CONVENTION AND RELATED DEFINITIONS .................................................. 14 
7.1 
Baseline Definition ................................................................................................. 14 
7.2 
Duplicate Data ....................................................................................................... 14 
7.3 
Handling of Missing Data ........................................................................................ 14 
7.3.1 
Handling of Missing Data for Efficacy Evaluations ...................................... 14 
7.3.2 
Handling of Missing Data for Safety Evaluations ......................................... 14 
7.4 
Multiplicity ............................................................................................................ 16 
7.5 
Covariates .............................................................................................................. 16 
7.6 
Stratification Factors ............................................................................................... 16 
7.7 
Subgroups .............................................................................................................. 16 
7.8 
Multicenter Clinical Trials ....................................................................................... 16 
7.9 
Standard Calculations ............................................................................................. 17 
7.9.1 
Age .......................................................................................................... 17 
7.9.2 
Height ...................................................................................................... 17 
7.9.3 
Weight ...................................................................................................... 17 
7.9.4 
Body Mass Index (BMI)............................................................................. 17 
7.9.5 
Change from Baseline ................................................................................ 17 
8. 
STATISTICAL METHODS ............................................................................................... 17 
8.1 
Disposition and Baseline Characteristics ................................................................... 18 
8.1.1 
Subject Disposition and Withdrawals .......................................................... 18 
8.1.2 
Major Protocol Deviations .......................................................................... 18 
8.1.3 
Demographics and Baseline Characteristics ................................................. 18 


Protocol: DA-9805-PD-001 
Statistical Analysis Plan 
Dong-A ST Co., Ltd. 
 
 
 
 
 
 
 
 
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8.1.4 
Prior and Concomitant Medications/Therapies ............................................. 19 
8.1.5 
Medical History ......................................................................................... 19 
8.1.6 
Treatment Compliance ............................................................................... 19 
8.2 
Analysis of Efficacy Outcome ................................................................................. 19 
8.2.1 
Primary Efficacy Outcome ......................................................................... 19 
8.2.2 
Secondary Efficacy Outcome ...................................................................... 20 
8.3 
Analysis of Safety Data ........................................................................................... 21 
8.3.1 
Adverse Events ......................................................................................... 21 
8.3.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................... 22 
8.3.3 
Clinical Laboratory Evaluations .................................................................. 22 
8.3.4 
Vital Signs and Weight .............................................................................. 23 
8.3.5 
ECG ......................................................................................................... 23 
8.3.6 
Physical Examination ................................................................................. 23 
9. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS .............................................................. 24 
10. 
APPENDIX 2 – PLANNED TLG ....................................................................................... 26 
10.1 
Planned by-subject listings ...................................................................................... 26 
10.2 
Planned Summary Tables ........................................................................................ 27 
11. 
VERSION HISTORY ........................................................................................................ 28 
12. 
REFERENCES .................................................................................................................. 29 


Protocol: DA-9805-PD-001 
Statistical Analysis Plan 
Dong-A ST Co., Ltd. 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
% 
Percent 
AE 
Adverse Event 
Amarex 
Amarex Clinical Research, LLC. 
ANCOVA 
Analysis of Covariance 
ASA 
American Statistical Association  
BMI 
Body Mass Index 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CI 
Confidence Interval 
CM 
Concomitant Medications 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
g/dL 
grams/deciliter 
H&Y 
Hoehn and Yahr 
IA 
Interim Analysis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Based Response System 
Kg 
Kilograms 
MAPK 
Mitogen-activated protein serine/threonine kinase 
MDS-UPDRS 
Movement Disorder Society - Unified Parkinson Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mg/dL 
Milligram/deciliter 


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Statistical Analysis Plan 
Dong-A ST Co., Ltd. 
 
 
 
 
 
 
 
 
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MMSE 
Mini-Mental State Examination 
N 
Number in sample 
PD 
Parkinson’s Disease 
PDQ 
Parkinson's Disease Questionnaire 
PE 
Physical Examination 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
MedDRA system organ class 
SOP 
Standard Operating Procedures 
S&E 
Schwab and England 
TEAE 
Treatment Emergent Adverse Event 
TID 
ter in die (Three times daily) 
TV 
Treatment Visit 
U/L 
Units/Liter 
USA 
United States of America 
WHO 
World Health Organization 
μL 
Microliter 


Protocol: DA-9805-PD-001 
Statistical Analysis Plan 
Dong-A ST Co., Ltd. 
 
 
 
 
 
 
 
 
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1. 
INTRODUCTION 
This Statistical Analysis Plan describes the planned analyses and reporting for the clinical trial 
protocol DA-9805-PD-001, sponsored by Dong-A ST Co., Ltd..  The reader of this Statistical 
Analysis Plan (SAP) is encouraged to review the complete protocol as this plan contains only a 
limited overview of protocol information.  The main objective of this plan is to provide details 
pertaining to statistical methodology, data conventions, and processes used for the analysis of data 
from this trial.  
The format and content of this Statistical Analysis Plan are structured to provide sufficient detail to 
meet the requirements specified by the International Conference on Harmonization (ICH) E9: 
Guidance on Statistical Principles in Clinical Trials.  All work planned and presented in this 
Statistical Analysis Plan will follow the ethical guidelines published by the American Statistical 
Association (ASA). 
The following documents and references [1-6], were reviewed in preparation of this Statistical 
Analysis Plan: 
• Version 3.0, protocol 12 July 2017 
• ASA Ethical Guidelines for Statistical Practice (2016) 
• The Royal Statistical Society: Code of Conduct (2014) 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3, 1996) 
• ICH Guideline on General Considerations for Clinical Trials (ICH E8, 1997) 
• ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9, 1998) 
 
2. 
PROTOCOL DESIGN AND OBJECTIVES 
2.1 Study Objectives 
The primary objective of this study is: 
• To evaluate the safety and tolerability of DA-9805 at 45mg, 90mg compared to Placebo (0 
mg) in subjects with Parkinson’s Disease. 
The secondary objective of this study is:  
• To evaluate DA-9805 at 45mg, 90mg compared to Placebo (0 mg), in terms of efficacy in 
subjects with Parkinson’s Disease. 


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2.2 Design Overview 
This is a phase IIa, first in human, randomized, double-blind, multicenter study to evaluate the 
safety, tolerability and efficacy of DA-9805 at 45mg, 90mg versus placebo in subjects with early 
diagnosed Parkinson’s disease. 
The study will include three parts: a 2-week Screening part, a 12-week Double-Blind Treatment 
part, and a 4-week Follow-up part. The detailed study schedule and assessments in each visit are 
provided in Appendix I of this SAP. For a schematic of the study design, see Figure 2-1. 
Study Visits: 
• Screening Visit (Day -14 to Day -1), up to 14 days:  
Screening part is designed to determine subject’s eligibility to proceed to Randomization and 
the Treatment Phase of the study. During this part, a series of assessments will be performed to 
determine subject eligibility as per inclusion and exclusion criteria. 
At the Screening Visit, prior to any study-related procedures, a written informed consent will be 
obtained from the subject by the Investigator or suitable qualified personnel. Subjects who meet 
eligibility criteria, but have some abnormal laboratory values, based on PI review a repeat 
laboratory sample may be collected. The repeat laboratory reports should be reviewed by the PI 
to confirm eligibility prior to randomization. 
Subjects who fail to meet eligibility criteria during the Screening part will be considered screen 
failures and will be exited from the study. Subjects who have successfully completed the 
Screening part will enter the Double-Blind treatment part of the study. Treatment part followed 
by randomization will last for 12 weeks. Subjects will take the randomized treatment, DA-9805 
at 45mg, 90mg or placebo for 12 weeks. 
• Visit 0: Randomization/Baseline Visit (Day 0) (TV0):  
On Day 0 prior to randomization, the subject’s continued eligibility will be evaluated. Subjects 
who continue to be eligible will be randomized in a 1:1:1 ratio to one of the following treatment 
groups and assigned the study treatment kit: 
 
o Group 1: DA-9805 45mg tablet 
o Group 2: DA-9805 90mg tablet 


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o Group 3: placebo (0 mg DA-9805) tablet 
 
DA-9805 and matching placebo are oral tablets that will be taken three times daily during this 
study.  
 
• Treatment Visits 1 (TV1) through Treatment Visit 3 (TV3):  
Clinic treatment visits TV1 through TV3 will be conducted every four (4) week (± 3 days).  
During each of these visits, study evaluations will be conducted per the study schedule of events 
(Refer to section 4.1.3), and sufficient supply of DA-9805 or placebo till the next treatment visit 
will be dispensed.  
Treatment Visit 3 (TV3) will be considered the end of treatment (EOT) clinic visit. Study 
evaluations, review of the adverse events and concomitant medications and final study 
treatment accountability will be conducted. 
 
• Follow-up Part (4 weeks ± 3 days) 
The follow-up part will consist of a follow-up visit at the end of the Double-Blind Treatment 
part.  
 
   
 
 


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Figure 2-1: 
Study Flow Diagram 
Screening Part
SCREENING PHASE
14-day 
Screening
Period
RANDOMIZATION/TREATMENT PHASE
Confirmation of 
Continued Eligibility
Is Subject 
Still Eligible for 
Randomization?
Randomization &
Treatment 
Administration
TV0
Treatment Visits
TV0 to TV3
End of Study
FOLLOW UP PHASE
No
Yes
End of Study
Yes
Yes
 
No
No
Does 
Subject Meet 
Inclusion/Exclusion 
Criteria?
Screen 
Failure
Screen 
Failure
Criteria Met for Withdrawal
Follow Up Part
 (Week 4)
Informed 
Consent
Did Subject complete
TV3?
Continue treatment 
(Max. 12 weeks per 
subjects)
Yes
 
 
 
 


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2.3 Study Treatments and treatment assignments 
2.3.1 Treatment Groups 
The three treatment groups to be assessed in this trial are described below  
Table 2-1: Treatment Groups 
Group 
Description 
1 
DA-9805  (45 mg/day – 15mg TID) for 12 weeks 
2 
DA-9805  (90 mg/day – 30mg TID) for 12 weeks 
3 
Placebo (0 mg/day) for 12 weeks 
 
2.3.2 Method of Treatment Assignment, Randomization Ratio, and Stratification  
The randomization in this multi-center study will be applied centrally across the sites and will use a 
mixed block size of 3 and 6 with a 1:1:1 ratio of DA-9805 (45mg/day), DA-9805 (90mg/day) and 
Placebo Treatment groups.  
Subjects who have provided written informed consent and have met all the inclusion criteria and 
none of the exclusion criteria will be randomized to one of the treatment groups mentioned in Table 
2-1 based on a randomization schedule. An individual, independent of the clinical trial team, will 
develop the randomization schedules. 
The actual randomization assignment will be made through an Interactive Web Based System 
(IWRS) called WebView (Amarex Clinical Research, Germantown MD).  WebView is a Secure 
Socket Layer (SSL) web portal that allows 24/7 access to clinical trial information.  Authorization 
is based on approved access control list (ACL) that determines a user’s access to the site.  The 
Amarex Technology department, who is not otherwise involved with the study, is responsible for 
the implementation and maintenance of WebView.  Each user will be trained in how to use the 
website.  A WebView user manual will be supplied to all study personnel with instructions on using 
the website.   
The Randomization/Supply module of WebView allows authorized users to request randomization 
(Site Personnel only) into the trial.  The detailed description and instructions are included in the 


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WebView user manual. Amarex Clinical Research has further documentation and validation of 
WebView specifically with regards to preserving the blinding of this study.  
2.4 Blinding 
As this is a double-blind trial, the subjects, investigators and their staff, and all Sponsor/CRO 
personnel involved in the management, and data collection in this study will be blinded to the 
treatment assignments.  
Treatment unblinding for the study will only occur:  
1. at the time of final analysis after all clinical data have been received, data 
inconsistencies/queries have been resolved, and the database is locked 
2. for emergency unblinding in the event of safety concerns for individual subjects; these 
special cases will be documented and reported.   
The process for unblinding will be outlined in the Randomization Plan.  In addition, any subject 
with emergency unblinding for any reason will be identified and discussed in the final clinical study 
report.  
3. STUDY ASSESSMENTS/ OUTCOME 
3.1 Efficacy Assessments  
3.1.1 Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study is Change in motor MDS-Unified Parkinson 
Disease Rating Scale (MDS-UPDRS) total score from baseline at week 12.  
3.1.2 Secondary Efficacy Outcome Measures:  
There are multiple secondary outcomes in this trial as follows:  
• Change in total MDS- UPDRS total score from baseline at week 12. 
• Change in MDS-UPDRS subscale scores from baseline at week 12. 
• Change in Schwab and England (S&E) Scale total score from baseline at week 12. 
• Change in Parkinson's Disease Questionnaire (PDQ-39) total score from baseline at week 


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12.  
• Change in Hoehn and Yahr (H&Y) scale total score from baseline at week 12.  
• Change in Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-
Improvement (CGI-I) scale score from baseline at week 12. 
3.2 Safety Assessments 
• Incidence of Treatment-Emergent Adverse Events (AEs). 
• Incidence of withdrawals due to AEs. 
• Change/shifts in laboratory values. 
• Change in vital signs. 
• Change in Electrocardiogram (ECG) parameters. 
• Change in Columbia- Suicide Severity Rating Scale from baseline at week 12.  
4. 
SAMPLE SIZE DETERMINATION AND RATIONALE 
It is planned to randomize a total of 60 subjects (20 subjects per group) with early Parkinson’s 
disease in this trial. This sample size is selected on the basis of clinical judgment and not based on 
statistical power calculation; it is deemed adequate to provide clinically meaningful descriptive 
results consistent with the study objectives. 
5. 
INTERIM ANALYSIS  
There is no interim analysis planned for this study.      
6. 
ANALYSIS POPULATIONS  
6.1 Intent-to-Treat (ITT) population 
The Intent-to-Treat (ITT) population is defined as all randomized subjects who have received at 
least one dose of study treatment and undergone at least one post-randomization efficacy 
assessment.  
6.2 Per Protocol (PP) Population 
The Per Protocol (PP) population is defined as the set of subjects who meet the ITT population 


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requirements, and were not associated with a major protocol violation. This population will be 
identified before the database lock, and before the treatment assignments are revealed.     
The primary analysis of the primary and secondary outcomes will be conducted using the PP 
population.  
6.3 Safety Population 
The Safety population is defined as all subjects receiving at least one dose of the treatment after 
randomization. This population will be used for the analyses of safety parameters. 
7. 
DATA CONVENTION AND RELATED DEFINITIONS   
7.1 Baseline Definition 
For all parameters, baseline will be defined as the last available value before the randomized 
treatment.   
7.2 Duplicate Data  
For unplanned duplicate data within a protocol-specified visit, the last measured value will be used 
for the analysis.  If it is not possible to identify the “last measured value” the average of the 
duplicate values will be used.  
No data will be excluded.  All collected data will be listed.  
7.3 Handling of Missing Data  
7.3.1 Handling of Missing Data for Efficacy Evaluations  
There is no imputation of missing data planned for efficacy evaluations.  
7.3.2 Handling of Missing Data for Safety Evaluations  
Adverse Event (AE) Summaries 
With respect to summaries of AEs, only AEs that were treatment emergent will be tabulated.  
Treatment–emergent is defined as AEs with start date ≥ date of first treatment administration. 
1) If AE start date is completely missing, the date of first treatment administration will be 
taken as the start date of the event.  
2) If AE start date is partially missing:  


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a. If the day part of the start date is missing, the start date will be estimated to be equal 
to the date of first treatment administration, provided the start month and year are the 
same as the date of first treatment administration and the stop date either after the 
date of first treatment administration or completely missing. Otherwise, the AE will 
be assumed to have started on the first day of the month (01/MMM/YYYY) 
b. If the month part of the start date is missing, the start month will be estimated to be 
equal to the month of the date of first treatment administration or the following 
month after the month of the date of first treatment administration depending on the 
day part of the start date provided that the start year is the same as the year of date of 
first treatment administration and the stop date is either after date of first treatment 
administration or completely missing. Otherwise, the AE will be assumed to have 
started on the first month of the year (DD/Jan/YYYY) 
c. If both the day and month parts of the start date are missing, the start date will be 
estimated to be equal to the date of first treatment administration, provided the start 
year is the same as year of date of first treatment administration and the stop date is 
either after the date of first treatment administration or completely missing. 
Otherwise, the AE will be assumed to have started on first day and first month of the 
year (01/Jan/YYYY) 
d. If all day, month and year parts of the start date are missing, the start date will be 
estimated to be equal to the date of first treatment administration (and thus treatment 
emergent) provided that the stop date is either after the date of first treatment 
administration or completely missing. Otherwise, the start date will be estimated to 
be the first day of the same year as the stop date.  
3) If AE stop date is partially or completely missing:   
a. If only the day portion of the stop date is unknown, the day will be assumed to be 
last date of the month (e.g., ??-Jan-2004 will be treated as 31-Jan-2004). 
b. If both the day and month of stop date are unknown, the event will be assumed to 
have ceased on the last day of the year (e.g., ??-???-2004 will be treated as 31-Dec-
2004). 


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c.  If the stop date is completely missing, the event will be assumed to be “Ongoing”.  
Concomitant medications (CM) Summaries  
1) If CM start date is completely missing then the date of first treatment administration will be 
taken as the start date of the medication  
2) If CM start date is partially missing:  
a. If the Day part of the start date is missing, the CM will be assumed to have started 
on the first day of the month (01/MMM/ YYYY) 
b. If the month part of the start date is missing, the CM will be assumed to have started 
on the first month of the year (dd/Jan/YYYY) 
c. If both the day and month parts of the start date are missing, the CM will be assumed 
to have started on first day and first month of the year (01/Jan/YYYY) 
7.4 Multiplicity 
No Multiplicity adjustment will be implemented for this Phase 2 clinical trial.  
7.5 Covariates 
Baseline values will be used as covariates for efficacy analysis.  
7.6 Stratification Factors 
There are no stratification factors for this study.  
7.7 Subgroups 
There are no pre-planned subgroup analyses, however subgroup analyses will be done as needed.  
7.8 Multicenter Clinical Trials  
This is a randomized study with multiple centers.  


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7.9 Standard Calculations  
7.9.1 Age 
Age will be calculated as the number of completed years between the date of informed consent and 
the subject’s birth date.  
Age (years) = integer of [(date of informed consent – date of birth)/ 365.25+ 0.5] 
7.9.2 Height 
For summary purposes height will be expressed in centimeters.  Entries made in inches will be 
converted to centimeters using the formula noted below.  
Height (cm) = Height (in)*2.54 
7.9.3 Weight 
For summary purposes weight will be expressed in kilograms.  Entries made in pounds will be 
converted to kilograms using the formula noted below.  
Weight (kg) = Weight (lb)/ 2.2046 
7.9.4 Body Mass Index (BMI)  
BMI will be calculated using height (in cm) and weight (in kg) according to the formula noted 
below. 
BMI (kg/m2) = weight (kg) / [height (cm)/100]2 
7.9.5 Change from Baseline 
For any of the effectiveness measurements change from baseline will be calculated using the 
formula noted below. 
Change from baseline =  
Post Baseline Measurement – Baseline Measurement 
 
8. STATISTICAL METHODS 
All data collected during this study will be presented in subject data listings.  
All statistical analyses will be performed using SAS® for Windows, version 9.4 or later.  For 


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continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum and 
maximum) will be presented by treatment group. For categorical variables both frequencies and 
percentages will be presented by treatment group.  
8.1 Disposition and Baseline Characteristics  
8.1.1 Subject Disposition and Withdrawals 
There will be a detailed accounting of all subjects that signed the informed consent to participate in 
this trial.  The following will be summarized by treatment group:   
• The number of subjects who signed the informed consent 
• The number of subjects who are screen failures 
• The number of subjects who are randomized 
• The number of subjects who received at least one study drug administration   
• The number of subjects who completed the study 
• The number of subjects who discontinued  
Reasons for discontinuation will also be summarized.  
In addition, there will also be a listing of all discontinued subjects, which will provide the clinical 
trial center, treatment group and the specific reason for discontinuation.   
8.1.2 Major Protocol Deviations 
The deviations occurring during the clinical trial will be summarized descriptively according to the 
following categories: 
• Entrance criteria deviation 
• Withdrawal criteria deviation  
• Received wrong treatment or incorrect dose 
• Received an excluded medication  
• All other major protocol deviations  
Additionally a by-subject listing of all deviations will also be prepared.   
8.1.3 Demographics and Baseline Characteristics 
Demographic (age, race, gender, ethnicity) and other basic baseline characteristics will be 
summarized and/or listed, descriptively, by treatment groups for the Safety population.   


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Medical history results will be provided as by-subject listings.  
8.1.4 Prior and Concomitant Medications/Therapies 
Prior and concomitant medications/therapies will be summarized for the Safety population.   
All prior and concomitant medications recorded in the case report form will be coded to all 
matching Anatomic Therapeutic Classification codes using the most recent version of WHO Drug. 
 Descriptive summaries, by treatment group, will be prepared using the coded generic term.  All 
prior and concomitant medications recorded in the case report form will be listed.   
8.1.5 Medical History 
The medical history will be summarized and/or listed descriptively. 
8.1.6 Treatment Compliance 
All treatment compliance data will be summarized and/or listed descriptively for the Safety 
population.   
8.2 Analysis of Efficacy Outcome 
The primary analysis of the primary and secondary outcomes will be conducted using the PP 
population. 
To assess the consistency of the Primary Analysis results, a supportive analysis will be conducted 
using the ITT population. Statistical methodology for the supportive analyses will be the same as 
that of the primary analysis, with the exception of the analysis population.  
All statistical tests for efficacy will be two-sided tests, with α=0.05.   
8.2.1 Primary Efficacy Outcome  
The primary efficacy outcome for this study is change in motor MDS-Unified Parkinson Disease 
Rating Scale (MDS-UPDRS) total score from baseline at week 12. 
Change in motor MDS-UPDRS total score from baseline at week 12 will be calculated for each 
subject using the formula in Section 7.9.5. Both Treatment Group 1 and 2 will be compared with 
Group 3 using Analysis of Covariance (ANCOVA) with baseline value as a covariate to compare 
the change in motor MDS-UPDRS total score from baseline at week 12. 95% confidence interval 


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around the difference and P value for the treatment effect will be reported. 
8.2.2 Secondary Efficacy Outcome 
The secondary efficacy outcome measures will be analyzed as follows:  
8.2.2.1 Change in total MDS-UPDRS total score from baseline at week 12. 
Change in total MDS-UPDRS total score from baseline at week 12 will be calculated for each 
subject using the formula in Section 7.9.5, similar statistical methods as the primary outcome will 
be used for inferential statistics. 
8.2.2.2 Change in MDS-UPDRS subscale scores from baseline at week 12. 
Change in total MDS-UPDRS subscale scores from baseline at week 12 will be calculated for each 
subject using the formula in Section 7.9.5, similar statistical methods as the primary outcome will 
be used for inferential statistics. 
8.2.2.3 Change in Schwab and England (S&E) Scale total score from baseline at week 12. 
Change in Schwab and England (S&E) Scale total score from baseline at week 12 will be calculated 
for each subject using the formula in Section 7.9.5, similar statistical methods as the primary 
outcome will be used for inferential statistics.  
8.2.2.4 Change in Parkinson's Disease Questionnaire (PDQ-39) total score from baseline at 
week 12.  
Change in Parkinson's Disease Questionnaire (PDQ-39) total score from baseline at week 12 will be 
calculated for each subject using the formula in Section 7.9.5, similar statistical methods as the 
primary outcome will be used for inferential statistics. 
8.2.2.5 Change in Hoehn and Yahr (H&Y) scale total score from baseline at week 12. 
Change in Hoehn and Yahr (H&Y) scale total score from baseline at week 12 will be calculated for 
each subject using the formula in Section 7.9.5, similar statistical methods as the primary outcome 
will be used for inferential statistics. 


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8.2.2.6 
Change in Clinical Global Impression-Severity (CGI-S) and Clinical Global 
Impression-Improvement (CGI-I) scale score from baseline at week 12. 
Change in Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-
Improvement (CGI-I) scale score from baseline at week 12 will be calculated for each subject using 
the formula in Section 7.9.5, similar statistical methods as the primary outcome will be used for 
inferential statistics. 
8.3 Analysis of Safety Data 
For continuous variables data will be summarized by treatment using n, mean, SD, minimum and 
maximum values.  
For categorical variables data will be summarized by treatment using frequency and percentage.  
8.3.1 Adverse Events 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment Emergent AE’s (TEAE) are defined as events with an onset on or 
after the first randomized treatment. TEAEs will be summarized by treatment group, System Organ 
Class, and preferred term. The following TEAE summaries will be provided: 
• Overall (i.e., regardless of severity or relationship to treatment) 
• By severity grade (mild, moderate, severe, life threatening or death for SAEs) 
• By relationship to clinical trial treatment according to the mapping scheme below: 
o Potentially related:  will include all adverse events with a relationship rating of 
“definitely”, “probably” or “possibly”.   
o Unlikely/not related:  will include all adverse events with a relationship rating of 
“unlikely” or “unrelated”.   
Unless otherwise specified, at each level of subject summarization, a subject will be counted only 
once.  If there is more than one occurrence of an event, the event of the worst severity or the worst-
case relationship category will be summarized. 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 


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AEs leading to premature discontinuation of clinical trial treatment, AEs that lead to study 
discontinuation, AEs that lead to death and Serious Adverse Events (SAEs) will also be 
summarized by treatment group and relationship.   
8.3.2 Columbia-Suicide Severity Rating Scale (C-SSRS) 
All the data from C-SSRS will be listed and descriptive summaries will be presented for each of the 
subscales (i.e. Suicidal Ideation and Suicidal Behavior). 
8.3.3 Clinical Laboratory Evaluations 
The laboratory assessments in this study include Biochemistry, Hematology and Urine analysis. All 
available data will be summarized or presented as a by-subject listing as follows:   
8.3.3.1 Laboratory Values over Time  
Summary statistics of raw data and change from baseline values for each laboratory parameter will 
be presented by treatment group and time point. Data will be summarized as appropriate for the 
variable type. 
• For continuous data, summaries will include the number of observations, mean, SD, median, 
minimum, and maximum values. 
• For categorical data, frequency counts and percentages will be used. 
For change from baseline summaries, subjects with an undefined change from baseline, because of 
missing data, will be excluded. 
8.3.3.2 Individual Subject Changes (Shift Tables) 
Individual subject changes will be identified through shift tables. Shift tables will be presented for 
each laboratory parameter with counts and percentages of subjects, by treatment group and time 
point, for shift (change) from baseline, using the normal ranges from the laboratory. 
8.3.3.3 Individual Clinically Significant Abnormalities 
Clinically significant laboratory abnormalities (i.e., those laboratory abnormalities recorded as AEs) 
will be listed. 
All results of laboratory evaluations will be presented as by-subject listings 


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8.3.4 Vital Signs and Weight 
Tabulations of raw data and change from baseline values will be presented by time point for each 
vital sign parameter and weight.   
Tabulations will include the number of observations, mean, standard deviation, median, and 
minimum and maximum values.  For change from baseline summaries, subjects with an undefined 
change from baseline, because of missing data, will be excluded.    
8.3.5 ECG 
All ECG findings will be listed and/or summarized. Shift tables will also be presented to show any 
abnormality shifts from baseline to post baseline visits. 
8.3.6 Physical Examination  
All physical examination findings will be listed and/or summarized by treatment group.  Shift tables 
will also be presented to show any abnormality shifts from baseline to post baseline visits. 


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9. APPENDIX 1: SCHEDULE OF ASSESSMENTS  
Study Parts 
                                      
Screening Part 
(2 weeks) 
Double-Blind Treatment Part 
(12 weeks) 
Follow-up Part 
Follow-up visit 
(4 weeks) 
Treatment Visits 
 
TV0 
Randomization 
TV1 
TV2 
TV3  
FUV  
Weeks from Randomization Date 
(window period: ± days)              
- 2 
 
Day 0 
+ 4 
(± 3) 
+ 8 
 (± 3) 
+ 12 
 (± 3) 
+ 16 
(± 3) 
Pre- 
Post- 
Written Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Schedule Randomization Day 
X 
 
 
 
 
 
 
Continued Eligibility 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
Height1 and Weight 
X 
X 
 
 
 
X 
 
ECG 
X 
X 
 
X 
 
X 
 
Serum Hematology2  
X 
 
 
X 
X 
X 
 
Serum Chemistry2 
X 
 
 
X 
X 
X 
 
Urine Analysis2 
X 
 
 
X 
X 
X 
 
Urine Pregnancy Test3 
X 
X 
 
 
 
X 
 
MDS-UPDRS 
 
X 
 
X 
X 
X 
 
H & Y 
X 
X 
 
X 
X 
X 
 
S & E 
 
X 
 
X 
X 
X 
 
PDQ-39 
 
X 
 
X 
X 
X 
 
CGI-S and CGI-I4 
X 
X 
 
X 
X 
X 
 
C-SSRS 
X 
X 
 
X 
X 
X 
 
MMSE 
X 
X 
 
 
 
 
 
Dispense the DA-9805 or placebo5 
 
 
X 
X 
X 
 
 
DA-9805 
or 
Placebo 
first 
dose 
administration 
 
 
X 
 
 
 
 
Study treatment accountability 
 
 
 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
 
X 
X 
X 
X 


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1 Height only at Screening. 
2 Subjects who meet eligibility criteria, but have some abnormal laboratory values, based on PI review a repeat laboratory sample may be collected. The repeat laboratory reports 
should be reviewed by the PI to confirm eligibility prior to randomization. 
3 Only for female subjects of childbearing potential. 
4 CGI-I will be done only at Treatment Visit 1 to Treatment Visit 3 
5 Dispense the DA-9805 or placebo at each of the clinic treatment visit, except TV3 which is the End of Treatment visit (EOT). 
 
 
 


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10. APPENDIX 2 – PLANNED TLG 
10.1 Planned by-subject listings  
DISPOSITION/WITHDRAWALS (LISTINGS 16.2.1.X) 
ELIGIBILTY AND PROTOCOL DEVIATIONS (LISTINGS 16.2.2.X) 
EXCLUDED SUBJECTS (LISTINGS 16.2.3.X) 
DEMOGRAPHICS, 
POPULATION, 
AND 
BASELINE 
CHARACTERISTICS 
(LISTINGS 16.2.4.X) 
DRUG COMPLIANCE AND DRUG CONCENTRATION LISTINGS (LISTINGS 
16.2.5.X) 
EFFICACY RESPONSE (LISTINGS 16.2.6.X) 
ADVERSE EVENT DATA (LISTINGS 16.2.7.X) 
SAFETY DATA (LISTINGS 16.2.8.1.X) 
 
 
 
 


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10.2 Planned Summary Tables  
 
POPULATION DISPOSITION AND PROTOCOL DEVIATIONS 
POPULATION DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
CONCOMITANT MEDICATION USAGE 
EFFICACY SUMMARIES 
SAFETY SUMMARIES  
ADVERSE EVENT SUMMARIES  
SERIOUS ADVERSE EVENTS  
LABORATORY 
VITAL SIGNS AND PHISICAL EXAMINATION (PE) 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
OTHER SAFETY 
 
 
 


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11. 
VERSION HISTORY  
This is the first version.  
 
 
 


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12. 
REFERENCES 
1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April, 2016.  
2. The Royal Statistical Society: Code of Conduct (2014). 
3. E8 General Considerations for Clinical Trials, ICH Guidance, Federal Register, 1997. 
4. E9 Statistical Principles for Clinical Trials, ICH Guideline, Federal Register, 1998 
5. Guideline for the Format and Content of the Clinical and Statistical Section of an 
Application, 1988. 
6. Guideline for Industry:  Structure and Content of Clinical Study Reports (ICH E3), July 
1996.