Clinical trial NCT03187301
Conditions: Parkinson's Disease Off Episodes of Parkinson Disease
Keywords: Parkinson's Disease Off episodes
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2017-08-03; Completion date: 2017-12-21
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A cardiac safety study of an investigational drug to see how it affects the heart in people with Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)

Detailed description:
This multi-center, Phase 2, Randomized, Double-Blind, Placebo Controlled, 3-Period Crossover, Positive Control study designed to evaluate the QT interval prolongation potential of 10 mg to 60 mg doses of APL-130277 compared to placebo and the positive control, 400mg moxifloxacin in subjects with Parkinson's Disease (PD) who experience motor fluctuations ("OFF" episodes) The patient is titrated to the highest tolerated dose from 10mg to 60mg, and then is randomized to one of six crossover sequences. Each sequence includes treatment with the following:

1. Treatment A: APL-130277 at the dose determined in the Dose Titration Phase,
2. Treatment B: Matched placebo,
3. Treatment C: A single 400 mg dose of moxifloxacin

Arms: arm 1: APL-130277 at the dose determined in the dose titration phase arm 2: Placebo arm 3: moxifloxacin at a single 400mg dose
Interventions: intervention 1: APL-130277 intervention 2: Placebo intervention 3: Moxifloxacin
Intervention descriptions: intervention 1: APL-130277 single dose intervention 2: Placebo single dose intervention 3: moxifloxacin 400mg single dose

Protocol documents:
Prot_000.pdf: 
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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
The information cannot be disclosed to any third party or 
predecessors, subsidiaries or affiliates). 
used for any purpose other than the purpose for which it is being submitted without the prior 
written consent of the appropriate Sumitomo Dainippon Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
Sumitomo Dainippon Pharma Co. Ltd. and
 You may disclose 
/or Sunovion Pharmaceuticals Inc.
the contents of this protocol to the study personnel under your supervision and to your 
Institutional Review Board or Independent Ethics Committee for the above purpose. You may 
not disclose the contents of this protocol to any other parties, unless such disclosure is required 
by government regulations or laws, without the prior written permission of Sumitomo Dainippon 
Pharma Co. Ltd. and
 
/or Sunovion Pharmaceuticals Inc.
Any data gathered during the conduct of this protocol and supplemental information (eg, a 
 
protocol amendment) that may be added to this document is also proprietary to Sumitomo 
Dainippon Pharma Co. Ltd. and
, and should be handled 
/or Sunovion Pharmaceuticals Inc.
consistently with that stated above. 
 


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1 
EMERGENCY CONTACT INFORMATION 
Sponsor Contact: 
  
Senior Director Clinical Development  
Sunovion Pharmaceuticals Inc. 
84 Waterford Drive Marlborough, MA  
  
 
 
North American Medical Monitor: 
  
Medical Director  
INC Research  
  
  
 
European Union Medical Monitor 
  
Executive Medical Director  
INC Research  
  
   
 
SAE Reporting 
 
 
 
 


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2 
INVESTIGATOR APPROVAL STATEMENT 
I have read the protocol, CTH-201, Version 5.0, “A Phase 2, Randomized, Double-Blind, 
Placebo Controlled 3-Period Crossover, Positive Control, QT-Evaluation Study of APL-130277 
in Subjects with Parkinson’s Disease Complicated by Motor Fluctuations (“OFF” Episodes),” 
and agree that it contains all necessary details for conducting the study and to conduct the study 
in strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of 
IRB/REB/IEC approval. 
Principal Investigator 
 
Printed Name: 
 
Signature: 
 
Date: 
 
 
 
PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo Controlled, 3-Period Crossover, Positive 
Control, QT-Evaluation Study of APL-130277 in Subjects with Parkinson’s Disease 
Complicated by Motor Fluctuations (“OFF” Episodes) 
Protocol: 28 Aug 2017  
 
Version: 5.0 
 


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3 
PROTOCOL SYNOPSIS 
TITLE 
A Phase 2, Randomized, Double-Blind, Placebo Controlled 3-Period Crossover, Positive 
Control, QT-Evaluation Study of APL-130277 in Subjects with Parkinson’s Disease 
Complicated by Motor Fluctuations (“OFF” Episodes) 
STUDY PHASE 
Phase 2 
OBJECTIVES 
The primary objective is to evaluate the effect of APL-130277 compared to placebo on 
QTc intervals in subjects with Parkinson’s disease (PD) complicated by motor 
fluctuations. 
The secondary objectives include the evaluation of safety and pharmacokinetics of APL-
130277 and the comparison of efficacy of the highest tolerated dose level and the lowest 
APL-130277 dose resulting in a full “ON” during the Dose Titration Phase. 
NUMBER OF 
SUBJECTS 
The study will require forty-two (42) subjects to complete the 3-period, single dose 
crossover phase. Recruitment will continue until the required number of subjects 
complete the study. 
PATIENT 
POPULATION 
Inclusion Criteria 
Subjects who meet each of the following criteria will be eligible for participation in the 
study: 
1. Male or female ≥ 18 years of age. 
2. Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria 
(excluding the “more than one affected relative” criterion). 
3. Clinically meaningful response to Levodopa (L-Dopa). Subjects with or without 
well-defined “OFF” episodes, as determined by the Investigator, will be allowed. 
4. Receiving stable doses of L-Dopa/carbidopa (immediate or sustained release) 
administered at least 3 times per day OR Rytary™ administered 3 times per day, 
for at least 4 weeks before the initial Screening Visit (SV1). Subjects receiving 
L-Dopa/carbidopa 3 times a day must also be on stable treatment with adjunctive 
PD medication regimens. These regimens must be maintained at a stable dose 
for at least 4 weeks prior to the initial Screening Visit (SV1) with the exception 
that MAO-B inhibitors must be maintained at a stable level for at least 8 weeks 
prior to the initial Screening Visit (SV1). 
5. No planned medication change(s) or surgical intervention anticipated during the 
course of study. 
6. The subject must be able to have a drug withdrawal induced “OFF” episode. 
7. Stage III or less on the modified Hoehn and Yahr scale in the “ON” state. 
8. Mini–Mental State Examination (MMSE) score > 21. 
9. If female and of childbearing potential, must agree to use one of the following 
methods of birth control throughout the study and until at least 30 days after 
final drug administration: 
• 
Oral contraceptive; 
• 
Contraceptive patch; 


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• 
Barrier (diaphragm, sponge or condom) plus spermicidal preparations; 
• 
Intrauterine contraceptive system; 
• 
Levonorgestrel implant; 
• 
Medroxyprogesterone acetate contraceptive injection; 
• 
Complete abstinence from sexual intercourse; 
• 
Hormonal vaginal contraceptive ring; or 
• 
Surgical sterilization or partner sterile (must have documented proof). 
10. Male subjects must be either surgically sterile, agree to be sexually abstinent or 
use a barrier method of birth control (e.g., condom) from first study drug 
administration until at least 30 days after final drug administration. 
11. Willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study-related procedures to complete the study. 
12. Able to understand the consent form, and to provide written informed consent. 
13. Must be approved as a satisfactory candidate by the Enrollment Authorization 
Committee (EAC) and the Sponsor. 
 
Exclusion Criteria 
Subjects will be excluded from participation in the study for any of the following reasons: 
1. Atypical or secondary parkinsonism. 
2. Nausea associated with the use of dopamine agonists that requires treatment with 
an anti-emetic. 
3. Previous treatment with any of the following: a neurosurgical procedure for PD; 
continuous subcutaneous (s.c.) apomorphine infusion; or Duodopa/Duopa. 
4. Treatment with any form of s.c. apomorphine within 7 days prior to the initial 
Screening Visit (SV1). Subjects that stopped s.c. apomorphine for any reason 
other than systemic safety concerns or lack of efficacy may be considered. 
5. Contraindications to moxifloxacin or APOKYN® or hypersensitivity to 
apomorphine hydrochloride or any macrolide antibiotic or any of the ingredients 
of APOKYN® (notably sodium metabisulfite). 
6. Female who is pregnant or lactating. 
7. Participation in a clinical trial within 30 days prior to the initial Screening Visit 
(SV1), with the exception of clinical studies related to APL-130277. 
8. Receipt of any investigational (i.e., unapproved) medication within 30 days prior 
to the initial Screening Visit (SV1), with the exception of APL-130277. 
9. Any selective 5HT3 antagonists (i.e., ondansetron, granisetron, dolasetron, 
palonosetron, 
alosetron), 
dopamine 
antagonists 
(including 
Tigan 
[trimethobenzamide] and domperidone, but excluding quetiapine or clozapine) 
or dopamine depleting agents within 30 days prior to initial Screening Visit 
(SV1). 
10. Drug or alcohol dependency in the past 12 months. 
11. Subject has a history of malignancy within 5 years prior to SV1, except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical 


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cancer. Pituitary tumors of any duration are excluded. 
12. Documented abnormalities with ECGs including, arrhythmias, clinically 
meaningful interval irregularities, structural heart abnormalities, myocardial 
infarction, presence or history of a pacemaker, or any abnormality of the ECG, 
that in the opinion of the Investigator, would interfere with the ability to measure 
the QT interval, or correct the QT interval for heart rate. 
13. Male subjects with a screening corrected QT interval using Fridericia’s formula 
(QTcF) of ≥ 450 ms; female subjects with a screening QT interval ≥ 470 ms. 
Eligibility will be based on the core laboratory ECG interpretation report. 
14. HR at screening < 45 bpm or > 100 bpm. 
15. QRS duration at screening > 120 ms. 
16. PR interval at screening > 200 ms. 
17. Subjects with a history of cataplexy, unexplained syncope or seizures. 
18. Family history of sudden cardiac death. 
19. Heart failure (NYHA Class II or greater) and/or a myocardial infarction. 
20. Current use of any concomitant mediations that prolong the QT/QTc interval. 
Refer to https://crediblemeds.org for listing. 
21. History of additional risk factors for TdP (i.e., heart failure, hypokalemia, family 
history of Long QT Syndrome). 
22. Clinically significant medical, surgical, or laboratory abnormality in the opinion 
of the Investigator. 
23. Subject has a positive screening laboratory test result for human 
immunodeficiency virus (HIV). 
24. Subject has a positive screening laboratory test result for hepatitis B surface 
antigen or hepatitis C antibodies and has liver function test results at screening 
above the ULN for the reference laboratory. 
25. Major psychiatric disorder including, but not limited to, dementia, bipolar 
disorder, psychosis (including Parkinson’s disease psychosis), or any disorder 
that, in the opinion of the Investigator, requires ongoing treatment that would 
make study participation unsafe or make treatment compliance difficult. 
26. History of clinically significant impulse control disorder(s). 
27. Dementia that precludes providing informed consent or would interfere with 
participation in the study. 
28. Current suicidal ideation within one year prior to the second Screening Visit 
(SV2) as evidenced by answering “yes” to Questions 4 or 5 on the suicidal 
ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or 
attempted suicide within the last 5 years.  
29. Donation of blood plasma in the 30 days prior to first dosing. 
STUDY DESIGN 
Study Procedures 
Screening 
Before any study procedures are performed on any subject, informed consent must be 
obtained at an initial Screening Visit (SV1). Subjects recruited to participate in the study, 


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and who have provided full consent to participate, will be asked to attend a second 
Screening Visit (SV2), having taken their last dose of L-Dopa and any other adjunctive 
PD medication no later than midnight the evening prior to the visit. Their normal morning 
dose of L-Dopa (without adjunctive PD medication) will be administered in the clinic 
following confirmation of an “OFF” episode by the Investigator, to ensure that they 
experience an “ON” response. Eligibility criteria will be assessed by the Investigator and 
approved by the EAC prior to enrollment. 
Subjects will be asked to return to the clinic the morning of Titration Visit 1 (TV1) for 
the Dose Titration Phase of the study. 
Dose Titration Phase 
Depending on the Investigator's decision, subjects will be asked to arrive at the clinic: 
• 
after their usual morning dose of PD medications; but before taking their next 
dose of medication; OR 
• 
after withholding their normal morning dose of L-dopa (ie, in the practically 
defined "OFF" state with no anti-parkinsonian medication after midnight the 
night prior). 
During the Dose Titration Phase of the study, subjects will start with a dose of 10 mg 
APL-130277 and increase in 5 mg increments up to 40 mg and then in 10 mg increments 
for the 50 mg and 60 mg dose levels until the subject reaches a full “ON” state. Once a 
full “ON” state is achieved, dosing will continue for 2 additional visits to a maximum 
dose of 60 mg (i.e., if a subject experiences the first full “ON” at 10 mg, dosing will 
continue up until a dose of 20 mg). 
For those subjects who do not achieve a full "ON" response, titration should continue 
until the maximum tolerated dose of APL-130277 is determined. 
Note: For subjects who have previously participated in the CTH-300 or CTH-301 study, 
the subject will begin titration at the effective dose used in the respective previous study. 
Similarly dose titration of these subjects will increase in 5 mg increments up to 40 mg 
and then in 10 mg increments for the 50 mg and 60 mg dose levels until the subject 
reaches a full “ON” state. Once a full “ON” state is achieved, dosing will continue for 
2 additional visits to a maximum dose of 60 mg (i.e., if a subject experiences the first full 
“ON” at 35 mg, dosing will continue up until a dose of 50 mg). 
At Titration Visit 1 (TV1), once the subject's “OFF” state has been confirmed by both the 
Investigator and subject, the subject will be treated with 10 mg APL-130277. Subjects 
who tolerate the 10 mg APL-130277 will restart their normal PD medications and will be 
asked to return to the clinic the next business day for Titration Visit 2 (TV2), to assess the 
next highest dose (i.e., 15 mg) in a manner identical to that of Titration Visit 1 (TV1). 
Doses of APL-130277 will increase in 5 mg increments up to 40 mg and then in 10 mg 
increments for the 50 mg and 60 mg dose levels until a full “ON” state is achieved, then 
dosing will continue for 2 additional visits to a maximum dose of 60 mg. This will 
sequentially be 20 mg [TV3], 25 mg [TV4], 30 mg [TV5], 35 mg [TV6], 40 mg [TV7], 
50 mg [TV8] and 60 mg [TV9]. 
For Titration Visit 3 (TV3), Titration Visit 4 (TV4), Titration Visit 5 (TV5), and Titration 
Visit 6 (TV6) subjects should be dosed with the next highest dose of study medication 
within 4 hours of the initial dose, as long as the subject achieves another “OFF” state that 


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day. TV3 should be paired with TV4 (20 mg and 25 mg can be dosed on the same day), 
TV4 should be paired with TV5 (25 mg and 30 mg can be dosed on the same day), TV5 
should be paired with TV6 (30 mg and 35 mg can be dosed on the same day) and TV6 
should be paired with TV7 (35 mg and 40 mg can be dosed on the same day). 
Should the subject be unable to tolerate either of the two additional dose levels after 
reaching a full “ON” state, in the Investigator’s opinion, due to adverse events commonly 
associated with apomorphine (e.g., orthostatic hypotension, nausea, vomiting, etc.), 
subjects will be randomized to the previous dose. 
Dosing days in the Dose Titration Phase should be scheduled on consecutive business 
days and a maximum of 2 days between visits may be permitted with Medical Monitor 
approval. All visits in the Dose Titration Phase must be completed within 14 days.  
Safety and efficacy assessments will be performed at each visit according to the protocol. 
Three-Way Balanced Randomized Crossover Assessment Phase (Period 1, Period 2, 
Period 3) 
Subjects who successfully complete the Dose Titration Phase of the study, and are 
approved by the Sponsor to proceed to randomization, will be asked to return to the clinic 
for Period 1 Dosing Visit 1 (P1V1). This visit will occur between 2 and 7 days after the 
final visit in the Dose Titration Phase of the study. Depending on the Investigator's 
decision, subjects will be asked to arrive at the clinic: 
• 
after their usual morning dose of PD medications; but before taking their next 
dose of medication; OR 
• 
after withholding their normal morning dose of L-dopa (ie, in the practically 
defined "OFF" state with no anti-parkinsonian medication after midnight the 
night prior). 
Subjects will be randomized in equal numbers to six possible sequences of each of the 
three treatments being studied: 
1. 
Treatment A: APL-130277 at the dose determined in the Dose Titration 
Phase, 
2. 
Treatment B: Matched placebo APL-130277, 
3. 
Treatment C: A single 400 mg dose of moxifloxacin. 
Following confirmation by both the Investigator and subject that the subject is in the 
“OFF” state, the subject will be dosed according to the subject's random treatment 
assignment. APL-130277 and placebo APL-130277 will be administered in a double-
blind fashion and moxifloxacin will be administered open-label in a three-way balanced 
crossover. All subjects will be exposed to all three treatments. The six possible treatment 
sequences are: 1) ABC; 2) ACB; 3) BCA; 4) BAC; 5) CAB; and 6) CBA. 
Subjects will return to clinic 3 days after Period 1 and will be dosed for Period 2 with one 
of the other two treatments. 
Subjects will return to clinic 3 days after Period 2 and will be dosed for Period 3 with the 
third and last treatment. 
INVESTIGATIONAL 
DRUG 
APL-130277 (10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg [given as 2 sublingual thin 
films consisting of 20 mg followed by 15 mg], 40 mg [given as 2 sublingual thin films 
consisting of 20 mg followed by 20 mg], 50 mg [given as 2 sublingual thin films 


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consisting of 25 mg followed by 25 mg] and 60 mg [given as 2 sublingual thin films 
consisting of 30 mg followed by 30 mg]). 
To administer the 35 mg dose, study staff will administer the 20 mg sublingual thin film 
under the tongue first, and then after 3 minutes has elapsed, immediately administer the 
15 mg sublingual thin film for another 3 minutes (total dosing time should be 6 minutes). 
To administer the 40 mg dose, study staff will administer the 20 mg sublingual thin film 
under the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to 
consume approximately 1 teaspoon of water immediately prior to dosing the second 
20 mg dose, and staff will ensure the sublingual space is free of excess water. The second 
20 mg sublingual thin film will be administered under the tongue for another 3 minutes 
(total dosing time should be 6 minutes). To administer the 50 mg dose, study staff will 
administer the 25 mg sublingual thin film under the tongue first, and then after 3 minutes 
has elapsed, subjects will be instructed to consume approximately 1 teaspoon of water 
immediately prior to dosing the second 25 mg dose, and staff will ensure the sublingual 
space is free of excess water. The second 25 mg sublingual thin film will be administered 
under the tongue for another 3 minutes (total dosing time should be 6 minutes). To 
administer the 60 mg dose, study staff will administer the 30 mg sublingual thin film 
under the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to 
consume approximately 1 teaspoon of water immediately prior to dosing the second 30 
mg dose, and staff will ensure the sublingual space is free of excess water. The second 
30 mg sublingual thin film will be administered under the tongue for another 3 minutes 
(total dosing time should be 6 minutes). 
REFERENCE 
PRODUCT 
Matching Placebo APL-130277 
Moxifloxacin 400 mg 
TREATMENT 
REGIMENS 
Dose Titration starting at 10 mg APL-130277 will be administered in 5 mg increments up 
to 40 mg and then in 10 mg increments for the 50 mg and 60 mg dose levels until the 
subject reaches a full “ON” state and will continue titration for two additional visits to a 
maximum dose of 60 mg. This will be followed by a three-way balanced randomized 
crossover phase using the highest APL-130277 tolerated dose or matched placebo 
APL-130277, in a double-blind fashion, or treatment with open-label moxifloxacin. 
CONCOMITANT 
AND CO- 
ANALGESIC 
TREATMENT 
All subjects: stable doses of a L-Dopa formulation and other stable adjunctive PD 
medications. 
PROHIBITED 
TREATMENT 
• Any form of s.c. apomorphine from 7 days prior to the initial Screening Visit 
(SV1) until study completion. 
• Any selective 5HT3 antagonist (i.e., ondansetron, granisetron, dolasetron, 
palonosetron, alosetron) from 30 days prior to the initial Screening Visit (SV1) 
until study completion. 
• Dopamine antagonists (including Tigan [trimethobenzamide] and domperidone, 
but excluding quetiapine or clozapine) or dopamine depleting drugs. 
• Deep brain stimulation or other neurosurgical PD treatment, continuous s.c. 
apomorphine infusion, or Duodopa/Duopa. 


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• Any medication that can prolong QT. Refer to https://crediblemeds.org for listing. 
STUDY DURATION 
Participation is anticipated to be a maximum of 46 days. 
INVESTIGATIVE 
SITES OR 
COUNTRIES 
This is a multicenter study to be conducted at up to 10 sites in Europe and up to 20 sites 
in North America. 
STUDY ENDPOINTS 
Primary Endpoint 
1. Time-matched change from baseline in QTc, placebo-adjusted and corrected for 
HR based on the Fridericia correction method (QTcF) method (∆∆QTcF). Assay 
sensitivity will be demonstrated by inclusion of a positive control, moxifloxacin. 
Secondary Endpoints 
1. Pharmacokinetics of apomorphine and apomorphine metabolites. 
2. Evaluation of safety and tolerability of APL-130277 as measured by adverse 
events, physical examination including assessment of oropharyngeal adverse 
events, 12-lead ECGs, vital signs including orthostatic hypotension (OH), 
clinical laboratory tests, and C-SSRS assessments. 
3. ECG assessments including QTc with Bazett correction (QTcB), heart rate, PR 
interval, QRS interval, uncorrected QT interval, ECG morphology and presence 
of cardiac arrhythmias such as ventricular tachycardia or Torsade de 
Pointes (TdP). 
4. MDS-UPDRS Part III change from pre-dose to 30, 60, 90 minutes after dosing 
during the titration phase at the highest tolerated APL-130277 dose level and the 
lowest APL-130277 dose resulting in a full “ON”. 
5. Time to “ON” during Titration Phase at the highest tolerated APL-130277 dose 
level and the lowest APL-130277 dose resulting in a full “ON”. 
6. Duration of “ON” during Titration Phase at the highest tolerated APL--130277 
dose level and the lowest APL-130277 dose resulting in a full “ON”. 
 
STATISTICAL 
METHODS 
SUMMARY 
All subjects who receive at least one dose of study medicine `will be included in the 
safety analysis set. The PK analysis set includes all subjects with at least one PK 
evaluation. The efficacy analysis set includes subjects who have efficacy assessments at 
the lowest dose level resulting in a full “ON”. The super-efficacy analysis set includes 
subjects who have efficacy assessments at both the lowest dose that provides a full “ON”, 
the highest tolerated dose level during the Titration Phase. 
The evaluation of the ECG data is focused on the corrected QT interval (QTc). Both the 
formula by Bazett and by Fridericia will be used for the correction, though the Fridericia 
correction will be considered primary, and the Bazett correction data is presented for 
historical purposes. Both central tendency (mean changes from pre-dose) and outliers will 
be evaluated. 
Assay sensitivity will be demonstrated by evaluating the placebo corrected change from 
baseline for QTcF for the positive control, moxifloxacin, at predesignated timepoints. 
The pharmacokinetic parameters will be summarized with descriptive statistics for each 
dose level. 


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The safety data other than ECG (vital signs including orthostatic blood pressure, physical 
examinations including oral assessments, premature discontinuations, adverse events, 
C-SSRS, and safety laboratory variables) will be summarized with descriptive statistics 
for APL-130277 overall and separately for each dose level. 
The main efficacy endpoint of this study is the change in MDS-UPDRS Part III at 
30 minutes. The MDS-UPDRS Part III will be analyzed using a Mixed Model for 
Repeated Measures with data from the lowest dose level resulting in a full "ON" and at 
the highest tolerated dose level during the Titration Phase as response variables. The 
baseline (SV2) value will be included as a covariate and the day (1 = assessment at the 
lowest dose level resulting in a full “ON”, 2 = assessment at the highest tolerated dose 
level) and dose level (10 mg, 15 mg, 20 mg, …, 60 mg) as fixed factors in the model. 
Separate models will be used for each time point (30, 60 and 90 minutes). 
 
SAMPLE SIZE 
CALCULATION 
Forty-two (42) subjects will provide approximately 80% power to detect a mean 
difference of 7 ms in the change in QTc between APL-130277 and placebo, assuming 
that the true difference between APL-130277 and placebo can be up to 3 ms, (adding up 
to the predefined threshold of 10 ms) and a standard deviation of 14 ms 12 for ΔΔQTcF 
with one-sided significance level of 0.05. 
 


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4 
STUDY DESIGN FLOW CHART 
4.1 
Schedule of Events Table 
Procedures 
Screening Visits2 
Titration Visit 11 
Titration Visit 21 
Titration Visit 31, 15 
Titration Visit 41, 15 
Titration Visit 51, 15 
Titration Visit 61, 15 
Titration Visit 71 
Titration Visit 81 
Titration Visit 91 
Randomization Procedures16 
Period 1 Dosing Visit 
Period 2 Dosing Visit 
Period 3 Dosing visit 
End of Study  
Visit 
Study Visit 
SV1 
SV2 
TV1 
TV2 
TV3 
TV4 
TV5 
TV6 
TV7 
TV8 
TV9 
P1V1 
P2V2 
P3V3 
EOS 
Day  
-14 to -3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 
3 days 
after 
P1V1 
3 days 
after 
P2V2 
3-5 days 
after 
P3V3 
Maximum Study Duration 
(days) 
1 to 14 
15 to 28 
 
35 
38 
41 
44 to 46 
Outpatient Visit3 
X 
X 
X3 
X3 
X3 
X3 
X3 
X3 
X 
X 
X 
 
X 
X 
X 
X 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reconfirmation of Consent 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Review Entry Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Restriction Criteria 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Medical History/Demographics 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam, 
including Oropharyngeal 
Exam4 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated Physical Exam, 
including Oropharyngeal 
Exam5 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
BMI, Weight and Height6 
 
X2 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Vital Signs (BP, HR, RR and 
Temp)7, 8 
 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
12-Lead ECG (Holter)8, 9 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
12-Lead ECG (Resting)8, 10 
 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 


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Procedures 
Screening Visits2 
Titration Visit 11 
Titration Visit 21 
Titration Visit 31, 15 
Titration Visit 41, 15 
Titration Visit 51, 15 
Titration Visit 61, 15 
Titration Visit 71 
Titration Visit 81 
Titration Visit 91 
Randomization Procedures16 
Period 1 Dosing Visit 
Period 2 Dosing Visit 
Period 3 Dosing visit 
End of Study  
Visit 
Study Visit 
SV1 
SV2 
TV1 
TV2 
TV3 
TV4 
TV5 
TV6 
TV7 
TV8 
TV9 
P1V1 
P2V2 
P3V3 
EOS 
Day  
-14 to -3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 
3 days 
after 
P1V1 
3 days 
after 
P2V2 
3-5 days 
after 
P3V3 
Maximum Study Duration 
(days) 
1 to 14 
15 to 28 
 
35 
38 
41 
44 to 46 
Clinical Laboratory Tests11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PK8, 12 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
MMSE 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Hoehn and Yahr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MDS-UPDRS Part III8, 13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Confirmation of L-Dopa 
Responsiveness 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Confirmation of “OFF” 
or full “ON” 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Subject Confirmation of “OFF” 
or full “ON” 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Subject “OFF” versus “ON” 
Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-Clinic Dosing 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
AEs/Serious AEs (SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Previous/Current Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
C-SSRS14 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
1 Dosing days in the Dose Titration Phase should be scheduled the following business day of the previous visit and all visits must be completed within 14 days. 
A maximum of 2 days between visits may be permitted with Medical Monitor approval. 
2 All screening procedures to be conducted within 14 days prior to Titration Visit 1 (TV1). If required by the Investigator, and following receipt of subject 


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Version: 5.00 
consent, the Investigator may review the subjects’ medical history, BMI, height, weight, vital signs, 12-Lead ECG (in triplicate) and perform a complete 
physical examination at SV1 to determine if the subject may be eligible for study participation. Procedures performed on SV1 will not be repeated at SV2. 
3 Subjects may be monitored in the clinic overnight before Dose Titration Visits if such facilities exist and the subject consents. 
4 Physical examination to include the following: head-eyes-ears-nose and throat; respiratory system; cardiovascular system; gastrointestinal system, including 
mouth – oral cavity; musculoskeletal system; central and peripheral nervous system; and skin. The oropharyngeal cavity examination should include a visual 
inspection of the inside of each cheek, the inside of the upper and lower lip, the surface of the tongue, and under the tongue. 
5 Abbreviated 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 120 minutes 
after dosing at TV1 to TV9, Period 1, Period 2, and Period 3. The oropharyngeal cavity examination should include a visual inspection of the inside of each 
cheek, the inside of the upper and lower lip, the surface of the tongue, and under the tongue. 
6 Both height and weight captured at the Screening Visit (SV2) to calculate BMI; only weight captured at all other indicated visits. 
7 Vital signs will be assessed at the Screening Visit (SV2) and End of Study (EOS); TV1 to TV9 and during Period 1, 2 and 3 at t = 0 minutes (just prior to 
dosing), 15, 45 and 60 minutes. Blood pressure to be measured supine and standing (measured within 3 minutes of standing) at all timepoints. 
8 Suggested Sequence of Assessments at Pre-Dose: ECG – PK – Vitals – Efficacy. Sequence of Assessments after dosing (where applicable): MDS-UPDRS Part 
III - Subject “OFF”/”ON” status – ECG – PK – Vitals. 
9 12-lead ECG (Triplicate; Holter): Period 1: Obtain three (3) sets of triplicate ECGs over approximately 1-hour (prior to dosing) as the baseline assessment; and 
obtain triplicate ECG at t = 15, 30, 45, 60 minutes and 2, 3, 4, 8, 12, 24 hours after dosing. Period 2 and Period 3: Obtain triplicate ECG at t = 0 (just prior to 
dosing), 15, 30, 45, 60 minutes and 2, 3, 4, 8, 12, 24 hours after dosing.  
10 12-lead ECG (Single; Resting): Obtain at the Screening Visit in triplicate (SV2). TV1 to TV9: ECG at t = 0 (just prior to dosing) and 45 minutes after dosing. 
Period 1, Period 2 and Period 3 at 60 minutes after dosing. EOS:  A triplicate ECG will be obtained. ECGs will be assessed by the Investigator at each visit. 
11 Blood and urine collection for clinical laboratory tests will occur at Screening Visit (SV2) and at the End of Study Visit (EOS). In addition, serum pregnancy 
test will be performed on all females of childbearing potential. 
12 PK will be assessed for APL-130277 and placebo dosing days at t = 0 (just prior to dosing), 30, 45, 60 minutes and 2, 4 hours after dosing. PK will be assessed 
on the moxifloxacin dosing day at t = 0 (just prior to dosing), 30, 60 minutes and 2, 3, 4, 6, 8 hours after dosing. 
13 MDS-UPDRS Part III (Motor Function) to be assessed at t = 0 (just prior to dosing), 30, 60 and 90 minutes after L-Dopa administration at the second 
Screening Visit (SV2); the modified Hoehn and Yahr will be used during the Screening Visit (SV2). Assessments during the Titration Phase at t = 0 (just prior 
to dosing), 30, 60 and 90 minutes after dosing; these assessments will exclude the “Dyskinesia Impact on Part III Ratings” and the Hoehn and Yahr staging. 
14 “Screening” scale to be used at the Screening Visit (SV2); “Since Last Visit” to be used at all other visits. 
15 Optional Dosing Regimen:  For TV3, TV4, TV5 and TV6 only subjects can be dosed with the next highest dose of study medication within 4 hours of the 
previous dose, as long as the subject achieves another “OFF” state that day. 
16 Following completion of the Dose Titration Phase of the study, Sponsor approval is required prior to randomization in the Three-Way Balanced Crossover 
Phase. Additional details are available in the Enrollment and Randomization Adjudication Process, which is contained in a separate document. 


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Randomized to Highest APL-130277 
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Open-Label Titration Phase
APL-130277 Dose Titration
Moxifloxacin
Placebo Strip 
APL-130277
1 day
1 day
1 day
3 days
15 mg
20 mg
25 mg
30 mg
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Sunovion Pharmaceuticals Inc. 
 
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Version: 5.00 
4.3 
Titration Phase Dosing Paradigm 
 
 
“OFF”
20 mg 
“OFF”
Dose Titration Phase 
TV2 
15 or 20 or 
25 mg 
50 or 60 mg 
Full “ON” 
TV4 
“OFF” 
25 or 30 or 
35 mg 
Full “ON” 
30 mg 
35 mg 
20 mg 
25 mg 
Full “ON” 
60 mg 
60 mg 
TV9 
TV7 
TV6 
“OFF” 
35 or 40 or 
50 mg 
Full “ON” 
40 mg 
50 mg 
35 mg 
TV3 
“OFF” 
20 or 25 or 
30 mg 
Full “ON” 
30 mg 
25 mg 
Continue 2 Additional Titration 
Visits after Full “ON” State Has 
Been Achieved (if tolerated) 
TV1 
10 or 15 or 
20 mg 
Full “ON” 
Randomized to 
Highest dose of APL-
130277 Tolerated 
20 mg 
10 mg 
15 mg 
15 mg 
TV5 
“OFF” 
30 or 35 or 
40 mg 
Full “ON” 
30 mg 
40 mg 
25 mg 
40 or 50 or 
60 mg 
Full “ON” 
50 mg 
60 mg 
40 mg 
“OFF” 
TV8 
Full “ON” 
60 mg 
50 mg 
35 mg 
“OFF” 


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4.4 
Titration Phase Optional Dosing Regimen 
 


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5 
TABLE OF CONTENTS 
1 
EMERGENCY CONTACT INFORMATION ....................................................3 
2 
INVESTIGATOR APPROVAL STATEMENT ..................................................4 
3 
PROTOCOL SYNOPSIS ......................................................................................5 
4 
STUDY DESIGN FLOW CHART .....................................................................13 
4.1 
Schedule of Events Table.....................................................................................13 
4.2 
Study Design .........................................................................................................16 
4.3 
Titration Phase Dosing Paradigm ......................................................................17 
4.4 
Titration Phase Optional Dosing Regimen ........................................................18 
5 
TABLE OF CONTENTS .....................................................................................19 
6 
LIST OF ABBREVIATIONS ..............................................................................23 
7 
INTRODUCTION................................................................................................25 
7.1 
Background ..........................................................................................................25 
7.2 
Drug Substance ....................................................................................................26 
7.3 
Drug Product (APL-130277 Sublingual Film) ...................................................27 
7.4 
Clinical Experience ..............................................................................................29 
7.5 
Summary of Potential Risks and Benefits .........................................................30 
7.6 
Rationale ...............................................................................................................31 
8 
ETHICS ................................................................................................................32 
9 
OBJECTIVES AND STUDY ENDPOINTS ......................................................33 
9.1 
Objectives..............................................................................................................33 
9.2 
Study Endpoints ...................................................................................................33 
9.2.1 
Primary Endpoint ...................................................................................................33 
9.2.2 
Secondary Endpoints .............................................................................................33 
10.1 
General Overview ................................................................................................34 
10.1.1 
Screening Visits .....................................................................................................34 
10.1.2 
Dose Titration Phase ..............................................................................................34 
10.1.3 
Three-Way Balanced Randomized Crossover Assessment Phase: Period 1, 
Period 2, Period 3 ......................................................................................................................36 
10.1.4 
Enrollment Adjudication Committee (EAC) .........................................................36 
11 
PATIENT POPULATION ..................................................................................38 
11.1 
Selection of Study Population ..............................................................................38 
11.1.1 
Inclusion Criteria ...................................................................................................38 
11.1.2 
Exclusion Criteria ...................................................................................................39 
11.2 
Prior and Concomitant Treatments....................................................................41 
11.2.1 
Prohibited Treatments ............................................................................................41 
11.2.2 
Permitted Treatments .............................................................................................41 
11.3 
Subject Withdrawal from the Study ...................................................................42 


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12 
STUDY PROCEDURES ......................................................................................43 
12.1 
Screening Visits (SV1 and SV2) ..........................................................................43 
12.2 
Dose Titration Phase (TV1 to TV9) ....................................................................45 
12.3 
Three-Way Balanced Randomized Crossover Assessment Phase:  Period 1, 
Period 2, Period 3 .................................................................................................48 
12.3.1 
Double-Blind APL-130277 and Placebo Treatment Periods .................................48 
12.3.2 
Open-Label Moxifloxacin Treatment Period .........................................................50 
12.4 
End of Study Visit ................................................................................................51 
12.5 
Duration of Treatment .........................................................................................51 
12.6 
Assessments ..........................................................................................................52 
12.6.1 
Order of Assessments ............................................................................................52 
12.6.2 
Clinical Safety Assessments ..................................................................................52 
12.6.2.1 Physical Examinations ...........................................................................................52 
12.6.2.2 Vital Signs ..............................................................................................................53 
12.6.2.3 12-Lead ECG .........................................................................................................53 
12.6.2.4 Modified Hoehn and Yahr ......................................................................................54 
12.6.2.5 Mini-Mental State Examination .............................................................................54 
12.6.2.6 Clinical Laboratory Tests .......................................................................................55 
12.6.2.7 Specimen Handling Requirements ..........................................................................55 
12.6.2.8 C-SSRS ...................................................................................................................55 
12.6.2.9 Medical History .....................................................................................................56 
12.6.3 
Efficacy Assessments.............................................................................................56 
12.6.3.1 Confirmation of “OFF” or “ON” Episodes ..........................................................56 
12.6.3.2 MDS-UPDRS Part III ............................................................................................58 
12.6.3.3 Pharmacokinetic (PK) Evaluation .........................................................................58 
13 
ADVERSE EVENTS ............................................................................................59 
13.1.1 
Definition of Adverse Events .................................................................................59 
13.1.2 
Definition of Serious Adverse Events ....................................................................59 
13.1.3 
Definition of Severity .............................................................................................60 
13.1.4 
Definition of Start Date, Stop Date, and Duration .................................................60 
13.1.5 
Action(s) Taken .....................................................................................................60 
13.1.6 
Definition of Expectedness ....................................................................................61 
13.1.7 
Adverse Events of Special Interest ........................................................................61 
13.1.8 
Definition of Relationship to Investigational Drug(s) ............................................62 
13.1.9 
Definition of Outcome at the Time of Last Observation ........................................62 
13.1.10 
Documentation of Adverse Events .........................................................................63 
13.1.11 
Follow-up of Subjects With an Adverse Event.......................................................63 
13.1.12 
Special Procedures for Managing AEs/SAEs and Need for Unblinding ...............63 
13.1.13 
Notification of Serious Adverse Events .................................................................63 


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13.1.14 
Notification of Adverse Events of Special Interest ................................................65 
14 
TREATMENTS....................................................................................................66 
14.1 
Treatments Administered ....................................................................................66 
14.2 
Administration of Study Medication ..................................................................66 
14.3 
Storage ..................................................................................................................67 
14.4 
Packaging and Labeling ......................................................................................68 
14.5 
Drug Accountability .............................................................................................68 
14.6 
Method of Assigning Subjects to Treatment Groups ........................................69 
14.7 
ECG Methodology: Central Laboratory ...........................................................69 
14.8 
Randomization .....................................................................................................71 
14.9 
Blinding .................................................................................................................71 
15 
STATISTICAL ANALYSES ..............................................................................73 
15.1 
Statistical Analysis Plan ......................................................................................73 
15.2 
Analysis Populations ............................................................................................73 
15.2.1 
Safety Analysis Set ................................................................................................73 
15.2.2 
PK Analysis Set .....................................................................................................73 
15.2.3 
Efficacy Analysis Set .............................................................................................73 
15.2.4 
ECG and PK-PD Analysis Sets .............................................................................73 
15.3 
Sample Size Calculation ......................................................................................73 
15.4 
ECG and Concentration-QTc Effect Analysis ..................................................74 
15.4.1 
Primary Endpoint ...................................................................................................74 
15.4.2 
Secondary Endpoints .............................................................................................74 
15.4.3 
Central Tendency Analyses ...................................................................................74 
15.4.4 
Establishment of Assay Sensitivity ........................................................................75 
15.4.5 
Outlier Analyses.....................................................................................................75 
15.4.6 
Morphologic Analyses ...........................................................................................76 
15.4.7 
Pharmacokinetic-Pharmacodynamic Analyses ......................................................77 
15.4.8 
Safety Analysis ......................................................................................................77 
15.5 
Pharmacokinetic Analysis ...................................................................................78 
15.6 
Efficacy Analysis ..................................................................................................79 
16 
STUDY CONDUCT .............................................................................................80 
16.1 
Regulations and Guidelines .................................................................................80 
16.2 
Study Initiation .....................................................................................................80 
16.3 
Study Documentation ...........................................................................................81 
16.3.1 
Investigator’s Regulatory Documents ....................................................................81 
16.3.2 
Case Report Forms .................................................................................................81 
16.3.3 
Source Documents .................................................................................................82 
16.4 
Data Quality Assurance .......................................................................................83 
16.4.1 
Monitoring the Study .............................................................................................83 


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16.4.2 
Routine Data Collection .........................................................................................83 
16.4.3 
Expedited Data Collection .....................................................................................84 
16.4.4 
Data Management ..................................................................................................84 
16.4.5 
Study Termination ..................................................................................................84 
16.4.6 
Clinical Site Closure...............................................................................................84 
17 
GENERAL CONSIDERATIONS .......................................................................86 
17.1 
Changes to the Protocol .......................................................................................86 
17.2 
Use of Information and Publication....................................................................86 
17.3 
Records Retention ................................................................................................86 
17.4 
Sample Retention ..................................................................................................87 
17.5 
Subject Injury .......................................................................................................87 
18 
REFERENCES .....................................................................................................88 
19 
APPENDICES ......................................................................................................89 
19.1 
APPENDIX I: APOKYN® Prescribing Information and APO-go® Summary 
of Product Characteristics ..................................................................................89 
19.2 
APPENDIX II: Regulations and Guidelines ......................................................90 
19.2.1 
Declaration of Helsinki ..........................................................................................90 
19.2.2 
Approval by an IRB/REB/IEC ...............................................................................90 
19.2.3 
Regulatory Authority/Agency ................................................................................90 
19.3 
APPENDIX III: Modified Hoehn and Yahr Scale ............................................91 
19.4 
APPENDIX IV: Movement Disorder Society - Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) ...............................................................................92 
19.5 
APPENDIX V: Columbia Suicide Severity Rating Scale (C-SSRS) .............125
19.6 
APPENDIX VI: United Kingdom Parkinson’s Disease Brain Bank Clinical 
Diagnostic Criteria .............................................................................................132 
 


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6 
LIST OF ABBREVIATIONS 
5HT3 
5-hydroxy tryptophan (serotonin) 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
APO-go®  
apomorphine hydrochloride injection 
APOKYN® 
apomorphine hydrochloride injection 
API 
active pharmaceutical ingredients 
AUClast 
area under the concentration-time curve from time zero to the last 
measurable plasma concentration-time curve using the linear up log 
down trapezoidal rule. 
AUCinf 
area under the concentration-time curve from time zero extrapolated to 
infinity using the linear up log down trapezoidal rule. 
AST 
aspartate aminotransferase 
b.i.d. 
twice daily 
BLQ 
Below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed plasma concentration 
COMT 
Catechol O-methyltransferase 
CR 
chronic release 
CRA 
Clinical Research Associate 
CRF 
case report form 
CSA 
clinical study agreement 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV% 
coefficient of variation 
EAC 
enrollment adjudication committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized as Safe 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
L-Dopa 
L-3,4-dihydroxyphenylalanine or Levodopa 
LC-MS/MS 
liquid chromatography-tandem mass spectrometry 
λz 
terminal-phase rate constant 
MAO-B 
monoamine oxidase B  
MCH 
mean corpuscular hemoglobin 
MCHC 
MCH concentration 
MDS-UPDRS 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measurements 
MRT 
mean residence time 
MMSE 
Mini-Mental State Examination 
NYHA 
New York Heart Association 
OH 
Orthostatic Hypotension 
PD 
Parkinson’s disease 
PK 
pharmacokinetic 
PKAP 
pharmacokinetic analysis plan 
PMAP 
pharmacokinetic modeling analysis plan 
QTc 
Corrected QT interval 
RBC 
red blood cell 
REB 
Research Ethics Board 
RR 
respiratory rate 
SAE 
serious adverse event 
s.c. 
subcutaneous 
SD 
standard deviation 
SOP 
Standard Operating Procedure 
Sunovion 
Sunovion Pharmaceuticals Inc. 
t½ 
Terminal-phase half-life 
TdP 
Torsades de Pointes 
TEAE 
treatment emergent adverse events 
Temp 
temperature 
t.i.d. 
three times daily 
Tmax 
observed time of the maximum concentration 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 


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7 
INTRODUCTION 
7.1 
Background 
Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s 
disease. PD has a prevalence of approximately 0.5% to 1% among persons 65 to 69 years of age, 
rising to 1% to 3% among persons 80 years of age and older.1 The disease is characterized by 
progressive degeneration of the dopaminergic nigrostriatal system and depletion of dopamine, 
which results in the core motor symptoms of bradykinesia, rigidity, tremor, and postural 
instability.2 During the early stages of the disease, motor symptoms are well controlled with 
L-Dopa plus a dopamine decarboxylase inhibitors, dopamine agonists or MAO-B inhibitors. 
However, as the disease progresses, PD subjects develop motor complications which consist of 
dyskinesia and motor fluctuations. Motor fluctuations represent periods of “OFF” time and 
include wearing-“OFF”, delayed “ON” (if with first morning dose termed morning akinesia), 
unexpected “OFF” or “ON”/“OFF” fluctuations. These motor fluctuations can be either 
predictable or unpredictable. The mechanisms by which response fluctuations occur are only 
partially understood but are thought to include presynaptic neuronal degeneration leading to a 
lack of buffering of released L-Dopa, postsynaptic changes in dopamine receptor sensitivity and 
number, and pharmacokinetic and pharmacodynamic influences of exogenously administered 
dopaminergic agents.3,4 Fluctuations in plasma levels of L-Dopa occur due to the short half-life 
of L-Dopa and the unpredictable variability of gastric emptying. In general, approximately 40% 
of subjects with PD experience motor fluctuations and/or dyskinesias after 4 to 6 years of 
L-Dopa therapy, with close to 90% of subjects experiencing these symptoms after 9 or more 
years of treatment.5  
Predictable motor fluctuations (i.e. wearing-“OFF”) can be treated by increasing the dose or 
frequency of L-Dopa or by adding adjunctive PD medications (Catechol O-methyltransferase 
[COMT] inhibitors, MAO-B inhibitors, dopamine agonists). However, over time this becomes 
less effective. Treatment of unpredictable motor fluctuations (i.e. delayed “ON”, sudden “OFF”, 
“ON”/”OFF” fluctuations) is limited. Some subjects take oral L-Dopa immediate release as 
needed but this is of limited value as higher doses of L-Dopa can result in dyskinesia and 
perpetuates the development of further motor complications. The only approved treatment for 
acute management of “OFF” episodes in North America, Europe and Asia is apomorphine 
delivered subcutaneously (s.c.). Although efficacious, s.c. apomorphine has limited use due to its 
parenteral administration and since it may be difficult for a PD patient to deliver. There remains 
a huge unmet medical need for easy to administer, rapid, safe, effective and reliable rescue 
medications for the treatment of these “OFF” episodes in PD subjects. APL-130277, sublingually 
administered apomorphine, provides a more patient-friendly, easy to administer medication for 
the management of both predictable and unpredictable “OFF” episodes. 


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Apomorphine is a non-ergot dopamine agonist that binds to D1-like and D2-like receptors. First 
used as a treatment for PD as early as 1951, its clinical use was first reported in 1970 although its 
emetic properties and short half-life made oral use impractical. A later study found that 
combining the drug with 10 mg domperidone improved results significantly.6-10 
APOKYN® and APO-go® (apomorphine hydrochloride injection, see APPENDIX I: APOKYN® 
Prescribing Information and APO-go® Summary of Product Characteristics) are prescription 
medicines that reverses “OFF” episodes (end-of-dose wearing-“OFF” and unpredictable “ON”-
“OFF” episodes) associated with advancing PD. APOKYN®, which are indicated for the acute, 
intermittent treatment of hypomobility, “OFF” episodes associated with advanced PD, has been 
studied as an adjunct to other PD medications. Therapeutic use in PD is effective because of the 
drug's strong dopaminergic action. When administered subcutaneously, apomorphine is the most 
effective dopamine agonist. Within 3-20 minutes of injection, apomorphine demonstrates a 
magnitude of effect (ability to convert the patient with PD to the “ON” state) that is comparable 
to L-Dopa. The effects of a single s.c. injection last for 60 minutes. Apomorphine can be used in 
combination with L-Dopa. L-Dopa dosing may need to be readjusted (decreased) to reduce dopa-
induced dyskinesias periods.6-10 
Subcutaneous injection of apomorphine was developed to avoid first-pass metabolism as 
apomorphine is almost completely metabolized when delivered orally (between 1-2% of the total 
dose enters the bloodstream following oral administration). The total daily dose can range up to 
20-25 mg/daily. Domperidone, a peripheral dopamine antagonist, may be administered to avoid 
emesis, bradycardia and hypotension caused by apomorphine's peripheral dopaminergic action. 
Subjects on chronic apomorphine treatment may be able to discontinue domperidone 
co-administration after about 2 months without recurrence of the dopaminergic adverse effects of 
apomorphine. Domperidone is not available in the US, where trimethobenzamide is used. 
There is a small dose related prolongation of QTc interval with single doses of APOKYN®/APO-
go® greater than 6 mg (see APPENDIX I: APOKYN® Prescribing Information and APO-go® 
Summary of Product Characteristics). This study will evaluate the QT interval prolongation 
potential of APL-130277. 
7.2 
Drug Substance 
The active ingredient is apomorphine hydrochloride hemihydrate (C17H17NO2•HCl •½H2O(salt)). 
Apomorphine is synthesized from morphine, but it is not a narcotic, nor is it a controlled 
substance. Apomorphine hydrochloride appears as white or greyish-white glistening crystals or 
white powder. The R-enantiomer is used clinically. 
The drug substance, apomorphine hydrochloride hemihydrate, is manufactured by Sanofi-
Aventis. Apomorphine hydrochloride is manufactured from morphine monohydrate in the 
presence of orthophosphoric acid, ethyl acetate and hydrochloric acid. Purification is performed 


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in the presence of water, sodium chloride, sodium sulfite, ethyl acetate and silica gel. 
A summary of physico-chemical data are provided below: 
Active Pharmaceutical 
Ingredients (API) Common 
Name 
Apomorphine Hydrochloride Hemihydrate 
Production Site 
Manufacturer of Active Pharmaceutical Ingredient 
for Clinical Batches: 
Sanofi Aventis (Aramon Site) 
SANOFI CHIMIE 
Route d’Avignon 
30390 Aramon 
France 
IUPAC nomenclature 
4H-Dibenzo [de, g] quinoline-10, 11-diol, 5, 6, 6a, 
7-tetrahydro-6-methyl hydrochloride, hemihydrate 
Synonyms, common names 
Apomorphine hydrochloride, SR94013A, 6a,beta-
aporphine-10,11-diol hydrochloride 
CAS number 
41372-20-7 
Formula 
C17H17NO2•HCl•1/2H2O 
Molecular weight 
312.79 g/mol 
Specific Rotation 
-60.5o to -63.0o 
pKa 
pKa: 7.0, 8.9 
pH 
4.3 
Water solubility 
Sparingly soluble in water and alcohol; slightly 
soluble in chloroform  
7.3 
Drug Product (APL-130277 Sublingual Film) 
The product under development, APL-130277, is a soluble thin film for sublingual 
administration. APL-130277 is designed to deliver apomorphine systemically through absorption 
from the oral cavity mucosa, thus bypassing the extensive first pass metabolism associated with 
gastrointestinal absorption of the compound. The product is intended to be an alternative to the 
injectable form of apomorphine hydrochloride, which is marketed in North America as 
APOKYN® and in most of Europe and Asia as APO-go®. 
APL-130277 is manufactured for clinical studies as a bilayer thin film with one layer containing 
the active ingredient, apomorphine hydrochloride, and the other layer containing a buffer, 
pyridoxine. Dosage units of 10, 15, 20, 25, and 30 mg are achieved from a single formulation by 
cutting different sized rectangular thin films from sheets of bulk film as shown in the table 
below. Identifying marks are printed in white ink on the buffer (pyridoxine) side of the 


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sublingual thin film. 
APL-130277 Dose 
(mg) 
Length 
(mm) 
Width (mm) 
Area 
(mm2) 
Identifying 
Mark 
10 
22 
8.8 
193.6 
C1 
15 
22 
13.2 
290.4 
C2 
20 
22 
17.6 
387.2 
C3 
25 
22 
22 
484.0 
C4 
30 
22 
26.4 
580.8 
C5 
 
To administer the 35 mg dose, study staff will administer the 20 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, immediately administer the 15 mg 
sublingual thin film for another 3 minutes (total dosing time should be 6 minutes).  
To administer the 40 mg dose, study staff will administer the 20 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to consume 
approximately 1 teaspoon of water immediately prior to dosing the second 20 mg dose, and staff 
will ensure the sublingual space is free of excess water. The second 20 mg sublingual thin film 
will be administered under the tongue for another 3 minutes (total dosing time should be 
6 minutes). 
To administer the 50 mg dose, study staff will administer the 25 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to consume 
approximately 1 teaspoon of water immediately prior to dosing the second 25 mg dose, and staff 
will ensure the sublingual space is free of excess water. The second 25 mg sublingual thin film 
will be administered under the tongue for another 3 minutes (total dosing time should be 
6 minutes). 
To administer the 60 mg dose, study staff will administer the 30 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to consume 
approximately 1 teaspoon of water immediately prior to dosing the second 30 mg dose, and staff 
will ensure the sublingual space is free of excess water. The second 30 mg sublingual thin film 
will be administered under the tongue for another 3 minutes (total dosing time should be 
6 minutes). 
The APL-130277 finished drug product will be manufactured at ARx, LLC facilities at: 
400 Seaks Run Road Glen Rock, PA 17327, USA. 
The formulations for each of the dosage strengths have exactly the same proportions of active 
pharmaceutical ingredient and inactive excipients. 
The formulation consists of pharmaceutically acceptable cellulosic film formers along with 
glycerin as a plasticizer; and flavor, sweetener and colour additives for patient 


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acceptability. Other excipients include sodium hydroxide to modify pH and sodium metabisulfite 
as an antioxidant/preservative. The formulation also includes pyridoxine HCL as a buffer 
component. The excipients used in formulating APL-130277 sublingual thin films, are 
compendial (USP, NF or FCC) items and/or are Generally Recognized as Safe (GRAS) and/or 
have precedent for use in pharmaceutical products approved in the US. 
7.4 
Clinical Experience 
This is the twelfth planned in-man study for APL-130277. Previous studies CTH-101, CTH-102, 
CTH-103, CTH-104, CTH-106, CTH-107 and CTH-200 were performed in healthy volunteers in 
Malaysia, all at Info Kinetics. The first study completed in a PD patient population, CTH-105, 
was conducted at 4 sites in North America. CTH-203, CTH-300 and CTH-301, evaluating 
APL-130277 in a PD patient population, are being conducted and CTH-302 is planned for later 
this year. 
The healthy volunteer studies are summarized in considerable detail in the Investigator’s 
Brochure (IB). Adverse events were those expected to be seen with apomorphine, with the most 
common AEs being somnolence, dizziness and nausea. No dose limiting side effects were 
encountered and no subjects discontinued APL-130277 treatment due to an AE.  
The healthy volunteer studies confirmed the method of administration, allowed further 
refinement of the formulation and confirmed PK comparability of APL-130277 to s.c. 
apomorphine. The CTH-103 and CTH-104 PK study results demonstrated dose proportionality 
of the doses of APL-130277 tested (10 mg, 15 mg, 25 mg) and that the 25 mg dose is sustained 
over an extended period of time (162 minutes) above the minimal efficacious plasma 
concentration of apomorphine (approximately 3 ng/mL), believed to be a level demonstrating 
symptomatic relief of “OFF” symptoms. The Tmax for the 25 mg dose of APL-130277 was 
approximately 40 minutes, which was similar for the 10 mg and 15 mg doses of 
APL-130277. The rapid uptake of apomorphine in the APL-130277 sublingual thin film is 
comparable to that described in the s.c. apomorphine labels (i.e., between 10 and 60 minutes).  
The PD subjects dosed in CTH-105 (19 subjects) displayed similar side effects to that seen in 
healthy volunteers; the most common AEs (seen in 2 or more subjects) were dizziness, 
somnolence, nausea, yawning, headache and hyperhidrosis. Most of these AEs were mild to 
moderate in severity. There was no dose-response relationship seen with the most common AEs 
and no subjects discontinued due to an AE. Local irritation of the oral mucosa was monitored in 
the study and none was noted. 
The CTH-105 study demonstrated that APL-130277 provided rapid, clinically meaningful 
improvement in MDS-UPDRS Part III scores for PD subjects in the “OFF” state and converted 
most subjects from the “OFF” state to the “ON” state. Much of the benefit was sustained through 
90 minutes. A range of doses were utilized but over half of the subjects responded to the two 


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lowest doses (10 and 15 mg). 
The CTH-106 study results demonstrated that the orientation of the thin film does not have a 
meaningful impact on the bioavailability of apomorphine. 
In CTH-107 and CTH-200, similar AEs were seen as in the previous healthy volunteer studies, 
and study analysis is ongoing. 
7.5 
Summary of Potential Risks and Benefits 
APL-130277 
Given that APL-130277 uses the same active pharmaceutical ingredient (API) as APOKYN® and 
APO-go®, and the pharmacokinetic profile is comparable between the sublingual thin film and 
the s.c. injection, the risks associated with the drug will be the same as those seen in the 
APOKYN® and APO-go® Product Inserts (see APPENDIX I: APOKYN® Prescribing 
Information and APO-go® Summary of Product Characteristics), except for the significant 
injection site reactions. It is assumed that the bioavailability of APL-130277 will be consistent in 
CTH-201 with that found in previous experience with APL-130277 compared with APOKYN® 
and APO-go®. 
The buffer contained in the inactive layer of APL-130277 is designed to mitigate potential 
irritation of the oral mucosa seen in other buccal formulations of apomorphine as well as assist in 
maintaining a stable pH and optimal absorption kinetics. A preclinical hamster study 
demonstrated no evidence of microscopic or macroscopic irritation. No local irritation was noted 
in the CTH-105 study. In other ongoing clinical studies of APL-130277, non-serious AE reports 
of irritation of the oral mucosa have been received. Local irritation will be closely monitored 
throughout study participation. The goal of this development program, however, is to formulate a 
medication that provides the PD patient with an easier delivery system. We hypothesize that an 
orally available formulation will be easier to use, allow quicker control over predicted “OFF” 
periods, be more readily accessible to the patient when unpredicted “OFF” episodes occur during 
activities of daily living, and potentially be used by the milder PD patient when “OFF” episodes 
begin during the advancement of the disease. 
Moxifloxacin 
Moxifloxacin is an antibiotic belonging to the fluoroquinolones family and will be used as a 
reference product in this study. 
Changes in cardiac electrophysiology have been observed following exposure to moxifloxacin, 
in the form of QT prolongation and is therefore contraindicated in patients with: 
• Congenital or documented acquired QT prolongation; 
• Electrolyte disturbances, particularly in uncorrected hypokalaemia; 


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• Clinically relevant bradycardia; 
• Clinically relevant heart failure with reduced left-ventricular ejection fraction; 
• Previous history of symptomatic arrhythmias. 
The risk of cardiac abnormalities may increase with increased dose. There is a rare chance that 
patients may experience a severe, sudden allergic reaction (an anaphylactic reaction/shock) with 
the following symptoms: tightness in the chest, feeling dizzy, feeling sick or faint, or experience 
dizziness on standing. Moxifloxacin may cause inflammation of the liver, diarrhea (during or 
after taking this type of antibiotic), and may occasionally cause pain and inflammation of 
tendons. Quinolone antibiotics may make the patient's skin become more sensitive to sunlight or 
UV light. 
7.6 
Rationale 
This multi-center, Phase 2 study is designed to evaluate the QT interval prolongation potential of 
10 mg to 60 mg doses of APL-130277 compared to placebo and the positive control, 400 mg 
moxifloxacin in subjects with PD who experience motor fluctuations (“OFF” episodes).  
 


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8 
ETHICS 
This study will be conducted in compliance with the principles established by the World Medical 
Assembly in the Declaration of Helsinki - Ethical Principles for Medical Research Involving 
Human Subjects and all applicable amendments, the ICH Principles of Good Clinical Practice 
(GCP) (including archiving of essential study documents), and applicable regulatory 
requirements and guidelines. 
A properly constituted, valid Institutional Review Board (IRB) or Research Ethics Board (REB) 
or Independent Ethics Committee (IEC) must review and approve the protocol, each 
Investigator’s Informed Consent Form (ICF), and related subject information before the start of 
the study, and any subject recruitment material(s) before they are provided to subjects. During 
the Clinical Trial, any amendment or modification to the protocol should be submitted to the 
IRB/REB/IEC. The IRB/REB/IEC should also be informed of any event likely to affect the 
safety of subjects or the continued conduct of the study, in particular any changes in safety. All 
updates to the IB will be sent to the IRB/REB/IEC. 
It is the responsibility of each Investigator to ensure that written informed consent is obtained 
from the subject before any study activity or procedure is undertaken. 


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9 
OBJECTIVES AND STUDY ENDPOINTS 
9.1 
Objectives 
The primary objective is to evaluate the effect of APL-130277 compared to placebo on QTc 
intervals in subjects with Parkinson’s disease (PD) complicated by motor fluctuations. 
The secondary objectives include the evaluation of safety and pharmacokinetics of APL-130277 
and the comparison of efficacy of the highest tolerated dose level and the lowest APL-130277 
dose resulting in a full “ON” during the Dose Titration Phase. 
9.2 
Study Endpoints 
9.2.1 
Primary Endpoint 
1) Time-matched change from baseline in QTc, placebo-adjusted and corrected for HR based 
on the Fridericia correction method (QTcF) method (∆∆QTcF). Assay sensitivity will be 
demonstrated by inclusion of a positive control, moxifloxacin. 
9.2.2 
Secondary Endpoints 
1) Pharmacokinetics of apomorphine and apomorphine metabolites; 
2) Evaluation of safety and tolerability of APL-130277 as measured by adverse events, 
physical examination including assessment of oropharyngeal adverse events, 12-lead 
ECGs, vital signs including orthostatic hypotension (OH), clinical laboratory tests, and 
C-SSRS assessments; 
3) ECG assessments including QTc with Bazett correction (QTcB), heart rate, PR interval, 
QRS interval, uncorrected QT interval, ECG morphology and presence of cardiac 
arrhythmias such as ventricular tachycardia or Torsade de Pointes (TdP);  
4) MDS-UPDRS Part III change from pre-dose to 30, 60, 90 minutes after dosing during the 
Titration Phase at the highest tolerated APL-130277 dose level and the lowest 
APL-130277 dose resulting in a full “ON”; 
5) Time to “ON” during Titration Phase at the highest tolerated APL-130277 dose level and 
the lowest APL-130277 dose resulting in a full “ON”; 
6) Duration of “ON” during Titration Phase at the highest tolerated APL-130277 dose level 
and the lowest APL-130277 dose resulting in a full “ON”. 


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10 
STUDY DESIGN 
This is a multi-center, phase 2, randomized, double-blind, placebo controlled, 3-period 
crossover, positive control, QT-evaluation study of APL-130277 in subjects with PD 
complicated by motor fluctuations (“OFF” episodes). 
10.1 
General Overview 
This study will commence with initial Screening Visits, followed by an open-label Dose 
Titration Phase in which individual responses to single doses of APL-130277 are evaluated in 
order to determine the dose for the Randomized Assessment Phase. APL-130277 and placebo 
will be double-blinded and randomized in a balanced three-way crossover Williams design with 
open-label moxifloxacin treatment (Period 1, Period 2 and Period 3).11 
10.1.1 
Screening Visits 
Before any study procedures are performed on any subject, informed consent must be obtained at 
an initial Screening Visit (SV1). Subjects recruited to participate in the study, and who have 
provided full consent to participate, will be asked to attend a second Screening Visit (SV2), 
having taken their last dose of L-Dopa and any other adjunctive PD medication no later than 
midnight the evening prior to the visit. Their normal morning dose of L-Dopa (without 
adjunctive PD medication) will be administered in the clinic following confirmation of an “OFF” 
episode by the Investigator and subject, to ensure that they experience an “ON” response. 
Eligibility criteria will be assessed by the Investigator and approved by the Enrollment 
Authorization Committee (EAC) prior to enrollment. 
Subjects will be asked to return to the clinic the morning of Titration Visit 1 (TV1) to start the 
Dose Titration Phase of the study. 
If needed, the site will arrange subject transfers. Alternatively, subjects may be monitored in the 
clinic overnight to facilitate “OFF” evaluation the following morning if such facilities exist and 
the subject consents. These occurrences will not be considered a SAE. 
10.1.2 
Dose Titration Phase 
Depending on the Investigator's decision, subjects will be asked to arrive at the clinic: 
• after their usual morning dose of PD medications; but before taking their next dose of 
medication; OR 
• after withholding their normal morning dose of L-dopa (ie, in the practically defined 
"OFF" state with no anti-parkinsonian medication after midnight the night prior). 
During the Dose Titration Phase of the study, subjects will start with a dose of 10 mg 
APL-130277 and increase in 5 mg increments up to 40 mg and then in 10 mg increments for the 
50 mg and 60 mg dose levels until the subject reaches a full “ON” state. Once a full “ON” state 


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is achieved, dosing will continue for 2 additional visits to a maximum dose of 60 mg (i.e., if a 
subject experiences the first full “ON” at 10 mg, dosing will continue up until a dose of 20 mg). 
For those subjects who do not achieve a full "ON" response, titration should continue until the 
maximum tolerated dose of APL-130277 is determined. 
Note: For subjects who have previously participated in the CTH-300 or CTH-301 study, the 
subject will begin titration at the effective dose used in the respective previous study. Similarly 
dose titration of these subjects will increase in 5 mg increments up to 40 mg and then in 10 mg 
increments for the 50 mg and 60 mg dose levels until the subject reaches a full “ON” state. Once 
a full “ON” state is achieved, dosing will continue for 2 additional visits to a maximum dose of 
60 mg (i.e., if a subject experiences the first full “ON” at 35 mg, dosing will continue up until a 
dose of 50 mg). 
At Titration Visit 1 (TV1), once the subject's “OFF” state has been confirmed by both the 
Investigator and subject, the subject will be treated with 10 mg APL-130277. Subjects who 
tolerate the 10 mg APL-130277 will restart their normal PD medications and will be asked to 
return to the clinic the next business day for Titration Visit 2 (TV2), to assess the next highest 
dose (i.e., 15 mg) in a manner identical to that of Titration Visit 1 (TV1).  
Doses of APL-130277 will increase in 5 mg increments up to 40 mg and then in 10 mg 
increments for the 50 mg and 60 mg dose levels until a full “ON” state is achieved, then dosing 
will continue for 2 additional visits to a maximum dose of 60 mg. This will sequentially be 
20 mg (TV3), 25 mg (TV4), 30 mg (TV5), 35 mg (TV6), 40 mg (TV7), 50 mg (TV8) and 60 mg 
(TV9).  
For Titration Visit 3 (TV3), Titration Visit 4 (TV4), Titration Visit 5 (TV5) and Titration Visit 6 
(TV6) subjects should be dosed with the next highest dose of study medication within 4 hours of 
the dose, as long as the subject achieves another “OFF” that day. TV3 should be paired with TV4 
(20 mg and 25 mg can be dosed on the same day); TV4 should be paired with TV5 (25 mg and 
30 mg can be dosed on the same day), TV5 should be paired with TV6 (30 mg and 35 mg can be 
dosed on the same day) and TV6 should be paired with TV7 (35 mg and 40 mg can be dosed on 
the same day). 
Should the subject be unable to tolerate either of the two additional dose levels after reaching a 
full “ON” state, in the Investigator’s opinion, due to adverse events commonly associated with 
apomorphine (e.g., orthostatic hypotension, nausea, vomiting, etc.), subjects will be randomized 
to the previous dose. 
Dosing days in the Dose Titration Phase should be scheduled on consecutive business days and a 
maximum of 2 days between visits may be permitted with Medical Monitor approval. All visits 
in the Dose Titration Phase must be completed within 14 days. 
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10.1.3 
Three-Way Balanced Randomized Crossover Assessment Phase: Period 1, 
Period 2, Period 3 
Subjects who successfully complete the Dose Titration Phase of the study, and are approved by 
the Sponsor to proceed to randomization, will be asked to return to the clinic for Period 1 Dosing 
Visit 1 (P1V1). This visit will occur between 2 and 7 days after the final visit in the Dose 
Titration Phase of the study. Depending on the Investigator's decision, subjects will be asked to 
arrive at the clinic: 
• after their usual morning dose of PD medications; but before taking their next dose of 
medication; OR 
• after withholding their normal morning dose of L-dopa (ie, in the practically defined 
"OFF" state with no anti-parkinsonian medication after midnight the night prior). 
Subjects will be randomized in equal numbers to six possible sequences of each of the three 
treatments being studied:  
1. 
Treatment A: APL-130277 at the dose determined in the Dose Titration Phase, 
2. 
Treatment B: Matched placebo APL-130277, 
3. 
Treatment C: A single 400 mg dose of moxifloxacin. 
Following confirmation by both the Investigator and subject that the subject is in the “OFF” 
state, the subject will be dosed according to the subject's random treatment assignment. 
APL-130277 and placebo APL-130277 will be administered in a double-blind fashion and 
moxifloxacin will be administered open-label in a three-way balanced crossover. All subjects 
will be exposed to all three treatments. The six possible treatment sequences are: 1) ABC; 2) 
ACB; 3) BCA; 4) BAC; 5) CAB; and 6) CBA. 
Subjects will return to clinic 3 days after Period 1 and will be dosed for Period 2 with one of the 
other two treatments. 
Subjects will return to clinic 3 days after Period 2 and will be dosed for Period 3 with the third 
and last treatment. 
At the Period 1 Dosing Visit 1 (P1V1), three (3) sets of triplicate 12-Lead ECGs will be obtained 
using a continuous 12-lead Holter monitor over approximately 1-hour (prior to dosing) as the 
baseline assessment for analyses defined in Section 15.4.3. 
10.1.4 
Enrollment Adjudication Committee (EAC) 
The Investigator must obtain approval from the EAC and Sponsor prior to enrolling any subject 
into the study. The EAC will determine the subject’s appropriateness for inclusion in the study, 
independent of the entry criteria. The EAC will consult with the Medical Monitor, and the 
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The EAC review should be completed within 48 hours of submitting a request, and the 
Investigator will be informed of the decision. Following EAC/Sponsor approval, the final 
determination of eligibility for enrollment in the study will be made by the Investigator, who will 
then submit a request via the IWRS for enrollment into the Dose Titration Phase of the study. In 
case of refusal, the decision will be accompanied by a rationale. For additional details, please 
refer to the Enrollment and Randomization Adjudication Process, which is contained in a 
separate document. 
A dedicated charter will be developed in order to address the mode of operations of the EAC to 
ensure the integrity of the study will be protected. The communication from the EAC, 
documenting review and approval of the subject, will serve as EAC documentation for inclusion 
into the study and must be stored in the site study file. 


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11 
PATIENT POPULATION 
11.1 
Selection of Study Population 
A screening log of potential study candidates and an enrollment log of enrolled subjects must be 
maintained at each study site. 
The study will require forty-two (42) subjects to complete the 3-period, single dose crossover 
phase. Recruitment will continue until the required number of subjects completes the study. 
11.1.1 
Inclusion Criteria  
Subjects who meet each of the following criteria will be eligible for participation in the study: 
1) Male or female ≥ 18 years of age. 
2) Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria (excluding 
the “more than one affected relative” criterion). 
3) Clinically meaningful response to Levodopa (L-Dopa). Subjects with or without 
well-defined “OFF” episodes, as determined by the Investigator, will be allowed. 
4) Receiving stable doses of L-Dopa/carbidopa (immediate or sustained release) 
administered at least 3 times per day OR Rytary™ administered 3 times per day, for at 
least 4 weeks before the initial Screening Visit (SV1). Subjects receiving 
L-Dopa/carbidopa 3 times a day must also be on stable treatment with adjunctive PD 
medication regimens. These regimens must be maintained at a stable dose for at least 
4 weeks prior to the initial Screening Visit (SV1) with the exception that MAO-B 
inhibitors must be maintained at a stable level for at least 8 weeks prior to the initial 
Screening Visit (SV1). 
5) No planned medication change(s) or surgical intervention anticipated during the course of 
study. 
6) The subject must be able to have a drug withdrawal induced “OFF” episode. 
7) Stage III or less on the modified Hoehn and Yahr scale in the “ON” state. 
8) Mini–Mental State Examination (MMSE) score > 21. 
9) If female and of childbearing potential, must agree to use one of the following methods of 
birth control throughout the study and until at least 30 days after final drug administration: 
• Oral contraceptive; 
• Contraceptive patch; 
• Barrier (diaphragm, sponge or condom) plus spermicidal preparations; 


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• Intrauterine contraceptive system; 
• Levonorgestrel implant; 
• Medroxyprogesterone acetate contraceptive injection; 
• Complete abstinence from sexual intercourse; 
• Hormonal vaginal contraceptive ring; or 
• Surgical sterilization or partner sterile (must have documented proof). 
10) Male subjects must be either surgically sterile, agree to be sexually abstinent or use a 
barrier method of birth control (e.g., condom) from first study drug administration until at 
least 30 days after final drug administration. 
11) Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study-related procedures to complete the study. 
12) Able to understand the consent form, and to provide written informed consent. 
13) Must be approved as a satisfactory candidate by the Enrollment Authorization Committee 
(EAC) and the Sponsor. 
11.1.2 
Exclusion Criteria  
Subjects will be excluded from participation in the study for any of the following reasons: 
1) Atypical or secondary parkinsonism. 
2) Nausea associated with the use of dopamine agonists that requires treatment with an anti-
emetic. 
3) Previous treatment with any of the following: a neurosurgical procedure for PD; 
continuous subcutaneous (s.c.) apomorphine infusion; or Duodopa/Duopa. 
4) Treatment with any form of s.c. apomorphine within 7 days prior to the initial Screening 
Visit (SV1). Subjects that stopped s.c. apomorphine for any reason other than systemic 
safety concerns or lack of efficacy may be considered. 
5) Contraindications to moxifloxacin or APOKYN®, or hypersensitivity to apomorphine 
hydrochloride or any macrolide antibiotic or any of the ingredients of APOKYN® (notably 
sodium metabisulfite). 
6) Female who is pregnant or lactating. 
7) Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1), 
with the exception of clinical studies related to APL-130277. 
8) Receipt of any investigational (i.e., unapproved) medication within 30 days prior to the 
initial Screening Visit (SV1), with the exception of APL-130277. 


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9) Any selective 5HT3 antagonists (i.e., ondansetron, granisetron, dolasetron, palonosetron, 
alosetron), dopamine antagonists (including Tigan [trimethobenzamide] and domperidone, 
but excluding quetiapine or clozapine) or dopamine depleting agents within 30 days prior 
to initial Screening Visit (SV1). 
10) Drug or alcohol dependency in the past 12 months. 
11) Subject has a history of malignancy within 5 years prior to SV1, except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer. Pituitary tumors 
of any duration are excluded. 
12) Documented abnormalities with ECGs including, arrhythmias, clinically meaningful 
interval irregularities, structural heart abnormalities, myocardial infarction, presence or 
history of a pacemaker, or any abnormality of the ECG, that in the opinion of the 
Investigator, would interfere with the ability to measure the QT interval, or correct the QT 
interval for heart rate. 
13) Male subjects with a screening corrected QT interval using Fridericia’s formula (QTcF) of 
≥ 450 ms; female subjects with a screening QT interval ≥ 470 ms. Eligibility will be based 
on the core laboratory ECG interpretation report.  
14) HR at screening < 45 bpm or > 100 bpm. 
15) QRS duration at screening > 120 ms. 
16) PR interval at screening > 200 ms. 
17) Subjects with a history of cataplexy, unexplained syncope or seizures. 
18) Family history of sudden cardiac death. 
19) Heart failure (NYHA Class II or greater) and/or a myocardial infarction. 
20) Current use of any concomitant mediations that prolong the QT/QTc interval. Refer to 
https://crediblemeds.org for listing. 
21) History of additional risk factors for TdP (i.e., heart failure, hypokalemia, family history 
of Long QT Syndrome). 
22) Clinically significant medical, surgical, or laboratory abnormality in the opinion of the 
Investigator. 
23) Subject has a positive screening laboratory test result for human immunodeficiency virus 
(HIV). 
24) Subject has a positive screening laboratory test result for hepatitis B surface antigen or 
hepatitis C antibodies and has liver function test results at screening above the ULN for 
the reference laboratory. 


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25) Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, 
psychosis (including Parkinson’s disease psychosis), or any disorder that, in the opinion of 
the Investigator, requires ongoing treatment that would make study participation unsafe or 
make treatment compliance difficult. 
26) History of clinically significant impulse control disorder(s). 
27) Dementia that precludes providing informed consent or would interfere with participation 
in the study. 
28) Current suicidal ideation within one year prior to the second Screening Visit (SV2) as 
evidenced by answering “yes” to Questions 4 or 5 on the suicidal ideation portion of the 
Columbia-Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 
5 years. 
29) Donation of blood or plasma in the 30 days prior to first dosing. 
11.2 
Prior and Concomitant Treatments 
11.2.1 
Prohibited Treatments 
The following concomitant treatments will not be allowed during the course of this study: 
• Any form of s.c. apomorphine from 7 days prior to the initial Screening Visit (SV1) until 
study completion. 
• Any selective 5HT3 antagonist (i.e., ondansetron, granisetron, dolasetron, palonosetron, 
alosetron) from 30 days prior to the initial Screening Visit (SV1) until study completion. 
• Dopamine antagonists (including Tigan [trimethobenzamide] and domperidone, but 
excluding quetiapine or clozapine) or dopamine depleting drugs.  
• Deep brain stimulation or other neurosurgical procedure for the treatment of PD, 
continuous s.c. apomorphine infusion, or Duodopa/Duopa. 
• Any medication that can prolong QT. Refer to https://crediblemeds.org for listing. 
11.2.2 
Permitted Treatments 
The following concomitant treatments will be allowed during the course of the study: 
• Stable doses of an L-Dopa formulation with or without other stable adjunctive PD 
therapies (from at least 4 weeks prior to the initial Screening Visit (SV1), with no 
planned medication changes during the study). 
• Any other medication other than those identified in Section 11.2.1 are allowed, provided 
they are stable, with no planned medication changes scheduled during the study. Other 
therapies should only be administered as necessary for the treatment of the subject, at the 


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discretion of the Investigator. All concomitant medications must be recorded in the 
appropriate Case Report Form (CRF) for the subject. 
11.3 
Subject Withdrawal from the Study 
Subjects may be withdrawn from participating in this study for the following: 
1) If QT/QTc is > 500 ms and is an increase from screening of > 60 ms (to be confirmed by 
triplicate ECG). If a subject experiences an adverse event suggestive of torsade de pointes 
(TdP) the immediate management of TdP will be according to standard medical care as 
directed by the Investigator/primary care physician; 
2) In order to protect their safety and/or well-being; 
3) If they are unwilling or unable to comply with required study procedures; 
4) If they withdraw their consent to participate in the study; 
5) If the study is prematurely terminated by the Sponsor or Regulatory Authorities; 
6) If they no longer meet the inclusion/exclusion criteria within the study. 
Subjects will be advised that they are free to withdraw from the study at any time, for any reason, 
and without prejudice. Every reasonable and appropriate effort should be made by the 
Investigator to keep subjects in the study. However, subjects must be withdrawn from the study 
if the subject withdraws his or her consent to participate. In the event of subject withdrawal, the 
Investigator should attempt to determine the reason for the subject’s withdrawal. 
The reason for discontinuation and the date of withdrawal from the study will be recorded in the 
appropriate CRF. The Investigator should make at least 3 documented attempts to contact a 
subject who is lost to follow-up, with at least 1 attempt made by a certified letter. Documentation 
of contact attempts must be made in the subject’s record. 
Neither subjects withdrawing from the study nor those removed by the Investigator or Sponsor 
will be replaced. Subjects who are withdrawn from this study may not re-enter the study at a later 
date. The screening number for a withdrawn subject will not be reassigned to another subject. 
If a subject is removed or withdraws from the study, the procedures outlined in the EOS Visit 
will be performed, where possible. 


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12 
STUDY PROCEDURES 
This study will consist of the following: 
1) Screening Visits (SV1 and SV2) 
2) Dose Titration Phase 
a. Titration Visit 1 (TV1) 
b. Titration Visit 2 (TV2) 
c. Titration Visit 3 (TV3) 
d. Titration Visit 4 (TV4) 
e. Titration Visit 5 (TV5) 
f. Titration Visit 6 (TV6) 
g. Titration Visit 7 (TV7) 
h. Titration Visit 8 (TV8) 
i. Titration Visit 9 (TV9) 
3) Three-Way Balanced Randomized Crossover Assessment Phase 
a. Period 1 Dosing Visit (P1V1) 
b. Period 2 Dosing Visit (P2V2) 
c. Period 3 Dosing Visit (P3V3) 
4) End of Study Visit (EOS) 
12.1 
Screening Visits (SV1 and SV2)  
Subjects must sign an ICF before any screening-related procedures are performed at an initial 
Screening Visit (SV1). Following receipt of subject consent, the subject will be asked to return to 
the clinic for the second Screening Visit (SV2). All screening assessments must be performed 
within 14 days before Titration Visit 1 (TV1). 
If required by the Investigator, and following receipt of subject consent, the Investigator may 
review the subject’s medical history, BMI, height, weight, vital signs, ECGs and perform a 
complete physical examination at SV1 to determine if the subject may be eligible for study 
participation. If these assessments are done at SV1, the remaining procedures outlined below for 
SV2, including the assessment of L-Dopa responsiveness, will only be performed. 
The following procedures will be performed by study staff at SV2: 
• Reconfirm consent. 


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• Review inclusion/exclusion criteria. 
• Record demographics and detailed medical history, including review of medications 
taken within 6 months prior to the initial Screening Visit (SV1), current treatment 
regimens, drug, alcohol and smoking history. 
• Perform a complete physical examination, including an oropharyngeal examination. The 
oropharyngeal cavity examination should include a visual inspection of the inside of each 
cheek, the inside of the upper and lower lip, the surface of the tongue, and under the 
tongue. 
• Measure height and weight; calculate BMI. 
• Obtain a 12-lead ECG in triplicate using a resting ECG device for eligibility. Triplicate 
ECG should be completed within 5 minutes. ECGs will be centrally reviewed by the 
ECG laboratory and the result provided for eligibility. 
• Record vital signs (BP, HR, RR and Temp), after the subject has been in a supine 
position for 5 minutes. Subject BP to be measured both supine and standing (within 3 
minutes of standing). 
• Collect blood and urine sample for clinical laboratory tests (hematology, chemistry, 
urinalysis and serology). Serum pregnancy test for females of child-bearing potential 
only.  
• Assess suicidal ideation using C-SSRS (see APPENDIX V: Columbia Suicide Severity 
Rating Scale (C-SSRS)). The “Screening” scale should be used at this visit. 
• Perform a MMSE. 
• Assess subject using the Modified Hoehn and Yahr scale (see APPENDIX III: Modified 
Hoehn and Yahr Scale). 
• Assess subject motor function using MDS-UPDRS Part III at t = 0 (just prior to L-Dopa 
administration), 30, 60 and 90 minutes after L-Dopa administration (see APPENDIX IV: 
Movement 
Disorder 
Society 
- 
Unified 
Parkinson’s 
Disease 
Rating 
Scale 
(MDS-UPDRS). These assessments will exclude the “Dyskinesia Impact on Part III 
Ratings” and the Hoehn and Yahr staging. 
• Perform subject training in order to distinguish “OFF’ versus “ON” episodes (see 
Section 12.6.3.1). 
• Investigator confirmation of “OFF” or “ON”. The subject must be in an “OFF” state prior 
to dosing to ensure they experience an “ON” response. 
• Subject confirmation of “OFF” or “ON”. 


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• Confirm L-Dopa responsiveness. Subjects will take their normal dose of L-Dopa without 
their normal adjunctive PD medication. 
• Record any AEs/SAEs that have occurred after the informed consent was obtained. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
• Subject inclusion into the study to be approved by the EAC. 
The Investigator will review all information obtained from the screening procedures. If the 
subject is not eligible, the subject will be a screening failure and will not attend any other visits. 
Subjects who fulfill all entry criteria will be found eligible to participate in the trial and an 
appointment for Titration Visit 1 (TV1) will be made. 
Eligible subjects will be asked to return to the clinic the morning of Titration Visit 1 (TV1) to 
start the Dose Titration Phase of the study. 
12.2 
Dose Titration Phase (TV1 to TV9) 
Depending on the Investigator's decision, subjects will be asked to arrive at the clinic: 
• after their usual morning dose of PD medications; but before taking their next dose of 
medication; OR 
• after withholding their normal morning dose of L-dopa (ie, in the practically defined 
"OFF" state with no anti-parkinsonian medication after midnight the night prior). 
Once the subject's “OFF” state has been confirmed by both the Investigator and subject, the 
subject will be treated with 10 mg APL-130277 (TV1). Subjects who tolerate the 10 mg 
APL-130277 will restart their normal PD medication and will be asked to return to the clinic the 
next business day for Titration Visit 2 (TV2) to assess the next highest dose in a manner identical 
to that of TV1. 
During the Dose Titration Phase of the study, subjects will start with 10 mg and increase in 5 mg 
increments up to 40 mg and in 10 mg increments for the 50 mg and 60 mg dose levels until the 
subject reaches a full “ON” state. Once a full “ON” state is achieved, dosing will continue for 
2 additional visits to a maximum dose of 60 mg (e.g., if a subject experiences the first full “ON” 
at 10 mg, dosing will continue up until a dose of 20 mg). Dosing days in the Dose Titration 
Phase should be scheduled the next business day after the previous visit and must be completed 
within 14 days. 
• Titration Visit 1 (TV1) – 10 mg APL-130277; 
• Titration Visit 2 (TV2) – 15 mg APL-130277; 
• Titration Visit 3 (TV3) – 20 mg APL-130277; 


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• Titration Visit 4 (TV4) – 25 mg APL-130277; 
• Titration Visit 5 (TV5) – 30 mg APL-130277; 
• Titration Visit 6 (TV6) – 35 mg APL-130277 (20 mg sublingual thin film under the 
tongue for 3 minutes before placing the second 15 mg sublingual thin film, sequentially 
for another 3 minutes [total dosing time should be 6 minutes]); 
• Titration Visit 7 (TV7) - 40 mg APL-130277 (20 mg sublingual thin film under the 
tongue for 3 minutes before placing the second 20 mg sublingual thin film, sequentially 
for another 3 minutes [total dosing time should be 6 minutes]); 
• Titration Visit 8 (TV8) - 50 mg APL-130277 (25 mg sublingual thin film under the 
tongue for 3 minutes before placing the second 25 mg sublingual thin film, sequentially 
for another 3 minutes [total dosing time should be 6 minutes]); 
• Titration Visit 9 (TV9) - 60 mg APL-130277 (30 mg sublingual thin film under the 
tongue for 3 minutes before placing the second 30 mg sublingual thin film, sequentially 
for another 3 minutes [total dosing time should be 6 minutes]). 
For Titration Visit 3 (TV3), Titration Visit 4 (TV4), Titration Visit 5 (TV5) and Titration Visit 6 
(TV6) only, subjects can be dosed with the next highest dose of study medication within 4 hours 
of the initial dose, as long as the subject achieves another “OFF” state that day. 
• TV3 should be paired with TV4 (20 mg and 25 mg can be dosed on the same day);  
• TV4 should be paired with TV5 (25 mg and 30 mg can be dosed on the same day)  
• TV5 should be paired with TV6 (30 mg and 35 mg can be dosed on the same day). 
• TV6 should be paired with TV7 (35 mg and 40 mg can be dosed on the same day). 
After reaching a full “ON” state, the subject will continue with the next two Titration Visits. 
Should the subject be unable to tolerate one of the two additional dose levels after reaching a full 
“ON” state, in the Investigator’s opinion, due to adverse events commonly associated with 
apomorphine (e.g., orthostatic hypotension, nausea, vomiting, etc.), subjects will be randomized 
to the previous dose. 
Study staff will perform the following procedures at each Titration Visit: 
• Reconfirm consent. 
• Review restriction criteria. 
• Perform an abbreviated physical examination, including oropharyngeal examination at 
t = 0 (just prior to dosing) and 120 minutes after dosing at TV1 to TV9. The 
oropharyngeal cavity examination should include a visual inspection of the inside of each 
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tongue. 
• Single 12-lead ECG will be obtained using a resting ECG device at t = 0 (just prior to 
dosing) and 45 minutes after dosing as a safety evaluation; assessment by the 
Investigator/ECG qualified person to be completed at the visit. 
• Record vital signs (BP, HR, RR and Temp) at t = 0 minutes (just prior to dosing), 15, 45 
and 60 minutes after dosing. Blood pressure to be measured both supine and standing 
(measured within 3 minutes of standing). 
• Assess subject motor function using MDS-UPDRS Part III at t = 0 (just prior to dosing), 
30, 60 and 90 minutes after dosing (see APPENDIX IV: Movement Disorder Society - 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)). These assessments will 
exclude the “Dyskinesia Impact on Part III Ratings” and the Hoehn and Yahr staging. 
• Investigator confirmation of “OFF” or “ON”. The subject must be in an “OFF” state prior 
to dosing in order to proceed with dosing. Investigator will assess “OFF”/”ON” state as 
part of the MDS-UPDRS Part III assessments. 
• Subject confirmation of “OFF” or “ON”. The subject must be in an “OFF” state prior to 
dosing in order to proceed with dosing. 
• When subject is in the “OFF” state, dose with APL-130277. 
• Subject will report the time when they turned to a full “ON” (if applicable) and report the 
time when they turned “OFF” following dosing (if it occurs within 90 minutes of dosing). 
• Record any AEs/SAEs that have occurred since the last visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
• Assess suicidal ideation using C-SSRS (see APPENDIX V: Columbia Suicide Severity 
Rating Scale (C-SSRS)). The “Since Last Visit” scale should be used at this visit. 
• Subject inclusion into the Crossover Phase to be approved by Sponsor prior to 
Randomization. 
If in the opinion of the Investigator the subject can no longer tolerate the “OFF” state at any 
point during the visit, the subject may receive rescue L-Dopa (± other adjunctive PD medication) 
at a dosage considered appropriate by the Investigator to achieve a full “ON” state. Where 
possible, administration of rescue L-Dopa should be delayed until after the 60 minute efficacy 
assessments are complete. 
If the subject receives rescue L-Dopa (± other adjunctive PD medication) as described above, 
subjects can return to the clinic on another day to resume the titration with the next highest dose. 


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12.3 
Three-Way Balanced Randomized Crossover Assessment Phase:  Period 1, Period 2, 
Period 3 
Subjects who successfully completed the Dose Titration Phase will be asked to return to the 
clinic for Period 1 Dosing Visit 1 (P1V1). This visit will occur between 2 and 7 days after the 
final visit in the Dose Titration Phase of the study. Depending on the Investigator's decision, 
subjects will be asked to arrive at the clinic: 
• after their usual morning dose of PD medications; but before taking their next dose of 
medication; OR 
• after withholding their normal morning dose of L-dopa (ie, in the practically defined 
"OFF" state with no anti-parkinsonian medication after midnight the night prior). 
Following confirmation by both the Investigator and subject that the subject is in the “OFF” 
state, the subject will be randomized using the Williams design. Subjects will be randomized in 
equal numbers to six possible sequences of each of the three treatments being studied:  
1. 
Treatment A: APL-130277 at the dose determined in the Dose Titration Phase, 
2. 
Treatment B: Matched placebo APL-130277, 
3. 
Treatment C: A single 400 mg dose of moxifloxacin. 
APL-130277 and placebo will be administered in a double-blind fashion and moxifloxacin will 
be administered open-label in a three-way balanced crossover. All subjects will be exposed to all 
three treatments. The six possible treatment sequences are: 1) ABC; 2) ACB; 3) BCA; 4) BAC; 
5) CAB; and 6) CBA. In Period 1, regardless of the randomized treatment assignment, the 
baseline ECG will be obtained over approximately 1-hour (prior to dosing) using a Holter 
monitor device. Three (3) sets of triplicate 12-lead ECGs will be used as the baseline assessment 
for analyses as defined in Section 15.4.3. Triplicate 12-lead ECGs will also be obtained at t = 15, 
30, 45, 60 minutes after dosing and at 2, 3, 4, 8, 12, 24 hours after dosing. 
Subjects will return to clinic 3 days after Period 1 and will be dosed for Period 2 with one of the 
other two treatments. 
Subjects will return to clinic 3 days after Period 2 and will be dosed for Period 3 with the third 
and last treatment. 
12.3.1 
Double-Blind APL-130277 and Placebo Treatment Periods 
The following procedures will take place at these visits except where explicitly noted: 
• Reconfirm consent. 
• Review restriction criteria. 
• Perform an abbreviated physical examination, including oropharyngeal examination at 


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t = 0 (just prior to dosing) and 120 minutes after dosing. The oropharyngeal cavity 
examination should include a visual inspection of the inside of each cheek, the inside of 
the upper and lower lip, the surface of the tongue, and under the tongue. 
• Measure body weight. 
• Triplicate 12-lead ECG will be obtained using a Holter monitor device at t = 0 (just prior 
to dosing), 15, 30, 45, 60 minutes after dosing and at 2, 3, 4, 8, 12, 24 hours after dosing. 
If the treatment is administered in Period 1, t = 0 will be omitted and replaced by the 
baseline ECG baseline assessment described above in Section 12.3. 
• A single 12-lead ECG will be obtained using a resting ECG device 60 minutes after 
dosing as a safety evaluation; assessment by the Investigator/ECG qualified person to be 
completed at the visit. 
• Record vital signs (BP, HR, RR and Temp) at t = 0 minutes (just prior to dosing), and at 
15, 45 and 60 minutes after dosing. Blood pressure to be measured both supine and 
standing (measured within 3 minutes of standing). 
• Collection and processing of blood samples for PK assessment will occur at the following 
time points: t = 0 (just prior to dosing), 30, 45, 60 minutes after dosing and at 2, 4 hours 
after dosing. 
• Investigator confirmation of “OFF” or “ON”. The subject must be in an “OFF” state prior 
to dosing in order to proceed with dosing. 
• Subject confirmation of “OFF” or “ON”. The subject must be in an “OFF” state prior to 
dosing in order to proceed with dosing. 
• When subject is in the “OFF” state, proceed with dosing according to the randomization 
scheme. 
• Record any AEs/SAEs that have occurred since the last visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
• Assess suicidal ideation using C-SSRS (see APPENDIX V: Columbia Suicide Severity 
Rating Scale (C-SSRS)). The “Since Last Visit” scale should be used at this visit. 
If in the opinion of the Investigator the subject can no longer tolerate the “OFF” state at any 
point during the visit, the subject may receive rescue L-Dopa (± other adjunctive PD medication) 
at a dosage considered appropriate by the Investigator to achieve a full “ON” state. Where 
possible, administration of rescue L-Dopa should be delayed until 120 minutes after dosing. 


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12.3.2 
Open-Label Moxifloxacin Treatment Period 
The following procedures will be conducted at this visit except where explicitly noted: 
• Reconfirm consent. 
• Review restriction criteria. 
• Perform an abbreviated physical examination, including oropharyngeal examination at 
t = 0 (just prior to dosing) and 120 minutes after dosing. The oropharyngeal cavity 
examination should include a visual inspection of the inside of each cheek, the inside of 
the upper and lower lip, the surface of the tongue, and under the tongue. 
• Measure body weight. 
• Triplicate 12-lead ECG will be obtained using a Holter monitor device at t = 0 (just prior 
to dosing), 15, 30, 45, 60 minutes after dosing and at 2, 3, 4, 8, 12, 24 hours after dosing. 
If the treatment is administered in Period 1, t = 0 will be omitted and replaced by the 
baseline ECG baseline assessment described above in Section 12.3. 
• A single 12-lead ECG will be obtained using a resting ECG device 60 minutes after 
dosing as a safety evaluation; assessment by the Investigator/ECG qualified person to be 
completed at the visit. 
• Record vital signs (BP, HR, RR and Temp) at t = 0 minutes (just prior to dosing), 15, 45 
and 60 minutes after dosing. Blood pressure to be measured both supine and standing 
(measured within 3 minutes of standing). 
• Collection and processing of blood samples for PK assessment will occur at the following 
time points: t = 0 (just prior to dosing), 30, 60 minutes after dosing and at 2, 3, 4, 6, 
8 hours after dosing. 
• Investigator confirmation of “OFF” or “ON”. The subject must be in an “OFF” state prior 
to dosing in order to proceed with dosing. 
• Subject confirmation of “OFF” or “ON”. The subject must be in an “OFF” state prior to 
dosing in order to proceed with dosing. 
• When subject is in the “OFF” state, dose with 400 mg moxifloxacin. 
• Record any AEs/SAEs that have occurred since the last visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
• Assess suicidal ideation using C-SSRS (see APPENDIX V: Columbia Suicide Severity 
Rating Scale (C-SSRS)). The “Since Last Visit” scale should be used at this visit. 


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If in the opinion of the Investigator the subject can no longer tolerate the “OFF” state at any 
point during the visit, the subject may receive rescue L-Dopa (± other adjunctive PD medication) 
at a dosage considered appropriate by the Investigator to achieve a full “ON” state. Where 
possible, administration of rescue L-Dopa should be delayed until 120 minutes after dosing. 
12.4 
End of Study Visit 
Approximately 7 days following the completion of the study (after P3V3), subjects will be asked 
to return to the clinic for a final safety assessment visit. The following procedures will take place 
at this visit: 
• Reconfirm consent. 
• Perform a complete physical examination, including an oropharyngeal examination. The 
oropharyngeal cavity examination should include a visual inspection of the inside of each 
cheek, the inside of the upper and lower lip, the surface of the tongue, and under the 
tongue. 
• Measure body weight. 
• Triplicate 12-lead ECG will be obtained using a resting ECG device. Triplicate ECG 
should be completed within 5 minutes; assessment by the Investigator/ECG qualified 
person to be completed at the visit. 
• Record vital signs (BP, HR, RR and Temp), after the subject has been in a supine 
position for 5 minutes. Subject BP to be measured both supine and standing (within 
3 minutes of standing). 
• Collect blood and urine sample for clinical laboratory tests (hematology, chemistry, 
urinalysis). Serum pregnancy test for females of child-bearing potential only. 
• Assess suicidal ideation using C-SSRS (see APPENDIX V: Columbia Suicide Severity 
Rating Scale (C-SSRS)). The “Since Last Visit” scale should be used at this visit. 
• Record any AEs/SAEs that have occurred since the last visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.5 
Duration of Treatment 
Subject participation in this study from Screening until final study completion is anticipated to be 
a maximum of 46 days. 


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12.6 
Assessments 
12.6.1 
Order of Assessments 
The following summarizes the suggested sequence of assessments prior to dosing during SV2, 
Dose Titration Phase and Periods 1, 2, and 3 of the study: 
ECG – PK – Vitals – Efficacy  
The following summarizes the suggested sequence of assessments after dosing during Dose 
Titration Phase and Periods 1, 2, and 3 of the study: 
MDS-UPDRS Part III - Subject “OFF”/”ON” status – ECG – PK – Vitals  
In the event the completion of the MDS-UPDRS Part III at a previous timepoint conflicts with 
other assessments that are scheduled, priority should be given to completing the MDS-UPDRS 
Part III first before conducting the remaining assessments. 
12.6.2 
Clinical Safety Assessments 
12.6.2.1 Physical Examinations 
Complete physical examinations at all scheduled timepoints must include the following: head-
eyes-ears-nose and throat; respiratory system; cardiovascular system; gastrointestinal system, 
including the oral cavity (and oropharyngeal cavity examination); musculoskeletal system; 
central and peripheral nervous system; and skin; to be done at the second Screening Visit (SV2) 
and End of Study (EOS) Visit. 
Abbreviated physical examinations at all scheduled timepoints must include head-eyes-ears-nose 
and throat; heart, lungs; abdomen; oropharyngeal cavity examination; and skin; to be done at 
t = 0 (just prior to dosing) and 120 minutes after dosing at visits TV1 to TV9, Period 1, Period 2, 
and Period 3. 
All physical examinations performed in this study, whether complete or abbreviated, will include 
an oropharyngeal cavity examination by the Investigator (or designate trained to perform this 
examination) and will include a visual inspection of the inside of each cheek, the inside of the 
upper and lower lip, the surface of the tongue, and under the tongue. Each location within the 
oropharyngeal examination will be scored and graded as follows: 
• Finding 
o None 
o Focal reddening 
o Multiple foci of reddening 
o Edema 
o Ulceration 


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• Grade 
o Mild 
o Moderate 
o Severe 
All abnormal findings at baseline will be recorded on the Medical History/Concomitant 
Diagnoses page (or equivalent) of the CRF. New abnormal findings or a worsening of baseline 
conditions detected at follow-up physical examinations will be recorded as AEs on the CRF. 
The Investigator (or designate) should evaluate each finding against AE criteria and complete the 
AE CRF, as appropriate. Photographs for reference may be taken by the Investigator (or 
designate) provided the subject provides consent to do so. 
12.6.2.2 Vital Signs 
Vital signs (HR, RR, BP and body temperature) will be measured at various timepoints after the 
subject has been in a supine position for 5 minutes. Vital signs will be measured at t = 0 (just 
prior to dosing), 15, 45, 60 minutes after dosing at all scheduled study visits. Vital signs (BP 
only) will also be measured within three minutes of standing at all timepoints. The same arm 
should be used during each assessment of BP and HR. If the subject is unable to stand due to 
orthostatic symptoms such as light-headedness, dizziness, or changes in sensorium upon 
standing, every attempt should be made to obtain BP and HR in the sitting position. 
Study personnel will carefully monitor subjects for signs of OH; defined as: 
• a systolic BP decrease of ≥ 20 mmHg within three minutes of standing up from a supine 
position; and/or 
• a diastolic BP decrease of ≥ 10 mmHg within three minutes of standing up from a supine 
position. 
12.6.2.3 12-Lead ECG 
12-lead ECGs will be performed as outlined in the protocol using two modalities, a continuous 
Holter monitor and a resting ECG device. Detailed instructions will be provided to study staff 
and subjects. 
12-lead Holter Monitor:  At the Period 1 Dosing Visit 1 (P1V1), three (3) sets of triplicate 
12-lead ECGs will be obtained over approximately 1-hour (prior to dosing) as the baseline 
assessment for analyses defined in Section 15.4.3. Triplicate 12-lead ECGs will also be obtained 
at t = 15, 30, 45, 60 minutes after dosing and at 2, 3, 4, 8, 12, 24 hours after dosing. In Period 2 
and Period 3, triplicate 12-lead ECG will be obtained at t = 0, 15, 30, 45, 60 minutes and at 2, 3, 
4, 8, 12, 24 hours after dosing. At each ECG extraction time points the subject must have 
rested in the supine position for 10 minutes prior to the nominal timepoint and 10 minutes 


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after. 
ECGs obtained using the continuous Holter monitor will be sent directly to the central core ECG 
laboratory contracted by the Sponsor and/or its designate. The Holter monitor results will not be 
provided to the site. 
Resting ECG Device:  At Screening Visit 2 (SV2) a triplicate 12-lead ECG will be obtained. 
Triplicate ECG should be completed with 5 minutes. The screening ECG will be centrally 
reviewed by the ECG Laboratory and the result provided for eligibility. 
At each Titration Visit, a single 12-lead ECG will be performed at t = 0 (just prior to dosing) and 
45 minutes after dosing. In Period 1, Period 2 and Period 3, a single ECG will be performed at 
t = 60 minutes after dosing. At the End of Study Visit (EOS), a triplicate 12-lead ECG will be 
obtained. 
ECGs obtained using a resting ECG device will be used as a safety evaluation and assessed by 
the Investigator/ECG qualified person at each visit. 
The following parameters will be reported in the CRF based on the safety ECGs: 
• Heart rate 
• PR interval 
• QRS interval 
• RR interval 
• QT interval 
• QTc Interval (Fridericia’s correction) 
• QTc Interval (Bazett’s correction) 
All safety ECGs should be assessed by the Investigator and deemed “Normal”, “Abnormal, not 
clinically significant” or “Abnormal, clinically significant”. Abnormal readings that, in the 
opinion of the Investigator are deemed clinically significant should be reported as AEs on the 
appropriate CRF page. 
12.6.2.4 Modified Hoehn and Yahr 
The Modified Hoehn and Yahr scale will be administered at the second Screening Visit (SV2) to 
verify subjects meet the eligibility criteria for this study. This will be conducted in the “ON” 
state. 
12.6.2.5 Mini-Mental State Examination 
Mini-Mental State Examination (MMSE) is used to evaluate a person’s cognitive and mental 
function and will be administered at the second Screening Visit (SV2) to verify subjects meet the 


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eligibility criteria for this study. 
12.6.2.6 Clinical Laboratory Tests 
The following clinical laboratory test samples will be collected where documented: 
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, vitamin B6. 
Serum pregnancy test will be performed on all females of child-
bearing potential only. 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones.  
Serology (at the 
Screening Visit only): 
Human immunodeficiency virus (HIV), Hepatitis B surface antigen, 
Hepatitis C antibodies. 
12.6.2.7 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all personnel involved in the drawing of blood and the handling of specimens in 
both the clinic and laboratory settings. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and 
shipping of infectious samples may be outlined in the study Laboratory Manual. It is the 
responsibility of the Investigator to ensure all study samples that are to be transported to another 
location are appropriately packed and shipped according to the applicable regulations. 
Blood and urine samples for hematology, serum chemistry, urinalysis, and serology will be sent 
to a central laboratory for analyses. Please see the Laboratory Manual for details. 
12.6.2.8 C-SSRS 
Formal assessments of subject suicidal ideation and behavior will be assessed at the second 
Screening Visit (SV2) and all following visits through to the End of Study (EOS). A final 
assessment will be performed at the time of termination, regardless if it is scheduled (i.e., at 
EOS) or an early termination/withdrawal. 


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At SV2 the C-SSRS ‘Screening’ assessment tool will be used. Subjects who answer ‘Yes’ to 
Questions 4 and 5 at this Visit should be excluded from participation in the study. All subsequent 
evaluations will utilize the C-SSRS ‘Since Last Visit’ assessment. 
12.6.2.9 Medical History 
At the Screening Visit (SV2), the Investigator (or designate) will review the subject’s medical 
history in order to ascertain the subject’s eligibility. The medical history should assess the 
subject’s current PD medications, including medication name, dose, number of tablets per dose 
(if applicable), dosage units and frequency per day. 
The medical history assessment will include a detailed assessment of the subjects PD history, 
including, but not limited to: 
• Year of Diagnosis; 
• Presence of a rest tremor at the time of diagnosis; 
• Year when motor fluctuations began; 
• Type of “OFF” episodes experienced (e.g., morning akinesia, wearing-“OFF”, 
delayed “ON”, dose failure, sudden “OFF”); 
• Number of “OFF” episodes per day; 
• Typical length of “OFF” episodes. 
• PD medications previously or currently taken, including: 
o Dopamine agonists; 
o MAO-B inhibitors; 
o COMT inhibitors; 
o Amantadine; 
o Anti-cholinergics. 
12.6.3 
Efficacy Assessments 
12.6.3.1 Confirmation of “OFF” or “ON” Episodes 
“OFF” and “ON” Training of Subjects at SV2 
At Screening Visit 2 (SV2), subjects will present to the clinic having taken their last dose of 
L-Dopa and any other adjunctive PD medication no later than midnight the evening prior to the 
visit. Their normal morning dose of L-Dopa (without adjunctive PD medication) will be 
administered in the clinic. Prior to administration of their L-Dopa dose, subjects will be 
examined by the Investigator in order to verify that they are in the “OFF” state. If they are in the 
“OFF” state, the Investigator will educate the subject that this is an “OFF” period or “OFF” 


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episode. The Investigator should clearly explain to the subject that this “OFF” time is when their 
medication has worn off, and does not provide benefits in terms of mobility, slowness and 
stiffness.  
Subjects will then take their next scheduled dose of L-Dopa. Once the Investigator determines 
that the subject is experiencing an “ON” state, they should educate the subject that this is an 
“ON” state. The Investigator should clearly explain to the subject that an “ON” episode is the 
period of time where their medication is providing benefit with regard to mobility, slowness and 
stiffness, and they feel they can perform normal daily activities. Once the subject has 
demonstrated understanding of the “OFF” and “ON” state, the training is complete. Successful 
completion and understanding of this training should be noted in the appropriate CRF. 
Any subject who cannot differentiate between an “ON” and “OFF” state will be deemed a screen 
failure.  
Definitions of Full “ON” and “OFF” 
The following definitions will be used in this study: 
“OFF” – defined as: 
• A period of time when medication has worn off and is no longer providing benefit with 
regard to mobility, slowness, and stiffness; 
• Confirmed by the Investigator using their clinical judgement as “OFF”. 
• Confirmed by the subject as “OFF”. 
Full “ON” as assessed by the subject – defined as: 
• A period of time where medication is providing benefit with regard to mobility, stiffness 
and slowness and where a subject feels he/she can perform normal daily activities.  
• A response comparable to or better than their normal response to PD medications prior to 
enrolling in the study. 
Full “ON” as assessed by the Investigator – defined as: 
• Based on clinical judgment, it is the period of time where the Investigator feels the 
medication is providing benefit with regard to mobility, stiffness and slowness and the 
subject has adequate motor function to allow them to perform their normal daily 
activities.  
Clinical confirmation of the “OFF” state must occur prior to dosing a subject with study 
medication (or their standard L-Dopa dose at the second Screening Visit (SV2)). The same 
assessor should be utilized for each subject throughout the study. 
Subjects must confirm they are in an “OFF” state prior to dosing with study medication (or their 


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standard L-Dopa dose at the second Screening Visit (SV2)). 
The Investigator will assess “OFF”/” ON” state as part of the MDS-UPDRS Part III assessments.  
At each Dose Titration, the subject will report the time when they turned to full “ON” (if 
applicable) and will report the time when they turned “OFF” following dosing (if it occurs within 
90 minutes of dosing). The timing of this should begin when the subject is dosed with the study 
medication, APL-130277, and recorded with a suitable timing device. These times are to be 
documented on the appropriate form of the CRF. 
12.6.3.2 MDS-UPDRS Part III 
The Motor Function section (Part III) of the MDS-UPDRS will be administered at all visits 
where it is indicated. 
Administration will be performed at t = 0 (just prior to dosing), 30, 60 and 90 minutes after 
dosing at the second Screening Visit (SV2) and during the Dose Titration Phase. 
These assessments will exclude the “Dyskinesia Impact on Part III Ratings” and the Hoehn and 
Yahr staging. The modified Hoehn and Yahr will be used during the Screening Visit (SV2). 
The MDS-UPDRS can only be performed by the Principal Investigator or Sub-Investigator who 
has been trained to perform this evaluation. In specific cases, another appropriately experienced 
and certified study staff member can perform the assessment if approved by the Sponsor. 
12.6.3.3 Pharmacokinetic (PK) Evaluation 
Blood draws for PK analyses on APL-130277 and placebo treatment days will occur at t = 0 (just 
prior to dosing), 30, 45, 60 minutes after dosing and at 2, 4 hours after dosing. On the 
moxifloxacin treatment day, blood draws will occur at t = 0 (just prior to dosing), 30, 60 minutes 
after dosing and at 2, 3, 4, 6, 8 hours after dosing. Sampling should occur as close as possible to 
the target time. 
Instructions specific to PK draws will be outlined in the PK lab manual. 
 
 


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13 
ADVERSE EVENTS 
Adverse events will be recorded from the time of signing of the ICF by the subject through to 
30 days after study completion or earlier, if warranted by a subject discontinuation. 
13.1.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject (or patient) or clinical investigation 
subject (or patient) administered a pharmaceutical product that does not necessarily have a causal 
relationship with the product. An AE can therefore be any unfavorable and unintended sign 
(including a new, clinically important abnormal laboratory finding), symptom, or disease, 
temporally associated with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. 
13.1.2 
Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening; 
• Requires in-subject hospitalization (being admitted) or prolongation of existing 
hospitalization; 
• Results in permanent (persistent) disability/incapacity; 
• Is a congenital anomaly; 
• Is an important medical event. 
Medical and scientific judgment should be exercised in deciding whether it is appropriate to 
consider other situations serious, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
(or patient) or may require intervention to prevent another of the outcomes listed in the definition 
above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the investigational 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition 
or event as an SAE. 
A spontaneous abortion or congenital anomaly in an infant born to a mother who was exposed to 


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the investigational drug during pregnancy is an SAE. Because the effect of APL-130277 or 
apomorphine on human male reproduction has not been determined, all pregnancies (in the 
subject or the subject's partner) will be documented on the Pregnancy Reporting Form with 
expressed consent. 
Due to the nature of subjects being enrolled in this study, and the given study objectives, 
subjects who are hospitalized for their titration and Period 1, 2 and 3 visit “OFF” episodes 
will not be considered a SAE. 
13.1.3 
Definition of Severity 
The clinical “severity” of an AE will be classified as: 
Mild: 
Causes no limitation of usual activities. 
Moderate: 
Causes some limitation of usual activities. 
Severe: 
Prevents or severely limits usual activities. 
 
13.1.4 
Definition of Start Date, Stop Date, and Duration 
Start Date: 
The date at which the AE is first noted. 
Stop Date: 
The date at which the AE is known to be resolved. If it is not known to 
have stopped, then indicate “ongoing”. 
Duration: 
A time in days, hours or minutes (this is optional). 
 
13.1.5 
Action(s) Taken 
Actions taken may consist of: 
None: 
No actions taken. 
Discontinued Investigational 
Drug: 
Investigational drug was permanently discontinued because 
of the AE. 
Change Investigational Drug: 
Investigational drug was given at a lower dose, at a longer 
interval between doses, or was temporarily withheld 
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Treatment: 
Specified medication (to be listed on the concomitant 
medication chart) was used as a countermeasure. 
Others: 
Other actions, such as an operative procedure, were 
required because of the AE. 
 
13.1.6 
Definition of Expectedness 
An expected AE is an AE for which the nature or severity is consistent with the known AE 
profile of the product. For an investigational drug, the known information is contained in the IB. 
For a marketed product, the known information is contained in the current package insert for the 
product. 
An unexpected AE is an AE for which the specificity or severity is not consistent with the 
current IB. For example, hepatic necrosis would be unexpected (greater severity) if the IB only 
listed elevated hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (greater specificity) if the IB only listed cerebral vascular 
accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected events. Examples would be (a) acute 
renal failure as an expected adverse reaction with a subsequent new occurrence of interstitial 
nephritis and (b) hepatitis with a first occurrence of fulminate hepatitis. 
13.1.7 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) for APL-130277 pertaining to irritation of the oral 
mucosa require immediate reporting (see Section 13.1.14) no matter if the event is serious or 
non-serious. These AESIs include, but are not limited to: 
• Stomatitis 
• Oral Ulcers 
Note: Per their discretion, Investigators may use other terminology and/or descriptors pertaining 
to irritation of the oral mucosa. 
Other AESIs for APL-130277 should be immediately reported only if they meet the serious 
criteria or lead to the discontinuation of the subject from the study. These AESIs include: 
• Changes in QT. 
• Orthostatic Hypotension. 


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13.1.8 
Definition of Relationship to Investigational Drug(s) 
The categories for classifying the Investigator’s opinion regarding the relationship of an AE to 
investigational drug(s) are listed below: 
Certain: 
An AE occurring in a plausible time relationship to 
investigational drug administration and which cannot be 
explained by a concurrent disease or other drugs or events. 
The response to withdrawal of the drug (dechallenge) is 
clinically reasonable. 
Probable (likely): 
An AE with a reasonable time sequence to administration of 
the investigational drug and which is unlikely to be attributed 
to concurrent disease or other drugs or events. The response to 
withdrawal of the drug (dechallenge) is clinically reasonable. 
Possible: 
An AE with a reasonable time sequence to administration of 
the investigational drug, but which could also be explained by 
concurrent disease or other drugs or events. Information on 
drug withdrawal may be lacking or unclear. 
Unlikely: 
An AE, including laboratory test abnormality, with a temporal 
relationship to investigational drug administration that makes a 
causal relationship improbable and in which other drugs, 
events, or underlying disease provide plausible explanations. 
Not related: 
An AE with sufficient evidence to accept that there is no 
causal relationship to investigational drug administration (e.g., 
no temporal relationship to drug administration, because the 
drug was administered after onset of event; investigation 
shows that the drug was not administered; another cause was 
proven; etc.). 
13.1.9 
Definition of Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Resolved; 
• Resolved with sequelae; 
• Ongoing; 
• Death; 


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• Unknown. 
Death should only be selected as an outcome when the AE resulted in death. If more than 1 AE is 
possibly related to the subject’s death, the outcome of death should be indicated for the AE 
attributed as the cause of death in the death certificate or summary. 
13.1.10 
Documentation of Adverse Events 
The Investigator will monitor and/or ask about or evaluate AEs using non-leading questions at 
each visit or evaluation. The occurrence of all AEs will be documented in the CRF with the 
following information, where appropriate: 
• AE name or term; 
• When the AE first occurred (start date); 
• When the AE stopped (stop date), or an indication of “ongoing”; 
• How long the AE persisted (optional); 
• Severity of the AE; 
• Seriousness; 
• Actions taken; 
• Outcome; 
• Investigator opinion regarding the relationship of AE to the investigational drug(s). 
13.1.11 
Follow-up of Subjects With an Adverse Event 
Any AE will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by another known cause(s) (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. All findings relevant to the final 
outcome of an AE must be reported in the subject’s medical record. 
13.1.12 
Special Procedures for Managing AEs/SAEs and Need for Unblinding 
If AEs occur in a subject which are not tolerable, or for which continued administration of 
investigational drug is not reasonable in view of the potential benefit to subject, the Investigator 
must decide whether to stop investigational treatment and/or treat the subject. Subject 
withdrawal should be avoided, if possible. If discontinuation of treatment occurs, every attempt 
should be made to restart study drug if medically appropriate, whatever the duration of 
discontinuation. 
13.1.13 
Notification of Serious Adverse Events 
The Investigator must report all SAEs and pregnancies promptly to Sunovion or its designee, by 
completing the SAE form and submit by email (or fax) within 24 hours of first becoming aware of 


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the event. Email: sunovionsafety@druginfo.com or Fax: 1-855-278-6344. 
The Investigator will be able to contact the study medical monitors. The North American 
Medical Monitor is Dr. Poonam Hundal (mobile: +1 (919) 592-1802 or email: 
Poonam.Hundal@incresearch.com) 
and 
the 
European 
Union 
Medical 
Monitor 
is 
Dr. Souad-Amel 
Kechairi 
(mobile: +33 (0) 6 13 56 67 03 
or 
email: 
Souad-Amel.Kechairi@incresearch.com). 
If a SAE is reported via telephone, the Investigator must follow up the initial telephone 
notification by completing the SAE form and submit by email (or fax). 
At the time of the first notification of an SAE, the clinical site should provide the following 
information to the contact person, if available: 
• Subject’s study number and initials; 
• Subject’s date of birth; 
• Subject’s gender; 
• Date of first dose of investigational drug(s); 
• Date of last dose of investigational drug(s), if applicable; 
• AE term; 
• Time and date of occurrence of the event; 
• A brief description of the event, outcome to date, and any actions taken; 
• The seriousness criteria(on) that were met; 
• Concomitant medication at onset of the event; 
• Relevant medical history information; 
• Relevant laboratory test findings; 
• Investigator’s opinion of the relationship to investigational drug(s); 
• Whether and when the Investigator was unblinded as to the subject’s treatment 
assignment. 
Any missing or additional relevant information concerning the SAE should be provided in a 
written follow-up report. 
The Sponsor or designee will promptly notify all clinical sites and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB), Research Ethics Board (REB), or Independent Ethics Committee (IEC) by the 


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Investigator or the appropriate person at the clinical site if required per IRB/REB/IEC guidelines. 
13.1.14 
Notification of Adverse Events of Special Interest 
All AESIs pertaining to irritation of the oral mucosa (Section 13.1.7) must be reported 
immediately to the Sponsor regardless of seriousness or presumed relationship to study drug. All 
AESIs pertaining to irritation of the oral mucosa are considered immediately reportable events 
and must be reported within 1 business day of the Investigator or study center staff becoming 
aware of the event. 
Similarly, any AESI related to: 
• Changes in QT 
• Orthostatic Hypotension  
that meet the serious criteria or leads to the discontinuation of the subject from the study 
(Section 13.1.7), regardless of presumed relationship to study drug, must be reported to the 
Sponsor within 1 business day of the Investigator or study center staff becoming aware of the 
event.  
AESIs 
that 
require 
immediate 
reporting 
should 
be 
submitted 
via 
Email: 
sunovionsafety@druginfo.com or by Fax: 1-855-278-6344. 
 
 


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14 
TREATMENTS 
14.1 
Treatments Administered 
APL-130277 is a near square bilayer film containing apomorphine hydrochloride. APL-130277 
is intended for fast sublingual absorption for use in rescue therapy for acute intermittent “OFF” 
episodes experienced by PD subjects. APL-130277 bilayer is composed of 2 layers laminated 
together: a first layer is composed of cellulose-ether based film, containing drug substance, 
stabilizers and plasticizers; a second layer contains a pH-modifier (pyridoxine hydrochloride) 
contained within a similar cellulosic film base, flavor agents and a permeation enhancer. Buffer 
layer will be on the side of the sublingual film that has an alphanumeric printing. 
APL-130277 sublingual thin films will be provided in 5 strengths: 10 mg, 15 mg, 20 mg, 25 mg 
and 30 mg. Two sublingual thin films will be administered sequentially to form the 35 mg dose, 
40 mg dose, 50 mg dose and 60 mg dose (as described below). In this study, placebo sublingual 
thin films will be prepared, which will be identical in appearance, size and colour, but contain no 
active ingredient (i.e., apomorphine).  
Moxifloxacin 400 mg tablets will be provided to the site for oral administration. 
14.2 
Administration of Study Medication 
During all phases of this study; subjects will be dosed by study staff.  
Dose Administration for APL-130277 and Placebo: 
Before dosing, the study staff will read out to subjects:  
“The product is a film. It will be placed against the bottom of the tongue. After the dose is placed 
in the mouth, close your mouth naturally. Let your tongue take a natural position. Do not move 
the tongue around to try to taste the drug or change its position. Just let it slowly dissolve in 
place. It will dissolve in 3 to 4 minutes. During that time try not to swallow saliva or the film. 
When the film is dissolved, raise your hand to let the clinical staff know. We will ask that you 
open your mouth to show us.” 
Subjects will be instructed to consume a glass of water immediately prior to dosing, and staff 
will ensure the sublingual space is free of excess water.  
Using gloved hands, or a single-use plastic disposable tweezers, staff will place the product 
beneath the tongue, with the drug side facing up and placed against the bottom of the tongue 
(i.e., the side of the film that does not have an alphanumeric printing), and ask subjects to close 
their mouth naturally. Subjects should not swallow the medication and should also try not to 
swallow their saliva for at least 3 minutes. If, upon inspection at the 3 minute mark, the film is 
not completely dissolved, subjects should be instructed to close their mouth and hold the study 
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If the subject feels the film has fully dissolved prior to the 3 minute mark, they should indicate 
this to staff by raising their hand, who will then verify. If upon inspection, the film is not 
completely dissolved, subjects should be instructed to close their mouth again and hold the study 
medication under their tongue. Staff may verify at regular intervals, as appropriate, for a duration 
maximum of 4  minutes in total. 
To administer the 35 mg dose, study staff will administer the 20 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, immediately administer the 15 mg 
sublingual thin film for another 3 minutes (total dosing time should be 6 minutes). 
To administer the 40 mg dose, study staff will administer the 20 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to consume 
approximately 1 teaspoon of water immediately prior to dosing the second 20 mg dose, and staff 
will ensure the sublingual space is free of excess water. The second 20 mg sublingual thin film 
will be administered under the tongue for another 3 minutes (total dosing time should be 
6 minutes). 
To administer the 50 mg dose, study staff will administer the 25 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to consume 
approximately 1 teaspoon of water immediately prior to dosing the second 25 mg dose, and staff 
will ensure the sublingual space is free of excess water. The second 25 mg sublingual thin film 
will be administered under the tongue for another 3 minutes (total dosing time should be 
6 minutes). 
To administer the 60 mg dose, study staff will administer the 30 mg sublingual thin film under 
the tongue first, and then after 3 minutes has elapsed, subjects will be instructed to consume 
approximately 1 teaspoon of water immediately prior to dosing the second 30 mg dose, and staff 
will ensure the sublingual space is free of excess water. The second 30 mg sublingual thin film 
will be administered under the tongue for another 3 minutes (total dosing time should be 
6 minutes). 
Dose Administration for Moxifloxacin: 
A single dose of 400 mg of moxifloxacin tablet will be administered orally to the subjects by 
study staff. The tablet should be swallowed whole with plenty of water; do not crush or chew the 
tablet. 
14.3 
Storage 
The Investigator is responsible for ensuring the proper storage of study medication according to 
procedures agreed in advance. Each Investigator is required to keep investigational drug product 
in a locked cabinet or other secure storage contained with limited access to personnel. 
Temperature logs must be maintained for the storage room. 


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APL-130277/Placebo: Unit dose pouches must be stored at controlled room temperature: 68-
77°F (20-25°C). 
Moxifloxacin: Tablets must be stored at controlled room temperature 59-86oF (15-30°C). Avoid 
freezing. Store in the original package to protect from moisture. 
The Investigator must maintain accurate and adequate records including expiry dates, lot 
number, and quantities received, individual usage, etc. At the end of the study, the Investigator 
must also return unused supplies to the Sponsor giving an account of usage in a trial whether or 
not the trial is completed or terminated. At the time of return to the Sponsor, the Investigator 
must verify that all unused or partially used drug supplies have been returned and that no 
remaining supplies are in the Investigator's possession. Certificates of delivery and returns must 
be signed and filed in the clinical site file. 
14.4 
Packaging and Labeling 
Investigational drug product will be administered in the clinic. 
APL-130277 and Placebo:  
Each package of investigational drug product and matched placebo APL-130277 will be labeled 
with study specific information meeting all the applicable regulatory requirements, including 
specifying the dose of APL-130277. 
Individual sublingual thin films of APL-130277 and matched placebo APL-130277 will be 
supplied packed in individual unit dose pouches. 
Moxifloxacin 400 mg Tablets: 
Moxifloxacin film-coated tablets will be packaged according to the market authorization holder 
and labeled with study specific information meeting all the applicable regulatory requirements.  
14.5 
Drug Accountability 
Drug supplies, which will be provided by Sunovion or a CRO appointed by Sunovion, must be 
kept in a secure, limited access storage area. 
The Investigator, pharmacist, and/or investigational drug storage manager must maintain records 
of the product’s delivery to the trial site, the inventory at the site, the use by each subject, and the 
return to Sunovion of unused product(s). These records will include dates, quantities, batch/serial 
numbers, expiry dates, and the unique code numbers assigned to the investigational product(s) 
and trial subjects. The Investigator, pharmacist, and/or investigational drug storage manager will 
maintain records that document adequately that the subjects were provided the doses specified by 
the clinical trial protocol and reconcile all investigational product(s) received from Sunovion. At 
the time of return to Sunovion, the Investigator or site designate must verify that all unused or 
partially used drug supplies have been returned by the clinical trial subject and that no remaining 


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supplies are in the Investigator’s possession. 
Note: If any of the investigational drug is not dispensed; is lost, stolen, spilled, unusable; or 
arrives at the clinical site in a damaged container, this information must be documented and 
reported to Sunovion and appropriate regulatory agencies as required. The investigational drug 
will only be administered to subjects participating in this study. Only authorized clinical site 
personnel may supply or administer the investigational drug. 
14.6 
Method of Assigning Subjects to Treatment Groups 
In the Dose Titration Phase, all subjects will be assigned open-label APL-130277 treatment using 
an IWRS system. 
In the Three-Way Balanced Randomized Crossover Assessment Phase (Period 1, Period 2, 
Period 3) subjects will be randomized using the Williams Design such that subjects are 
randomized in equal numbers to six possible sequences of each of the three treatments being 
studied: 
1) APL-130277 at the dose determined in the Dose Titration Phase,  
2) Matched placebo APL-130277, 
3) A single 400 mg dose of moxifloxacin. 
APL-130277 and placebo will be administered in a double-blind fashion and moxifloxacin will 
be administered open-label in a three-way balanced crossover. The strength of APL-130277 or 
placebo (i.e., 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg) to be given will 
be determined based on safety/tolerability during the Dose Titration Phase of the study.  
14.7 
ECG Methodology: Central Laboratory 
ECGs obtained digitally using a continuous 12-lead Holter device will undergo central review. 
ECGs to be used in the analysis will be selected/extracted at predetermined time points and will 
be read centrally using a high-resolution manual on-screen caliper semiautomatic method with 
annotations. Triplicate (3) 12-lead ECGs at each timepoint specified will be downloaded from 
the continuous recording approximately one minute apart. The digital ECGs will undergo a 
treatment-blinded high-resolution measurement of the cardiac intervals and morphological 
assessment by a central cardiologist also blinded to the study treatment. 
Digital ECGs will be processed via the central core laboratory’s validated data management 
system, EXPERT. Interval duration measurements will be collected using computer assisted 
caliper placements on three consecutive beats. Trained analysts will review all ECGs for correct 
lead and beat placement and adjudicate the pre-placed algorithm calipers as necessary using a 
proprietary validated electronic caliper system applied on a computer screen (manual 
adjudication methodology). A cardiologist will then verify the interval durations and perform the 


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morphology analysis. The ECG interval duration measurements will be performed in Lead II and 
when Lead II is not analyzable in Lead V5, when Lead V5 is not analyzable in Lead V2, 
followed by the most appropriate lead, if necessary. 
On-screen measurements of the RR, PR, QRS, and QT interval durations will be performed and 
heart rate, QTcF and QTcB will be derived by the following process: 
Interval measurements will be obtained by the following method:  
• Three (3) R-R  
 
mean R-R Interval is reported 
• Three (3) PR   
 
mean PR Interval is reported 
• Three (3) QRS  
 
mean QRS Width is reported 
• Three (3) QT   
 
mean QT Interval is reported 
The following calculations will be made from the interval measurements: 
Three (3) QTcF measurements—QTc correction by the Fridericia’s formula 
• QTcF1 = QT1/3√RR1 
• QTcF2 = QT2/3√RR2 
• QTcF3 = QT3/3√RR3 
• Mean QTcF = (QTcF1 + QTcF2 + QTcF3)/3 
Three (3) QTcB measurements- QTc correction by the Bazett’s formula 
• QTcB1 = QT1/√RR1 
• QTcB2 = QT2/√RR2 
• QTcB3 = QT3/√RR3 
• Mean QTcB = (QTcB1 + QTcB2 + QTcB3)/3 
Three (3) Heart Rate measurements 
• HR1 = 60 / RR1  
• HR2 = 60 / RR2  
• HR3 = 60 / RR3  
• Mean HR = (HR1 + HR2 + HR3)/3 
Each fiducial point (onset of P wave, onset of Q wave, offset of S wave, and offset of T wave) 
will be marked. The original ECG waveform and such annotations will be saved separately in 
XML format for independent review. 


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14.8 
Randomization  
At Screening, the IWRS will assign a unique subject identification number to the subject known 
as the Screening Number. This number will be associated with the subject throughout the study. 
Every subject that signs an ICF must be entered into the IWRS regardless of eligibility in order 
to obtain a Screening Number. This 7-digit number will consist of a 4-digit site ID followed by a 
3-digit number assigned sequentially within each site starting at 001. 
Following Sponsor approval (additional details are available in the Enrollment and 
Randomization Adjudication Process, which is contained in a separate document), subjects will 
be randomized centrally at a study level after the Dose Titration Phase has been completed (prior 
to Period 1 Dosing Visit 1) to one of the six randomization sequences using the Williams design: 
1. APL-130277 – Placebo – Moxifloxacin 
2. APL-130277 – Moxifloxacin – Placebo 
3. Placebo – Moxifloxacin – APL-130277 
4. Placebo – APL-130277 – Moxifloxacin 
5. Moxifloxacin – Placebo – APL-130277 
6. Moxifloxacin – APL-130277 – Placebo  
No stratification factors will be used. The randomization scheme will be designed by the study 
statistician. Once designed, an independent randomization expert will execute the randomization 
in the IWRS. The 5-digit randomization number is used to identify the treatment sequence 
(APL-130277, placebo, moxifloxacin) of the kits that will be assigned to the subject during the 
Period 1, Period 2 and Period 3 of the Crossover Phase.  
A randomization number can only be assigned to one subject and cannot be reused once 
assigned. 
14.9 
Blinding 
This study will be open-label during the Dose Titration Phase and for moxifloxacin dosing 
during the Crossover Assessment Phase. 
APL-130277 and Placebo Dosing Visits will be double-blinded. 
An IWRS will allocate treatment for Period 1, Period 2 and Period 3 Dosing Visits based on a 
pre-specified randomization list, generated by the IWRS provider.  
For blinded Dosing Visits active and placebo study medication will be provided to each site 
participating in the study. For each dose, study medication and placebo packaging will be 
identical in size, shape, color and appearance. Investigators will not have access to the 
randomization (treatment) code except in case of a SAE. In this case, the code may be broken 


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only in exceptional circumstances when knowledge of the study medication is essential for 
treating the subject. Subjects and study staff members will be blinded to treatment assignments 
until the completion of the study. 
A list of treatment kit numbers for each treatment sequence is generated centrally by the vendor 
selected by the Sponsor to perform this function, and the treatment kits are prepared in 
accordance with this list. Numbers will not be reused regardless of the status of the use of the 
corresponding study drug. 


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15 
STATISTICAL ANALYSES  
15.1 
Statistical Analysis Plan 
Full statistical considerations and complete analysis of data collected in this study will be 
specified in a formal Statistical Analysis Plan (SAP). This section of the protocol prospectively 
outlines the analysis methods. The final SAP will be finalized prior to locking the database and 
prior to unblinding any study data. The SAP will serve as a complement to the study protocol 
and supersedes it in case of differences. In case of major differences between the study protocol 
and SAP (e.g. changes in the analysis related to the primary endpoint), a protocol amendment 
will be considered.  
15.2 
Analysis Populations 
15.2.1 
Safety Analysis Set 
All subjects who receive at least one dose of study medication will be included in the safety 
analysis set. The safety analysis set will be used for the analysis of the safety endpoints and the 
subjects will be grouped according to the treatment that they received. 
15.2.2 
PK Analysis Set 
The PK analysis set includes all subjects with at least one PK evaluation and will be used for the 
analysis of the PK data. 
15.2.3 
Efficacy Analysis Set 
The efficacy analysis set includes subjects who have efficacy assessments at the lowest or 
highest dose level resulting in a full “ON”. The efficacy analysis set will be used for the analysis 
of the efficacy data collected during the Dose Titration Phase. 
15.2.4 
ECG and PK-PD Analysis Sets 
The analysis populations for the ECG and pharmacokinetic-pharmacodynamic (PK-PD) analyses 
(Evaluable Population) will be comprised of all subjects who are randomized, receive at least 
one dose of study medication, and have at least one evaluable pre-dose ECG and one evaluable 
on-treatment post-dose ECG within the same Treatment Period. Additionally, for the PK-PD 
analysis (placebo corrected change in QTc vs. plasma concentration), a time-matched plasma 
concentration would also be necessary. 
15.3 
Sample Size Calculation 
The study is powered to detect a mean difference in the change in QTcF between APL-130277 
and placebo (∆∆QTcF) of 7 ms, assuming that the true difference between APL-130277 and 
placebo can be up to 3 ms, adding up to the predefined threshold of 10 ms. The standard 
deviation of ∆∆QTcF is assumed to be 14 ms.12 Assuming a one-sided significance level of 0.05, 


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42 subjects are required for the 3x3 cross-over phase to achieve approximately 80% power. 
15.4 
ECG and Concentration-QTc Effect Analysis  
15.4.1 
Primary Endpoint  
The primary endpoint for this trial will be the time-matched change from baseline in QTc, 
placebo-adjusted and corrected for HR based on the Fridericia correction method (QTcF) method 
(∆∆QTcF). 
15.4.2 
Secondary Endpoints 
Secondary endpoints will include: 
• QTc with Bazett correction (QTcB); 
• Heart rate; 
• PR interval; 
• QRS interval; 
• Uncorrected QT interval; 
• ECG morphology. 
15.4.3 
Central Tendency Analyses 
The primary analysis for the QT/QTc data in this study is based on the time-matched analysis for 
each treatment group. This time-matched analysis will be based upon the endpoint “change from 
baseline in the QTcF interval, placebo-adjusted – ΔΔQTc.” Baseline is defined as the mean of 
the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (P1V1). Note that the measurements 
from the three ECGs collected at a time point are averaged to produce a single value for each 
ECG interval for that time point. These baseline and Day 1 post-dose ECG data, for each 
Treatment Period, will then be subjected to a mixed effects model (using the SAS Procedure 
PROC MIXED) with the following covariates: time (categorical), treatment, time by treatment 
interaction, region, gender, and the baseline value of the parameter. Since this is a crossover 
design, period and sequence terms will necessarily also be included in the model. Subject will be 
included as a random effect. Gender and region effects will be investigated as specified below. 
Should a significant treatment by gender/region interaction be observed, it will also be included 
in the model. The estimates of the ΔΔQTc at each time point and its confidence intervals (CI) 
will be performed using a LSMEAN statement within PROC MIXED and a diff option. For this 
analysis a 90% two-sided confidence interval will be calculated. Hypotheses will be based upon 
the Intersection-Union test. Since the Intersection-Union test can be applied here, no multiple 
endpoint adjustment is needed. Based on the ICH E14 guidance, the hypothesis will be evaluated 
by observing if any of the time points have a two-sided 90% upper confidence bound (i.e. one-


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sided 95%) which is equal to, or exceeds, 10 ms. 
The upper limit of the two-sided 90% CI on treatment will be compared to the 10 ms bound only 
for APL-130277 versus placebo. If the upper limit of the two-sided 90% CI for APL-130277 
versus placebo falls below 10 ms, it will be concluded that APL-130277 does not prolong the 
QTc interval to a clinically significant degree. 
The 7 time points to be evaluated for the primary analysis include 15, 30, 45 60 minutes and 2, 3, 
and 4 hours post-dose. If only 1 or 2 of the 7 timepoints for APL-130277 just exceeded 10 ms, a 
determination of whether this is a false positive response relied on all of the study findings with 
special emphasis on the PK-PD model described below. 
The analysis also will be presented in a graphical manner: for each comparison of interest all 
CI’s (corresponding to the number of post-baseline time points) will be presented superimposed 
in one graph showing moxifloxacin and APL-130277, all of which have been placebo-adjusted. 
A similar analysis will be conducted for QTcB. 
15.4.4 
Establishment of Assay Sensitivity 
To establish assay sensitivity, there should be at least one time point where the lower confidence 
bound of the mean difference of moxifloxacin and placebo is greater than 5 ms. The same model 
as described for the time-matched analyses will be used for this analysis. 
The hypothesis of assay sensitivity will be rejected if the lower limit of the one-sided 
(Bonferroni corrected) 95% confidence interval is never above 5 ms. However, detecting the 
positive control’s effect will establish the ability of the study to detect such an effect of the study 
drug. 
For purposes of determining assay sensitivity, 4 time points (i.e., hours 1, 2, 3, and 4) will be 
utilized for calculating the one-sided 95% (i.e. two-sided 90%) confidence limits. In this case, 
since the alternative hypothesis is that at least one of the time points is greater than or equal to 
5 ms, a multiplicity adjustment is necessary. Therefore, the confidence intervals will be 
calculated using Bonferroni adjustment, specifically an adjusted alpha error level of 
0.05/4 = 0.0125. Note that although only these time points will be used to assess assay 
sensitivity, the calculated upper and lower confidence bounds (Bonferroni-corrected) for the 
entire moxifloxacin profile will be displayed. 
15.4.5 
Outlier Analyses 
An outlier or categorical analysis supplements the central tendency analysis by determining if 
there were subjects who had an exaggerated effect on any ECG interval that would not be 
revealed in a mean change from baseline central tendency analysis. Each subject would be 
considered having an outlier value based on the most extreme value across all of the time points.  
The following criteria (“study endpoints”) are defined for this analysis: 


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• Heart rate: A value for a subject is considered to be an outlier at a pre-determined post-
dose time point if the heart rate measurement at that time point is < 50 bpm and the 
measure is at least a 25% decrease from the subject’s baseline mean heart rate (i.e., a 
bradycardic event) or if the heart rate measurement at the pre-determined post-dose time 
point is > 100 bpm and the measure is at least a 25% increase from the baseline mean 
heart rate (i.e., a tachycardic event). 
• PR interval: A value for a subject is considered to be an outlier at a pre-determined post-
dose time point if the PR interval at that follow-up time point is > 200 ms and it is at least 
a 25% increase from the subject’s baseline mean PR interval. 
• QRS interval: A value for a subject is considered to be an outlier at a pre-determined 
post-dose time point if the QRS interval at that follow-up time point is > 100 ms and it is 
at least a 25% increase from the subject’s baseline mean QRS interval. 
• QT interval: A value for a subject is considered to be an outlier at a pre-determined post-
dose time point if the QT interval at that follow-up time point is > 500 ms and the 
subject’s baseline mean QT interval is ≤ 500 ms. 
• QTcF: A value for a subject is considered to be an outlier at a pre-determined post-dose 
time point if the QTcF interval at that follow-up time point is > 500 ms and the subject’s 
baseline mean QTcF interval is ≤ 500 ms. Outlier values will also be presented if the 
QTcF interval at a pre-determined post-dose time point is > 480 ms when the subject’s 
baseline mean QTcF interval is ≤ 480 ms and when a pre-determined post-dose time 
point is > 450 ms when the subject’s baseline mean QTcF interval is ≤ 450 ms. In 
addition, the proportion of subjects with changes from baseline in > 30-60 ms and 
> 60 ms will be reported. 
• QTcB: A value for a subject is considered to be an outlier at a pre-determined post-dose 
time point if the QTcB interval at that follow-up time point is > 500 ms and the subject’s 
baseline mean QTcB interval is ≤ 500 ms. Outlier values will also be presented if the 
QTcB interval at a pre-determined post-dose time point is > 480 ms when the subject’s 
baseline mean QTcB interval is ≤ 480 ms and when a pre-determined post-dose time 
point is > 450 ms when the subject’s baseline mean QTcB interval is ≤ 450 ms. In 
addition, the proportion of subjects with changes from baseline in > 30-60 ms and 
> 60 ms will be reported. 
15.4.6 
Morphologic Analyses 
Morphological analyses will be performed with regard to the ECG waveform interpretation as 
defined by the central ECG laboratory’s cardiologist. Changes from baseline to on-treatment will 
be evaluated. 


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All findings will be presented in the ECG listings. New onset findings will be presented as the 
percentage of subjects meeting the “new” criteria within each Treatment Period (“new” means 
not present on any baseline ECG and becomes present on at least one on-treatment ECG) for the 
following variables: 
• Second degree heart block;  
• Third degree heart block; 
• Atrial fibrillation or atrial flutter; 
• Complete right bundle branch block;  
• Complete left bundle branch block;  
• ST segment change (elevation and depression separately);  
• T wave abnormalities (negative T waves only); 
• Myocardial infarction pattern; and 
• Any new abnormal U waves. 
15.4.7 
Pharmacokinetic-Pharmacodynamic Analyses 
A concentration-QTc analysis will be conducted to evaluate the relationship between the 
placebo-corrected (placebo-adjusted) change from baseline in QTc intervals (QTcF and QTcB 
and plasma concentrations of APL-130277). The analysis will be done as a separate standalone 
analysis and a detailed PK modeling analysis plan (PMAP) will be generated to describe the 
planned evaluation. 
15.4.8 
Safety Analysis 
Disposition 
The number of subjects who failed the screening will be summarized along with the reason for 
exclusion. The premature discontinuation will be summarized by study phase and treatment 
group/dose level along with the reason for the discontinuation. 
Adverse events 
The adverse event data will be summarized for the overall APL-130277 treatment and further 
classified by the dose level at the time of the onset of the event. In addition, the adverse events 
starting during the placebo and moxifloxacin treatment will be summarized. Adverse events will 
be tabulated by treatment group and dose level according to the Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment-emergent adverse events (TEAEs) will be 
summarized by body system and preferred term. Descriptive statistics will be used to compare 
the overall incidence of TEAEs between the treatment groups. 


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Safety laboratory variables 
The changes in safety laboratory variables from Screening to the end of the study will be 
summarized with descriptive statistics or listed only. 
Vital signs 
The vital signs, including orthostatic blood pressure will be summarized with descriptive 
statistics as changes from pre-dose to post dose time points by treatment group/dose level. 
Oral irritation 
The data on oral irritation will be summarized with descriptive statistics. 
The full details of the safety analysis will be provided in the SAP. 
15.5 
Pharmacokinetic Analysis  
The stand-alone non-compartmental PK analysis of the plasma PK concentration data will be 
described in details in a separate PK analysis plan (PKAP). 
Apomorphine levels and metabolites (norapomorphine and apomorphine sulphate) will be 
measured in plasma using a validated liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) method. 
Pharmacokinetic parameters will be derived using noncompartmental methods employing a 
validated installation of Phoenix WinNonlin® version 6.3 or higher (Pharsight, St Louis, MO) 
software. 
The following PK parameters will be estimated or calculated using plasma apomorphine, 
norapomorphine and apomorphine sulphate concentration-time data. Other PK parameter may be 
calculated as appropriate. Actual elapsed time from dosing will be used to determine all 
individual PK parameters. 
Cmax 
Maximum drug concentration in plasma, determined directly from the 
concentration-time profile. 
Tmax 
Time of Cmax in plasma, determined directly from the concentration-time 
profile. 
AUC0-t 
Area under the plasma concentration vs. time curve from time of dosing to 
last measurable concentration, calculated using the linear up, log down 
trapezoidal rule. 
AUCinf 
AUC extrapolated to infinity (AUClast + last quantifiable concentration/λz), 
calculated using the linear-up/log-down trapezoidal rule. 
λz 
The terminal phase rate constant; estimated by linear regression through the 


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terminal phase of the log concentration-time profile, using at least 3 data 
points. 
t½ 
The terminal phase half-life calculated as: 
z
λ
)
2
λn(
t½ =
 
CL/F 
Plasma clearance, calculated as Dose/AUCinf after single dose (apomorphine only). 
MRT 
Mean residence time calculated using the following equation: MRT = 
AUMCinf/AUCinf. AUMCinf is the area under the first moment curve. 
M/P Ratio 
Metabolite to Parent exposure ratio (Cmax and AUC). 
 
Linear and semi-log plots of the concentration-time data for apomorphine and metabolites will 
be presented by subject and treatment.  
Plasma 
apomorphine 
and 
metabolites 
(norapomorphine 
and 
apomorphine 
sulphate) 
concentrations will be summarized using descriptive statistics (including N, mean, standard 
deviation (SD), coefficient of variation (CV%), median, minimum, and maximum). 
Concentrations below the limit of quantitation (BLQ) will be treated as zero for the computation 
of descriptive statistics and for construction of mean concentration-time profiles. 
Actual elapsed time from dosing will be used to determine all individual PK parameters. Plasma 
PK parameters will be tabulated by dose level, and summary statistics that are presented will 
include the arithmetic and geometric mean, geometric CV%, SD of the arithmetic mean, median, 
minimum, maximum, and N. 
15.6 
Efficacy Analysis  
The main efficacy endpoint of this study is the change in MDS-UPDRS Part III at 30 minutes. 
The MDS-UPDRS Part III will be analyzed using a Mixed Model for Repeated Measures with 
data from the lowest dose level resulting in a full “ON” and at the highest tolerated dose level 
during the Titration Phase as response variables. The baseline (SV2) value will be included as a 
covariate and the day (1 = assessment at the lowest dose level resulting in a full “ON”, 
2 = assessment at the highest tolerated dose level) and dose level (10 mg, 15 mg, 20 mg, 25 mg, 
30 mg, 35 mg, 40 mg, 50 mg, 60 mg) as fixed factors in the model. Separate models will be used 
for each time point (30, 60 and 90 minutes).  
The other efficacy endpoints will be analyzed with similar principles. These analyses will be 
defined in the SAP. 


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16 
STUDY CONDUCT 
Steps to assure the accuracy and reliability of data include the selection of qualified Investigators 
and appropriate clinical site, review of protocol procedures with the Investigator and associated 
personnel prior to the study, periodic monitoring visits, and meticulous data management. 
16.1 
Regulations and Guidelines 
By signing this study protocol, the Investigator agrees to conduct this study in accordance with 
all laws, regulations and guidelines of the pertinent regulatory authorities, including and in 
accordance with the April 1996 ICH Guidance for Industry E6 GCP and in agreement with the 
Declaration of Helsinki (including all applicable amendments). While delegation of certain 
aspects of the study to Sub-Investigators and study coordinators is appropriate, the Principal 
Investigator (PI) will remain personally accountable for closely overseeing the study and for 
ensuring compliance with the protocol and all applicable regulations and guidelines. The PI is 
responsible for maintaining a list of all persons that have been delegated study-related 
responsibilities (e.g., Sub-Investigators and study coordinators) and their specific study related 
duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, investigational drugs, 
and their specific duties within the context of the study. Investigators are responsible for 
providing Sunovion with documentation of the qualifications, GCP training, and research 
experience for themselves and their staff as required by Sunovion and the relevant governing 
authorities. 
See APPENDIX II: Regulations and Guidelines for additional information. 
16.2 
Study Initiation 
Clinical study staff may not screen or enroll subjects into the study until receiving notification 
from Sunovion or its designee that the study can be initiated at the clinical site. The clinical site 
will not be authorized for study initiation until: 
• The Sponsor has received the appropriate Regulatory Authority/Agency approval for the 
protocol and ICF; 
• The clinical site has received the appropriate IRB/REB/IEC approval for the protocol and 
the IRB/REB/IEC-approved ICF; 
• The clinical site has a Clinical Trial Agreement in place; 
• The clinical site personnel, including the Investigator, have participated in a study 
initiation meeting. 


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16.3 
Study Documentation 
16.3.1 
Investigator’s Regulatory Documents 
The regulatory documents listed below must be received from the Investigator and reviewed and 
approved by Sunovion or its designee before the clinical site can initiate the study and before 
Sunovion will authorize shipment of investigational drug to the clinical site. Copies of the 
Investigator’s regulatory documents must be retained at the clinical site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the 
APL-130277 IB, copies of regulatory references, copies of IRB/REB/IEC correspondence, and 
investigational drug accountability records must be retained as part of the Investigator’s 
regulatory documents. It is the Investigator’s responsibility to ensure that copies of all required 
regulatory documents are organized, current, and available for inspection. 
Documents Required for Regulatory Packet: 
Confidentiality Agreement 
Signed Clinical Trial Agreement 
Final Protocol 
PI CV 
Final Protocol Amendments (if any) 
PI Medical License 
Protocol Signature Pages 
Sub-Investigator CV 
Protocol Amendment Signature Pages  
(if any) 
Sub-Investigator License 
APL-130277 IB 
IRB Approvals 
Signed Financial Disclosure 
IRB Membership List / Assurance Statement  
Regulatory Agency Approval  
Approved Informed Consent Template(s) 
 
Additional documentation requirements may be communicated by Sunovion staff (or it’s 
designate). 
16.3.2 
Case Report Forms 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain accurate CRFs and source documentation as part of the case histories for all subjects 
who sign an ICF. 
The vendor selected to perform CRF design will be responsible for drafting CRFs for the study, 
which Sunovion will review and approve before implementation. An electronic CRF may be 
used instead of paper CRFs, and the term CRF is synonymous for both types of CRFs. 


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CRFs are considered confidential documents and should be handled and stored accordingly. 
Sunovion or its designee will provide the necessary training on the use of the specific CRF 
system used during the study to ensure that the information is captured accurately and 
appropriately. 
In order to ensure data accuracy, CRF data for individual subject visits should be completed as 
soon as possible following the visit in accordance with the site Clinical Trial Agreement in place. 
CRFs will be reviewed by the Clinical Research Associate (CRA) during monitoring visits. The 
CRA will verify data recorded with source documents. 
A copy of all the CRFs will be sent securely to Sunovion at the end of the study. 
If the study is managed using an Electronic Data Capture (EDC) system, the Investigator agrees 
to maintain accurate CRFs/EDC modules and source documentation as part of the case histories 
for all subjects who sign an ICF. 
CRFs/EDC modules are considered confidential documents and should be handled and stored 
accordingly. Sunovion or its designee will provide the necessary training on the use of the 
specific EDC system used during the study to ensure that the information is captured accurately 
and appropriately. 
In order to ensure data accuracy, EDC module data for individual subject visits should be 
completed as soon as possible following the visit and in accordance with the site Clinical Trial 
Agreement in place. EDC data will be reviewed by the CRA during monitoring visits. The CRA 
will verify data recorded with source documents. 
All corrections or changes requested to the study data must be made as soon as possible by the 
study site, and verified by the Investigator. When all incorrect and/or inconsistent data has been 
accounted for, EDC data will be considered complete. 
The site is expected to notify the Study Medical Monitor before breaking the study blind, unless 
it is in the subject’s best interest if the blind is broken immediately. All corrections or changes 
made to any study data must be appropriately tracked in an audit trail. When all incorrect and/or 
inconsistent data has been accounted for, CRFs will be considered complete. 
16.3.3 
Source Documents 
All information recorded in the CRF must be supported by corresponding source documentation. 
Examples of acceptable source documentation include but are not limited to hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. If available, source documents for at least the 
2 years prior to screening will be reviewed by the CRA to verify the subject’s eligibility for the 
study. 
Original versions of the laboratory reports and ECG tracings will be retained at the clinical site 


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with the subject’s source documents. 
16.4 
Data Quality Assurance 
Sunovion and its designees will perform quality control and assurance checks on all clinical 
studies that it sponsors. Sunovion, or its designee, will be responsible for additional data quality 
assurance related to the clinical data being generated, entered and maintained as part of this 
clinical study. 
16.4.1 
Monitoring the Study 
Clinical monitors will conduct site visits to the study facilities to monitor the study. The 
Investigator agrees to allow these monitors and other authorized Sunovion personnel access. The 
clinical site will be monitored by Sunovion and/or it’s designate to ensure compliance with the 
protocol, GCP, and applicable regulations and guidelines. As representatives of Sunovion, CRAs 
are responsible for following the study protocol closely and notifying project management of any 
noted deviations. The assigned CRA(s) will visit the Investigator and clinical site at periodic 
intervals and maintain periodic communication. The CRA(s) will maintain current knowledge of 
the study through observation, review of study records and source documentation, and discussion 
of the conduct of the study with the Investigator and staff. While on site, the CRA(s) will review 
regulatory documents, compare entries in the source documents, and review investigational drug 
accountability records. The CRA will ask for clarification and/or correction of any noted 
inconsistencies. 
By signing the protocol, the Investigator agrees to meet with the CRA during clinical site visits, 
to ensure that study staff is available to the CRA(s) as needed, to provide the CRA(s) access to 
all study documentation and medical records, to the clinical supplies dispensing and storage area, 
and agrees to assist the monitors in their activities, if requested. The Investigator also agrees to 
allow inspectors from regulatory agencies to review records and to assist the inspectors in their 
duties, if requested. 
16.4.2 
Routine Data Collection 
CRFs will be reviewed by the CRA during monitoring visits. The CRA will verify data with 
source documents. If the CRA’s comparison of the original CRF data with source documents 
reveals data discrepancies or omissions that require study staff to make corrections, corrections 
will be made. After the CRF data have been monitored and all corrections have been made, the 
Investigator must appropriately document within the data system his/her agreement with the data 
contained therein. If corrections are required subsequent to the Investigator’s signature, the 
Investigator must document his/her agreement with the CRF data to confirm the accuracy of the 
changed data. A copy of all CRF data will be retained at the clinical site. If corrections are 
required after all data have been electronically transferred, corrections that have been made must 
be verified in writing by the Investigator, and new data provided to Sunovion. 


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Should an EDC system be implemented, the CRA will verify data with source documents. If the 
CRA’s comparison of the original EDC module data with source documents reveals data 
discrepancies or omissions that require study staff to make corrections, the corrections will be 
made as outlined in the Study Monitoring Plan. After the EDC module data have been monitored 
and all corrections have been made, the Investigator must appropriately document within the data 
system his/her agreement with the data contained therein. If corrections are required subsequent 
to the Investigator’s signature, the Investigator must document his/her agreement with the EDC 
module data to confirm the accuracy of the changed data. A copy of all EDC module data will be 
retained at the clinical site. If corrections are required after all data have been electronically 
transferred, the corrections must be made as instructed in site training. 
16.4.3 
Expedited Data Collection 
Monitoring of selected CRF data may occur following the CRF submission, using data from the 
data system and source documents as necessary. Any post submission/transfer corrections of 
CRF data must be verified in writing by the Investigator, and new data provided to Sunovion. 
16.4.4 
Data Management 
A vendor contracted by Sunovion will provide the data management system and data 
management services for the study. An EDC system may be implemented. 
Clinical site personnel will be responsible for providing resolutions to all data queries. The 
Investigator will be required to review and document data to ensure the accuracy of the corrected 
and/or clarified data. If an EDC system is implemented, this documentation will be electronic. 
Query forms or documentation must be generated and filed by the site. 
16.4.5 
Study Termination 
The study may be terminated at Sunovion’s discretion at any time for any reason. If Sunovion 
discovers conditions that warrant early termination of the study, the Investigator will be notified 
by Sunovion or its designee. Examples of conditions that may warrant premature termination of 
the study include, but are not limited to the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study; and 
• The decision on the part of Sunovion to suspend or discontinue testing, evaluation, or 
development of the investigational product. 
16.4.6 
Clinical Site Closure 
On termination of the study, all screening and ongoing study related procedures conducted at the 
clinical site will be closed. Sunovion may terminate participation of the clinical site at any time. 
Examples of conditions that may warrant premature termination of a clinical site include, but are 
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• Noncompliance with the protocol and/or applicable regulations and guidelines; 
• Inadequate subject enrollment; 
• Administrative reasons. 


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17 
GENERAL CONSIDERATIONS 
17.1 
Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Sunovion. The protocol amendment must be signed by the 
Investigator and approved by the IRB/REB/IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
17.2 
Use of Information and Publication 
All information concerning APL-130277, Sunovion’s operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information supplied by 
Sunovion to the Investigator and not previously published, is considered confidential and 
remains the sole property of Sunovion. The CRFs also remain the property of Sunovion. The 
Investigator agrees to use this information for purposes of study execution through finalization. 
The information developed in this study will be used by Sunovion in connection with the 
continued development of APL-130277 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
Publication or other public presentation of APL-130277 data resulting from this study requires 
prior review and written approval of Sunovion, which will not be unreasonably withheld. 
Abstracts, manuscripts, and presentation materials should be provided to Sunovion for review at 
least 30 days prior to the relevant submission deadline. 
After publication of the results of the multi-center study or 24 months after the clinical study 
report has been finalized, whichever comes first, the Sponsor acknowledges the Investigator's 
rights to publish results from this study. Any such scientific paper, presentation, communication, 
or other information concerning the study described in this protocol must be submitted to the 
Sponsor for review prior to submission for publication/presentation. 
17.3 
Records Retention 
The Investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including but not limited to those defined by GCP as essential, for the longer of: (1) 
2 years after the last marketing authorization for the investigational drug has been approved or 
Sunovion has discontinued its research with respect to such drug; or (2) such longer period as 
required by applicable global regulatory requirements. At the end of such period, the Investigator 
shall notify Sunovion in writing of its intent to destroy all such material. Sunovion shall have 
30 days to respond to the Investigator’s notice, and Sunovion shall have a further opportunity to 
retain such materials at Sunovion’s expense. 


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17.4 
Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
study team has determined that specimens are no longer needed and the decision has been made 
that there are no samples to be re-assayed. In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 
17.5 
Subject Injury 
In general, specific to provisions in the clinical trial agreement, if a subject is injured as a direct 
result of a test article and the site, its staff and Investigators have followed the protocol and all 
documentation supporting the proper running of the trial, Sunovion will pay for reasonable and 
necessary medical treatment for the injury. If laws or regulations of the locality in which the 
study is taking place require additional payment of expenses, Sunovion shall comply with such 
laws or regulations. Where applicable, Sunovion has taken specific national insurance. 


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18 
REFERENCES 
1) Tanner CM, Goldman SM. Epidemiology of Parkinson's disease. Neurol Clin. 
1996;14:317-35. 
2) Hornykiewicz O. Basic research on dopamine in Parkinson's disease and the discovery of 
the nigrostriatal dopamine pathway:  the view of an eyewitness. Neurodegener Dis. 
2008;5:114–7. 
3) Mouradian MM, Heuser IJ, Baronti F, et al. Pathogenesis of dyskinesias in Parkinson's 
disease. Ann Neurol. 1989;25(5):523-6. 
4) Stocchi F, Vacca L, Ruggieri S, et al. Intermittent vs. continuous levodopa administration 
in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch 
Neurol. 2005;62(6):905-10. 
5) Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor 
fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16(3):448-58. 
6) APOMORPHINE treatment for morphine addiction. Br J Addict Alcohol Other Drugs. 
1949;46(2):93-101. 
7) Cotzias GC, Papavasiliou PS, Fehling C, Kaufman B, Mena I. Similarities between 
neurologic effects of L-dipa and of apomorphine. N Engl J Med. 1970;282(1):31-3. 
8) Corsini GU, Del Zompo M, Gessa GL, Mangoni A. Therapeutic efficacy of 
apomorphine combined with an extracerebral inhibitor of dopamine receptors in 
Parkinson's disease. Lancet. 1979;1(8123):954-6. 
9) Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A. 
Differential actions of antiparkinson agents at multiple classes of monoaminergic 
receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and 
cloned human receptor subtypes. J Pharmacol Exp Ther. 2002;303(2):791-804. 
10) Schwab RS, Amador LV, Lettvin JY. Apomorphine in Parkinson's disease. Trans Am 
Neurol Assoc. 1951;56: 251–3. 
11) Wang BS, Wang XJ, Gong, LK. The Construction of a Williams Design and 
Randomization in a Cross-Over Clinical Trials Using SAS. J Stat Softw. 2009;29(1):1-10. 
12) Mendzelevski B, Sprenger CR, Spiegelstein O, Rabinovich-Guilatt L. Cardiac safety of 
rasagiline, a selective monoamine oxidase type B inhibitor for the treatment of 
Parkinson's disease: a thorough QT/QTc study. Int J Clin Pharmacol Ther. 2014 
Mar;52(3):192-201. 
 


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19 
APPENDICES 
19.1 
APPENDIX I: APOKYN® Prescribing Information and APO-go® Summary of 
Product Characteristics 
https://www.apokyn.com/sites/all/themes/apokyn/content/resources/Apokyn_PI.pdf 
 
https://www.medicines.org.uk/emc/medicine/12941 
 
 
 
 


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19.2 
APPENDIX II: Regulations and Guidelines 
19.2.1 
Declaration of Helsinki 
The Policy of the World Medical Association is available at URL: https://www.wma.net/policies-
post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-
subjects/ 
19.2.2 
Approval by an IRB/REB/IEC 
This protocol must be reviewed and approved by a valid IRB/REB/IEC prior to initiation of the 
study. Written notification of approval is to be submitted by the Investigator to Sunovion 
monitor prior to shipment of investigational drug supplies, and will include the date of the 
committee's approval and the chairperson's signature. This written approval will consist of a 
completed Institutional Review Board Approval form or Research Ethics Board Approval form, 
or written documentation from the IRB or REB containing the same information. 
Until written approval by the IRB/REB/IEC has been received by the Investigator, no subject 
may undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB/REB/IEC. Written 
approval from the IRB/REB/IEC, or a designee, must be received by Sunovion, before 
implementation. This written approval will consist of a completed approval form, or written 
documentation from the IRB/REB/IEC containing the same information. 
19.2.3 
Regulatory Authority/Agency 
For Investigational New Drug (IND) studies, the minimum standards of study conduct and 
requirements for informed consent are defined in the applicable regulations of the country in 
which the study is conducted. 
This protocol must be reviewed and approved by the country specific Regulatory 
Authority/Agency prior to initiation of the study. The Sponsor or authorized delegate will be 
responsible for the submission.  
 
 
 


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19.3 
APPENDIX III: Modified Hoehn and Yahr Scale 
Modified Hoehn & Yahr 
0: 
Asymptomatic. 
1:  
Unilateral involvement only. 
1.5:  
Unilateral and axial involvement 
2:  
Bilateral involvement without impairment of balance. 
2.5:  
Mild bilateral disease with recovery on pull test. 
3:  
Mild 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. 
 
 
 


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19.4 
APPENDIX IV: Movement Disorder Society - Unified Parkinson’s Disease Rating 
Scale (MDS-UPDRS) 


MDS-UPDRS Permissions  
 
Permission is required to use the MDS-developed Rating Scales (with the exception of 
personal/individual use). Reproduction, translation, modification, sale, or distribution of any 
portion of the MDS Rating Scales is strictly prohibited. MDS Rating Scales may not be 
incorporated into clinical trials, training or certification programs or materials, software programs, 
or otherwise except through use of the Permissions Request Form and payment of applicable 
fees. 
 
 
Continue to p. 2 to view the MDS-UPDRS  
 
________________________________________________________________________ 
 


Page 1 
 
 
                   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 MDS 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 III (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 III 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 III:  Stanley Fahn (chair), Joseph Jankovic, C. Warren Olanow 
Part IV:  Pablo Martinez-Martin (chair), Andrew Lees, Olivier Rascol, Bob van Hilten 
Development Standards: Glenn T. Stebbins (chair), Robert Holloway, David Nyenhuis 
Appendices:  Cristina Sampaio (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
July 1, 2008 


Page 2 
 
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 1B is a component of the self-administered Patient Questionnaire that covers seven 
questions on non-motor experiences of daily living.  
  
Part 1A:  
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 0 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 
responses to the patient as the responses use clinical terminology.  You will be asking enough probing questions to 
determine the response 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. 
Is this item normal for you? 
Consider mild (2) as a reference point 
and then compare with slight (1). 
Consider moderate (3) to see if this 
answer fits better. 
Consider severe (4) to see if this 
answer fits better. 
‘Yes, severe is closest.’ 
‘No, I have problems.’ 
If mild is closer than slight. 
Mark (0) Normal. 
Confirm and mark (1) Slight. 
Confirm and mark (2) Mild. 
Confirm and mark (3) Moderate. 
Confirm and mark (4) Severe. 
If moderate is closer than mild. 
‘Yes’. 
‘Yes, slight is closest’. 
‘No, moderate is too severe’. 
‘No, severe is too severe’. 
July 1, 2008


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July 1, 2008 
                 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: 
  
  Patient  
   Caregiver  
   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.  
SCORE 
 
 
 
 
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]   
 
 
0:  Normal:        No cognitive impairment. 
 
1:  Slight: 
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.  
 
 
 
___ ___ - ___ ___  - ___ ___ ___ ___     
(mm-dd-yyyy)     
Assessment Date 
 
____ ____ ____ 
 
Site ID 
 
____ ____ ____ ____ ____ ____ ____ ____ 
 
                 Patient Name or Subject ID 
 
 
____ ____ ____ 
 
Investigator’s Initials 


Page 4 
 
 
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 caregiver]: 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]  
 
0:  Normal:        No hallucinations or psychotic behaviour. 
 
1:  Slight: 
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. 
 
 
SCORE 
 
 
 
 
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]  
 
0:  Normal:       No depressed mood. 
 
1:  Slight: 
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. 
 
2:  Mild:  
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.  
 
 
 
July 1, 2008


Page 5 
 
 
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 caregiver]: 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: 
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. 
 
2:  Mild: 
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.  
 
SCORE 
 
 
 
 
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.]  
 
0:  Normal: 
 No apathy. 
 
1:  Slight: 
Apathy appreciated by patient and/or caregiver, but no interference with daily 
activities and social interactions. 
 
2:  Mild:  
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. 
 
July 1, 2008 


Page 6 
 
 
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.   
 
0:  Normal:        No problems present.  
 
1:  Slight:  
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 
 
 
 
 
 
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 II [Motor Experiences of Daily Living].   
July 1, 2008 


Page 7 
 
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 0 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): 
 Patient 
        Caregiver         Patient and Caregiver in Equal Proportion  
Patient Questionnaire:   
July 1, 2008


Page 8 
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:  
No problems. 
 
1:  Slight: 
Sleep problems are present but usually do not cause trouble 
getting a full night of sleep.  
 
2:  Mild:  
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. 
SCORE 
 
 
 
 
1.8  DAYTIME SLEEPINESS 
 
Over the past week, have you had trouble staying awake during the daytime?   
 
0:  Normal:  
No daytime sleepiness. 
 
1:  Slight: 
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  
eating or talking with other people. 
 
4:  Severe:  
I often fall asleep when I should not.  For example, while eating or 
talking with other people.  
 
July 1, 2008


Page 9 
 
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 
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. 
 
SCORE 
 
 
 
 
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. 
 
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.    
 
 
July 1, 2008


Page 10 
 
1.11  CONSTIPATION PROBLEMS 
 
Over the past week have you had constipation troubles that cause you difficulty 
moving your bowels?    
 
0:  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 
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.  
SCORE 
 
 
 
 
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?  
 
0:  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 
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.   
 
July 1, 2008


Page 11 
 
July 1, 2008 
 
1.13  FATIGUE 
 
Over the past week, have you usually felt fatigued?  This feeling is not part of being 
sleepy or sad  
 
0:  Normal: 
No fatigue. 
 
1:  Slight:  
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.   
  
SCORE 
 
 
 
 
2.1  SPEECH 
 
Over the past week, have you had problems with your speech?  
 
0:  Normal: 
Not at all (no problems). 
 
1:  Slight: 
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.     
 
Part II:  Motor Aspects of Experiences of Daily Living (M-EDL) 
   


Page 12 
 
2.2   SALIVA & DROOLING    
 
Over the past week, have you usually had too much saliva during when you are awake 
or when you sleep?   
 
0:  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 
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. 
SCORE 
 
 
 
 
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?  
 
0:  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 
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 


Page 13 
 
 July 1, 2008 
 
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?   
 
0:  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 
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. 
SCORE 
 
 
 
 
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?  
 
0:  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).  
 
3:  Moderate: 
I need help for many dressing tasks.   
 
4:  Severe: 
I need help for most or all dressing tasks.  
 


Page 14 
 
  July 1, 2008 
 
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. 
 
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. 
 
SCORE 
 
 
 
2.7  HANDWRITING 
 
Over the past week, have people usually had trouble reading your handwriting?  
 
0:  Normal: 
Not at all (no problems). 
 
1:  Slight: 
My writing is slow, clumsy or uneven, but all words are clear.  
 
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.   
 
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.  
 
 


Page 15 
 
 July 1, 2008
 
2.9  TURNING IN BED 
 
Over the past week, do you usually have trouble turning over in bed?   
 
0:  Normal: 
Not at all (no problems). 
 
1:  Slight: 
I have a bit of trouble turning, but I do not need any help. 
 
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.  
 
SCORE 
 
 
 
2.10  TREMOR 
 
Over the past week, have you usually had shaking or tremor?  
 
0:  Normal: 
Not at all. I have no shaking or tremor. 
 
1:  Slight: 
Shaking or tremor occurs but does not cause problems with any 
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?   
 
0:  Normal: 
Not at all (no problems). 
 
1:  Slight: 
I am slow or awkward, but I usually can do it on my first try. 
 
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.  
 
 


Page 16 
 
 July 1, 2008 
 
2.12  WALKING AND BALANCE 
 
Over the past week, have you usually had problems with balance and walking?  
 
0:  Normal: 
Not at all (no problems). 
 
1:  Slight: 
I am slightly slow or may drag a leg. I never use a walking aid. 
 
2:  Mild:   
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: 
I usually use the support of another persons to walk safely without 
falling. 
 
SCORE 
 
 
 
 
 
 
 
 
2.13  FREEZING 
 
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.  
 
0:  Normal:  
Not at all (no problems). 
 
1:  Slight: 
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. 
 
2:  Mild: 
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.    
 
 
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.    


Page 17 
 
  July 1, 2008 
Part III:  Motor Examination    
 
Overview:  This portion of the scale assesses the motor signs of PD.  In administering Part III 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?         No     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:  
 
 ON:  On is the typical functional state when patients are receiving medication and have a good response.   
 
 OFF:  Off is the typical functional state when patients have a poor response in spite of taking medications. 
  
 
3c   Is the patient on  Levodopa ?            No     Yes 
3.C1 If yes, minutes since last levodopa dose:  _____________   
 


Page 18 
 
  July 1, 2008 
 
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).  
 
0:  Normal: 
No speech problems. 
 
1:  Slight: 
Loss of modulation, diction or volume, but still all words easy to understand.  
 
2:  Mild: 
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.  
SCORE 
 
 
 
 
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.  
 
0:  Normal: 
Normal facial expression. 
 
1:  Slight: 
Minimal masked facies manifested only by decreased frequency of blinking.  
 
2:  Mild: 
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.  
 


Page 19 
 
 July 1, 2008 
 
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.   
 
0:  Normal:   
No rigidity. 
 
1:  Slight:  
Rigidity only detected with activation maneuver.   
 
2:  Mild:  
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.  
 
SCORE 
 
Neck 
 
 
RUE 
 
 
LUE 
 
 
RLE 
 
 
LLE 
 
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:  
No problems. 
 
1:  Slight: 
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. 
   
2:  Mild: 
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.  
 
R 
 
 
L 


Page 20 
  July 1, 2008 
 
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. 
 
0:  Normal:  
No problem. 
 
1:  Slight: 
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.  
 
2:  Mild: 
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.  
 
SCORE 
 
 
 
 
 
 
 
R 
 
 
L 
 
 
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 10 times as fast and as 
fully as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude. 
 
0:  Normal: 
 No problems. 
 
1:  Slight: 
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.  
 
2:  Mild: 
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.  
 
R 
 
 
L 


Page 21 
 
  July 1, 2008 
 
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 10 times as big and as fast as possible. Rate each side separately, evaluating speed, 
amplitude, hesitations, halts and decrementing amplitude. 
 
0: Normal:  
No problem. 
 
1:  Slight: 
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) amplitude 
decrements near the end of the ten taps.  
 
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.  
 
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.   
 
4:  Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements.  
SCORE 
 
 
 
 
 
 
 
R 
 
 
L 
 
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 10 times as high and 
as fast as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude.  
 
0:  Normal:  
No problems. 
 
1:  Slight:   
Any of the following: 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.  
 
2:  Mild:  
Any of the following: a) 3 to 5 interruptions during the movements; b) mild 
slowness; c) 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 in speed; c) 
amplitude decrements after the first tap.  
 
4:  Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements.  
 
R 
 
 
L 


Page 22 
  July 1, 2008 
 
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 in 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 
 
0:  Normal:  
No problems. Able to arise quickly without hesitation.  
 
1:  Slight: 
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.  
 
2:  Mild:  
Pushes self up from arms of chair without difficulty. 
 
3:  Moderate:   
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. 
 
4:  Severe:   
Unable to arise without help.  
SCORE 
 
 
 
 
3.10  GAIT      
   
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 
 
0:  Normal:   
No problems. 
 
1:  Slight:  
Independent walking with minor gait impairment.    
  
2:  Mild:  
Independent walking but with substantial gait impairment.  
 
3:  Moderate:   
Requires an assistance device for safe walking (walking stick, walker) but not a 
person.   
 
4: Severe:  
Cannot walk at all or only with another person’s assistance.  
 


Page 23 
    
   July 1, 2008 
 
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.   
 
0:  Normal:           No freezing. 
 
1:  Slight:              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. 
 
2:  Mild:                 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. 
 
3:  Moderate:         Freezes once during straight walking.  
 
4:  Severe:             Freezes multiple times during straight walking.  
SCORE 
 
 
 
 
 
 
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:  
No problems:  Recovers with one or two steps.   
 
1:  Slight:  
3-5 steps, but subject recovers unaided.   
 
2:  Mild: 
More than 5 steps, but subject recovers unaided. 
 
3:  Moderate: 
Stands safely, but with absence of postural response; falls if not caught by 
examiner. 
 
4:  Severe:  
Very unstable, tends to lose balance spontaneously or with just a gentle pull on 
the shoulders.  
 


Page 24 
  July 1, 2008 
 
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, tell 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.  
 
SCORE 
 
 
 
 
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
, 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.  
 
 
R 
 
 
L 
: All tremor, including re-emergent rest tremor


Page 25 
 
 July 1, 2008 
 
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 
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.  
 
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 
 
 
R 
 
 
L 
 
3.17   REST TREMOR AMPLITUDE   
  
Instructions to examiner: This and the next item have been placed purposefully at the end of the
e rater to gather observations on rest tremor that may appear at any time
en quietly sitting, during walking and during activities when some body p
t rest.  Score the maximum amplitude that is seen at any time as the fin
 and not the persistence or the intermittency of the tremor. 
e patient should sit quietly in a chair with the hands placed on the arms 
 
examination to allow th
 during 
the exam, including wh
arts are 
moving but others are a
al score. 
Rate only the amplitude
As part of this rating, th
of the 
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.    
 
 
 
 
Extremity ratings 
 
  
0:  Normal:  
No tremor.  
 
1:  Slight.: 
< 1 cm in maximal amplitude.  
 
2:  Mild: 
> 1 cm but < 3 cm in maximal amplitude.  
 
3:  Moderate: 
3 - 10 cm in maximal amplitude.    
       
4:  Severe: 
> 10 cm in maximal amplitude.  
 
 
 
Lip/Jaw ratings 
 
0:  Normal:  
No tremor.  
 
 
1:  Slight: 
< 1 cm in maximal amplitude.  
 
 
2:  Mild: 
> 1 cm but < 2 cm in maximal amplitude.  
 
 
3:  Moderate: 
> 2 cm but < 3 cm in maximal amplitude.  
 
 
 
4:  Severe: 
> 3 cm in maximal amplitude.  
 
 
  
 
RUE 
 
 
LUE 
 
 
RLE 
 
 
LLE 
 
Lip/Jaw 


Page 26 
  July 1, 2008 
 
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. 
 
0:  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.  
 
SCORE 
 
 
 
 
 
 
 
 
 
 
DYSKINESIA IMPACT ON PART III RATINGS 
 
A.  Were dyskinesias (chorea or dystonia) present during examination?        No     Yes 
 
B.  If yes, did these movements interfere with your ratings?                           No     Yes  
 
 
HOEHN AND YAHR STAGE 
       0:  Asymptomatic. 
       1:  Unilateral involvement only. 
       2:  Bilateral involvement without impairment of balance. 
       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. 
 
 


  July 1, 2008                                                                                                                                                                                                                                       Page 27 
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 will 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 wiggling, jerking and irregular movements.  Add 
up all the time 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. 
 
3:  Moderate: 
51 - 75% of waking day. 
 
4:  Severe: 
> 75% of waking day. 
SCORE 
 
 
 
1.  Total Hours Awake:                     _____ 
 
2.  Total Hours with Dyskinesia:       _____ 
 
3.  % Dyskinesia = ((2/1)*100):      _____ 


Page 28 
  July 1, 2008 
 
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? 
 
0:  Normal: 
No dyskinesias or no impact by dyskinesias on activities or social interactions. 
 
1:  Slight: 
Dyskinesias impact on a few activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods.   
 
2:  Mild: 
Dyskinesias impact on many activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods.    
 
3:  Moderate: 
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.    
 
4:  Severe: 
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.  
 
SCORE 
 
 
 
 
4.3  TIME SPENT IN THE OFF STATE  
 
Instructions to examiner:
     Some patients with Parkinson's disease have a good effect 
from 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 
low level or OFF function  ____ (Use this number for your calculations). 
 
0:  Normal:   
No OFF time. 
 
1:  Slight:  
≤ 25% of waking day. 
 
2:  Mild: 
26 - 50% of waking day. 
 
3:  Moderate: 
51 - 75% of waking day. 
 
4:  Severe: 
> 75% of waking day. 
 
B . MOTOR FLUCTUATIONS 
  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.  Additionally 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]:
1.  Total Hours Awake:       _____ 
 
2.  Total Hours OFF:           _____ 
 
3.  % OFF = ((2/1)*100):     _____ 


Page 29 
   
   July 1, 2008 
 
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 0 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? 
 
0:  Normal: 
No fluctuations or No impact by fluctuations on performance of activities or 
social interactions.  
 
1:  Slight: 
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.   
 
2:  Mild: 
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.   
 
3:  Moderate: 
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.    
   
4:  Severe: 
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.  
 
SCORE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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?” 
 
0:  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%).  
 


Page 30 
 
 July 1, 2008
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?  
 
0:  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. 
 
Summary statement to patient:  READ TO PATIENT 
 
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.   
1.  Total Hours Off:  
                     _____ 
 
2.  Total Off Hours w/Dystonia:           _____ 
                   
3.  % Off Dystonia = ((2/1)*100):         _____ 


Copyright © 2008 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 
 
_________________________ 
___ ___ ___ 
___ ___ - ___ ___  - ___ ___ ___ ___ 
___ ___ ___ 
Patient Name or Subject ID 
Site ID  
(mm-dd-yyyy) 
Assessment Date 
Investigator’s Initials 
     MDS UPDRS Score Sheet   
3.3b  
Rigidity– RUE  
 
1.A  
Source of information   
  Patient   
  Caregiver 
  Patient + Caregiver  
3.3c  
Rigidity– 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   
3.6b  
Pronation- supination movements– Left hand   
 
1.6a  Who is filling out questionnaire  
  Patient   
  Caregiver 
  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 leg  
 
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/jaw  
 
2.11  
Getting out of bed  
 
3.18  
Constancy of rest   
 
2.12  
Walking and balance  
 
 
Were dyskinesias presen  
  No 
 Yes  
2.13  
Freezing  
 
 
Did these movements interfere with ratings?  
  No 
 Yes  
3a  
Is the patient on medication?  
  No  
 Yes  
 
Hoehn and Yahr Stage 
 
3b  
Patient’s clinical state  
 Off   
  On  
Part IV 
3c  
Is the patient on Levodopa?  
 No  
 Yes  
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  


Sunovion Pharmaceuticals Inc.  
CTH-201 
28 Aug 2017  
CONFIDENTIAL 
Version: 5.00 
19.5 
APPENDIX V: Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
 


 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Screening 
Version 1/14/09 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Past  
X Months 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
 
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Screening (Version 1/14/09)    
 
 
                                             Page 1 of 2 


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Past X Years 
or 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy, 
or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck 
but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did 
anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal         
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Screening (Version 1/14/09)    
 
 
                                             Page 2 of 2 


 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
                          Page 1 of 2       


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
                          Page 2 of 2                  


Sunovion Pharmaceuticals Inc.  
CTH-201 
28 Aug 2017  
CONFIDENTIAL 
Version: 5.00 
19.6 
APPENDIX VI: United Kingdom Parkinson’s Disease Brain Bank Clinical 
Diagnostic Criteria 
Step 1 - Diagnosis of Parkinsonian Syndrome 
• Bradykinesia 
• At least one of the following 
o Muscular rigidity 
o 4-6 Hz rest tremor 
o Postural instability not caused by primary visual, vestibular, cerebellar, or 
proprioceptive dysfunction 
Step 2 - Exclusion criteria for PD 
• History of repeated strokes with stepwise progression of Parkinsonian features 
• History of repeated head injury 
• History of definite encephalitis 
• Oculogyric crises 
• Neuroleptic treatment at onset of symptoms 
• Sustained remission 
• Strictly unilateral features after 3 years 
• Supranuclear gaze palsy 
• Cerebellar signs 
• Early severe autonomic involvement 
• Early severe dementia with disturbances of memory, language, and praxis 
• Babinski sign 
• Presence of cerebral tumor or communication hydrocephalus on imaging study 
• Negative response to large doses of L-Dopa in absence of malabsorption 
• MPTP exposure 


Sunovion Pharmaceuticals Inc.  
CTH-201 
28 Aug 2017  
CONFIDENTIAL 
Version: 5.00 
Step 3 - Supportive prospective positive criteria for PD 
Three or more required for diagnosis of definite Parkinson’s disease in combination with step 
one 
• Unilateral onset 
• Rest tremor present 
• Progressive disorder 
• Persistent asymmetry affecting side of onset most 
• Excellent response (70-100%) to L-Dopa 
• Severe L-Dopa-induced chorea 
• L-Dopa response for 5 years or more 
• Clinical course of ten years or more 
 
Reference: Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of 
idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg 
Psychiatry. 1992;55(3):181-4. 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
A Phase 2, Randomized, Double-Blind, Placebo Controlled, 3-Period Crossover, Positive 
Control, QT-Evaluation Study of APL-130277 in Subjects with Parkinson’s Disease Complicated 
by Motor Fluctuations (“OFF” Episodes) 
 
 
Study code: CTH-201 
 
Phase II study 
 
 
 
STATISTICAL ANALYSIS PLAN 


 
Statistical Analysis Plan      
 
Page 2 (30) 
 
Sponsor: Sunovion Pharmaceuticals, Inc. 
Final 1.0 
21 Dec 2017 
Study: CTH-201 
 
 
 
 
 
Signatures: 
 
 
Statistical Analysis Plan was prepared by: 
 
 
 
 
 
Date 
Consulting Statistician, Clintrex 
 
 
 
 
Statistical Analysis Plan was reviewed/approved by: 
 
 
 
 
 
 
Date 
CEO, Clintrex 
 
 
 
 
 
Date 
Biostatistics, Sunovion 
 
 
 
 
 
 
Date 
Medical Lead, Sunovion 
 
 
 
 
 


 
Statistical Analysis Plan      
 
Page 3 (30) 
 
Sponsor: Sunovion Pharmaceuticals, Inc. 
Final 1.0 
21 Dec 2017 
Study: CTH-201 
 
Table of Contents 
 
1 
Abbreviations ...................................................................................................................................... 5 
2 
Introduction......................................................................................................................................... 7 
3 
Study objectives .................................................................................................................................. 7 
4 
Design and type of the study ............................................................................................................... 7 
4.1 
Screening Visits ........................................................................................................................... 8 
4.2 
Dose Titration Phase .................................................................................................................... 8 
4.3 
Three-Way Balanced Randomized Crossover Assessment Phase ............................................. 10 
5 
Endpoints .......................................................................................................................................... 10 
5.1 
Primary endpoint ........................................................................................................................ 10 
5.2 
Secondary endpoints .................................................................................................................. 11 
5.3 
Exploratory efficacy endpoints .................................................................................................. 13 
6 
Sample size considerations ............................................................................................................... 14 
7 
Statistical hypotheses ........................................................................................................................ 14 
8 
Analysis sets ..................................................................................................................................... 14 
8.1 
All Available population ............................................................................................................ 15 
8.2 
ECG population ......................................................................................................................... 15 
8.3 
Completer population ................................................................................................................. 15 
8.4 
Efficacy population .................................................................................................................... 15 
8.5 
Safety population ....................................................................................................................... 15 
8.6 
Crossover Phase Safety population ............................................................................................ 15 
8.7 
PK population ............................................................................................................................ 16 
9 
General statistical considerations ..................................................................................................... 16 
9.1 
Adjustment for covariates .......................................................................................................... 16 
9.2 
Handling of drop-outs or missing data ....................................................................................... 16 
9.3 
Interim analyses and data monitoring ........................................................................................ 16 
9.4 
Multiple comparison/multiplicity .............................................................................................. 17 
9.5 
Examination of subgroups ......................................................................................................... 17 
10 
Disposition .................................................................................................................................... 17 
11 
Demographic and other baseline characteristics ........................................................................... 18 
12 
Concomitant medication/treatment ............................................................................................... 19 
13 
Medical history .............................................................................................................................. 20 
14 
Analysis of Primary and Secondary Endpoints ............................................................................. 20 
14.1 
Primary endpoint ................................................................................................................. 20 
14.1.1 
Central Tendency Analysis .................................................................................................. 20 
14.1.2 
Assay sensitivity .................................................................................................................. 21 
14.1.3 
Sensitivity analyses of the primary endpoint ....................................................................... 21 
14.1.4 
Graphical summaries of the primary endpoint .................................................................... 22 
14.1.5 
Outlier analysis .................................................................................................................... 22 
14.2 
Secondary endpoints ............................................................................................................ 23 


 
Statistical Analysis Plan      
 
Page 4 (30) 
 
Sponsor: Sunovion Pharmaceuticals, Inc. 
Final 1.0 
21 Dec 2017 
Study: CTH-201 
 
14.3 
Exploratory efficacy endpoints ............................................................................................ 24 
15 
Analysis of safety and tolerability ................................................................................................. 25 
15.1 
Extent of exposure ............................................................................................................... 25 
15.2 
Compliance .......................................................................................................................... 25 
15.3 
Adverse events .................................................................................................................... 25 
15.4 
Laboratory safety variables .................................................................................................. 27 
15.5 
Vital signs ............................................................................................................................ 27 
15.6 
12-Lead ECG (resting) ........................................................................................................ 28 
15.7 
Other safety variables .......................................................................................................... 29 
16 
Other variables .............................................................................................................................. 29 
17 
Deviations from the analyses planned in the study protocol ......................................................... 29 
18 
Execution of statistical analyses .................................................................................................... 30 
19 
Hardware and software .................................................................................................................. 30 
20 
References ..................................................................................................................................... 30 
21 
Appendices .................................................................................................................................... 31 
21.1 
Table and figure plan ........................................................................................................... 31 
21.2 
Data listing plan .................................................................................................................. 32 
 


 
Statistical Analysis Plan      
 
Page 5 (30) 
 
Sponsor: Sunovion Pharmaceuticals, Inc. 
Final 1.0 
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Study: CTH-201 
 
1 
Abbreviations 
 
AAP  
All Available Population 
AE 
 
Adverse Event 
ATC  
Anatomical Therapeutic Chemical 
AUC0-t 
Area under the concentration-time curve from time zero to the last measurable plasma 
concentration-time curve using the linear up log down trapezoidal rule 
AUCinf  
Area under the concentration-time curve from time zero extrapolated to infinity using 
the linear up log down trapezoidal rule 
BLQ  
Below the Limit of Quantitation 
BP 
 
Blood Pressure 
CI 
 
Confidence Interval 
CL/F   
Plasma clearance 
Cmax   
Maximum observed plasma concentration 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
 
Coefficient of Variation 
ECG  
Electrocardiogram 
HR 
 
Heart Rate 
L-Dopa 
Levodopa 
λz  
 
Terminal-phase rate constant 
LS 
 
Least Square 
M/P 
 
Metabolite to Parent 
MDS  
Movement Disorders Society 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MMSE 
Mini–Mental State Examination 
MRT  
Mean Residence Time 
OH 
 
Orthostatic Hypotension 
P1V1  
Period 1 Dosing Visit 1 
PD 
 
Parkinson’s Disease 
PK 
 
Pharmacokinetics 


 
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Placebo 
Placebo for APL-130277 
PT 
 
Preferred Term 
QTc 
Corrected QT interval 
QTcB 
Corrected QT interval based on the Bazett correction method 
QTcF 
Corrected QT interval based on the Fridericia correction method 
REML  
Restricted Maximum Likelihood 
RR 
 
Respiratory Rate 
SAP 
 
Statistical Analysis Plan 
SD 
 
Standard Deviation 
SEM  
Standard Error of the Mean 
SI 
 
International System of Units 
SOC  
System Organ Class 
SV 
 
Screening Visit 
t½  
 
Terminal-phase half-life 
TEAE  
Treatment-Emergent Adverse Event 
Tmax 
 
Observed time of the maximum concentration 
TV 
 
Titration Visit 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
WHO-DD  
World Health Organization Drug Dictionary 


 
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2 
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analysis as it is foreseen at the time of 
planning the study. The SAP will serve as a compliment to the study protocol and supersedes it in case 
of differences.  In case of major differences between the study protocol and SAP (e.g. changes in the 
analysis related to the primary endpoint), a protocol amendment will be considered. The SAP may be 
updated during the conduct of the study and will be finalized before breaking the blind. 
3 
Study objectives 
The primary objective is to evaluate the effect of APL-130277 compared to placebo on corrected QT 
(QTc) intervals in subjects with Parkinson’s disease (PD) complicated by motor fluctuations. 
The secondary objectives include the evaluation of safety and pharmacokinetics (PK) of APL-130277. 
A comparison of efficacy of the highest APL-130277 dose and the lowest APL-130277 dose resulting 
in a full “ON” during the Dose Titration Phase will be included as an exploratory objective. 
4 
Design and type of the study 
This is a multi-center, phase 2, randomized, double-blind, placebo controlled, 3-period crossover, 
positive control, QT-evaluation study of APL-130277 in subjects with PD complicated by motor 
fluctuations (“OFF” episodes). The term placebo in this SAP refers to the placebo for APL-130277 or 
“placebo APL-130277”. 
This study will commence with initial Screening Visits, followed by an open-label Dose Titration Phase 
in which individual responses to single doses of APL-130277 are evaluated in order to determine the 
dose for the Randomized Assessment Phase. APL-130277 and placebo will be double-blinded and 
randomized in a balanced three-way crossover Williams design with open-label moxifloxacin treatment 
(Period 1, Period 2 and Period 3). 
The study design is summarized in Figure 1. 


 
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Figure 1 Study Design 
 
4.1 
Screening Visits 
Before any study procedures are performed on any subject, informed consent must be obtained at an 
initial Screening Visit (SV1). Subjects recruited to participate in the study, and who have provided full 
consent to participate, will be asked to attend a second Screening Visit (SV2), having taken their last 
dose of levodopa (L-Dopa) and any other adjunctive PD medication no later than midnight the evening 
prior to the visit. Their normal morning dose of L-Dopa (without adjunctive PD medication) will be 
administered in the clinic following confirmation of an “OFF” episode by the Investigator and subject, 
to ensure that they experience an “ON” response. Eligibility criteria will be assessed by the Investigator 
and approved by the Enrollment Adjudication Committee prior to enrollment. 
4.2 
Dose Titration Phase 
Subjects will be asked to return to the clinic the morning of Titration Visit 1 (TV1) for the Dose 
Titration Phase of the study. 
Depending on the Investigator's decision, subjects will be asked to arrive at the clinic: 
 after their usual morning dose of PD medications; but before taking their next dose of 
medication; OR 
 after withholding their normal morning dose of L-dopa (ie, in the practically defined "OFF" 
state with no anti-parkinsonian medication after midnight the night prior). 


 
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During the Dose Titration Phase of the study, subjects will start with a dose of 10 mg APL-130277 and 
increase in 5 mg increments up to 40 mg and then in 10 mg increments for the 50 mg and 60 mg dose 
levels until the subject reaches a full “ON” state. Once a full “ON” state is achieved, dosing will 
continue for 2 additional visits to a maximum dose of 60 mg (i.e., if a subject experiences the first full 
“ON” at 10 mg, dosing will continue up until a dose of 20 mg). 
For those subjects who do not achieve a full "ON" response, titration should continue until the 
maximum tolerated dose of APL-130277 is determined to a maximum dose of 60 mg. 
Note: For subjects who have previously participated in the CTH-300 or CTH-301 study, the subject 
will begin titration at the effective dose used in the respective previous study. Similarly dose titration of 
these subjects will increase in 5 mg increments up to 40 mg and then in 10 mg increments for the 50 mg 
and 60 mg dose levels until the subject reaches a full “ON” state. Once a full “ON” state is achieved, 
dosing will continue for 2 additional visits to a maximum dose of 60 mg (i.e., if a subject experiences 
the first full “ON” at 35 mg, dosing will continue up until a dose of 50 mg). 
At Titration Visit 1 (TV1), once the subject's “OFF” state has been confirmed by both the Investigator 
and subject, the subject will be treated with 10 mg APL-130277. Subjects who tolerate the 10 mg APL-
130277 will restart their normal PD medications and will be asked to return to the clinic the next 
business day for Titration Visit 2 (TV2), to assess the next highest dose (i.e., 15 mg) in a manner 
identical to that of Titration Visit 1 (TV1).  
Doses of APL-130277 will increase in 5 mg increments up to 40 mg and then in 10 mg increments for 
the 50 mg and 60 mg dose levels until a full “ON” state is achieved, then dosing will continue for 2 
additional visits to a maximum dose of 60 mg. This will sequentially be 20 mg [TV3], 25 mg [TV4], 
30 mg [TV5], 35 mg [TV6], 40 mg [TV7], 50 mg [TV8] and 60 mg [TV9].  
For Titration Visit 3 (TV3), Titration Visit 4 (TV4), Titration Visit 5 (TV5), and Titration Visit 6 
(TV6) subjects should be dosed with the next highest dose of study medication within 4 hours of the 
initial dose, as long as the subject achieves another “OFF” state that day. TV3 should be paired with 
TV4 (20 mg and 25 mg can be dosed on the same day), TV4 should be paired with TV5 (25 mg and 
30 mg can be dosed on the same day), TV5 should be paired with TV6 (30 mg and 35 mg can be dosed 
on the same day) and TV6 should be paired with TV7 (35 mg and 40 mg can be dosed on the same 
day). 
Should the subject be unable to tolerate either of the two additional dose levels after reaching a full 
“ON” state, in the Investigator’s opinion, due to adverse events commonly associated with 
apomorphine (e.g., orthostatic hypotension, nausea, vomiting, etc.), subjects will be randomized to the 
previous dose. 
Safety and efficacy assessments will be performed at each visit. Efficacy will be assessed using 
Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III. Safety 
assessments will include adverse events (AEs); electrocardiograms (ECGs); and vital signs, including 
supine and standing blood pressure (BP) to assess OH. ECGs will be obtained using a 12-lead resting 
ECG device just prior to dosing and 45 minutes after dosing as a safety evaluation and assessed by the 


 
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Investigator at each Titration Visit. 
4.3 
Three-Way Balanced Randomized Crossover Assessment Phase 
Subjects who successfully complete the Dose Titration Phase of the study, and are approved by the 
Sponsor to proceed to randomization, will be asked to return to the clinic for Period 1 Dosing Visit 1 
(P1V1). This visit will occur between 2 and 7 days after the final visit in the Dose Titration Phase of the 
study. Depending on the Investigator's decision, subjects will be asked to arrive at the clinic: 
 after their usual morning dose of PD medications; but before taking their next dose of 
medication; OR 
 after withholding their normal morning dose of L-dopa (ie, in the practically defined "OFF" 
state with no anti-parkinsonian medication after midnight the night prior). 
Subjects will be randomized in equal numbers to six possible sequences of each of the three treatments 
being studied: 
1. Treatment A: APL-130277 at the dose determined in the Dose Titration Phase, 
2. Treatment B: Matched placebo APL-130277, 
3. Treatment C: A single 400 mg dose of moxifloxacin. 
Following confirmation by both the Investigator and subject that the subject is in the “OFF” state, the 
subject will be dosed according to the subject's random treatment assignment. APL-130277 and placebo 
will be administered in a double-blind fashion and moxifloxacin will be administered open-label in a 
three-way balanced crossover. All subjects will be exposed to all three treatments. The six possible 
treatment sequences are: 1) ABC; 2) ACB; 3) BCA; 4) BAC; 5) CAB; and 6) CBA. 
Subjects will return to clinic 3 days after Period 1 and will be dosed for Period 2 with one of the other 
two treatments. Subjects will return to clinic 3 days after Period 2 and will be dosed for Period 3 with 
the third and last treatment. 
At P1V1, three (3) sets of triplicate 12-Lead ECGs will be obtained using a continuous 12-lead Holter 
monitor over approximately 1-hour (prior to dosing) as the baseline assessment. 
5 
Endpoints 
5.1 
Primary endpoint 
The primary endpoint of this study is the time-matched change from baseline in QTc, placebo-adjusted 
and corrected for HR based on the Fridericia correction method (QTcF) using delta delta method 
(ΔΔQTcF). Assay sensitivity will be demonstrated by inclusion of a positive control, moxifloxacin. 


 
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Baseline is defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (P1V1). 
In case any of the 9 ECGs is missing, the baseline is defined as the mean of the available baseline 
values.  
The post-dose ECGs are recorded at 15, 30, 45 and 60 minutes and 2, 3, 4, 8, 12 and 24 hours post-dose 
at Period 1, Period 2 and Period 3. One set of triplicate ECGs (3 ECGs) is obtained at each of the 10 
time points. For each of the 10 time points, an average value will be calculated based on the 3 (or all 
available) ECGs. These average values will be used in all calculations. For the primary analysis, the 
following 7 time points will be evaluated: 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose. The 
endpoint will be calculated as the difference between each of the 7 post-dose ECGs and baseline 
(P1V1), separately for each of the 3 periods. For each of the 7 time points, the changes from baseline 
will be compared between APL-130277 and placebo using the ΔΔQTcF method. 
The endpoints for the assay sensitivity comparison will be derived in a similar way. For assay 
sensitivity, the changes from baseline at 4 selected time points (60 minutes and 2, 3 and 4 hours post-
dose) will be compared between moxifloxacin and placebo using the ΔΔQTcF method. 
The QTcF will be calculated as follows: 
 QTcF1 = QT1/RR1
1/3, where RR1 is 60/HR1 
 QTcF2 = QT2/RR2
1/3, where RR2 is 60/HR2 
 QTcF3 = QT3/RR3
1/3, where RR3 is 60/HR3 
 Mean QTcF = (QTcF1 + QTcF2 + QTcF3)/3 (rounded to whole number) 
The values provided by the central core laboratory will be used in all calculations. 
5.2 
Secondary endpoints 
The secondary endpoints will be evaluated without any hierarchical order. Due to this, no confirmatory 
claims will be made on the secondary endpoints. 
 PK of apomorphine and apomorphine metabolites 
Blood draws for PK analyses on APL-130277 and placebo treatment days will occur at t = 0 (just 
prior to dosing), 30, 45, 60 minutes after dosing and at 2, 4 hours after dosing. On the moxifloxacin 
treatment day, blood draws will occur at t = 0 (just prior to dosing), 30, 60 minutes after dosing and 
at 2, 3, 4, 6, 8 hours after dosing. The PK endpoints include both the concentration data and PK 
parameters. 
Concentration levels of apomorphine and metabolites (norapomorphine and apomorphine sulphate) 
will be measured in plasma using a validated liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) method. PK parameters will be derived using noncompartmental methods employing 
a validated installation of WinNonlin® Phoenix version 6.3 (Pharsight, St Louis, MO) software. 


 
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The following PK parameters will be estimated or calculated using plasma apomorphine, 
norapomorphine and apomorphine sulphate concentration-time data. Other PK parameter may be 
calculated as appropriate. Actual elapsed time from dosing will be used to determine all individual 
PK parameters. 
o Cmax: Maximum drug concentration in plasma, determined directly from the concentration-
time profile. 
o Tmax: Time of Cmax in plasma, determined directly from the concentration-time profile. 
o AUC0-t: Area under the plasma concentration vs. time curve from time of dosing to last 
measurable concentration, calculated using the linear up, log down trapezoidal rule. 
o AUCinf: AUC extrapolated to infinity (AUClast + last quantifiable concentration/λz), 
calculated using the linear-up/log-down trapezoidal rule. 
o λz: The terminal phase rate constant; estimated by linear regression through the terminal 
phase of the log concentration-time profile, using at least 3 data points. 
o t½: The terminal phase half-life calculated as ln(2) / λz. 
o CL/F: Plasma clearance, calculated as Dose/AUCinf after single dose (apomorphine only). 
o MRT: Mean residence time calculated using the following equation: MRT = 
AUMCinf/AUCinf. AUMCinf is the area under the first moment curve. 
o M/P Ratio: Metabolite to Parent exposure ratio (Cmax and AUC). 
 Safety and tolerability of APL-130277 as measured by AEs, physical examination including 
assessment of oropharyngeal AEs, 12-lead ECGs (resting), vital signs including orthostatic 
hypotension, clinical laboratory tests, and Columbia Suicide Severity Rating Scale (C-SSRS) 
assessments. 
The safety endpoints are defined in Section 15 of this SAP. 
 Pharmacodynamic assessments including QTc based on the Bazett correction method (QTcB), heart 
rate (HR), PR interval, QRS interval, uncorrected QT interval, ECG morphology and correlation 
between the QTcF change from baseline and plasma concentrations of APL-130277 
The continuous ECG endpoints (QTcB, HR, PR interval, QRS interval, uncorrected QT interval) 
will be derived similarly as QTcF described above. The QTcB will be calculated as QT / (RR)½ and 
rounded to a whole number similarly as QTcF.  The rest of the parameters will be calculated as 
mean values of the available observations without rounding. The values provided by the central 
core laboratory will be used in all calculations of the continuous ECG endpoints. 
For the ECG morphology, the overall interpretation and the presence of the following abnormalities 
will be defined by the cardiologist of the central core laboratory: 
o Atrial fibrillation 
o Atrial flutter 


 
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o Second degree heart block 
o Third degree heart block 
o Complete right bundle branch block 
o Complete left bundle branch block 
o ST segment elevation 
o ST segment depression 
o T wave abnormalities (negative T waves only) 
o Myocardial infarction pattern 
o New abnormal U waves. 
 Presence of cardiac arrhythmias such as ventricular tachycardia or Torsade de Pointes 
The presence of the cardiac arrhythmias will be defined by the cardiologist of the central core 
laboratory. 
5.3 
Exploratory efficacy endpoints 
 MDS-UPDRS Part III change from pre-dose to 30, 60, 90 minutes after dosing during the Titration 
Phase at the highest APL-130277 dose and the lowest APL-130277 dose resulting in a full “ON” 
The MDS-UPDRS Part III score will be calculated as the sum of the individual items of the MDS-
UPDRS Part III questionnaire (items 3.1 – 3.18) and will be obtained separately at each assessment 
time point. Missing individual items will be imputed using the 2 non-missing values at time points 
adjacent to the missing item on the same date. The maximum of the 2 adjacent values will be 
assigned as the score for the missing item. However, pre-dose values will not be assigned as post-
dose values and if one of the adjacent values for a post-dose value is a pre-dose value, only 1 
adjacent value will be used. If there are more than three missing individual items at a given time 
point, no imputation will be performed for the time point in question and the score will be set as 
missing. If a pre-dose value is missing, the pre-dose value at the prior visit will be used. The MDS-
UPDRS Part III score will be calculated after imputation of the missing item(s) as described above. 
 Time to “ON” during Titration Phase at the highest APL-130277 dose and the lowest APL-130277 
dose resulting in a full “ON” 
The subjects will report the time when they turned to a full “ON” if it occurs within 90 minutes of 
dosing. The time to “ON” will be calculated as minutes from the time when the subject received the 
study medication until the time when turning fully “ON”. If the subject did not turn fully “ON” by 
90 minutes the data will be censored at 90 minutes. 
 Duration of “ON” during Titration Phase at the highest APL-130277 dose and the lowest APL-
130277 dose resulting in a full “ON”.  


 
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The subjects will report the time when they turned “OFF” (in case they first turned fully “ON”) if it 
occurs within 90 minutes of dosing. The duration of “ON” will be calculated as minutes from the 
time when the subject turned fully “ON” until the time when turning “OFF”. If the subject did not 
turn fully “ON” within 90 minutes the duration of “ON” will be defined as zero minutes. If the 
subject turned fully “ON” and did not turn “OFF” by 90 minutes, the data will be censored at 90 
minutes minus the time when the subject turned fully “ON”. 
6 
Sample size considerations 
The study is powered to detect a mean difference in the change in QTcF between APL-130277 and 
placebo APL-130277 (∆∆QTcF) of 7 ms, assuming that the true difference between APL-130277 and 
placebo APL-130277 can be up to 3 ms, adding up to the predefined threshold of 10 ms. The standard 
deviation of ∆∆QTcF is assumed to be 14 ms. Assuming a one-sided significance level of 0.05, 42 
subjects are required for the 3x3 Crossover Phase to achieve approximately 80% power. 
7 
Statistical hypotheses 
The primary objective of this study is to evaluate the effect of APL-130277 compared to placebo on 
QTc intervals in subjects with PD complicated by motor fluctuations. 
The hypothesis of no difference in QTc time between APL-130277 and placebo will be evaluated by 
observing if any of the evaluation time points have a two-sided 90% upper confidence bound (i.e. one-
sided 95%) which is equal to, or exceeds, 10 ms. If the upper limits of the two-sided 90% confidence 
intervals (CIs) for APL-130277 versus placebo fall below 10 ms, it will be concluded that APL-130277 
does not prolong the QTc interval to a clinically significant degree.  
If the upper bound of only 1 or 2 of the 7 time points just exceeds 10 ms, a determination of whether 
this is a false positive response will be based on all of the study findings with special emphasis on the 
PK-Pharmacodynamics evaluation. 
The assay sensitivity will be evaluated by comparing moxifloxacin and placebo. The hypothesis of 
assay sensitivity will be rejected if the lower bound of the one-sided (Bonferroni-corrected) 95% 
confidence interval is below 5 ms at all of the 4 evaluation time points (60 minutes and 2, 3 and 4 
hours). The assay sensitivity is considered to be demonstrated if there is at least one time point where 
the lower confidence bound of the mean difference of moxifloxacin and placebo APL-130277 is greater 
than or equal to 5 ms. The Bonferroni-corrected CIs will be calculated by using the coverage of 
0.05/4=0.0125 for the 4 CIs. 
8 
Analysis sets 
The following analysis sets will be used for the analysis of the disposition and ECG (holter), efficacy, 
safety and PK data. 


 
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8.1 
All Available population 
The All Available Population (AAP) includes all subjects who consented for the study, including 
screening failures. Unless specified otherwise, the AAP will be used for subject listings and for the 
summary of subject disposition. 
8.2 
ECG population 
The ECG population includes all randomized subjects who have evaluable baseline ECG (holter) data 
from P1V1 and at least one evaluable post-dose ECG (holter) assessment during the Crossover Phase. 
The ECG population will be used for the analysis of the primary endpoint and secondary endpoints 
related to ECG (holter) data. The treatment (APL-130277, placebo or moxifloxacin) actually received 
during each crossover period will be used to group the patients.    
8.3 
Completer population 
The Completer population includes all randomized subjects who have any evaluable pre-dose and post-
dose ECG (holter) data from all three periods of the Crossover Phase. The Completer population will 
be used for a sensitivity analysis of the primary endpoint. The treatment (APL-130277, placebo or 
moxifloxacin) actually received during each crossover period will be used to group the patients.   
8.4 
Efficacy population 
The Efficacy population includes all subjects who have efficacy assessments at the lowest dose level 
resulting in a full “ON” and at a higher dose level during the Dose Titration Phase. The patient is 
regarded as having reached full “ON” based on the Case Report Form assessing the time when the 
patient turned “ON”. The efficacy population will be used for the analysis of the efficacy data. 
8.5 
Safety population 
The Safety population includes all subjects who were enrolled and received at least one dose of APL-
130277. The Safety population will be used for the analysis of the safety data from the Dose Titration 
Phase and for the pooled data from Dose Titration Phase and Randomized Crossover Phase. 
8.6 
Crossover Phase Safety population 
The Crossover Phase Safety population includes all randomized subjects who received at least one dose 
of study medication (APL-130277, placebo or moxifloxacin) after the randomization. The Crossover 
Phase Safety population will be used for the analysis of the safety data from the Randomized Crossover 
Phase. The treatment (APL-130277, placebo or moxifloxacin) actually received during each crossover 
period will be used to group the patients. 


 
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8.7 
PK population 
The PK population includes all subjects with sufficient data for PK analysis and will be used for the 
analysis of the PK data. 
9 
General statistical considerations 
All data from the APP entered into the database will be included in subject data listings. The listings 
will be generally sorted by center and subject number (and by visit and by time point, if applicable), 
unless specified otherwise. All applicable data will be summarized by treatment group (APL-130277, 
placebo or moxifloxacin). Unscheduled or repeat assessments will not be included in summary tables, 
but will be included in listings.  
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Standard error of the mean (SEM) will also be 
provided for summaries of efficacy data, if relevant. Additionally, geometric mean and geometric 
coefficient of variation (CV%) will be included in the summaries of the PK data. Descriptive statistics 
for categorical data will include frequency counts and percents. The total number of subjects in the 
treatment group overall (N) will be used as the denominator for percent calculations, unless stated 
otherwise.  
Significance testing will be 2-sided using α = 0.05, unless otherwise specified.  
All statistical analyses and summaries will be produced using SAS version 9.3 or higher. Deviations 
from the statistical plan will be reported in the clinical study report, including the rationale for change. 
9.1 
Adjustment for covariates 
For the analysis of ECG (holter) endpoints, the baseline ECG value (average value of the pre-dose 
ECGs at P1V1) of the endpoint in question will be included as a baseline covariate (for continuous 
endpoints). For the analysis of the continuous efficacy endpoints, the assessment at SV2 will be used as 
the covariate. 
9.2 
Handling of drop-outs or missing data 
All observed data will be included in the primary analysis. The missing and incomplete data will be 
managed using likelihood-based mixed effects modeling. Sensitivity analysis will be conducted in 
subjects with complete data from all study periods. 
9.3 
Interim analyses and data monitoring 
No interim analyses are foreseen. 


 
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9.4 
Multiple comparison/multiplicity 
This study has a single primary endpoint, ΔΔQTcF. The primary endpoint will be evaluated at 7 
different time points for non-inferiority (no meaningful difference between APL-130277 and placebo) 
using the intersection-union testing approach. This is a conservative approach, as non-inferiority must 
be met at each of the 7 time points.  
Assay sensitivity may be demonstrated at any of the 4 time points. Due to this, Bonferroni-adjustment 
will be used for this analysis. 
The secondary endpoints will be evaluated without any hierarchical order. Due to this, no confirmatory 
claims will be made on the secondary endpoints. 
9.5 
Examination of subgroups 
At least the following subgroup analyses have been pre-planned. The subgroup analyses will be 
performed for selected ECG (holter) endpoints (at least the primary endpoint) and for adverse events. 
Selected baseline data will be presented for the subgroups as well. 
 Non-elderly (<65 years) versus elderly (≥65 years) subjects 
 Male versus female subjects 
 Region (US versus non-US) 
 Subjects who had final dose level (i.e. the dose to which the subject was randomized to) of <35 mg 
of less versus subjects with final dose level of ≥35 mg. The dose level documented on the Case 
Report Form page “Randomization” will be used for this classification. 
In addition, for the clinical efficacy endpoints (MDS-UPDRS scores, time to “ON” and duration of 
“ON”), additional exploratory subgroup analyses may be conducted based on the observed patient 
characteristics. These additional subgroup analyses will not be included in the clinical study report. 
10 Disposition 
The subject disposition will be summarized as follows. The percentages will be calculated based on the 
number of enrolled subjects, unless otherwise specified. 
 The number of subjects screened (i.e. the number of subjects in the AAP) 
 The number (%) of subjects who failed screening (% calculated from the AAP), including the 
distribution of reasons for failing the screening. In case the subject fails the screening multiple 
times, all reasons leading to the exclusion will be summarized as event count (i.e. there can be 
multiple reasons for the same subject). 
 The number (%) of subjects enrolled into the study (% calculated from the AAP) 


 
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 The number (%) of subjects who received at least one dose of study medication (Safety 
Population) 
 The number (%) of subjects in the Efficacy population 
 The number (%) of subjects who discontinued the study prematurely before Randomization, 
presented by highest dose level received, including the distribution of reasons for 
discontinuations 
 The number (%) of subjects randomized to the Crossover Phase 
 The subjects who were randomized to the Crossover Phase will be presented by the final 
randomized dose level (% calculated from all randomized subjects) 
 The number (%) of subjects who received at least one dose of study medication during the 
Crossover Phase, i.e. Crossover Phase Safety Population (% calculated from all randomized 
subjects) 
 The number (%) of subjects in the ECG Population (% calculated from all randomized subjects) 
 The number (%) of subjects in the Completer Population (% calculated from all randomized 
subjects) 
 The number (%) of subjects who completed the study (% calculated from all randomized 
subjects) 
 The number (%) of subjects who discontinued the study prematurely after Randomization 
including the distribution of reasons for premature discontinuations after Randomization (% 
calculated from all randomized subjects); presented by the treatment group (APL-130277, 
placebo or moxifloxacin). The APL-130227 group will be further broken down by dose level. 
11 Demographic and other baseline characteristics 
Demographics and baseline characteristics will be summarized descriptively for the ECG and Safety 
populations. The following variables will be summarized: 
 Demographics: (age (continuous), age categorized as <65 years versus ≥65 years, gender, 
ethnicity, race, height, weight, BMI, country) 
 Smoking history 
 PD history (time since diagnosis of PD measured in years at time of first dose at TV1, presence 
of a rest tremor at the time of diagnosis, time since initiation of L-Dopa treatment, time since 
onset of motor fluctuations, type of OFF episodes experienced, number of OFF episodes/day, 
typical length of OFF episodes) 
 Cognitive status: Mini–Mental State Examination (MMSE) total score (as categorical, % of 
subjects with a score of 30, 29, 28, 27, 26 or <26) 
 Modified Hoehn and Yahr scale in “ON” state 


 
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 Baseline MDS-UPDRS Part III (Motor Examination) assessed in an “OFF” state prior to L-
Dopa administration at SV2 
 Change in MDS-UPDRS part III (Motor Examination ) at SV2 from pre-dose to 30 minutes 
post-dose 
 Total daily L-Dopa dose at screening.  
12 Concomitant medication/treatment 
All medications will be classified using the Anatomical Therapeutic Chemical (ATC) classification 
codes and preferred drug names from the World Health Organization Drug Dictionary (WHO-DD).  
Medications with a stop date before the first date of study drug dosing will be considered prior 
medications. Medications with start date or stop date on or after the first date of study drug dosing will 
be considered concomitant medications. The prior medications will be listed and the concomitant 
medications will be summarized. 
Summaries of concomitant PD treatment medications (medications which start with ATC code N04) 
will be presented in tabular form using the ATC Level 4 and preferred term. Other concomitant 
medications will be presented in tabular form using the ATC Level 1, ATC Level 2, and Preferred 
Term (PT). The tables will be sorted by overall descending frequency of ATC Level(s) and then, within 
an ATC Level, by overall descending frequency of PT. 
If the medication start date is incomplete, then it will be imputed as follows for the purpose of 
determining concomitant use:  
 If the start date is completely missing, the start date will be equal to the first dose date. 
However, if the stop date is not missing and is before the first dose date, then the stop date will 
be used instead.  
 If the start day is missing: check if month is the same as the month of the first dose. If this is the 
case, use the first dose date as start date. Otherwise the first day of the month will be used. 
o However, if the stop date is not missing and is before the first dose date or the imputed 
start date (as defined above), then the stop date will be used instead.  
 If the start day and month are missing: check if year is the same as the year of the first dose. If 
this is the case, use the first dose date as start date. Otherwise the first month of the year 
(January) will be used. 
o However, if the stop date is not missing and is before the first dose date or the imputed 
start date (as defined above), then the stop date will be used instead. 
If the medication stop date is partial, then it will be imputed as follows for the purpose of determining 
concomitant use:  


 
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 If the stop date is completely missing and the medication is not ongoing, the stop date will be 
equal to the last dose date or date of completion/withdrawal, whichever is the latest.  
 If the stop day is missing, the last day of the month will be used.  
 If the stop day and month are missing, then the last day of the last month (December) will be 
used. 
The summary of concomitant medications will be done for the Safety population. 
13 Medical history 
Medical history data will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The medical history data will be summarized with frequencies and percentages of subjects with at least 
one medical history item, and subject frequencies and percentages on the System Organ Class (SOC) 
and PT levels. The number of events will also be summarized. The table will be sorted by overall 
descending frequency of SOC and then, within a SOC, by overall descending frequency of PT.  
The summary of medical history data will be done for the Safety population. 
14 Analysis of Primary and Secondary Endpoints 
14.1 
Primary endpoint 
14.1.1 Central Tendency Analysis 
The primary analysis for the QTcF data in this study is the central tendency analysis which is based on 
the time-matched comparisons using the ΔΔQTcF approach with a mixed model, as proposed by Tao et 
al (2015), with the exception of the covariance structure. The mixed model includes treatment group 
(APL-130227, placebo or moxifloxacin; actual treatment received will be used), time (15, 30, 45 and 
60 minutes and 2, 3 and 4 hours), interaction between treatment group and time, period (1, 2 or 3), 
sequence (ABC, ACB, BCA, BAC, CAB or CBA, randomized sequence will be used), region (US 
versus non-US) and gender as fixed factors. The baseline QTcF (average of the pre-dose assessments at 
P1V1) will be included as a covariate. Restricted Maximum Likelihood (REML) estimation method 
will be used. The subject nested within sequence will be included as a random effect and a spatial 
power covariance structure for the unequally spaced time points will be assumed for the repeated 
measures over the time points. The denominator degrees of freedom will be calculated with Kenward-
Rogers algorithm. All observed change from baseline values from the 7 time points will be used as 
response variables. The ECG population will be used for the primary analysis. The SAS code used for 
the modelling is outlined below. 
proc mixed; 
class TRTA ATPTN APERIOD TRTSEQP USUBJID SEX CNTRYGR1; 
model CHG = BASE TRTA ATPTN TRTA*ATPTN APERIOD TRTSEQP SEX CNTRYGR1 / ddfm=kr; 


 
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random USUBJID(TRTSEQP); 
repeated ATPTN / subject=TRTA*USUBJID(TRTSEQP) type=sp(pow)(atptn2); 
where 0 < ATPTN <= 4; 
run; 
In case the model does not converge, the fixed factors for gender and region will be excluded. If the 
model still does not converge, a more simple covariance structure will be used, e.g. AR(1) or CS.  
The least square (LS) mean, standard error, and LS mean difference between APL-130277 and placebo 
at all 7 time points along with the 2-sided 90% CIs for the treatment difference will be provided. The 
descriptive statistics will be presented for the absolute values by treatment group and time point, 
changes from baseline by treatment group and time point and within-subject differences between APL-
130277 and placebo by time point.  
Subgroup analyses will be performed for factors defined in section 9.5 of this document. Each subgroup 
will be summarized separately with descriptive statistics. In addition, for each of the subgroup factors, a 
mixed model similar to the primary model will be used, including additional fixed factors for the 
subgroup variable and the interactions between the treatment group and subgroup variable, time point 
and subgroup variable and the three-way interaction term between subgroup variable, treatment group 
and time point. However, if the three-way interaction term is not statistically significant (p>0.05) or if 
the model does not converge, the three-way interaction term will be excluded from the model. The 
influence of each subgroup factor will be investigated using the p-value for the interaction terms 
(treatment group x time point x subgroup variable (if applicable), treatment group x subgroup variable) 
calculated with this model. In addition, the treatment difference (APL-130277 versus placebo) will be 
estimated using confidence intervals with similar coverage as for the primary analysis.  
14.1.2 Assay sensitivity 
Moxifloxacin will be included as a positive control to validate the sensitivity of the assay to detect 
small increases from baseline for QTcF. The assay sensitivity will be evaluated by comparing 
moxifloxacin and placebo. To establish the assay sensitivity, there should be at least one time point 
where the lower confidence bound of the mean difference of moxifloxacin and placebo is greater than 
or equal to 5 ms. This analysis will use the same model as described for the time-matched central 
tendency analysis. The difference along with 2-sided 90% CIs (Bonferroni-corrected) between 
moxifloxacin and placebo will be estimated for the 4 evaluation time points (60 minutes and 2, 3 and 4 
hours) from the model which includes all 7 time points, as specified above.  
14.1.3 Sensitivity analyses of the primary endpoint 
The following sensitivity analyses will be performed for the primary endpoint. 
 Completer analysis: The analysis as specified above will be repeated for the Completer population 


 
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 Time-averaged analysis: In this analysis, the mean of all baseline ECGs is subtracted from the mean 
of all on-treatment ECG values through 4 hours post-dose for a given subject at a given visit. The 
mean will be calculated as mean of the 7 time points (i.e., the mean of the replicates at each time 
point is calculated prior to calculating the mean across the 7 time-points). These data will be 
analyzed with a mixed model similar to the one used for the primary analysis, but without the fixed 
effect for time and treatment group by time interaction term. The overall difference between APL-
130227 and placebo APL-130277 will be estimated from this model. This analysis will use the ECG 
population. 
14.1.4 Graphical summaries of the primary endpoint 
The differences between APL-130277 and placebo estimated with the mixed model will be presented 
using forest plots. Each of the 7 time points will be presented in one graph showing the placebo-
adjusted estimates and 2-sided 90% CIs. In addition, the placebo-adjusted estimates and Bonferroni-
corrected 2-sided 90% CIs for moxifloxacin will be presented similarly. 
14.1.5 Outlier analysis 
An outlier or categorical analysis supplements the central tendency analysis by determining if there 
were subjects who had an exaggerated effect on any ECG interval that would not be revealed in a mean 
change from baseline central tendency analysis.  
The following criteria are defined for the outlier analysis. The criteria will be tested separately for each 
time point. The number and proportion of subjects with outlier events will be tabulated by treatment, 
time point and overall (number of subjects with an outlier value at least once). Each outlier category 
will be tabulated separately. In addition, the number of subjects with abnormality in at least one 
category will be tabulated. For all the criteria listed below, the baseline refers to the average of the pre-
dose assessments at P1V1. The ECG population will be used for the outlier analysis. 
 Heart rate (HR): 
o Bradycardic event: Post-dose HR <50 bpm and a decrease of at least a 25% from the 
baseline 
o Tachycardic event: Post-dose HR >100 bpm and an increase of at least a 25% from the 
baseline 
o Either bradycardic or tachycardic event. 
 PR interval: Post-dose PR interval >200 ms and an increase of at least a 25% from the baseline. 
 QRS interval: Post-dose QRS interval >100 ms and an increase of at least a 25% from baseline. 
 QT interval: Post-dose QT interval >500 ms and the subject’s baseline is ≤500 ms. 
 QTcF: 


 
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o Post-dose QTcF interval >500 ms and the subject’s baseline ≤500 ms   
o Post-dose QTcF interval >480 ms and the subject’s baseline is ≤480 ms 
o Post-dose QTcF interval >450 ms and the subject’s baseline is ≤450 ms 
o Change from baseline >30-60 ms  
o Change from baseline >60 ms 
o Any of the criteria above for QTcF. 
 QTcB:  
o Post-dose QTcB interval >500 ms and the subject’s baseline ≤500 ms   
o Post-dose QTcB interval >480 ms and the subject’s baseline is ≤480 ms 
o Post-dose QTcB interval >450 ms and the subject’s baseline is ≤450 ms 
o Change from baseline >30-60 ms  
o Change from baseline >60 ms 
o Any of the criteria above for QTcB. 
14.2 
Secondary endpoints 
The following secondary endpoints will be analyzed. 
 PK of apomorphine and metabolites 
The non-compartmental analysis of the apomorphine plasma concentration data methods and results 
will be described in detail in a separate PK document(s). 
 Safety of APL-130277, including orthostatic BP and oral irritation (assessed with oropharyngeal 
examination)  
See Section 15 of the SAP. 
 Pharmacodynamic assessments including QTc based on the Bazett correction method (QTcB), heart 
rate (HR), PR interval, QRS interval, uncorrected QT interval, ECG morphology and correlation 
between the QTcF change from baseline and plasma concentrations of APL-130277 
The continuous ECG endpoints (QTcB, HR, PR interval, QRS interval, uncorrected QT interval) 
will be analyzed similarly as the primary endpoint, using the central tendency approach, i.e. by 
calculating 90% confidence intervals using the mixed model. The ECG population will be used for 
these analyses. 
The number and proportion of subjects with ECG morphology will be tabulated by treatment group. 
Each morphology category will be tabulated separately. In addition, the number of subjects with 


 
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abnormality in at least one category will be tabulated. The ECG population will be used for the 
morphology analysis. 
The details on the PK-Pharmacodynamic analysis (correlation between the QTcF change from 
baseline and plasma concentrations of APL-130277 will be provided in a separate document. 
 Presence of cardiac arrhythmias such as ventricular tachycardia or Torsade de Pointes 
The number and proportion of subjects with cardiac arrhythmias will be tabulated by treatment 
group. Each type of event will be tabulated separately. In addition, the number of subjects with at 
least one event will be tabulated. The ECG population will be used for the analysis of cardiac 
arrhythmias. 
14.3 
Exploratory efficacy endpoints 
 MDS-UPDRS Part III change from pre-dose to 30, 60, 90 minutes after dosing during the Titration 
Phase at the highest APL-130277 dose compared to the lowest APL-130277 dose resulting in a full 
“ON”. 
A Mixed Model for Repeated Measures (MMRM) will be used for analysis of the MDS-UPDRS 
Part III scores. Separate model will be used for each time point (30 minutes, 60 minutes and 90 
minutes). Response data include data from two study days: day when the lowest APL-130277 dose 
resulting in a full “ON” was given (Day 1) and day when the highest APL-130277 dose level was 
given (Day 2). The model will include the changes from pre-dose to the analysis time point (30 
minutes, 60 minutes or 90 minutes) as the response variables. The study day (Day 1 or Day 2) will 
be included as a fixed factor and the change from pre-dose to the respective analysis time point at 
SV2 as a covariate. The difference between the study days will be estimated with 2-sided 95% 
confidence intervals.  An unstructured covariance structure will be applied for MMRM.  The 
Kenward-Roger method will be used to compute degrees of freedom. The Efficacy population will 
be used for the analysis of the MDS-UPDRS data. 
 Time to “ON” during Titration Phase at the highest APL-130277 dose and the lowest APL-130277 
dose resulting in a full “ON” 
The time to “ON” will be described using Kaplan-Meier plots. Separate Kaplan-Meier analysis will 
be done for the day when the lowest APL-130277 dose resulting in a full “ON” was given (Day 1) 
and for the day when the highest APL-130277 dose was given (Day 2). The median time to “ON” 
along with 25% and 75% quartiles (if applicable) will be estimated with the Kaplan-Meier analysis. 
In addition, the number of subjects who turned “ON” will be summarized. The Efficacy population 
will be used for the analysis of the time on “ON”. 
 Duration of “ON” during Titration Phase at the highest APL-130277 dose and the lowest APL-
130277 dose resulting in a full “ON”. 


 
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The duration of “ON” will be evaluated similarly as the time to “ON”. The Efficacy population will 
be used for the analysis of the duration on “ON”. 
15 Analysis of safety and tolerability 
The population used for safety analyses will be the Safety Population and Crossover Phase Safety 
Population. In general, the safety data will be presented separately for the Dose Titration Phase (where 
applicable, using the Safety Population) and for the Crossover Phase (using the Crossover Phase Safety 
Population). The safety analysis of the Dose Titration Phase will summarize the safety data for the total 
Safety population while the analysis of the Crossover Phase will focus on the comparison of the APL-
130277 treated subjects versus placebo and moxifloxacin. In addition, separate summaries will be 
prepared for all subjects receiving APL-130277 either during the Dose Titration Phase or Crossover 
Phase by pooling the data from the two phases during the APL-130277 exposure (using the Safety 
Population). 
15.1 
Extent of exposure 
The following information will be summarized by treatment group (for the Crossover Phase) and 
overall. In addition, these summaries will be broken down by the dose level of APL-130277. 
 The number of subjects exposed to study treatment, defined separately for the Dose Titration Phase 
and for the Crossover Phase. 
 A cross-tabulation of the highest dose level received during the Dose Titration Phase and the 
randomized dose level. 
 A cross-tabulation of the highest dose level received  and the lowest dose level received resulting in 
a full “ON” during the Dose Titration Phase. 
15.2 
Compliance 
As this is a single-dose study, no analysis of compliance will be done. 
15.3 
Adverse events 
All AEs will be coded using MedDRA version 19.1. Treatment-emergent adverse events (TEAEs) are 
defined as all AEs that start after the subject receives the first dose of study treatment.  Events will be 
classified as drug-related if the AE is classified as possibly, probably, or certainly related to study drug.  
Events with a missing start time, but with a start date equal to the date of first dose of study treatment 
will be considered treatment-emergent.  If the AE start date is incomplete, it will be imputed as follows 
for the purpose of determining TEAE:  


 
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 If the start date is completely missing, the start date will be equal to the date of the first dose of 
study treatment.  However, if the stop date is not missing and is before the date of the first dose of 
study treatment, then the stop date will be used instead.  
 If the start day is missing: check if month is the same as the month of the first dose. If this is the 
case, use the first dose date as start date. Otherwise the first day of the month will be used. 
o However, if the stop date is not missing and is before the first dose date or the imputed start 
date (as defined above), then the stop date will be used instead.  
 If the start day and month are missing:check if year is the same as the year of the first dose. If this is 
the case, use the first dose date as start date. Otherwise the first month of the year (January) will be 
used. 
o However, if the stop date is not missing and is before the first dose date or the imputed start 
date (as defined above), then the stop date will be used instead. 
For the Crossover Phase, the AE will be assigned to the period that corresponds to the latest treatment 
received prior to the onset. 
The original date and time will be shown on all listings of AEs.  Listings will be provided for all AEs, 
serious AEs, AEs leading to study treatment discontinuation and deaths. The listings will display study 
day, calculated as the AE start date – date of first dose in the relevant study phase (first dose in the 
Dose Titration Phase or the date of the dose of the relevant study medication in the Crossover Phase) + 
1 for events occurring on or after the first dose in the Dose Titration phase, and as AE start date – date 
of first dose in the Dose Titration phase for AEs occurring prior to the first dose in the Dose Titration 
Phase. 
TEAEs will be summarized by SOC and PT and by treatment group when applicable. TEAEs with 
onset after the last dose of the study treatment period are attributed to the last treatment received. Both 
event and subject counts, where applicable, will be summarized. The counts will be complemented by 
percentages calculated for the subject counts unless otherwise specified. 
 An overall summary of the number and percentage of subjects reporting TEAEs and the number of 
TEAE events,  drug-related TEAEs, severe TEAEs, serious TEAEs, TEAEs leading to study 
treatment discontinuation and TEAEs leading to death 
 TEAEs by SOC and PT, both as event and subject counts 
 TEAEs by PT, both as event and subject counts 
 Drug-related TEAEs by PT, both as event and subject counts 
 Severe TEAEs by PT, both as event and subject counts 
 TEAEs by SOC, PT and severity, as event counts; percentages will be calculated for the event count 
out of total number of events 
 TEAEs by SOC, PT and relationship, as event counts; percentages will be calculated for the event 
count out of total number of events 


 
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 Serious TEAEs by PT, both as event and subject counts 
 TEAEs leading to study treatment discontinuation by PT, both as event and subject counts  
 TEAEs leading to study treatment temporary withdrawal by PT, both as event and patient counts 
 TEAEs leading to dose adjustment by PT, both as event and subject counts 
The tables will be sorted by overall descending frequency of SOC and then, within a SOC, by overall 
descending frequency of PT based on the subject count for the APL-130277 column. If only event 
count is presented, the sorting will be done based on the event count. 
Furthermore, the adverse events (by PT) will also be summarized by subgroups as defined in section 
9.5 of this document. In addition, the following tables will be summarized by dose of APL-130277 at 
AE onset: Serious TEAEs and TEAEs leading to study treatment discontinuation. 
Note: the AEs collected on the Case Report Form include a checkbox to indicate an AE of special 
interest. However, since the definition of AEs of special interest in this study may differ from other 
APL-130227 reports, the indicator for AEs of special interest will not be summarized or listed.   
15.4 
Laboratory safety variables 
All clinical laboratory parameters will be converted to consistent units according to the International 
System of Units (SI) before summarization. The following will be summarized: 
 Numeric laboratory parameters: Actual values and changes from baseline to the end or study for 
each parameter will be summarized with descriptive statistics. 
 Laboratory parameters which have an upper or lower reference range: Number and percentage of 
subjects with low, normal or high (i.e., below, within or above reference range) values at each visit 
for each parameter will be summarized 
o These values will be presented as a shift table, i.e. the distribution of the three response 
categories at the end-of-study visit will be classified by the baseline category. 
 Categorical laboratory parameters: The distribution of the categories will be summarized by visit. 
15.5 
Vital signs 
Standard vital sign measurements include heart rate (HR), respiratory rate (RR), blood pressure (BP) 
and body temperature. Vital signs will be measured at all scheduled study visits at various time points 
after the subject has been in a supine position for 5 minutes. BP will also be measured within three 
minutes of standing at all time points. In addition to the vital signs captured on the Case Report Form, 
the standing minus supine values (standing minus supine systolic BP, standing minus supine diastolic 
BP) will be evaluated. 
The following summaries will be done: 


 
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 Change from baseline (SV2) to other visit pre-dose values for each parameter (including the 
standing minus supine values). The change from baseline to the End of Study visit values will also 
be presented. 
 Actual values and change from pre-dose to post-dose, if applicable, at each visit for each parameter 
(including the standing minus supine values). 
Orthostatic hypotension will be defined as a reduction in systolic BP of 20 mmHg or more, and/or a 
reduction in diastolic BP of 10 mmHg or more, for the standing measurement compared to the supine 
measurement. The proportion of subjects with orthostatic hypotension will be tabulated and listed by 
visit and time point. 
15.6 
12-Lead ECG (resting) 
A standard single resting 12-lead ECG will be performed pre-dose and 45 or 60 minutes post-dose at all 
treatment visits. In addition, triplicate ECGs will be taken at SV2 and at the end of the study. The 
following parameters will be captured: Heart rate, PR interval, QRS interval, RR interval, QT interval, 
QTc Interval (Fridericia’s correction) and QTc Interval (Bazett’s correction).  
The following summaries will be done: 
 Change from baseline (SV2) to other visit pre-dose and post-dose values for each parameter. The 
change from baseline to the End of Study visit values will also be presented.  
 Actual values and change from pre-dose to post-dose, if applicable, at each visit for each parameter. 
The ECGs will be assessed by the investigator and deemed “Normal”, “Abnormal, not clinically 
significant” and “Abnormal, clinically significant” and tabulated by visit and time point.  
In addition, the QTc Intervals fulfilling the following criteria will be listed and tabulated separately 
using Fridericia’s correction and Bazett’s correction: 
 Values >500 ms 
 Values increasing >15% from baseline if baseline value is ≥440 ms 
 Values increasing >30% from baseline if baseline value is <440 ms 
 Values increasing >30 ms from baseline 
 Values increasing >60 ms from baseline 
 At least one of the abnormalities listed above. 


 
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15.7 
Other safety variables 
The C-SSRS is a measure of suicidal ideation and behavior. The rating scale has 4 general categories: 
suicidal ideation, intensity of ideation, suicidal behavior, and actual attempts. All C-SSRS data will be 
listed. The frequency and percentage of subjects with each response for suicidal ideation, intensity of 
ideation, and suicidal behavior items will be summarized as appropriate by treatment group and visit. 
The frequency and percentage of subjects with physical and oropharyngeal examination findings will be 
summarized by treatment group (when applicable), visit, time point (when applicable) and body system. 
In addition, the frequency and percentage of subjects with each type of oropharyngeal cavity 
examination finding will be summarized by treatment group, visit, time point (when applicable) and 
location. 
16 Other variables 
Major protocol deviations will be tabulated including the frequency and percentage of subjects with 
each type of deviation by treatment group. Deviations considered major will be identified as such prior 
to study unblinding. Summaries will be based on the Safety Population and provided for the combined 
Dose Titration Phase and Crossover Phase. All other data collected but not specifically mentioned will 
be listed. 
17 Deviations from the analyses planned in the study protocol 
This analysis plan presents the planned analyses in more detail and several details and analyses have 
been added. This SAP is based on study protocol version 5.00. The differences between the study 
protocol version 5.00 and this SAP are summarized below: 
Topic 
Protocol Version 5.00 
SAP 
Rationale for change 
Safety analysis sets 
One safety analysis set was 
defined. 
Separate safety analysis sets were 
defined for all subjects who 
received at least one dose of APL-
130277 and for all subjects who 
received study medication after 
randomization (during the 
Crossover Phase). 
Safety data will be analyzed 
separately for the Dose Titration 
Phase and for the  Crossover Phase. 
PK-PD Analysis 
Set 
PK-PD Analysis Set was 
defined. 
PK-PD Analysis Set was not 
defined. 
The analysis of PK-
pharmacodynamics will be defined in 
a separate analysis plan. 
ECG Analysis Set 
At least one evaluable pre-
dose ECG is required for 
inclusion. 
Evaluable baseline ECG data is 
required for inclusion. 
The analysis of the ECG (holter) data 
uses only baseline data (P1V1 pre-
dose), not the pre-dose data from the 
other visits 
Central tendency 
analysis 
Should a significant treatment 
by gender/region interaction 
be observed, it will also be 
included in the model. 
Interaction terms (other than 
treatment group by time point, 
which is required to estimate the 
treatment differences by time point) 
will not be included in the model. 
Inclusion of interaction terms in the 
model was not considered necessary. 


 
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MDS-UPDRS part 
III and other 
efficacy endpoints 
These endpoints will be 
evaluated as a secondary 
objective. 
These endpoints will be evaluated 
as an exploratory objective. 
The amended protocol allows 
enrolment of patients without at least 
one well defined “OFF” episode per 
day or with a total daily “OFF” time 
duration of < 2 hours. Due to this, the 
efficacy endpoints became less 
relevant, as all patients may not have 
enough pre-dose symptoms required 
for the efficacy evaluation. 
Analysis of MDS-
UPDRS part III 
Dose level will be included as 
a fixed factor in the model. 
Dose level will not be included in 
the model. 
As the number of patients per dose 
level will be small, this factor was not 
considered feasible. 
Other efficacy 
endpoints 
The other efficacy endpoints 
will be analyzed with similar 
principles as MDS-UPDRS 
Part III 
The other efficacy endpoints will be 
analyzed using time-to-event 
methods. 
Time-to-event methods allow 
censoring for patients who do not turn 
“ON” or “OFF”. 
18 Execution of statistical analyses 
Statistical analyses will be performed by 4Pharma Ltd supervised by CLINTREX LLC and/or Sunovion 
Pharmaceuticals. 
19 Hardware and software 
Statistical analysis, tables and subject data listings will be performed with SAS® version 9.3 or later for 
Windows (SAS Institute Inc., Cary, NC, USA) 
20 
References 
Clinical Study Protocol: Version 5.00 (28 August, 2017), Company: Sunovion Pharmaceuticals Inc. 
Tao J, Kiernan K, Gibbs P. Advanced Techniques for Fitting Mixed Models Using SAS/STAT® 
Software. Paper SAS1919-2015. 


 
Statistical Analysis Plan      
 
 
 
Sponsor: Sunovion Pharmaceuticals, Inc. 
Final 1.0 
21 Dec 2017 
Study: CTH-201 
 
21 
Appendices 
21.1 
Table and figure plan 


 
Statistical Analysis Plan      
 
 
 
Sponsor: Sunovion Pharmaceuticals, Inc. 
Final 1.0 
21 Dec 2017 
Study: CTH-201 
 
21.2 
Data listing plan