Clinical trial NCT02228590
Conditions: Parkinson's Disease
Keywords: Parkinson's Disease
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2014-08-31; Completion date: 2014-11-24
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the efficacy, tolerability and safety of single treatments of APL-130277 in 16 patients with Parkinson's Disease (PD)

Detailed description:

Arms: arm 1: open label baseline comparison
Interventions: intervention 1: APL-130277
Intervention descriptions: intervention 1: Apomorphine Hydrochloride, Sublingual Thin Film

Protocol documents:
Prot_000.pdf: 























































































































































SAP_001.pdf: 
Cynapsus Therapeutics, Inc. 
CTH-105 
Statistical Analysis Plan                                                                                                               Final Version 3 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Phase 2 Study to Examine the Safety, Tolerability and 
Efficacy of APL-130277 in Patients with Parkinson's Disease  
 
 
Phase: 
2 
 
 
Protocol No.: 
CTH-105 
 
 
Protocol Date 
10SEP2014 
Date of Amendments 
 
 
 
Analysis Plan Version and 
Date 
Final Version 3 02JUN2015 
 
 
Prepared By: 
 
PharPoint Research, Inc. 
5003 S. Miami Blvd., Suite 100 
Durham, North Carolina 27703 
 
 
Prepared For: 
Cynapsus Therapeutics, Inc. 
828 Richmond Street West 
Toronto, Ontario Canada 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION


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STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL 
This Statistical Analysis Plan has been prepared in accordance with team reviewers’ specifications.   
 
Prepared by: 
 
 
Senior Biostatistician 
PharPoint Research, Inc.  
 
Date 
 
 
Review:  
 
 
 
 
Chief Scientific Officer 
PharPoint Research, Inc.  
 
Date 
 
 
 
 
 
Chief Medical Officer 
Cynapsus Therapeutics Inc. 
 
Date 
 
 
 
 
 
VP, Clinical Development 
Cynapsus Therapeutics Inc. 
 
 
 
 
Date 
 
VP, Medical Affairs 
Cynapsus Therapeutics Inc. 
 
Date 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL .............................................. 2 
1. 
INTRODUCTION .................................................................................................................... 5 
1.1. 
Study Overview .................................................................................................................... 5 
1.2. 
Schedule of Events/Study Visits ......................................................................................... 7 
1.3. 
Glossary of Abbreviations ................................................................................................... 9 
2. 
OBJECTIVES ........................................................................................................................ 10 
3. 
GENERAL STATISTICAL CONSIDERATIONS ............................................................. 10 
3.1. 
Sample size ......................................................................................................................... 10 
3.2. 
Randomization and BLINDING ...................................................................................... 10 
3.3. 
Handling of data ................................................................................................................ 10 
3.3.1. Missing Data and Outliers ............................................................................................... 10 
3.3.2. Imputation of Incomplete Dates ...................................................................................... 10 
3.3.3. By-Study Visit Displays .................................................................................................. 11 
3.3.4. Definitions and Terminology .......................................................................................... 11 
4. 
ANALYSIS POPULATIONS ................................................................................................ 13 
4.1. 
Safety population ............................................................................................................... 13 
4.2. 
Modified Intention-to-treat population ........................................................................... 13 
4.3. 
Per-Protocol Population .................................................................................................... 13 
4.4. 
PK Population .................................................................................................................... 13 
4.5. 
Responder Population ....................................................................................................... 13 
5. 
STATISTICAL METHODS ................................................................................................. 14 
5.1. 
Patient Disposition, Demographic and Baseline Characteristics .................................. 14 


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5.2. 
Efficacy Analysis ................................................................................................................ 14 
5.2.1. Primary Efficacy Endpoints ............................................................................................ 14 
5.2.2. Primary Efficacy Analysis ............................................................................................... 15 
5.2.3. Secondary Efficacy Endpoint .......................................................................................... 15 
5.2.4. Secondary Efficacy Analysis ........................................................................................... 15 
5.3. 
Safety ................................................................................................................................... 16 
5.3.1. Safety Endpoints ............................................................................................................. 16 
5.3.2. Adverse Events ................................................................................................................ 16 
5.3.3. Concomitant Medications................................................................................................ 17 
5.3.4. Clinical Laboratory Assessments .................................................................................... 17 
5.3.5. 12-Lead ECG ................................................................................................................... 17 
5.3.6. Physical Examination ...................................................................................................... 18 
5.3.7. Vital Signs ....................................................................................................................... 18 
6. 
PROTOCOL VIOLATIONS ................................................................................................ 18 
7. 
CHANGES IN THE PLANNED ANALYSES .................................................................... 18 
8. 
REVISION HISTORY .......................................................................................................... 19 
9. 
PROGRAMMING CONVENTIONS................................................................................... 20 
10. 
PROPOSED TABLES, LISTINGS, AND FIGURES FOR FINAL ANALYSIS ......... 22 


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1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary 
and planned analysis of data from Protocol CTH-105. Background information is provided for the 
overall study design and objectives. The reader is referred to the study protocol and case report 
forms (CRFs) for details of study conduct and data collection and to the pharmacokinetic (PK) 
analysis plan and report for details on the PK analyses.  
1.1. 
STUDY OVERVIEW 
This multicenter Phase 2 open-label study is designed to determine the safety, tolerability and 
efficacy of a dose of APL-130277 needed to induce an ON response in patients with Parkinson’s 
disease (PD). After a screening visit (Visit 1), patients will be supplied with Tigan® (300 mg tid 
orally) which is to be started on Day -3 and they will be asked to return to clinic at Day -1 (Visit 2) 
to have pre-dosing assessments of safety completed. Patients will be asked to take their last dose of 
Levodopa no later than 10 PM on the evening of Day -1 and prepare to return to clinic the morning 
of Day 1.  Alternatively, patients may be monitored in the clinic overnight if such facilities exist 
and the patient consents.  On Dosing Day 1 (Visit 3), patients who are in an OFF state will be 
administered a starting dose of 10mg APL-130277. Safety assessments, PK samples (at select 
sites), and efficacy measures will be completed. If the patient does not move to an ON state within 
3 hours from initial dosing and does not experience protocol defined orthostatic hypotension, they 
will receive the 15mg dose of APL-130277. The same procedures will be repeated. If an ON state 
is not seen in 90 minutes, the patient will receive Levodopa at their standard dosage, or at a dosage 
considered appropriate by the investigator to achieve an ON state.  At any point in the Visit, if in 
the opinion of the investigator, the patient can no longer tolerate the OFF state, the patient will 
receive Levodopa at their standard dosage, or at a dosage considered appropriate by the 
investigator to achieve an ON state. 
The patient will be asked to take their last dose of Levodopa no later than 10 PM on the evening 
before Dosing Day 2 (Visit 4), and prepare to return the morning of Dosing Day 2 for dosing.  At 
clinical sites where this is a possibility, patients, at their request, may stay overnight in the clinic.   
Patients will be seen on the morning of Dosing Day 2 (Visit 4), perform pre-dosing safety 
assessments and clinical assessments to determine their OFF status.   
Patients who are in an OFF state will be treated as follows: 
If there was no response with either dose on Dosing Day 1: 
Administer: 20mg APL-130277. Safety assessments, PK samples (at select sites) and efficacy 
measures will be completed. If the patient does not move to an ON state within 3 hours from 
dosing, and does not experience protocol defined orthostatic hypotension, they will receive the 
25mg dose of APL-130277. The same procedures will be repeated. If an ON state is not seen in 90 


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minutes, the patient will receive Levodopa at a dose considered appropriate by the investigator to 
achieve an ON state.  At any point in the Visit, if in the opinion of the investigator, the patient can 
no longer tolerate the OFF state the patient will receive Levodopa at their standard dosage, or at a 
dosage considered appropriate by the investigator to achieve an ON state. 
If there was a response with either dose on Dosing Day 1: 
Administer the dose that elicited a response on Dosing Day 1. Safety assessments, PK samples (at 
select sites) and efficacy measures will be completed. If the patient does not move to an ON state 
within 3 hours from dosing, and does not experience orthostatic hypotension as defined in Section 
12.6 of the protocol, they will receive the next higher dose of APL-130277. The same procedures 
will be repeated. If an ON state is not seen in 90 minutes, the patient will receive Levodopa at a 
dose considered appropriate by the investigator to achieve an ON state.  At any point in the Visit, if 
in the opinion of the investigator, the patient can no longer tolerate the OFF state the patient will 
receive levodopa at their standard dosage, or at a dosage considered appropriate by the investigator 
to achieve an ON state. 
Patients who responded to the same dose at Dosing Day 1 and Dosing Day 2 (Visits 3 and 4) will 
be considered complete from a dosing perspective, and proceed to Day 7 (Visit 6). 
Patients who responded to a new dose at Visit 4, or who did not respond to either dose at Visit 4 
will proceed to Dosing Day 3 (Visit 5).  Patients will be asked to take their last dose of Levodopa 
no later than 10 PM on the evening before Dosing Day 3 (Visit 5), and prepare to return the 
morning of Dosing Day 3 for dosing. At clinical sites where this is a possibility, patients, at their 
request, may stay overnight in the clinic. If patients are evaluated to be in an OFF state, they will 
receive either the next higher dose of APL-130277, or the dose at Day 2 (Visit 4) that elicited an 
ON response. 
Procedures at Dosing Day 3 (Visit 5) will be identical to that of Dosing Day 2 (Visit 4). If the first 
dose administered at the visit is 30mg of APL-130277, the patient will proceed to the follow-up 
visit following a 90 minute assessment of response and resolution of the OFF episode with 
Levodopa if required. 
Dosing Days are not required to be sequential, but all dosing must be completed within 7 days.  
Investigators, at their discretion, and with patient consent, can opt to treat one dose at a time per 
dosing day. 
Patients will return to clinic on Day 7 for a full safety evaluation. 
 


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1.2. SCHEDULE OF EVENTS/STUDY VISITS 
 
Procedures 
Screen1 
Phone Call2 Baseline Day 
Dosing Day 1 
Dosing Day 2 Dosing Day 
315 
F/U13 
Study Visit 
Visit 1 
T1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day 
-21 to -2 
-4 
-1 
1 
2 
3 
7 
Outpatient Visit3 
X 
 
X3 
X3 
X3 
X 
X 
Written and Reconfirmation of Informed Consent 
X 
 
X 
X 
X 
X 
X 
Review Entry/Restriction Criteria 
X 
 
X 
X 
X 
X 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
Complete Physical Exam4 
X 
 
 
 
 
X 
Abbreviated Physical Exam5 
 
 
X 
X 
X 
 
Anti-nausea medication (starts on day-3) 
X 
 
X 
X 
X 
X 
 
BMI, weight and height6 
X 
 
 
 
 
 
X 
Vital Signs (BP, HR, RR and Temp.) 7, 14 
X 
 
X 
X 
X 
X 
12-Lead ECG8 
X 
 
X 
X 
X 
X 
Clinical Laboratory Tests9 
X 
 
 
 
 
 
X 
Hoehn and Yahr 
X 
 
 
 
 
 
 
MDS-UPDRS Motor Function10, 14 
X 
 
X 
X 
X 
X 
 
Clinical Confirmation of OFF or ON11, 14 
 
 
 
X 
X 
X 
 
Dosing of APL-130277  
 
 
X 
X 
X 
 
Blood Draw for Study Drug PK12, 14 
 
 
X 
X 
X 
 
AEs/SAEs 
 
 
X 
X 
X 
X 
X 
Conclusion of Participation 
 
 
 
 
 
 
X 
 


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1 All screening procedures to be conducted within 21 days prior to dosing (Day 1). 
2 Reminder phone call to patient to start their Tigan 300 mg tid on the morning of Day -3. 
3 Patients may be monitored in the clinic overnight before Dosing Visits if such facilities exist and the patient consents.  
4 Physical examination to include the following: head-eyes-ears-nose and throat; respiratory system; cardiovascular system; gastrointestinal system, including 
mouth; musculoskeletal system; central and peripheral nervous system; and skin. 
5Abbreviated physical exam to include head-eyes-ears-nose and throat; heart; lungs; abdomen; and skin; to be done at t = 0 (just prior to dosing) and at t = 1.5 post 
dosing (each dose) at Visits 3-5 
6 Both height and weight captured at Screening Visit to calculate BMI; only weight captured during Day -1, Day 1, and Final Visit. 
7 Vital signs will be assessed at Screening Visit, Visits 3-5 at t = 0 hrs (just prior to dosing) and at t =0.25, 0.5, 0.75, 1.0, 1.5, hrs post dosing and at Visit 6; Blood 
pressure to be measured sitting and standing (measured within 3 minutes of standing) at all time points at Visits 3-5  
 
8 Triplicate 12-lead ECG at screening; single ECGs at t = 0 (just prior to dosing) and at t = 0.5 post dosing (each dose) at Visits 3-5 and a single ECG at Visit 6 
9 Blood collection for clinical laboratory tests will occur at Screening Visit and on Visit 6. 
10 MDS-UPDRS Motor Function at Visits 1 and 2, and Visits 3-5 at t = 0 (just prior to dosing), and at t=0.25, 0.5, 0.75, 1.0, 1.5 hrs post dosing 
11 Investigator confirmation of OFF or ON at Visits 1 and 2, and Visits 3-5 at t=0.25, 0.5, 0.75, 1.0, 1.5 hrs post dosing 
12 Blood collection for APL-130277 pharmacokinetic (PK) analyses will occur at select sites only at Visits 3-5 at t = 0 (just prior to dosing) and at t = 10, 20, 30, 
45, 60 and 90 minutes after each dose administered  
13 The follow-up visit will be conducted for every patient dosed with APL-130277, and the timing of the Visit can be as soon as the day immediately following last 
dosing 
14 Suggested Sequence of Assessments Post-Dosing: PK blood draws – UPDRS – Assessment of OFF/ON– Vitals – ECGs 
15 Dosing must be completed within 7 days 
Note: Investigators, at their discretion, and with patient consent, can opt to treat one dose at a time per dosing day. All dosing must be completed within 7 days. 


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1.3. 
GLOSSARY OF ABBREVIATIONS 
AE  
adverse event 
ALT 
alanine aminotransferase 
APL-130277 
study drug, apomorphine hydrochloride 
AST 
aspartate transaminase 
BMI 
body mass index 
BP 
blood pressure 
CRF 
case report form 
ECG 
electrocardiogram 
EDC 
electronic data collection 
F/U 
follow-up 
HR 
heart rate 
LOCF 
last observation carried forward 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson's Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mITT 
modified Intent-to-Treat 
PD 
Parkinson's disease 
PK 
pharmacokinetic 
PP 
per-protocol 
RBC 
red blood cell 
RR 
respiratory rate 
SAE  
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAEs 
treatment-emergent adverse events 


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Temp. 
temperature 
WBC  
white blood cell 
WHO 
World Health Organization 
2. 
OBJECTIVES 
The primary objective of this study is to evaluate the efficacy, safety and tolerability of treatment 
with APL-130277 in 16 patients with PD. 
  
3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1. 
SAMPLE SIZE  
The sample size for this study was not based on statistical considerations.  Up to 24 patients will be 
screened to yield 16 patients who are enrolled into the study and proceed to the dosing day.   
3.2. 
RANDOMIZATION AND BLINDING 
This is an open-label trial, therefore no blinding is necessary.  All patients enrolled will follow the 
same treatment regimen, therefore randomization is not necessary. 
3.3. 
HANDLING OF DATA 
3.3.1. Missing Data and Outliers 
In general, missing or invalid data of efficacy assessments will be handled by individual scales or 
subscales on the basis of each individual assessment. Missing data for individual items will be 
assessed for each assessment of each scale and imputed with the mean score of the corresponding 
assessment and rounded up to the nearest integer if the number of items with missing data or 
invalid is less than or equal to 20% of total item number. Otherwise, the assessment score will be 
set to missing. 
For MDS-UPDRS assessments, missing data will be imputed using Last Observation Carried 
Forward (LOCF). 
For statistical analyses, missing data that result from either early study termination or unavailability 
will remain as missing for efficacy measures and safety measures, unless specified otherwise. 
3.3.2. Imputation of Incomplete Dates 
An incomplete date is any date for which either the day, month or year is unknown, but all 3 fields 
are not unknown. An incomplete date occurs when the exact date an event occurred or ended 
cannot be obtained from a patient. For many of the analyses, a complete date is necessary in order 


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to determine if the event should be included in the analysis (i.e., if the event is treatment-emergent) 
or to establish the duration of an event.  In such cases, incomplete dates will be imputed. 
For purposes of imputation of dates for AEs and concomitant medications, all events with an 
incomplete end date are assumed to have ended on or before the day the form was completed. In an 
effort to minimize bias, the project statistician will impute dates in a systematic, reasonable 
manner. If the month/year is the same as the Visit 3 month/year then the date will be set to the date 
of Visit 3. In other cases, missing days will be imputed as the day component of Visit 3; missing 
months/years will be imputed as the month/year of Visit 3. A list of incomplete and imputed dates 
will be prepared by the project statistician or statistical programmer(s) and will be submitted for 
review by the clinical project manager and sponsor.  
3.3.3. By-Study Visit Displays 
When data are collected serially over time, individual data presentations may include by-study visit 
displays for all scheduled study visits. Visits will be presented according to the nominal visit as 
obtained from the electronic data collection (EDC) system or laboratory data unless the visit is an 
unscheduled visit. All unscheduled visit values will be excluded from summary tables but will be 
included on data listings. If a patient has multiple non-missing values on the same date, then the 
last one is used, as determined by the time collected, if available. 
3.3.4. Definitions and Terminology 
 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last non-missing value obtained prior 
to initiation of APL-130277.  
 
Pre-Dose Value 
For purposes of analysis, the pre-dose value is defined as the value from the pre-dose (0 hour) time 
point for each dosing period (Visits 3 - 5). 
 
Post-Dose Values 
For purposes of analysis, the post-dose values are defined as the values from the  post-dose (.25, .5, 
.75, 1, and 1.5 hour) time points for each dosing period (Visits 3 - 5). 
 
Study Day  
Study Day is defined relative to Dosing Day 1 (Visit 3).  Thus, the study day of an event is 
calculated as: 
Study Day = (event date – date of Visit 3) +1 
Study Visit 
Study Visit is the nominal visit as recorded on the CRF. 
 


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Last Dose of Study Drug 
Last Dose of Study Drug is defined at the last date that the patient received APL-130277 as 
determined by last date of dosing as recorded on the APL-130277 Dosing CRF. 
Duration of Study Drug 
Duration of Study Drug is defined as the number of days from Visit 3 (Dosing Day 1) to the date of 
Last Dose of APL-130277. 
Change from Baseline  
Change from baseline for a given endpoint is defined as the Study Day X value minus the Baseline 
Value. 
Change from Pre-Dose  
Change from pre-dose for a given endpoint is defined as the Dosing Time Point X value minus the 
Pre-Dose Value. 
Treatment-emergent Adverse Event  
Treatment-emergent AEs are defined as AEs with onset at the time of or following the start of 
treatment with investigational drug and prior to 7 days after the end of treatment, or AEs starting 
prior to the start of treatment but increasing in severity or relationship at the time of or following 
the start of treatment.   
 
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of APL-130277 and 
prior to 7 days after the end of treatment.  This definition includes medications started prior to the 
initiation of APL-130277, but continuing concomitantly with APL-130277.   
 
Prior Medications 
Prior medications are those medications taken prior to the initiation of APL-130277, but stopped 
before initiation of APL-130277. 
 
MDS-UPDRS Scoring 
The total score is defined as the sum of scores from all of the questions, excluding the dyskinesia 
questions (i.e. the total score from questions 3.1 – 3.18). 
 
First Full ON Dose 
The first ON dose is defined as the earliest dose in which a subject achieves a Full  ON state as 
assessed by the Investigator. 
 
Duration of ON Response 
The duration of ON response is defined as the length of time in which a subject is confirmed ON 
within a dose. 
 


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Orthostatic Hypotension 
Orthostatic hypotension is defined as: 
 
a systolic BP decrease of ≥ 20 mmHg within three minutes of standing up from a sitting 
position; and/or 
 
a diastolic BP decrease of ≥ 10 mmHg within three minutes of standing up from a sitting 
position. 
 
4. 
ANALYSIS POPULATIONS 
The populations for analysis will include Safety, mITT, PP, PK, and Responder. 
4.1. 
SAFETY POPULATION 
The safety population is defined as all patients who are enrolled into the study and have received at 
least 1 dose of the study drug. 
4.2. 
MODIFIED INTENTION-TO-TREAT POPULATION  
The modified intention-to-treat (mITT) population is defined as all patients who have received at 
least 1 dose of study drug. 
4.3. 
PER-PROTOCOL POPULATION 
The per-protocol (PP) population is defined as all patients in the mITT population who complete 
the study and are deemed to be protocol-compliant. To be protocol-compliant, a patient will not 
have any major protocol violations during the entire study period.  Major protocol violations will 
be identified and assessed and decisions regarding the PP population will be made at the database 
lock meeting. 
4.4. 
PK POPULATION 
The PK population will be defined as those patients that complete the PK blood sampling 
procedures as outlined in the protocol. 
4.5. 
RESPONDER POPULATION 
The responder population is defined as all patients who have received at least 1 dose of study drug 
and have at least one investigator confirmation of Full ON. 
 


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5. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study, with hypothesis 
testing performed for the primary and other selected efficacy endpoints.  Unless stated otherwise, 
the term “descriptive statistics” refers to number of patients (n), mean, median, standard deviation 
(SD), minimum, and maximum for continuous data, and frequencies and percentages for 
categorical data.  All data collected during the study will be included in data listings.  Unless 
otherwise noted, the data will be sorted by patient number and by date within each patient number.  
The statistical analyses will be conducted with the SAS® software package version 9.1.3 or higher.  
All analyses will be subject to formal verification procedures. Specifically, results will be verified 
utilizing independent programming prior to issuance of the draft statistical report. All documents 
will be verified by the lead statistician to ensure accuracy and consistency of analyses. 
5.1. 
PATIENT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS  
Patient disposition will be presented for all patients. The number of patients who completed the 
study and discontinued from the study will be will be provided. The reasons for early 
discontinuation at any point also will be presented by treatment group. Additionally, the number of 
days on study and study drug will be summarized for all treated patients. 
Demographic data and baseline characteristics including age, gender, race, ethnicity, height, 
weight, BMI, history of Parkinson's disease, and medical history will be summarized using 
descriptive statistics for the Safety population.  This information will be reviewed  for baseline 
differences, but no statistical testing will be performed.   
5.2. 
EFFICACY ANALYSIS 
The first Full ON response will be used to calculate the primary and secondary endpoints. 
Any Partial ON recorded prior to the first Full ON response will not be used. 
5.2.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoints for the study are: 
 
Number of patients with resolution of an OFF episode to a Full ON state as assessed by the 
investigator at 15, 30, 45, 60 and 90 minutes after dosing.  The investigators will use their 
clinical judgment to assess resolution of the OFF episode. 
 
Time to Full ON from time of dosing 
 
Duration of Full ON response 
 
Tolerability: Percent of patients that complete trial and experience a Full ON episode 


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All efficacy analyses will be conducted on the mITT, Responder, and PP populations unless stated 
otherwise. 
5.2.2. 
Primary Efficacy Analysis 
The number and percentage of patients with resolution of an OFF episode to a Full ON state as 
assessed by the investigators overall and at 15, 30, 45, 60 and 90 minutes after dosing will be 
summarized across study treatment doses.  Event counts will also be summarized in order to 
account for the patients that have multiple resolutions within the same dose and time point.  A 
Wilcoxon signed-rank test will be implemented for comparison of each time point to pre-dose.  
Subgroup  analyses (age ≥65 versus <65 and Baseline OFF Episodes > 4 versus < 4) will also be 
presented. 
The time to Full ON state from time of dosing in minutes will be calculated from timing noted by 
the investigators and recorded in the eCRF, and summarized across study treatment. Values will be 
presented by dose and time point on a bar graph. 
The number and percentage of patients that complete trial and experience a Full ON episode as 
assessed by the investigators will be tabulated and summarized across study treatment doses.  
The duration of Full ON response in minutes will be calculated from the time noted by the 
investigators and recorded in the eCRF of an ON state to that of an OFF state on a per patient per 
dose basis and compared across study treatment doses.  A repeated measures analysis of variance 
(ANOVA) will be implemented for this comparison with treatment as the fixed effect. 
5.2.3. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint for the study is: 
 
Mean and Percent change in MDS-UPDRS Motor Score from pre-dose to 15, 30, 45, 60 
and 90 minutes after dosing for Full ON or last dose for those who do not convert to an 
ON. 
5.2.4. 
Secondary Efficacy Analysis 
The MDS-UPDRS Motor Score will be summarized across doses at pre-dose and 15, 30, 45, 60 
and 90 minutes after dosing.  The mean and percent change in score from pre-dose to 15, 30, 45, 60 
and 90 minutes after dosing will also be summarized.  The above measures will be calculated at 
Full ON for responders and last dose for those who do not convert to an ON state. A paired t-test 
will be implemented for comparison of each time point to pre-dose.  The UPDRS Motor Score will 
also be summarized in the same fashion as a sensitivity analysis.  Mean change from pre-dose will 
also be summarized as above for all Full ON doses and all Full ON doses excluding the first Full 
ON. 


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The number and percentage of patients with 5, 8, and 10 point score reduction and a 30% reduction 
from baseline and pre-dose in MDS-UPDRS Motor Score overall and across all time points at Full 
ON or last dose for those who do not convert to an ON will be presented.  The UPDRS Motor 
Score will also be summarized in the same fashion as a sensitivity analysis. 
Additional subgroup analyses for mean and percent change from pre-dose will be summarized by 
dose, age ≥65 versus <65 and ≥4 OFF episodes per day versus <4.  A paired t-test will be 
implemented for comparison of each time point and to pre-dose. 
Mean and percent change from pre-dose in MDS-UPDRS Motor Score for the first Full ON dose 
for responders and last dose for non-responders and all doses will be plotted over time across 15, 
30, 45, 60 and 90 minutes for the mITT population. 
Mean and percent change from pre-dose in MDS-UPDRS Motor Score for the first Full ON dose 
will be plotted over time by study population. 
5.3. 
SAFETY  
5.3.1. 
Safety Endpoints 
The safety and tolerability endpoints for the study are as follows: 
 
Evaluation of clinical laboratory tests 
 
12-lead ECGs 
 
Physical Examination 
 
Vital Signs (including body temperature and weight) 
 
Adverse Events 
All safety analyses will be conducted on the Safety Population. 
5.3.2. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
version 17.0 preferred term and system organ classification. If a patient experiences multiple events 
that map to a single preferred term, the greatest severity grade and strongest investigator 
assessment of relation to study medication will be assigned to the preferred term for the appropriate 
summaries. Should an event have a missing severity or relationship, it will be classified as having 
the highest severity and/or strongest relationship to study medication. The occurrence of treatment-
emergent adverse events (TEAEs) will be summarized by treatment group using preferred terms, 
system organ classifications, and severity. Separate summaries of treatment-emergent serious 
adverse events, TEAEs related to APL-130277, and events leading to the discontinuation of APL-
130277 will be generated. TEAEs will be summarized overall and by dose. All adverse events 
reported will be listed for individual patients showing both verbatim and preferred terms. All 


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adverse events that occurred prior to the initiation of study treatment or more than 7 days post-
discontinuation of treatment will be excluded from the tables but will be included in the listings.  
Missing onset dates will be imputed as previously outlined in Section 3.3.2 as required to 
determine TEAEs. 
5.3.3. Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
dictionary (Version: June, 2014). Concomitant medications will be summarized by frequency of 
ATC (Anatomical Therapeutic Chemical) classification and generic drug name. Prior and 
concomitant medications will be presented in a data listing.   
5.3.4. Clinical Laboratory Assessments 
The following clinical laboratory test samples will be collected at Visits 1 and Visit 6: 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin (MCH), MCH concentration (MCHC), platelet 
count (or estimate), white blood cell (WBC) count including differential,  
Serum Chemistry: 
albumin, total bilirubin, total protein, alkaline phosphatase, chloride, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood 
urea, creatinine, glucose, sodium, potassium, uric acid, globulin 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
 
Descriptive summaries including change from baseline of selected (quantitative) clinical laboratory 
results will be presented by study visit. 
 
Laboratory abnormalities will be determined according to the reference ranges. The number and 
percentage of patients with treatment-emergent (occurred at Follow-Up) abnormal findings in each 
category will be produced for each treatment group.  Clinically significant laboratory abnormalities 
will be summarized in a similar manner.  For all clinical laboratory tests, a shift table will be 
produced summarizing changes from normal to abnormal and vice-versa.  
5.3.5. 12-Lead ECG 
The number and percentage of patients with normal and abnormal ECG findings will be displayed 
for each treatment group at each time point.  Descriptive statistics including change from pre-dose 
of quantitative ECG variables also will be presented.   
 


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QTcB results > 500 ms and QTcF results > 60 ms over pre-dose will be flagged.  The number and 
percentage of patients with these criteria will be summarized by time point across doses. 
5.3.6. Physical Examination 
The number and percentage of patients with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group. 
5.3.7. Vital Signs 
Descriptive summaries including change from pre-dose of vital signs will be presented by study 
visit across doses.   
 
Also, the number and percentage of patients will be summarized based on the following criteria by 
time point across doses: 
 
Change in post-dose systolic and diastolic blood pressure from sitting to standing exceeds 
25%  
 
Change in post-dose systolic and diastolic blood pressure from sitting to standing exceeds 
25% and post-dose systolic blood pressure < 90 mmHg 
 
Change in post-dose systolic and diastolic blood pressure from sitting to standing exceeds 
25% and post-dose diastolic blood pressure < 45 mmHg 
 
Change in post-dose systolic and diastolic blood pressure from sitting to standing exceeds 
25%,  decrease in post-dose systolic blood pressure from sitting to standing ≥ 20 mmHg 
and/or decrease in post-dose diastolic blood pressure from sitting to standing ≥ 10 mmHg 
 
    
6. 
PROTOCOL VIOLATIONS 
Possible protocol deviations will be identified and displayed in a data listing and sorted by patient 
and study day (where applicable).  In addition, the following deviations may be identified from the 
database:  
 
Missing efficacy assessments  
 
Violations of inclusion/exclusion criteria  
 
Non-compliance with APL-130277 
 
7. 
CHANGES IN THE PLANNED ANALYSES 
Deviations from the protocol: 
1. A responder population has been added to the Analysis Populations (Section 4). 


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2. Orthostatic hypotension is defined as a decrease in systolic pressure < 90mmHg AND a 
decrease of >25% from Visit 3 pre-dose reading levels and/or a diastolic pressure < 
45mmHg AND a decrease of >25% from Visit 3 pre-dosing reading levels in Section 12.6 
of the protocol.  However, it was determined the more relevant definition to use for 
reporting purposes is defined in Section 3.3.4 of the SAP. 
3. Sensitivity analyses for First ON Dose results have been added throughout.  See Section 
3.3.4 for the definition for First ON Dose. 
4. See section 5.3.5.  Additional analyses have been added for 12-Lead ECG that are not 
defined in the protocol. 
5. See section 5.3.7.  Additional analyses have been added for Vital Signs that are not defined 
in the protocol. 
 
8. 
REVISION HISTORY 
Date 
Revision 
Rationale 
 
 
 


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9. 
PROGRAMMING CONVENTIONS 
 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation.  There should be a minimum of a 1.25” boundary on the upper (bound) 
edge, and a minimum of a 1.0” boundary on the remaining three edges. Output should be 
printed in Courier New with a point size of 8. Titles may be printed using a larger font (e.g., 
Arial point size 10). 
 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized. Listings will be prepared for all patients enrolled. 
 
Group headers: In the summary tables, the group headers will identify the summary group and 
the within-group sample size for the indicated analysis population. Of note, the header’s 
sample size does not necessarily equal the number of patients actually summarized within any 
given summary module; some patients in the analysis population may have missing values and 
thus may not be summarized. 
 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when 
the count is zero in order to draw attention to the non-zero counts. 
 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the 
number of patients actually contributing to the summary statistics presented in any given 
summary module. As mentioned above, this may be less than the number of patients in the 
analysis population. 
 In the quantitative modules describing continuous variables (and thus presenting sample 
size, means, and standard deviations), the sample size should be the number of non-
missing observations 
 For categorical variables that are presented in frequency tables, the module should present 
the total count in addition to the count in each category. Percentages should be calculated 
using this total as the denominator, and the percentage corresponding to the sum itself (that 
is, 100%) should be presented so as to indicate clearly to a reviewer the method of 
calculation. 
 
Sorting: Listings will be sorted by summary group, patient number and date, if applicable. If a 
listing is sorted in a different manner, a footnote will indicate as such.  
 
General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures. No intermediate rounding will 
be performed on derived variables. The standard rounding practice of rounding numbers 
ending in 0-4 down and numbers ending in 5-9 up will be employed.   
 
The presentation of numerical values will adhere to the following guidelines:  


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 Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRFs.   
 Standard deviations will be reported to one decimal place beyond the number of decimal 
places the original parameter is presented. 
 Means will be reported to the same number of significant digits as the parameter.  
 Calculated percentages will be reported with no decimals. 
 
Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data listings as 
recorded on CRFs. 
 
Time will be presented according to the 24-hour clock (HHMM). 
 


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10. 
PROPOSED TABLES, LISTINGS, AND FIGURES FOR FINAL ANALYSIS 
Summary Tables and Figures 
 
Accountability and Baseline Characteristics 
14.1.1 
Patient Disposition, All Patients 
14.1.2 
Demographics and Baseline Characteristics, Safety Population 
14.1.3 
Medical History and Concomitant Diagnosis, Safety Population 
14.1.4 
Prior Medications, Safety Population 
14.1.5 
Study Treatment Exposure, Safety Population 
 
Efficacy  
14.2.1.1 
Number of Patients with Resolution of an OFF Episode to an ON State - First Full 
 
ON Dose, mITT Population 
14.2.1.2 
Number of Patients with Resolution of an OFF Episode to an ON State - First Full 
 
ON Dose, Responder Population 
14.2.1.3 
Number of Patients with Resolution of an OFF Episode to an ON State - First Full 
 
ON Dose, PP Population 
14.2.1.4 
Number of Patients with Resolution of an OFF Episode to an ON State - All Full 
 
ON Doses, mITT Population 
14.2.2.1 
Time to ON State from Time of Dosing (in minutes) - First Full ON Dose, mITT 
 
Population 
14.2.2.2 
Time to ON State from Time of Dosing (in minutes) - First Full ON Dose, 
 
Responder Population 
14.2.2.3 
Time to ON State from Time of Dosing (in minutes) - First Full ON Dose, PP
 
Population 
14.2.2.4 
Time to ON State from Time of Dosing (in minutes) - All Full ON Doses, 
 
Responder Population 
14.2.3 
Proportion of Patients That Complete Trial and Experience ON Episode, mITT 
 
Population 
14.2.4.1 
Duration of ON Response (in minutes) - First Full ON Dose, mITT Population 
14.2.4.2 
Duration of ON Response (in minutes) - First Full ON Dose, Responder 
 
Population 
14.2.4.3 
Duration of ON Response (in minutes) - First Full ON Dose, PP Population 
14.2.4.4 
Duration of ON Response (in minutes) - All Full ON Doses, mITT Population 
14.2.5.1.1  
MDS-UPDRS Motor Score Mean Change from Pre-Dose by Population Summary 
 
- First Full ON Dose, mITT Population 


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14.2.5.1.2  
MDS-UPDRS Motor Score Percent Change from Pre-Dose by Population 
 
Summary - First Full ON Dose, mITT Population 
14.2.5.2.1  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - First Full 
 
ON Dose, mITT Population 
14.2.5.2.2  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - First Full 
 
ON Dose, Responder Population 
14.2.5.2.3  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - First Full 
 
ON Dose, PP Population 
14.2.5.2.4  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary, mITT 
 
Population 
14.2.5.2.5  
Sensitivity Analysis:  UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary - First Full ON Dose, mITT Population 
14.2.5.2.6  
Sensitivity Analysis:  UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary - First Full ON Dose, Responder Population 
14.2.5.2.7  
Sensitivity Analysis:  UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary - First Full ON Dose, PP Population 
14.2.5.2.8  
Sensitivity Analysis:  UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary, mITT Population 
14.2.5.3 .1 
MDS-UPDRS Motor Score Percent Change from Pre-Dose Summary - First Full 
 
ON Dose, mITT Population 
14.2.5.3.2  
MDS-UPDRS Motor Score Percent Change from Pre-Dose Summary - First Full 
 
ON Dose, Responder Population 
14.2.5.3.3  
MDS-UPDRS Motor Score Percent Change from Pre-Dose Summary - First Full 
 
ON Dose, PP Population 
14.2.5.3.4  
MDS-UPDRS Motor Score Percent Change from Pre-Dose Summary, mITT 
 
Population 
14.2.5.3.5  
Sensitivity Analysis:  UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary - First Full ON Dose, mITT Population 
14.2.5.3.6  
Sensitivity Analysis:  UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary - First Full ON Dose, Responder Population 
14.2.5.3.7  
Sensitivity Analysis:  UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary - First Full ON Dose, PP Population 
14.2.5.3.8  
Sensitivity Analysis:  UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary, mITT Population 
14.2.5.4.1  
MDS-UPDRS Motor Score Reduction Summary - First Full ON Dose, mITT 
 
Population 
14.2.5.4.2  
MDS-UPDRS Motor Score Reduction Summary - First Full ON Dose, Responder
 
Population 


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14.2.5.4.3  
MDS-UPDRS Motor Score Reduction Summary - First Full ON Dose, PP
 
Population 
14.2.5.4.4  
MDS-UPDRS Motor Score Reduction Summary, mITT Population 
14.2.5.4.5  
Sensitivity Analysis:  UPDRS Motor Score Reduction Summary - First Full ON 
 
Dose, mITT Population 
14.2.5.4.6  
Sensitivity Analysis:  UPDRS Motor Score Reduction Summary - First Full ON 
 
Dose, Responder Population 
14.2.5.4.7  
Sensitivity Analysis:  UPDRS Motor Score Reduction Summary - First Full ON 
 
Dose, PP Population 
14.2.5.4.8  
Sensitivity Analysis:  UPDRS Motor Score Reduction Summary, mITT 
 
Population 
14.2.5.5.1  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - All Full ON 
 
Doses, mITT Population 
14.2.5.5.2  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - All Full ON 
 
Doses, Responder Population 
14.2.5.5.3  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - All Full ON 
 
Doses, PP Population 
14.2.5.5.4  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - All Full ON 
 
Doses Excluding First Full ON, mITT Population 
14.2.5.5.5  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - All Full ON 
 
Doses Excluding First Full ON, Responder Population 
14.2.5.5.6  
MDS-UPDRS Motor Score Mean Change from Pre-Dose Summary - All Full ON 
 
Doses Excluding First Full ON, PP Population 
14.2.5.6.1  
Subgroup Analysis:  MDS-UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary (>= 4 versus <4  OFF Episodes Per Day) - First Full ON Dose, mITT 
 
Population 
14.2.5.6.2  
Subgroup Analysis:  MDS-UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary (>= 4 versus <4  OFF Episodes Per Day) - First Full ON Dose, 
 
Responder Population 
14.2.5.6.3  
Subgroup Analysis:  MDS-UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary (>= 4 versus <4  OFF Episodes Per Day) - First Full ON Dose, PP 
 
Population 
14.2.5.6.4  
Subgroup Analysis:  MDS-UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary (>= 4 versus <4  OFF Episodes Per Day) - First Full ON Dose, mITT 
 
Population 
14.2.5.6.5  
Subgroup Analysis:  MDS-UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary (>= 4 versus <4  OFF Episodes Per Day) - First Full ON Dose, 
 
Responder Population 


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14.2.5.6.6  
Subgroup Analysis:  MDS-UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary (>= 4 versus <4  OFF Episodes Per Day) - First Full ON Dose, PP 
 
Population 
14.2.5.7.1  
Subgroup Analysis:  UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary (>= 65 versus <65 Age) - First Full ON Dose, mITT Population 
14.2.5.7.2  
Subgroup Analysis:  UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary (>= 65 versus <65 Age) - First Full ON Dose, Responder Population 
14.2.5.7.3  
Subgroup Analysis:  UPDRS Motor Score Mean Change from Pre-Dose 
 
Summary (>= 65 versus <65 Age) - First Full ON Dose, PP Population 
14.2.5.7.4  
Subgroup Analysis:  UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary (>= 65 versus <65 Age) - First Full ON Dose, mITT Population 
14.2.5.7.5  
Subgroup Analysis:  UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary (>= 65 versus <65 Age) - First Full ON Dose, Responder Population 
14.2.5.7.6  
Subgroup Analysis:  UPDRS Motor Score Percent Change from Pre-Dose 
 
Summary (>= 65 versus <65 Age) - First Full ON Dose, PP Population 
14.2.5.7.7  
Subgroup Analysis:  Number of Patients with Resolution of an OFF Episode to 
 
an ON State (>= 65 versus <65 Age) - First Full ON Dose, mITT Population 
14.2.5.7.8  
Subgroup Analysis:  Number of Patients with Resolution of an OFF Episode to 
 
an ON State (>= 65 versus <65 Age) - First Full ON Dose, Responder Population 
14.2.5.7.9  
Subgroup Analysis:  Number of Patients with Resolution of an OFF Episode to 
 
an ON State (>= 65 versus <65 Age) - First Full ON Dose, PP Population 
 
Safety 
14.3.1.1 
Treatment-Emergent Adverse Events by System Organ Classification, Preferred 
 
Term, and Greatest Severity, Safety Population 
14.3.1.2 
Treatment-Emergent Serious Adverse Events by System Organ Classification and 
 
Preferred Term, Safety Population 
14.3.1.3 .1 
Treatment-Emergent Adverse Events by System Organ  Classification, Preferred 
 
Term, and Relationship to APL-130277, Safety Population 
14.3.1.3.2  
Treatment-Emergent Adverse Events by System Organ  Classification, Preferred 
 
Term, and Relationship to APL-130277 (Related/Not Related), Safety Population 
14.3.2  
Concomitant Medications, Safety Population 
14.3.3.1.1 
Summary of Hematology by Visit, Safety Population 
14.3.3.1.2 
Shift Table of Hematology, Safety Population 
14.3.3.1.3 
Summary of Abnormal and Clinically Significant Hematology at Follow-Up 
 
Visit, Safety Population 
14.3.3.2.1 
Summary of Serum Chemistry by Visit, Safety Population 
14.3.3.2.2 
Shift Table of Serum Chemistry, Safety Population 


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14.3.3.2.3 
Summary of Abnormal and Clinically Significant Serum Chemistry at Follow-Up 
 
Visit, Safety Population 
14.3.3.3.1 
Summary of Urinalysis by Visit, Safety Population 
14.3.3.3.2 
Shift Table of Urinalysis, Safety Population 
14.3.3.3.3 
Summary of Abnormal and Clinically Significant Urinalysis at Follow-Up 
 
Visit, Safety Population 
14.3.4.1 
Summary of 12-Lead ECG by Visit, Safety Population 
14.3.4.2 
Summary of QTcB (>500) and QTcF Change from Pre-Dose (>60), Safety 
 
Population 
14.3.5  
Summary of Physical Exam by Visit, Safety Population 
14.3.6.1 
Summary of Vital Signs Change from Pre-Dose, Safety Population 
14.3.6.2 
Summary of Blood Pressure Reduction > 25% Sitting to Standing Post-Dose by 
 
Time Point, Safety Population 
14.3.6.3 
Summary of Blood Pressure Reduction > 25% Sitting to Standing Post-Dose and 
 
Systolic < 90 mmHg or Diastolic < 45 mmHg by Time Point, Safety Population 
14.3.6.4 
Orthostatic Hypotension by Time Point, Safety  Population 
 
Figures 
15.1.1  
Mean Change from Pre-Dose MDS-UPDRS Motor Score - First Full ON Dose, 
 
mITT  Population 
15.1.2  
Percent Change from Pre-Dose MDS-UPDRS Motor Score - First Full ON Dose, 
 
mITT Population 
15.2  
Time to ON State from Time of Dosing (in minutes) by Time Point - First Full 
 
ON Dose, Responder Population 
15.3.1  
Mean Change from Pre-Dose MDS-UPDRS Motor Score by Population - First 
 
Full ON Dose, mITT Population 
15.4  
Percent Change from Pre-Dose MDS-UPDRS Motor Score by Population - First 
 
Full ON Dose, mITT Population 
 
Data Listings 
 
16.2.1.1 
Early Termination/Study Completion 
16.2.1.2 
Inclusion/Exclusion Criteria 
16.2.1.3 
Telephone Contact 
16.2.2 
Protocol Deviations 
16.2.3 
Study Populations 
16.2.4.1 
Demographics 


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16.2.4.2 
History of Parkinson's Disease 
16.2.4.3 
Hoehn and Yahr Scale 
16.2.4.4 
Medical History/Concomitant Diagnosis 
16.2.5.1.1 
Study Drug Administration 
16.2.5.1.2 
Levodopa Administration 
16.2.5.2 
Prior and Concomitant Medications 
16.2.6.1 
Clinical Confirmation of OFF and ON 
16.2.6.2 
MDS-UPDRS Motor Function 
16.2.7.1 
Adverse Events 
16.2.7.2 
Serious Adverse Events 
16.2.7.3 
Adverse Events Leading to Discontinuation 
16.2.8.1  
Laboratory Tests - Panel 
 
Hematology 
 
Serum Chemistry 
 
Urinalysis 
16.2.8.2.1  
Vital Signs 
16.2.8.2.2  
Orthostatic Hypotension 
16.2.8.3 
BMI 
16.2.8.4  
Physical Examination 
16.2.8.5.1  
12-Lead ECG 
16.2.8.5.2  
QTcB and QTcF Change from Pre-Dose 
16.2.8.6 
Pregnancy Test