Clinical trial NCT02542696
Conditions: Parkinson Disease
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2015-08-31; Completion date: 2022-11-08
Enrollment: 496 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An Open-Label Phase 3 Study to Examine the Long-Term Safety, Tolerability and Efficacy of APL-130277 for the Acute Treatment of "OFF" Episodes in Patients With Parkinson's Disease

Detailed description:

Arms: arm 1: APL-130277 sublingual thin film (10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg)
Interventions: intervention 1: APL-130277
Intervention descriptions: intervention 1: Used to treat up to 5 "OFF" episodes per day

Protocol documents:
Prot_000.pdf: 
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Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
2 
 
25 February 2019 
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 
predecessors, subsidiaries or affiliates). The information cannot be disclosed to any third party or 
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/or Sunovion Pharmaceuticals Inc. You may disclose 
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/or Sunovion Pharmaceuticals Inc., and should be handled 
consistently with that stated above. 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
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25 February 2019 
1.
EMERGENCY CONTACTS
Table 1: Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Responsible Physician 
O 
North America 
Medical Monitor 
 
European Union 
Medical Monitor 
 
SAE Reporting 
 


Protocol CTH-301, Version 5.00 
APL-130277 
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2.
INVESTIGATOR APPROVAL STATEMENT
I have read the protocol, CTH-301, Version 5.00, "An Open-Label, Phase 3 Study Examining the 
Long-Term Safety, Tolerability and Efficacy of APL-130277 in Levodopa Responsive Patients 
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 
An Open-Label, Phase 3 Study Examining the Long-Term Safety, Tolerability and 
Efficacy of APL-130277 in Levodopa Responsive Patients with Parkinson’s Disease 
Complicated by Motor Fluctuations ("OFF" Episodes) 
Protocol: 25 February 2019 
Version: 5.00 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
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25 February 2019 
3.
PROTOCOL SYNOPSIS
TITLE 
An Open-Label, Phase 3 Study Examining the Long-Term Safety, 
Tolerability and Efficacy of APL-130277 in Levodopa Responsive Patients 
with Parkinson’s Disease Complicated by Motor Fluctuations ("OFF" 
Episodes) 
STUDY PHASE 
Phase 3 
OBJECTIVES 
The primary objective is to evaluate the long-term safety and tolerability of 
APL-130277 in Subjects with Parkinson’s disease (PD). 
NUMBER OF 
Subjects 
The overall number of subjects is not pre-specified as this is an extension 
study. 
Subject 
POPULATION 
De Novo Subjects 
De Novo Subjects are defined as patients who have not previously 
participated in a study with APL-130277. 
Inclusion Criteria – De Novo Subjects 
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) as
determined by the Investigator.
4.
Receiving stable doses of L-Dopa/carbidopa (immediate or chronic
release [CR]) administered at least 4 times per day OR Rytary™
administered at least 3 times per day, for at least 4 weeks before the
initial Screening Visit (SV1). Adjunctive PD medication 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.
Subjects must experience at least one well defined "OFF" episode
per day with a total daily "OFF" time duration of ≥ 2 hours during
the waking day, based on patient self-assessment.
7.
Subject and/or caregiver must be trained in performing home
dosing diary assessments of the motor state and must be able to
recognize "ON" and "OFF" states.
8.
Stage III or less on the modified Hoehn and Yahr scale in the "ON"
state.
9.
Mini–Mental State Examination (MMSE) score > 25.
10. If female and of childbearing potential, must agree to be sexually


Protocol CTH-301, Version 5.00 
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abstinent or use one of the following highly effective methods of 
birth control: 
•
Hormonal contraceptives (eg, combined oral contraceptives,
patch, vaginal ring, injectables, and implants);
•
Intrauterine contraceptive system;
•
Surgical sterilization or partner sterile (must have documented
proof);
AND
One of the following effective methods of birth control: 
•
Male/female condom;
•
Cervical cap with spermicide;
•
Diaphragm with spermicide;
•
Contraceptive sponge.
11. Male subjects must be either surgically sterile, agree to be sexually
inactive or use a double-barrier method of birth control (eg, condom
and diaphragm with spermicide, condom with cervical cap and
spermicide) from first study drug administration until 90 days after
final drug administration.
12. Willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study-related procedures.
13. Able to understand the consent form, and to provide written
informed consent.
Exclusion Criteria – De Novo Subjects 
Subjects will be excluded from participation in the study for any of the 
following reasons: 
1.
Atypical or secondary parkinsonism.
2.
Previous treatment with any of the following: a neurosurgical
procedure for PD; continuous subcutaneous (s.c.) apomorphine
infusion; Duodopa/Duopa; or APL-130277.
3.
Treatment with any form of s.c. apomorphine within 7 days prior to
the second Screening Visit (SV2). Subjects that stopped
s.c. apomorphine for any reason other than systemic safety concerns
or lack of efficacy may be considered.
4.
Contraindications to APOKYN®, or hypersensitivity to
apomorphine hydrochloride or any of the ingredients of APOKYN®
(notably sodium metabisulfite).
5.
Female who is pregnant or lactating.
6.
Participation in a clinical trial within 30 days prior to the initial
Screening Visit (SV1).
7.
Receipt of any investigational (ie, unapproved) medication within
30 days prior to the initial Screening Visit (SV1).
8.
Currently taking selective 5HT3 antagonists (ie, ondansetron,
granisetron, dolasetron, palonosetron, alosetron), dopamine
antagonists (excluding quetiapine and clozapine) or dopamine


Protocol CTH-301, Version 5.00 
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depleting agents. 
9.
Drug or alcohol dependency in the past 12 months.
10. Subject has a history of malignancy within 5 years prior to the
Screening visit, except for adequately treated basal cell or
squamous cell skin cancer or in situ cervical cancer. Pituitary
tumors of any duration are excluded.
11. Clinically significant medical, surgical, or laboratory abnormality in
the opinion of the Investigator.
12. Major psychiatric disorder including, but not limited to, dementia,
bipolar disorder, 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.
13. History of clinically significant hallucinations during the past
6 months.
14. History of clinically significant impulse control disorder(s).
15. Dementia that precludes providing informed consent or would
interfere with participation in the study.
16. 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.
17. Donation of blood or plasma in the 30 days prior to first dosing.
18. Presence of canker or mouth sores within 30 days prior to the initial
Screening Visit (SV1), or other clinically significant oral pathology
in the opinion of the Investigator. The Investigator should follow-
up with an appropriate specialist on any finding, if indicated, before
enrolling a patient into the study.
Subject 
POPULATION 
Rollover Subjects 
Inclusion Criteria – Rollover Subjects 
Subjects who meet each of the following criteria will be eligible for 
participation in the study: 
1.
Completion of any of the following studies: CTH-201, CTH-203,
CTH-300, or CTH-302 and, in the opinion of the Investigator,
would benefit from continued treatment with APL-130277.
2.
No major changes in concomitant PD medications since completion
of any of the following studies: CTH-201, CTH-203, CTH-300, or
CTH-302. Any change in PD medications since the previous study
should be discussed with the Medical Monitor to determine subject
eligibility in the current study.
3.
If female and of childbearing potential, must agree to be sexually
abstinent or use one of the following highly effective methods of
birth control:
•
Hormonal contraceptives (eg, combined oral contraceptives,
patch, vaginal ring, injectables, and implants);
•
Intrauterine contraceptive system;


Protocol CTH-301, Version 5.00 
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25 February 2019 
• 
Surgical sterilization or partner sterile (must have documented 
proof);  
AND 
One of the following effective methods of birth control: 
• 
Male/female condom; 
• 
Cervical cap with spermicide; 
• 
Diaphragm with spermicide; 
• 
Contraceptive sponge. 
4. Male subjects must be either surgically sterile, agree to be sexually 
inactive or use a double-barrier method of birth control (eg, condom 
and diaphragm with spermicide, condom with cervical cap and 
spermicide) from first study drug administration until 90 days after 
final drug administration. 
5. Willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study-related procedures. 
6. Able to understand the consent form, and to provide written 
informed consent. 
Exclusion Criteria Rollover Subjects 
Subjects will be excluded from participation in the study for any of the 
following reasons: 
1. Female who is pregnant or lactating. 
2. Presence of any major psychiatric disorder including, but not 
limited to, dementia, bipolar disorder, psychosis (including 
clinically significant hallucinations during the past 6 months) or any 
disorder that, in the opinion of the Investigator, requires ongoing 
treatment that would make study participation unsafe or make 
treatment compliance difficult. 
3. Presence of any clinically significant medical (including but not 
limited to CNS, cardiovascular, hepatic, pulmonary, metabolic, or 
renal events), surgical, or laboratory abnormality that would make 
study participation unsafe or make treatment compliance difficult. 
Clinical significance to be determined by the Investigator.  
4. Receipt of any investigational (ie, unapproved) medication or 
participation in any clinical trial of an investigational product 
within 14 days of completing a previous study with APL-130277. 
5. Development of canker or mouth sores within 14 days of 
completing a previous study using APL-130277. For other 
clinically significant oral pathology, the Investigator should follow-
up with an appropriate specialist on any finding, if indicated, before 
enrolling such a subject into the study. Clinical significance to be 
determined by the Investigator. The eligibility of subjects who have 
experienced AEs related to the oral cavity during the previous study 
using APL-130277, should be reviewed with the medical monitor 
and approval obtained. 
6. Current suicidal ideation within one year of the screening visit, as 
evidenced by answering "yes" to Question 4 or 5 on the suicidal 


Protocol CTH-301, Version 5.00 
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25 February 2019 
ideation portion of the C-SSRS at Screening or attempted suicide 
within 5 years. 
Subject 
POPULATION 
CTH-301 Completer 
Subjects 
CTH-301 Completer Patients are defined as patients who have previously 
completed the CTH-301 study under protocol version 3.00. 
Inclusion Criteria - CTH-301 Completer Subjects 
Subjects who meet each of the following criteria will be eligible for 
participation in the study: 
1. Completion of the CTH-301 study under protocol version 3.00, and 
in the opinion of the Investigator, would benefit from continued 
treatment with APL-130277. 
2. If female and of childbearing potential, must agree to be sexually 
abstinent or use one of the following highly effective methods of 
birth control: 
• 
Hormonal contraceptives (eg, combined oral contraceptives, 
patch, vaginal ring, injectables, and implants);  
• 
Intrauterine contraceptive system; 
• 
Surgical sterilization or partner sterile (must have documented 
proof);  
AND 
One of the following effective methods of birth control: 
• 
Male/female condom; 
• 
Cervical cap with spermicide; 
• 
Diaphragm with spermicide; 
• 
Contraceptive sponge. 
3. Male subjects must be either surgically sterile, agree to be sexually 
inactive or use a double-barrier method of birth control (eg, condom 
and diaphragm with spermicide, condom with cervical cap and 
spermicide) from first study drug administration until 90 days after 
final drug administration. 
4. Willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study-related procedures. 
5. Able to understand the consent form, and to provide written 
informed consent. 
Exclusion Criteria - CTH-301 Completer Subjects 
Patients will be excluded from participation in the study for any of the 
following reasons: 
1. Female who is pregnant or lactating. 
2. Presence of any major psychiatric disorder including, but not 
limited to, dementia, bipolar disorder, psychosis (including 
clinically significant hallucinations during the past 6 months) or any 
disorder that, in the opinion of the Investigator, requires ongoing 
treatment that would make study participation unsafe or make 
treatment compliance difficult. 


Protocol CTH-301, Version 5.00 
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25 February 2019 
3. Presence of any clinically significant medical (including but not 
limited to CNS, cardiovascular, hepatic, pulmonary, metabolic, or 
renal events), surgical, or laboratory abnormality that would make 
study participation unsafe or make treatment compliance difficult. 
Clinical significance to be determined by the Investigator. 
4. Receipt of any investigational (ie, unapproved) medication or 
participation in any clinical trial since completing the CTH-301 
study. 
5. Development of canker or mouth sores since completing the 
CTH-301 study. For other clinically significant oral pathology, the 
Investigator should follow-up with an appropriate specialist on any 
finding, if indicated, before enrolling such a patient into the study. 
Clinical significance to be determined by the Investigator. 
6. Current suicidal ideation as evidenced by answering "yes" to 
Question 4 or 5 on the suicidal ideation portion of the C-SSRS at 
the Screening Visit Phase 2 (SVP2). 
STUDY DESIGN 
This is a multi-center, open-label, Phase 3 study in L-Dopa responsive PD 
subjects with motor fluctuations, designed to evaluate the long-term safety, 
tolerability and efficacy of APL-130277. 
 
Screening Procedures for De Novo Subjects 
De Novo subjects are defined as subjects who have not previously 
participated in a study with APL-130277. 
Before any study procedures are performed on any subject, informed 
consent must be obtained at an initial Screening Visit (SV1). 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, 
12-Lead ECG (in triplicate) and perform a complete physical examination at 
SV1 to determine if the subject may be eligible for study participation and 
continuation onto the second Screening Visit (SV2).  
Subjects recruited to participate in the study, and who have provided full 
consent to participate, will be asked to attend the second Screening Visit 
(SV2), and will be instructed to arrive at the clinic after their usual morning 
dose of PD medications; but before taking their next dose of medication. 
Their normal morning dose of L-Dopa (without adjunctive PD medication) 
will be administered in the clinic approximately two hours after their 
normally scheduled second dose of PD medication, following confirmation 
of an "OFF" episode by the Investigator, to ensure that they experience a 
full "ON" response. Eligibility criteria will be assessed and subject 
"ON"/"OFF" training will be performed. 
Subjects will be asked to return to clinic in the morning of Titration Visit 1 
(TV1) for the Dose Titration Phase of the study, and will be instructed to 
arrive at the clinic after their usual morning dose of PD medications; but 
before taking their next dose of medication. 
 
 


Protocol CTH-301, Version 5.00 
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25 February 2019 
Screening Procedures for Rollover Subjects 
Rollover subjects are defined as subjects who have previously completed 
any of the following studies: CTH-201, CTH-203, CTH-300, or CTH-302. 
Subjects will be required to attend the Screening Visit and applicable 
eligibility assessments will be performed. This visit will occur up to 14 days 
after the final visit of the previous APL-130277 study. Subjects will present 
to clinic following their normal PD medication regimen and should not 
withhold any of their normal PD medications. Screening procedures will be 
performed while subject is in the “ON” state. 
Subjects will begin treatment at the last APL-130277 dose level they were 
taking in the previous study. These subjects will not undergo titration. 
however, if during the screening visit, the Investigator determines a dose 
adjustment is necessary, the subject will have dose adjustment visits. 
Subjects who fail the screening process will be allowed to rescreen once if 
agreed by the Medical Monitor. 
 
Screening Procedures for CTH-301 Completer Subjects 
CTH-301 Completer subjects are defined as subjects who have previously 
completed the CTH-301 study under protocol version 3.00. 
Subjects who previously completed the CTH-301 study and are re-enrolling 
into CTH-301 will be required to attend the Screening Visit Phase 2 (SVP2) 
and applicable eligibility assessments will be performed.  
Eligibility criteria will be assessed and once a patient is deemed eligible, the 
site will contact the subject to have them return to the clinic 5 to 28 days 
later and follow study procedures beginning at LTS Visit 7. These subjects 
will resume treatment with APL-130277 at the dose he/she was 
administered prior to completing study CTH-301. If this dose is no longer 
effective, the subject will return to the clinic for dose adjustment visits. 
Subjects who fail the screening process will be allowed to rescreen once if 
agreed by the Medical Monitor. 
 
Dose Titration Phase - De Novo Subjects Only 
On Titration Visit 1 (TV1), 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. Subjects will be required to wait approximately two 
hours after their normally scheduled second dose of PD medications and 
following confirmation by both the Investigator and subject that they are in 
the "OFF" state, patients will be treated with 10 mg APL-130277. Efficacy 
(MDS-UPDRS Part III) will be performed prior to dosing, and at 15, 30, 60, 
and 90 minutes after dosing. Safety assessments (adverse events [AEs], 
vital signs [including supine and standing blood pressure (BP) to assess 
orthostatic hypotension (OH)] will be performed prior to dosing, and 
immediately after the 60 minute MDS-UPDRS Part III assessment. 
Electrocardiograms (ECGs) will be obtained prior to dosing and 
approximately 50 minutes after dosing. 
Subjects who respond to the 10 mg APL-130277 dose with a full "ON" 
response within 45 minutes at TV1, as assessed by both the patient and 


Protocol CTH-301, Version 5.00 
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Confidential and Proprietary 
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25 February 2019 
Investigator, will be considered complete from a Dose Titration Phase 
perspective, and can proceed to the Long-Term Safety (LTS) Phase of the 
study. These subjects will be asked to return to the clinic for LTS Visit 1 
(LTS V1). A full "ON", as assessed by the subject, is 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; AND the response is comparable to or better than their normal 
response to PD medications prior to enrolling in the study. A full "ON", as 
determined by the Investigator, is defined as: per clinical judgement, 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. 
Subjects who develop symptoms such as nausea and/or vomiting which 
warrant treatment may receive anti-emetic therapy (US sites – Tigan® 
[trimethobenzamide hydrochloride; 300 mg t.i.d.]; non-US sites – 
domperidone [10 mg b.i.d.]). If initiated, anti-emetic therapy should be 
stopped when clinically indicated. Anti-emetic medication should not be 
administered prophylactically. 
Subjects who do not achieve a full "ON" response (as defined above) with 
their 10 mg APL-130277 dose will restart their normal PD medications and 
will be asked to return to clinic within the next 3 days for Titration Visit 2 
(TV2), to assess the next highest dose (ie, 15 mg) in a manner identical to 
that on Titration Visit 1 (TV1), with identical evaluations. 
All 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. 
Subjects will be required to wait approximately two hours after their 
normally scheduled second dose of PD medications before being dosed with 
15 mg APL-130277. Subjects who achieve a full "ON" (as defined above) 
within 45 minutes of receiving the 15 mg dose will be considered complete 
from a Dose Titration Phase perspective, and can proceed to the LTS Phase. 
Subjects who do not achieve a full "ON" response (as defined above) within 
45 minutes of dosing at TV2 will restart their standard PD medications and 
be asked to return to the clinic within the next 3 days to assess the next 
highest dose of APL-130277 (20 mg [TV3], 25 mg [TV4], 30 mg [TV5] or 
35 mg [TV6], as appropriate). For subjects dosed with 35 mg, the first 
sublingual film (ie, 20 mg) will be placed under the tongue for 3 minutes 
before placing the second sublingual film (ie, 15 mg) under the tongue 
immediately after and without delay. 
For each visit in the Dose Titration Phase, the site will arrange subject 
transfers, if needed. Alternatively, subjects may be monitored in the clinic 
overnight if such facilities exist and the subject consents. These occurrences 
will not be considered a SAE. Safety and efficacy assessments will be 
performed at each visit exactly as described above. Subjects who achieve a 
full "ON" response at any titration visit may proceed to the LTS Phase. 
At all titration visits, at the discretion of the subject and/or Investigator, the 
next highest dose may be evaluated at a subsequent titration visit following 
a full "ON" response in order to assess the potential for the next highest 
dose in inducing an improved full "ON" response. If this dose produces an 


Protocol CTH-301, Version 5.00 
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Confidential and Proprietary 
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improved "ON" response relative to the lower dose without impacting 
subject safety and tolerability, the higher dose will be used during the LTS 
Phase of the study. If the "ON" response is the same or worse, or this higher 
dose is not well-tolerated, the previous dose will be used during the LTS 
Phase of the study. 
During the Dose Titration Phase visits, 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. If this occurs, subjects can return to the clinic on 
another day to resume the titration with the next highest dose. If a dose of 
APL-130277 cannot be found that provided a full "ON" response, the 
subject will be terminated from the study. 
In this study, the minimum titration dose is 10 mg APL-130277 and the 
maximum titration dose is 35 mg APL-130277. Any subjects who reach 
35 mg at Titration Visit 6 (TV6) and do not exhibit a full "ON" response (as 
defined above) within 45 minutes will be terminated from the study and will 
have the applicable procedures outlined in the Early Termination Visit 
performed. 
Dosing days in the Dose Titration Phase are not required occur 
consecutively, but the Dose Titration Phase must be completed within 
21 days. Following completion of the titration phase, subjects will return to 
clinic for LTS V1 where they will be given their open-label study 
medication (APL-130277) and appropriate training for self-administration. 
Titration in this study may be modified following a review of the Dose 
Titration Phase data from CTH-300 by a Data Safety Monitoring Board 
(DSMB). If, after review of the data from CTH-300, the DSMB determines 
that in-clinic titration is not necessary and that dose titration can be safely 
accomplished in an outpatient setting, the Dose Titration Phase paradigm 
may be modified. 
 
LTS Phase Year 1 – In-clinic Visits – De Novo and Rollover Subjects Only 
De novo subjects who successfully completed the Dose Titration Phase of 
the study will be asked to return to the clinic on LTS Day 1 (LTS V1) 
where they will be given their dose of APL-130277. This visit will up to 
21 days after the final visit in the Dose Titration Phase of the study. The 
dose given will be the same as that determined during the Dose Titration 
Phase of the study.  
Rollover subjects who successfully completed the Screening visit (SV1) 
will return to the clinic up to 21 days after SV1. These subjects will receive 
the same dose they received in the previous study, unless the Investigator 
deems a dose adjustment is necessary. 
All 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. 
Subjects will be required to wait approximately two hours after their 
normally scheduled second dose of PD medications. Following a confirmed 
"OFF" state by both the subject and Investigator, subjects will be dosed 
with their study medication and assessments of efficacy and safety will be 


Protocol CTH-301, Version 5.00 
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performed up to 90 minutes after dosing. During this visit, De novo subjects 
only, will be trained by clinic staff on how to remove study medication 
from its packaging and how to self-administer their dose using placebo 
sublingual films supplied to the site. Subjects should not self-administer the 
placebo sublingual films. Subjects cannot be discharged from the clinic 
until satisfactorily completing the training. 
At the in-clinic visits, staff will dose subjects with APL-130277 by 
placing the sublingual film under the subject’s tongue (see Section 14.2 
for full dosing details). Subjects will be asked to follow the same process 
of study drug administration during the at-home portions of the study. 
During LTS Phase Year 1 of the study, subjects will return to the clinic at 
4 weeks for LTS Visit 2 (LTS V2), 12 weeks for LTS Visit 3 (LTS V3), 
24 weeks for LTS Visit 4 (LTS V4), 36 weeks for LTS Visit 5 (LTS V5), 
and 48 weeks for LTS Visit 6 (LTS V6). At LTS V3, LTS V4, LTS V5, and 
LTS V6, subjects will be dosed with APL-130277 and the procedures 
performed at these visits will be similar to those performed at LTS V1. 
LTS V2 will be a safety visit only. 
At the LTS in-clinic visits where the subject is dosed with APL-130277, 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 90 minute 
efficacy assessments are complete. 
Following LTS V6, subjects will be asked to return to the clinic 
approximately 4 months (16 weeks ± 1 week) later for LTS Visit 7 
(LTS V7). 
Evaluation of subjects who choose to withdraw from the study at any time 
will be conducted in accordance with Section 12.8, Early Terminations. 
All PD medications must remain stable during LTS Phase Year 1, and any 
changes should be avoided unless absolutely necessary and approved by the 
Medical Monitor. Changes in medications for the treatment of other medical 
disorders are allowed with permission from the Medical Monitor. 
LTS Phase Year 1 – At Home Assessments – De Novo and Rollover Subjects 
Only 
During the LTS Phase, subjects will be instructed to continue with their 
regular PD medication regimen(s), but should dose themselves with their 
study treatment (APL-130277) if they experience an "OFF" episode 
(eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF", etc.) 
while on their current treatment regimen. Subjects will be instructed to dose 
up to 5 "OFF" episodes per day during the waking period. Subjects will be 
instructed to wait a minimum of 2 hours between doses taken at home. 
For 2 days prior to the in-clinic visits, subjects will be requested to 
complete a dosing diary that captures: 
• 
Time of APL-130277 treatment self-administration; 
• 
Subject "ON"/"OFF" states at 30 minutes after dosing. 
• 
The type of "OFF" experienced (ie, morning akinesia; delayed 


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"ON"; wearing "OFF"; no "ON"; or sudden "OFF"). 
Between each in-clinic visit, subjects will be contacted at the midpoint 
between visits by the site to assess subject well-being and safety. If required 
due to safety concerns or lack of efficacy, subjects will be asked to return to 
the clinic for additional evaluations at an unscheduled Dose Adjustment 
Visit. 
LTS Phase Years 2, 3, 4, and 5 – In-clinic Visits - All Subjects 
During LTS Phase Years 2 to 5, subjects will return to the clinic every 
4 months (16 weeks). These visits will be safety visits only. 
Subjects will return to the clinic to have safety assessed and receive 
additional study drug (APL-130277). 
Subjects may continue to participate in the study until the Sponsor 
terminates the study, or until commercial availability of APL-130277 in the 
patient's country. If a patient continues in the study beyond LTS Phase Year 
5, the protocol will be amended to accommodate additional in clinic visits 
every 4 months (16 weeks).  
Evaluation of subjects who choose to withdraw from the study at any time 
will be conducted in accordance with Section 12.8, Early Terminations. 
All PD medications should remain stable during LTS Phase Years 2 to 5, 
and any changes should be avoided unless approved by the Medical 
Monitor. Changes in medications for the treatment of other medical 
disorders are allowed with permission from the Medical Monitor. 
LTS Phase Years 2, 3, 4, and 5 – At Home Assessments – All Subjects 
During LTS Phase Years 2 to 5, subjects will be instructed to continue with 
their regular PD medication regimen(s), but should dose themselves with 
their study treatment (APL-130277) if they experience an "OFF" episode 
(eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF", etc.) 
while on their current treatment regimen. Subjects will be instructed to dose 
up to 5 "OFF" episodes per day. Subjects will be instructed to wait a 
minimum of 2 hours between doses taken at home. 
For 2 days prior to the in-clinic visits, subjects will be requested to 
complete a dosing diary that captures: 
• 
Time of APL-130277 treatment self-administration; 
• 
Subject "ON"/"OFF" states at 30 minutes after dosing. 
• 
The type of "OFF" experienced (ie, morning akinesia; delayed 
"ON"; wearing "OFF"; no "ON"; or sudden "OFF"). 
Between each in-clinic visit, subjects will be contacted at the midpoint 
between visits by the site to assess subject well-being and safety. If required 
due to safety concerns or lack of efficacy, subjects will be asked to return to 
the clinic for additional evaluations at an unscheduled Dose Adjustment 
Visit. 
INVESTIGATIONAL 
DRUG 
APL-130277 
Doses of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg (given as 2 films 
consisting of 20 mg and then 15 mg).  
For subjects dosed with 35 mg, instructions will be given to place the first 


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sublingual film (ie, 20 mg) under the tongue for 3 minutes before placing 
the second sublingual film (ie, 15 mg) under the tongue immediately and 
without delay. 
REFERENCE 
PRODUCT 
N/A 
TREATMENT 
REGIMENS 
Dose titration (De novo subjects only) from 10 mg up to 35 mg 
APL-130277 in 5 mg increments, and long-term outpatient treatment with 
dose adjustments based on efficacy, safety and tolerability. 
De novo subjects will receive the dose selected during the titration phase. 
Rollover Subjects will receive the same dose of APL-130277 that they 
received in their previous study. 
Completer subjects will receive the same dose of APL-130277 that they 
received previously. 
Dose adjustments are allowed for any subject. 
PRIOR AND 
CONCOMITANT 
TREATMENTS: 
PROHIBITED 
TREATMENT 
The following prior and/or concomitant treatments will not be allowed 
during the course of this study: 
• 
Treatment with any form of s.c. apomorphine is prohibited as 
follows:  
o from 7 days prior to the second Screening Visit (SV2) until 
study completion for De Novo subjects 
o from the time of the Screening Visit for Rollover subjects, 
until study completion 
o from the Screening Visit Period 2 (SVP2) for CTH-301 
Completer subjects until study completion.  
• 
Any selective 5HT3 antagonist (eg, ondansetron, granisetron, 
dolasetron, palonosetron, alosetron) are prohibited as follows: 
o from 30 days prior to the initial Screening Visit (SV1) for 
De Novo subjects until study completion 
o from 14 days prior to the Screening Visit for Rollover 
subjects until study completion 
o from the Screening Visit Period 2 (SVP2) for CTH-301 
Completer subjects until study completion. 
• 
Any dopamine antagonists or dopamine depleting drugs excluding 
anticholinergics and/or antihistamines with anticholinergic effects. 
Examples include, but are not limited to: 
o Antipsychotics - Both typical and atypical antipsychotics 
(except quetiapine and clozapine), including but not limited to: 
aripiprazole, fluphenazine, haloperidol, perphenazine, 
pimozide, thiothixene, trifluoperazine, loxapine, molindone, 
chlorpromazine, mesoridazine, thioridazine, olanzapine, 
risperidone, ziprasidone, depot neuroleptics; 
o Cinnarizine; 
o Flunarizine; 


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o Prochlorperazine; 
o Promethazine; 
o Tetrabenazine; 
o Lithium; 
o Metoclopropamide; 
o Reserpine. 
• 
Deep brain stimulation or other neurosurgical procedure for the 
treatment of PD. 
• 
Continuous s.c. apomorphine infusion. 
• 
Duodopa/Duopa. 
• 
Cisapride. 
• 
Dronedarone. 
• 
Any sublingual medicinal product, including Vitamin B6. 
• 
Any other preparation of Vitamin B6. 
• 
Medicinal/recreational marijuana. 
PRIOR AND 
CONCOMITANT 
TREATMENTS: 
PERMITTED 
TREATMENTS 
Anti-emetic medication is optional and can be initiated at the Investigator's 
discretion if clinically warranted. If initiated, anti-emetic therapy should be 
stopped when clinically indicated. Anti-emetic medication should not be 
administered prophylactically. 
The following concomitant treatments will be allowed during the course of 
the study: 
• 
Domperidone (10 mg b.i.d.; non-US sites) or Tigan® 
(trimethobenzamide hydrochloride; 300 mg t.i.d.; US sites) to 
overcome the potential nausea associated with apomorphine 
administration. NOTE: Domperidone is not indicated for longer 
than 7 continuous days of use. Extended use beyond 7 days should 
be discussed with the Medical Monitor. 
• 
Stable doses of an L-Dopa formulation with or without other stable 
adjunctive PD therapies is permitted with no planned medication 
changes during the study as follows: 
o from at least 4 weeks prior to the initial Screening Visit 
(SV1) for De Novo subjects 
o within 14 days of completing the previous study for 
Rollover subjects 
o from the Screening Visit Period 2 (SVP2) for CTH-301 
Completer subjects  
• 
MAO-B inhibitors will be allowed but must be stable as follows: 
o for at least 8 weeks prior to the initial Screening Visit 
(SV1) for De Novo subjects  
o for at least 14 days after completion of the previous study 
for Rollover subjects  
o from the Screening Visit Period 2 (SVP2) for CTH-301 
Completer subjects. 


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• 
Any other medication other than those identified as Prohibited 
Treatments are allowed, provided they are stable (within 14 days 
after completing the previous study for Rollover subjects or within 
4 weeks for De novo subjects). 
Other therapies should only be administered as necessary for the treatment 
of the subject, at the discretion of the Investigator. All concomitant 
medications must be recorded in the appropriate Case Report Form (CRF) 
for the subject. 
STUDY DURATION 
Subjects may participate in the study until the Sponsor terminates the study, 
or until commercial availability of APL-130277 in the patient's country. 
INVESTIGATIVE 
SITES OR 
COUNTRIES 
This multicenter study will be conducted worldwide. 
STUDY ENDPOINTS 
Primary Endpoint 
• 
Evaluation of safety and tolerability data collected, based on 
incidence of adverse events in the LTS Phase. 
Secondary Efficacy Endpoints 
• 
Mean change from pre-dose in MDS-UPDRS Part III Motor 
Examination (MDS-UPDRS MOTOR) score at 15, 30, 60, and 
90 minutes after dosing at Week 24, Week 36, and Week 48 visits 
(LTS V4, V5, and V6) of the LTS Phase. 
• 
Percentage of subjects with a subject-rated full "ON" response 
within 30 minutes at Week 24, Week 36, and Week 48 visits 
(LTS V4, V5, and V6) of the LTS Phase. 
• 
The percentage of instances where a full "ON" response was 
achieved within 30 minutes after self-administration of study 
medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, 
and V6) of the LTS Phase based on the dosing diary entries. 
Other Efficacy Endpoints 
• 
CGI-I post dosing. 
• 
PGI-I post dosing. 
• 
Change from baseline in the PDQ-39. 
• 
Change from baseline in the MDS-UPDRS – Part II: Motor Aspects 
of Experiences of Daily Living. 
• 
 Percentage of subjects with Investigator-rated full “ON” response 
within 30 minutes during the titration period. 
• 
Change from baseline in the Epworth Sleepiness Scale (ESS). 
Safety Endpoints 
• 
Observed values and Change in 12-lead ECGs,  
• 
Incidences of oropharyngeal and dopaminergic AEs,  
• 
C-SSRS, Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson's Disease Rating Scale (QUIP-RS) 


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STATISTICAL 
METHODS 
SUMMARY 
Analysis Sets 
All subjects who are enrolled into this study and receive at least one dose of 
study medication will be included in the full analysis set for each study 
phase. The safety and efficacy data will be primarily analyzed in the full 
analysis set in each study phase, but additional summaries will be done 
separately for De Novo Subjects and Rollover Subjects. 
Safety Analyses 
The analysis of the safety data will focus on data collected during the LTS 
Phase. In addition, all safety data will be reported separately for the Dose 
Titration Phase. Adverse events will be tabulated according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
adverse events (TEAEs) will be summarized by body system and preferred 
term. The AE analysis will focus on the dopaminergic (nausea, vomiting, 
OH) and oral TEAEs. Descriptive statistics will be used to summarize the 
overall incidence of TEAEs. 
Efficacy Analyses 
The efficacy endpoints will be analyzed both for the full analysis set and 
separately for Rollover Subjects and for De Novo Subjects. 
The changes from baseline in the continuous efficacy endpoints will be 
summarized descriptively. The categorical endpoints will be analyzed using 
subject counts and percentages. 


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4. 
STUDY DESIGN FLOW CHART 
Table 2: 
Table of Events - Screening (All Subjects) and Dose Titration Phase (De novo 
Subjects Only) 
Procedures 
Screening 
Dose Titration Phase 
(De novo Subjects Only)1 
Screening 
(de novo)2 
Screening 
(Rollover)2 
Screening 
(CTH-301 
Completer) 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
Study Visit 
SV1 
SV2 
SV 
SVP2 
TV1 
TV2 
TV3 
TV4 
TV5 
TV6 
Day (± 2 days) 
-28 to -1 
Up to 
21 
days 
-28 
to -1 
Day 1 up to 21 
Outpatient Visit4 
X 
X4 
X 
X 
X4 
X4 
X4 
X4 
X4 
X4 
Written Informed Consent 
X 
 
X 
X 
 
 
 
 
 
 
Review Entry Criteria 
X 
X 
X 
X 
 
 
 
 
 
 
Review Restriction Criteria 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History/Demographics 
X2 
X 
X 
 
 
 
 
 
 
Complete Physical Exam, 
including Oropharyngeal Exam5 
X2 
X 
X 
 
 
 
 
 
 
Abbreviated Physical Exam, 
including Oropharyngeal Exam6 
 
 
X 
X 
X 
X 
X 
X 
BMI, weight and height8 
X2 
X 
X 
 
 
 
 
 
 
Vital Signs 9, 10 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG10, 11 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests 
X 
X 
X 
 
 
 
 
 
 
MMSE 
 
X 
 
 
 
 
 
 
 
 
Modified Hoehn and Yahr 
X 
 
 
 
 
 
 
 
 
MDS-UPDRS Parts I, II and IV 
 
X 
X 
 
 
 
 
 
 
 
MDS-UPDRS Part III10, 12 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Confirmation of L-Dopa 
Responsiveness 
 
X 
 
 
 
Clinical Confirmation of "OFF" 
or full "ON"13 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Patient Confirmation of "OFF" or 
full "ON"13 
 
 
 
 
X 
X 
X 
X 
X 
X 
In-Clinic Dosing 
 
X 
X 
X 
X 
X 
X 


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Table 2: 
Table of Events - Screening (All Subjects) and Dose Titration Phase (De novo 
Subjects Only) (Continued) 
Procedures 
Screening 
Dose Titration Phase 
(De novo Subjects Only)1 
Screening 
(de novo)2 
Screening 
(Rollover)2 
Screening 
(CTH-301 
Completer) 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
Study Visit 
SV1 
SV2 
SV 
SVP2 
TV1 
TV2 
TV3 
TV4 
TV5 
TV6 
Day (± 2 days) 
-28 to -1 
Up to 
21 
days 
-28 
to -1 
Day 1 up to 21 
Provide Patient Dosing Diary15 
 
X16 
 
 
Patient "OFF" versus "ON" 
Training 
 
X17 
 
 
 
 
 
 
 
 
C-SSRS18 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PDQ-39 
 
X 
X 
 
 
ESS 
 
X 
X 
 
 
 
 
 
 
 
Caregiver Burden  
(Zarit Burden Interview [ZBI])23 
 
X 
X 
 
 
 
 
 
 
 
QUIP-RS 
 
X 
X 
 
 
 
 
 
 
 
AEs/Serious AEs (SAEs) 
X3 
X3 
X3 
X 
X 
X 
X 
X 
X 
Previous/Current Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Table Footnotes 
 


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Table 3: 
Table of Events - LTS Phase Year 1 (De Novo and Rollover Patients Only) 
Procedures 
LTS Phase Year 1 
Dose Adjustment Visit25 
Termination Visit 
LTS Visit 1 
Telephone Call 
LTS Visit 2 
Telephone Call 
LTS Visit 3 
Telephone Call 
LTS Visit 4 
Telephone Call 
LTS Visit 5 
Telephone Call 
LTS Visit 6 
Study Visit 
LTS 
V1 
T1 
LTS 
V2 
T2 
LTS 
V3 
T3 
LTS 
V4 
T4 
LTS 
V5 
T5 
LTS 
V6 
NA 
ET 
LTS Study Day (± 3 days) 
1 
14 
28 
56 
84 
126 
168 
210 
252 
294 
336 
- 
- 
LTS Study Week 
- 
2 
4 
8 
12 
18 
24 
30 
36 
42 
48 
- 
- 
LTS Study Month 7 
- 
- 
1 
- 
3 
- 
6 
- 
9 
- 
12 
- 
- 
Outpatient Visit4 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Review Restriction Criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam, 
including Oropharyngeal 
Exam5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Weight 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signs 9, 10 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECG10, 11 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Clinical Laboratory Tests 
 
 
X 
 
X 
 
X 
 
X 
 
X 
MDS-UPDRS Parts I, II 
and IV 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
MDS-UPDRS Part III10, 12 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Confirmation of 
"OFF" or full "ON"13 
X 
X 
X 
 
X 
 
X 
 
 
Patient Confirmation of 
"OFF" or full "ON"13 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
In-Clinic Dosing 
X14 
X14 
X14 
 
X14 
 
X14 
 
 
Dispense Study Medication 
assigned by the IWRS for 
Outpatient Dosing 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Collect Study Medication 
X 
X 
X 
 
X 
 
X 
X 
X22 
Provide Patient Dosing 
Diary15 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Collect Patient Dosing 
Diary15 
X15 
X 
X 
X 
 
X 
 
X 
X 
X22 


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Table 3: 
Table of Events - LTS Phase Year 1 (De Novo and Rollover Patients Only) 
(Continued) 
Procedures 
LTS Phase Year 1 
Dose Adjustment Visit25 
Termination Visit 
LTS Visit 1 
Telephone Call 
LTS Visit 2 
Telephone Call 
LTS Visit 3 
Telephone Call 
LTS Visit 4 
Telephone Call 
LTS Visit 5 
Telephone Call 
LTS Visit 6 
Study Visit 
LTS 
V1 
T1 
LTS 
V2 
T2 
LTS 
V3 
T3 
LTS 
V4 
T4 
LTS 
V5 
T5 
LTS 
V6 
NA 
ET 
LTS Study Day (± 3 days) 
1 
14 
28 
56 
84 
126 
168 
210 
252 
294 
336 
- 
- 
LTS Study Week 
- 
2 
4 
8 
12 
18 
24 
30 
36 
42 
48 
- 
- 
LTS Study Month 7 
- 
- 
1 
- 
3 
- 
6 
- 
9 
- 
12 
- 
- 
IP accountability and 
Treatment Compliance 
X 
X 
X 
 
X 
 
X 
X 
X22 
C-SSRS18 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PDQ-39 
X 
X 
 
X 
 
X 
 
X22 
PGI19 
X 
X 
 
X 
 
X 
 
X22 
CGI19 
X 
 
X 
 
X 
 
X 
 
X22 
ESS 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X22 
Caregiver Burden (Zarit 
Burden Interview [ZBI])23 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X22 
QUIP-RS 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X22 
Outpatient Self-
Administration Training 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for PK 
Analysis 
X20 
 
 
 
X20 
 
X20 
 
X20 
 
X20 
 
 
AEs/Serious AEs (SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/Current Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Reasons(s) for Dose 
Adjustment 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Table Footnotes 
 


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Table 4: 
Table of Events - LTS Phase Year 2 (All Patients) 
Procedures 
LTS Phase Year 2 
Dose Adjustment 
Visit25 
Termination Visit 
Telephone Call 
LTS Visit 7 
Telephone Call 
LTS Visit 8 
Telephone Call 
LTS Visit 9 
Study Visit 
T6 
LTS 
V7 
T7 
LTS 
V8 
T8 
LTS 
V9 
N/A 
ET 
LTS Study Week (± 1 week) 
56 
64 
72 
80 
88 
96 
- 
- 
LTS Study Month 7 
- 
16 
- 
20 
- 
24 
N/A 
- 
Outpatient Visit4 
 
X 
 
X 
 
X 
X 
X 
Review Restriction Criteria 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam, including 
Oropharyngeal Exam5 
 
X 
 
X 
 
X 
 
X 
Weight 
 
X 
 
X 
 
X 
 
X 
Vital Signs 9, 10 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECG10, 11 
 
X 24 
 
X 
 
X 
 
X 
Clinical Laboratory Tests 
 
X 24 
 
X 
 
X 
 
X 
Dispense Study Medication assigned 
by the IWRS for Outpatient Dosing 
 
X 
 
X 
 
X 
X 
 
Collect Study Medication 
 
X 24 
 
X 
 
X 
X 
X 
Provide Patient Dosing Diary15 
 
X 
 
X 
 
X 
X 
 
Collect Patient Dosing Diary15 
 
X 24 
 
X 
 
X 
X 
X 
IP accountability and Treatment 
Compliance 
 
X 24 
 
X 
 
X 
X 
X 
C-SSRS18 
 
X 
 
X 
 
X 
 
X 
AEs/Serious AEs (SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/Current Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Record Reason(s) for Dose 
Adjustment 
 
 
 
 
 
 
X 
 
PDQ-39 
 
 
 
 
 
 
 
X 
PGI19 
 
 
 
 
 
 
 
X 
CGI19 
 
 
 
 
 
 
 
X 
ESS 
 
 
 
 
 
 
 
X 


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Table 4: 
Table of Events - LTS Phase Year 2 (All Patients) (Continued) 
Procedures 
LTS Phase Year 2 
Dose Adjustment 
Visit25 
Termination Visit 
Telephone Call 
LTS Visit 7 
Telephone Call 
LTS Visit 8 
Telephone Call 
LTS Visit 9 
Study Visit 
T6 
LTS 
V7 
T7 
LTS 
V8 
T8 
LTS 
V9 
N/A 
ET 
LTS Study Week (± 1 week) 
56 
64 
72 
80 
88 
96 
- 
- 
LTS Study Month 7 
- 
16 
- 
20 
- 
24 
N/A 
- 
Caregiver Burden (Zarit Burden 
Interview [ZBI])23 
 
 
 
 
 
 
 
X 
QUIP-RS 
 
 
 
 
 
 
 
X 
Ease of Use Questionnaire 
 
 
 
 
 
 
 
X 
Table Footnotes 
  
 


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Table 5: 
Table of Events - LTS Phase Year 3 (All Patients) 
Procedures 
LTS Phase Year 3 
Dose Adjustment 
Visit25 
Termination Visit 
Telephone Call 
LTS Visit 10 
Telephone Call 
LTS Visit 11 
Telephone Call 
LTS Visit 12 
Study Visit 
T9 
LTS 
V10 
T10 
LTS 
V11 
T11 
LTS 
V12 
N/A 
ET 
LTS Study Week (± 1 week) 
104 
112 
120 
128 
136 
144 
 
- 
LTS Study Month 7 
- 
28 
- 
32 
- 
36 
N/A 
- 
Outpatient Visit4 
 
X 
 
X 
 
X 
X 
X 
Review Restriction Criteria 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam, including 
Oropharyngeal Exam5 
 
X 
 
X 
 
X 
 
X 
Weight  
 
X 
 
X 
 
X 
 
X 
Vital Signs 9, 10 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECG10, 11 
 
X 
 
X 
 
X 
 
X 
Clinical Laboratory Tests 
 
X 
 
X 
 
X 
 
X 
Dispense Study Medication assigned 
by the IWRS for Outpatient Dosing 
 
X 
 
X 
 
X 
X 
 
Collect Study Medication 
 
X 
 
X 
 
X 
X 
X 
Provide Patient Dosing Diary15 
 
X 
 
X 
 
X 
X 
 
Collect Patient Dosing Diary15 
 
X 
 
X 
 
X 
X 
X 
IP accountability and Treatment 
Compliance 
 
X 
 
X 
 
X 
X 
X 
C-SSRS18 
 
X 
 
X 
 
X 
 
X 
AEs/Serious AEs (SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/Current Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Record Reason(s) for Dose 
Adjustment 
 
 
 
 
 
 
X 
 
PDQ-39 
 
 
 
 
 
 
 
X 
PGI19 
 
 
 
 
 
 
 
X 
CGI19 
 
 
 
 
 
 
 
X 
ESS 
 
 
 
 
 
 
 
X 
Caregiver Burden (Zarit Burden 
Interview [ZBI])23 
 
 
 
 
 
 
 
X 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
27 
 
25 February 2019 
Table 5: 
Table of Events - LTS Phase Year 3 (All Patients) (Continued) 
Procedures 
LTS Phase Year 3 
Dose Adjustment 
Visit25 
Termination Visit 
Telephone Call 
LTS Visit 10 
Telephone Call 
LTS Visit 11 
Telephone Call 
LTS Visit 12 
Study Visit 
T9 
LTS 
V10 
T10 
LTS 
V11 
T11 
LTS 
V12 
N/A 
ET 
LTS Study Week (± 1 week) 
104 
112 
120 
128 
136 
144 
 
- 
LTS Study Month 7 
- 
28 
- 
32 
- 
36 
N/A 
- 
QUIP-RS 
 
 
 
 
 
 
 
X 
Ease of Use Questionnaire 
 
 
 
 
 
 
 
X 
Table Footnotes 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
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25 February 2019 
Table 6: 
Table of Events - LTS Phase Year 4 (All Patients) 
Procedures 
LTS Phase Year 4 
Dose Adjustment 
Visit25 
Termination Visit 
Telephone Call 
LTS Visit 13 
Telephone Call 
LTS Visit 14 
Telephone Call 
LTS Visit 15 
Study Visit 
T12 
LTS 
V13 
T13 
LTS 
V14 
T14 
LTS 
V15 
N/A 
ET 
LTS Study Week (± 1 week) 
152 
160 
168 
176 
184 
192 
 
- 
LTS Study Month 7 
- 
40 
- 
44 
- 
48 
N/A 
- 
Outpatient Visit4 
 
X 
 
X 
 
X 
X 
X 
Review Restriction Criteria 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam, including 
Oropharyngeal Exam5 
 
X 
 
X 
 
X 
 
X 
Weight 
 
X 
 
X 
 
X 
 
X 
Vital Signs 9, 10 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECG10, 11 
 
X 
 
X 
 
X 
 
X 
Clinical Laboratory Tests 
 
X 
 
X 
 
X 
 
X 
Dispense Study Medication assigned 
by the IWRS for Outpatient Dosing 
 
X 
 
X 
 
X 
X 
 
Collect Study Medication 
 
X 
 
X 
 
X 
X 
X 
Provide Patient Dosing Diary15 
 
X 
 
X 
 
X 
X 
 
Collect Patient Dosing Diary15 
 
X 
 
X 
 
X 
X 
X 
IP accountability and Treatment 
Compliance 
 
X 
 
X 
 
X 
X 
X 
C-SSRS18 
 
X 
 
X 
 
X 
 
X 
AEs/Serious AEs (SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/Current Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Record Reason(s) for Dose 
Adjustment 
 
 
 
 
 
 
X 
 
PDQ-39 
 
 
 
 
 
 
 
X 
PGI19 
 
 
 
 
 
 
 
X 
CGI19 
 
 
 
 
 
 
 
X 
ESS 
 
 
 
 
 
 
 
X 
Caregiver Burden (Zarit Burden 
Interview [ZBI])23 
 
 
 
 
 
 
 
X 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
29 
 
25 February 2019 
Table 6: 
Table of Events - LTS Phase Year 4 (All Patients) (Continued) 
Procedures 
LTS Phase Year 4 
Dose Adjustment 
Visit25 
Termination Visit 
Telephone Call 
LTS Visit 13 
Telephone Call 
LTS Visit 14 
Telephone Call 
LTS Visit 15 
Study Visit 
T12 
LTS 
V13 
T13 
LTS 
V14 
T14 
LTS 
V15 
N/A 
ET 
LTS Study Week (± 1 week) 
152 
160 
168 
176 
184 
192 
 
- 
LTS Study Month 7 
- 
40 
- 
44 
- 
48 
N/A 
- 
QUIP-RS 
 
 
 
 
 
 
 
X 
Ease of Use Questionnaire 
 
 
 
 
 
 
 
X 
Table Footnotes 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
30 
 
25 February 2019 
Table 7: 
Table of Events - LTS Phase Year 5 (All Patients) 
Procedures 
LTS Phase Year 5 
Dose Adjustment 
Visit25 
Termination Visit 
Telephone Call 
LTS Visit 16 
Telephone Call 
LTS Visit 17 
Telephone Call 
LTS Visit 18 
Study Visit 
T15 
LTS 
V16 
T16 
LTS 
V17 
T17 
LTS 
V18 
N/A 
ET 
LTS Study Week (± 1 week) 
200 
208 
216 
224 
232 
240 
 
- 
LTS Study Month 7 
- 
52 
- 
56 
- 
60 
N/A 
- 
Outpatient Visit4 
 
X 
 
X 
 
X 
X 
X 
Review Restriction Criteria 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam, including 
Oropharyngeal Exam5 
 
X 
 
X 
 
X 
 
X 
Weight  
 
X 
 
X 
 
X 
 
X 
Vital Signs 9, 10 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECG10, 11 
 
X 
 
X 
 
X 
 
X 
Clinical Laboratory Tests 
 
X 
 
X 
 
X 
 
X 
Dispense Study Medication assigned 
by the IWRS for Outpatient Dosing 
 
X 
 
X 
 
X 
X 
 
Collect Study Medication 
 
X 
 
X 
 
X 
X 
X 
Provide Patient Dosing Diary15 
 
X 
 
X 
 
X 
X 
 
Collect Patient Dosing Diary15 
 
X 
 
X 
 
X 
X 
X 
IP accountability and Treatment 
Compliance 
 
X 
 
X 
 
X 
X 
X 
C-SSRS18 
 
X 
 
X 
 
X 
 
X 
AEs/Serious AEs (SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/Current Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Record Reason(s) for Dose 
Adjustment 
 
 
 
 
 
 
X 
 
PDQ-39 
 
 
 
 
 
 
 
X 
PGI19 
 
 
 
 
 
 
 
X 
CGI19 
 
 
 
 
 
 
 
X 
ESS 
 
 
 
 
 
 
 
X 
Caregiver Burden (Zarit Burden 
Interview [ZBI])23 
 
 
 
 
 
 
 
X 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
31 
 
25 February 2019 
Table 7: 
Table of Events - LTS Phase Year 5 (All Patients) (Continued) 
Procedures 
LTS Phase Year 5 
Dose Adjustment 
Visit25 
Termination Visit 
 
Telephone Call 
LTS Visit 16 
Telephone Call 
LTS Visit 17 
Telephone Call 
LTS Visit 18 
Study Visit 
T15 
LTS 
V16 
T16 
LTS 
V17 
T17 
LTS 
V18 
N/A 
ET 
LTS Study Week (± 1 week) 
200 
208 
216 
224 
232 
240 
 
- 
LTS Study Month 7 
- 
52 
- 
56 
- 
60 
N/A 
- 
QUIP-RS 
 
 
 
 
 
 
 
X 
Ease of Use Questionnaire 
 
 
 
 
 
 
 
X 
Table Footnotes 
1 Only De novo subjects will undergo dose titration. Dosing during the Dose Titration Phase must be completed 
within 21 days. The initial LTS Visit (LTS V1) must occur up to 21 days after the final Dose Titration Phase visit. 
2 All screening procedures are to be conducted within 28 days prior to Titration Visit 1 for De Novo subjects: 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, 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. Screening procedures are to be conducted up to 14 days after completion of the 
previous study for Rollover subjects and 5 to 21 days prior to LTS V1. 
3 Adverse event recording and serious adverse event reporting will begin when the subject signs the ICF. 
4 De novo Subjects may be monitored in the clinic overnight before Dosing Titration Visits if such facilities exist 
and the subject consents. 
5 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. Any subject 
who presents with an adverse event involving the oral cavity must be seen by a qualified dermatologist (or 
specialist in a related field) within 24 hours. The dermatologist (or specialist in a related field) must examine the 
subject, and provide a consultation report including photographs of the oral cavity (see Section 13.1.7). 
6 De novo subjects will undergo an 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 post dosing at TV1 to TV6. 
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. A window of +/- 10 minutes is given for 
post-dose abbreviated physical and oropharyngeal examinations during TV1 to TV6. 
7 Months are calculated as 4 weeks. 
8 Both height and weight captured at the Screening Visit (SV2 for De Novo subjects; SV1 for Rollover subjects; and 
SVP2 for CTH-301 Completer subjects) to calculate BMI; only weight captured at all other visits. 
9 Vital signs will be assessed once at the Screening Visit (SV2 for De Novo subjects; SV1 for Rollover subjects; and 
SVP2 for CTH-301 Completer subjects), all Dose Adjustment Visits, LTS V2, LTS V7 to LTS V17, and ET. At 
TV1 to TV6 (De novo subjects) and at LTS V1, LTS V3, LTS V4, LTS V5, and LTS V6 for all subjects vital signs 
will be assessed at t = 0 minutes (just prior to dosing) and immediately after the 60 minute MDS-UPDRS Part III 
assessment. Blood pressure will be measured in both supine and standing positions (to be measured within 
3 minutes of standing) at all timepoints. 
10 Suggested Sequence of Assessments at Pre-Dose: ECG – Vitals – Patient "OFF"/"ON" status - MDS-UPDRS 
Part III 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
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25 February 2019 
Suggested Sequence of Assessments Post-Dose where conflict arises: MDS-UPDRS Part III - Subject 
"OFF"/"ON" status - ECG – Vitals.  
If a previously scheduled MDS-UPDRS assessment is not complete prior to performing these assessments, it must 
be completed prior to performing any scheduled ECG and/or Vitals. 
11 Triplicate 12-lead ECG at the Screening Visit (SV2 for De Novo subjects; SV1 for Rollover subjects; and SVP2 
for CTH-301 Completer subjects); single ECGs at t = 0 (just prior to dosing) and approximately 50 minutes post 
dosing at TV1 to TV6 (De novo subjects) and at LTS V1, LTS V3, LTS V4, LTS V5, and LTS V6 for all subjects; 
single ECG at LTS V2 and ET. 
12 MDS-UPDRS Part III (Motor Function) to be assessed at t = 0 (just prior to dosing), 15, 30, 60 and 90 minutes 
post dosing at the Screening Visit (SV2; De Novo subjects only). If the patient does not experience an "ON" within 
90 minutes, the site should record the time when the subject turns "ON" and perform an additional MDS-UPDRS 
Part III assessment at this time. MDS-UPDRS Part III (Motor Function) will be assessed at t = 0 (just prior to 
dosing), 15, 30, and 60 minutes post dosing at TV1 to TV6, and LTS V1, LTS V3, LTS V4, LTS V5, and LTS V6. 
During the Dose Titration Phase only (De novo subjects only), these assessments may cease if the subject does not 
experience a full "ON" response within 30 minutes of dosing. 
All Part III assessments will exclude the "Dyskinesia Impact on Part III Ratings" and the Hoehn and Yahr staging. 
13 Investigator/subject confirmation of "OFF" or "ON" at SV2 (De Novo subjects only).  
At TV1 to TV6 and LTS V1, LTS V3, LTS V4, LTS V5, and LTS V6, the Investigator will assess "OFF/ON" state 
as part of the MDS-UPDRS Part III assessments, except at 30 minutes, which will be assessed independent of the 
MDS-UPDRS Part III. During the Dose Titration Phase (De novo subjects only), these assessments may cease if 
the patient does not experience a full "ON" response within 30 minutes of dosing. 
At TV1 to TV6 and LTS V1, LTS V3, LTS V4, LTS V5, and LTS V6, the subject should report: "OFF"/"ON" 
state at 0, 15, 30, 45 and 60 minutes after dosing. 
Subjects should also report the time to when the study medication is starting to have an effect (if applicable), and 
time to "OFF" following dosing (if it occurs within 60 minutes of dosing). Note: The timing of this should begin 
when the study medication sublingual film has fully dissolved, and can be recorded using a stopwatch or other 
suitable timing device. 
During the Dose Titration Phase only (De novo subjects only), these assessments may cease if the subject does not 
experience a full "ON" response within 30 minutes of dosing. 
14 Dosing in clinic from outpatient supplies. At LTS V1 De novo Subjects (only) will receive outpatient self-
administration training. 
15 Sites will call each patient 3 days before an applicable in-clinic LTS visit to remind patients to complete the 
Subject Dosing Diary. Diary will record: time when patient self-administers a dose; subject "ON"/"OFF" status at 
30 minutes following dosing; the type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; 
no "ON"; or sudden "OFF"). At LTS V1, the diary will be collected from De novo Subjects only. 
16 Subject Dosing Diary provided on TV1 (De novo subjects only) will be provided for training purposes only. 
During this phase, subjects should be instructed to use their scheduled PD medication administration as the 
reference point. At LTS V1, the diary will be collected from De novo Subjects. If needed, subjects will be 
retrained on LTS V1 in the use of the dosing diary.  
17 Subject "OFF" versus "ON" Training will occur as part of the L-Dopa challenge at SV2 (De Novo subjects only). 
18 "Screening" scale to be used at the Screening Visit (SV2 for De Novo subjects; SV1 for Rollover suubjects; and 
SVP2 for CTH-301 Completer subjects); "Since Last Visit" to be used at all other visits. 
19 –S to be used at first visit, -I to be used at all subsequent visits. 
20 Blood collection for APL-130277 PK analyses will occur in up to 24 subjects from up to 6 sites. Samples will be 
taken at t = 0 (just prior to dosing) and at t = 10, 20, 30, 60, 90, 120, 180, and 240 minutes post dosing. 
21 Intentionally skipped. 
22 Assessments will not be performed on subjects whose participation is terminated during the Dose Titration Phase 
of the study. 
23 Assessment optional; to be completed if caregiver is present and consent is provided. 
24 Excluding LTS V7 for CTH-301 Completer subjects. 
25 At the investigator’s discretion, the subject may receive the adjusted dose in-clinic and undergo efficacy 
(MDS-UPDRS part III and ON/OFF assessments up to 90 minutes), and additional safety assessments as deemed 
appropriate.  
Subjects will be contacted by telephone within 3 days after dose adjustment visits for assessment of effect of the 
dose adjustment and safety. 


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Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
34 
 
25 February 2019 
For De novo subjects, at all titration visits, at the discretion of the subject and/or Investigator, the 
next highest dose may be evaluated at a subsequent titration visit following a full "ON" response 
in order to assess the potential for the next highest dose in inducing an improved full "ON" 
response. If this dose produces an improved "ON" response relative to the lower dose without 
impacting subject safety and tolerability, the higher dose will be used during the LTS Phase of 
the study. If the "ON" response is the same or worse, or this higher dose is not well-tolerated, the 
previous dose will be used during the LTS Phase of the study. 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
35 
 
25 February 2019 
5. 
TABLE OF CONTENTS 
1. 
EMERGENCY CONTACTS .......................................................................................3 
2. 
INVESTIGATOR APPROVAL STATEMENT ...........................................................4 
3. 
PROTOCOL SYNOPSIS ..............................................................................................5 
4. 
STUDY DESIGN FLOW CHART ............................................................................20 
5. 
TABLE OF CONTENTS ...........................................................................................35 
6. 
LIST OF ABBREVIATIONS OR TERMS ................................................................41 
7. 
INTRODUCTION ......................................................................................................44 
7.1. 
Background .................................................................................................................44 
7.2. 
Drug Substance ...........................................................................................................45 
7.3. 
Drug Product (APL-130277 Sublingual Film) ............................................................46 
7.4. 
Summary of Potential Risks and Benefits ..................................................................47 
7.5. 
Rationale .....................................................................................................................48 
8. 
ETHICS ......................................................................................................................49 
9. 
OBJECTIVES AND STUDY ENDPOINTS ..............................................................50 
9.1. 
Objectives ...................................................................................................................50 
9.2. 
Study Endpoints ..........................................................................................................50 
9.2.1. 
Primary Endpoint ........................................................................................................50 
9.2.2. 
Secondary Efficacy Endpoints ....................................................................................50 
9.2.3. 
Other Efficacy Endpoints ...........................................................................................50 
9.2.4. 
Safety Endpoints .........................................................................................................50 
10. 
STUDY DESIGN ........................................................................................................51 
10.1. 
General Overview .......................................................................................................51 
10.1.1. 
Screening Visits ..........................................................................................................51 
10.1.1.1. 
Screening Procedures for De Novo Subjects ..............................................................51 
10.1.1.2. 
Screening Procedures for Rollover Subjects ..............................................................51 
10.1.1.3. 
Screening Procedures for CTH-301 Completer Subjects ...........................................52 
10.1.2. 
Dose Titration Phase - De Novo Subjects Only ..........................................................52 
10.1.3. 
Long-Term Safety Phase Year 1 – In-clinic Visits – De Novo and Rollover 
Subjects Only ..............................................................................................................54 
10.1.4. 
Long-Term Safety Phase Year 1 – At Home Assessments – De Novo and 
Rollover Subjects Only ...............................................................................................55 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
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25 February 2019 
10.1.5. 
Long-Term Safety Phase Years 2, 3, 4, and 5 – In-clinic Visits - All Patients ..........56 
10.1.6. 
LTS Phase Years 2, 3, 4, and 5 – At Home Assessments – All Patients ....................56 
10.2. 
Blinding ......................................................................................................................56 
10.3. 
Data Safety Monitoring Board ....................................................................................56 
11. 
SUBJECT POPULATION ..........................................................................................58 
11.1. 
Selection of Study Population .....................................................................................58 
11.1.1. 
Criteria for De Novo Subjects .....................................................................................58 
11.1.1.1. 
Inclusion Criteria – De Novo Subjects ........................................................................58 
11.1.1.2. 
Exclusion Criteria – De Novo Subjects .......................................................................59 
11.1.2. 
Criteria for Rollover Subjects .....................................................................................60 
11.1.2.1. 
Inclusion Criteria - Rollover Subjects ........................................................................60 
11.1.2.2. 
Exclusion Criteria – Rollover Subjects.......................................................................61 
11.1.3. 
Criteria for CTH-301 Completer Subjects ..................................................................61 
11.1.3.1. 
Inclusion Criteria - CTH-301 Completer Subjects .....................................................61 
11.1.3.2. 
Exclusion Criteria – CTH-301 Completer Subjects ...................................................62 
11.2. 
Prior and Concomitant Treatments .............................................................................63 
11.2.1. 
Prohibited Treatments .................................................................................................63 
11.2.2. 
Permitted Treatments ..................................................................................................64 
11.3. 
Subject Withdrawal from the Study ............................................................................65 
12. 
STUDY PROCEDURES ............................................................................................66 
12.1. 
Screening Visits ..........................................................................................................67 
12.1.1. 
Screening Procedures for De Novo Subjects ..............................................................67 
12.1.2. 
Screening Procedures for Rollover Subjects ..............................................................69 
12.1.3. 
Screening Procedures for CTH-301 Completer Subjects ...........................................70 
12.2. 
Dose Titration Phase (TV1 to TV6) - De Novo Subjects Only ..................................71 
12.2.1. 
TV1 to TV6 .................................................................................................................71 
12.3. 
Long-Term Safety (LTS) Treatment Phase Year 1 – De Novo and Rollover 
Subjects Only ..............................................................................................................73 
12.3.1. 
LTS V1, LTS V3, LTS V4, LTS V5, and LTS V6: In-Clinic Assessments...............74 
12.3.2. 
LTS V2: In-Clinic Assessment ...................................................................................76 
12.3.3. 
LTS Phase Year 1 – At Home Assessments ...............................................................77 
12.3.4. 
LTS Phase Year 1 – Telephone Contacts ...................................................................77 
12.4. 
Long-Term Safety (LTS) Treatment Phase Year 2 - All Subjects .............................77 


Protocol CTH-301, Version 5.00 
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Confidential and Proprietary 
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25 February 2019 
12.4.1. 
LTS V7, LTS V8, and LTS V9: In-Clinic Assessment ..............................................78 
12.4.2. 
LTS Phase Year 2 – At Home Assessments ...............................................................79 
12.4.3. 
LTS Phase Year 2 – Telephone Contacts ...................................................................79 
12.5. 
Long-Term Safety (LTS) Treatment Phase Year 3 - All Subjects .............................79 
12.5.1. 
LTS V10, LTS V11, and LTS V12: In-Clinic Assessment ........................................80 
12.5.2. 
LTS Phase Year 3 – At Home Assessments ...............................................................81 
12.5.3. 
LTS Phase Year 3 – Telephone Contacts ...................................................................81 
12.6. 
Long-Term Safety (LTS) Treatment Phase Year 4 - All Subjects .............................81 
12.6.1. 
LTS V13, LTS V14, and LTS V15: In-Clinic Assessment ........................................82 
12.6.2. 
LTS Phase Year 4 – At Home Assessments ...............................................................83 
12.6.3. 
LTS Phase Year 4 – Telephone Contacts ...................................................................83 
12.7. 
Long-Term Safety (LTS) Treatment Phase Year 5 - All Subjects .............................83 
12.7.1. 
LTS V16, LTS V17, and LTS V18: In-Clinic Assessment ........................................83 
12.7.2. 
LTS Phase Year 5 – At Home Assessments ...............................................................84 
12.7.3. 
LTS Phase Year 5 – Telephone Contacts ...................................................................85 
12.8. 
Early Termination Visit ..............................................................................................85 
12.9. 
Unscheduled Dose Adjustment Visits ........................................................................86 
12.10. 
Duration of Treatment .................................................................................................88 
12.11. 
Assessments ................................................................................................................88 
12.11.1. 
Order of Assessments .................................................................................................88 
12.11.2. 
Clinical Safety Assessments .......................................................................................88 
12.11.2.1. Physical Examinations ................................................................................................88 
12.11.2.2. Vital Signs ..................................................................................................................89 
12.11.2.3. 12-Lead ECGs ............................................................................................................89 
12.11.2.4. Modified Hoehn and Yahr ..........................................................................................90 
12.11.2.5. Clinical Laboratory Tests ............................................................................................90 
12.11.2.6. Specimen Handling Requirements ..............................................................................91 
12.11.2.7. C-SSRS .......................................................................................................................91 
12.11.2.8. Other Safety and Quality of Life Assessments ...........................................................91 
12.11.2.9. Medical History ..........................................................................................................92 
12.11.3. 
Efficacy Assessments .................................................................................................92 
12.11.3.1. Confirmation of "OFF" or "ON" Episodes "OFF" and "ON" Training of 
Subjects at SV2 ...........................................................................................................92 


Protocol CTH-301, Version 5.00 
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25 February 2019 
12.11.3.2. MDS-UPDRS Parts I, II and IV .................................................................................94 
12.11.3.3. MDS-UPDRS Part III .................................................................................................94 
12.11.3.4. Subject Dosing Diary ..................................................................................................95 
12.11.3.5. Optional Pharmacokinetic (PK) Evaluation ...............................................................95 
12.12. 
Assessment of Treatment Compliance .......................................................................95 
13. 
ADVERSE EVENTS ..................................................................................................97 
13.1.1. 
Definition of Adverse Events ......................................................................................97 
13.1.2. 
Definition of Serious Adverse Events .........................................................................97 
13.1.3. 
Definition of Severity .................................................................................................98 
13.1.4. 
Definition of Start Date, Stop Date, and Duration ......................................................98 
13.1.5. 
Action(s) Taken ..........................................................................................................98 
13.1.6. 
Definition of Expectedness .........................................................................................98 
13.1.7. 
Adverse Events of Special Interest .............................................................................99 
13.1.8. 
Definition of Relationship to Investigational Drug(s) .................................................99 
13.1.9. 
Definition of Outcome at the Time of Last Observation ...........................................100 
13.1.10. 
Documentation of Adverse Events ............................................................................100 
13.1.11. 
Follow-up of Subjects With an Adverse Event .........................................................101 
13.1.12. 
Special Procedures for Managing AEs/SAEs ............................................................101 
13.1.13. 
Notification of Serious Adverse Events ....................................................................101 
13.1.14. 
Notification of Oral Adverse Events of Special Interest ..........................................102 
14. 
TREATMENTS ........................................................................................................103 
14.1. 
Treatments Administered (APL-130277 and Matching Placebo) .............................103 
14.2. 
Administration of Study Medication (APL-130277 and Placebo 
APL--130277) ...........................................................................................................103 
14.3. 
Storage ......................................................................................................................104 
14.4. 
Packaging and Labeling ............................................................................................105 
14.5. 
Drug Accountability ..................................................................................................105 
14.6. 
Method of Assigning Subjects to Treatment Groups ................................................105 
14.7. 
Randomization and Blinding ....................................................................................106 
15. 
STATISTICAL ANALYSES ....................................................................................107 
15.1. 
Statistical Analysis Plan ...........................................................................................107 
15.2. 
Analysis Sets ..............................................................................................................107 
15.2.1. 
Titration Full Analysis Set ........................................................................................107 


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15.2.2. 
LTS Full Analysis Set ...............................................................................................107 
15.3. 
Sample Size Calculation. ..........................................................................................107 
15.4. 
Efficacy Analysis ......................................................................................................107 
15.5. 
Safety Analysis .........................................................................................................107 
15.6. 
Pharmacokinetic Analysis ........................................................................................107 
16. 
STUDY CONDUCT .................................................................................................110 
16.1. 
Regulations and Guidelines.......................................................................................110 
16.2. 
Study Initiation ..........................................................................................................110 
16.3. 
Study Documentation ................................................................................................110 
16.3.1. 
Investigator’s Regulatory Documents .......................................................................110 
16.3.2. 
Case Report Forms ....................................................................................................111 
16.3.3. 
Source Documents ....................................................................................................112 
16.4. 
Data Quality Assurance ............................................................................................112 
16.4.1. 
Monitoring the Study ................................................................................................112 
16.4.2. 
Routine Data Collection ............................................................................................113 
16.4.3. 
Expedited Data Collection ........................................................................................113 
16.4.4. 
Data Management .....................................................................................................113 
16.4.5. 
Study Termination ....................................................................................................113 
16.4.6. 
Clinical Site Closure .................................................................................................114 
16.4.7. 
Data Safety Monitoring Board ...................................................................................114 
17. 
GENERAL CONSIDERATIONS .............................................................................115 
17.1. 
Changes to the Protocol ............................................................................................115 
17.2. 
Use of Information and Publication ..........................................................................115 
17.3. 
Records Retention .....................................................................................................115 
17.4. 
Sample Retention ......................................................................................................115 
17.5. 
Subject Injury ............................................................................................................116 
18. 
REFERENCES .........................................................................................................117 
19. 
APPENDICES ..........................................................................................................118 
19.1. 
APPENDIX I: APOKYN® Prescribing Information and APO-go® Summary 
of Product Characteristics .........................................................................................118 
19.2. 
APPENDIX II: Regulations and Guidelines .............................................................119 
19.2.1. 
Declaration of Helsinki .............................................................................................119 
19.2.2. 
Approval by an IRB/REB/IEC ..................................................................................119 


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19.3. 
APPENDIX III: Modified Hoehn and Yahr Scale ...................................................120 
19.4. 
APPENDIX IV: Movement Disorder Society - Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) ...................................................................................121 
19.5. 
APPENDIX V: Home Dosing Diary (Sample) ........................................................154 
19.6. 
APPENDIX VI: Columbia Suicide Severity Rating Scale (C-SSRS) ......................155 
19.7. 
APPENDIX VII: Parkinson’s Disease Questionnaire (PDQ-39) .............................162 
19.8. 
APPENDIX VIII: Clinical Global Impression (CGI) ..............................................168 
19.9. 
APPENDIX IX: Patient Global Impression (PGI) ..................................................170 
19.10. 
APPENDIX X: Epworth Sleepiness Scale (ESS) .................................................... 172 
19.11. 
APPENDIX XI: Zarit Burden Interview (ZBI) ........................................................ 174 
19.12. 
APPENDIX XII: Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease – Rating Scale (QUIP-RS) ......................................................180 
19.13. 
APPENDIX XIII: European Quality of Life – 5 Dimensions (EQ-5D) ...................183 
19.14. 
APPENDIX XIV: United Kingdom Parkinson’s Disease Brain Bank Clinical 
Diagnostic Criteria ....................................................................................................186 
19.15. 
APPENDIX XV: Ease of Use Questionnaire ...........................................................188 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Table of Events - Screening (All Subjects) and Dose Titration Phase (De 
novo Subjects Only) ...................................................................................................20 
Table 3: 
Table of Events - LTS Phase Year 1 (De Novo and Rollover Patients Only) ............22 
Table 4: 
Table of Events - LTS Phase Year 2 (All Patients) ....................................................24 
Table 5: 
Table of Events - LTS Phase Year 3 (All Patients) ....................................................26 
Table 6: 
Table of Events - LTS Phase Year 4 (All Patients) ....................................................28 
Table 7: 
Table of Events - LTS Phase Year 5 (All Patients) ....................................................30 
Table 8: 
Summary of Apomorphine Physico-Chemical Data ..................................................46 
Table 9: 
Physical APL-130277 Characteristics ........................................................................47 
Table 10: Pharmacokinetic Parameters to be Estimated ...........................................................108 
Table 11: Documents Required for Regulatory Packet .............................................................111 
LIST OF FIGURES 
Figure 1: 
Dose Titration Phase Dosing Paradigm (De novo Subjects Only) .............................33 


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6. 
LIST OF ABBREVIATIONS OR TERMS 
Abbreviation or 
specialist term 
Explanation 
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. 
AUC∞ 
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 
CGI 
Clinical Global Impression 
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 
CTH-301 Completer 
Patients 
patients who have previously completed the CTH-301 study 
CV% 
coefficient of variation 
De Novo Patients 
patients who have not previously participated in a study with APL-130277 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
EDC 
electronic data capture 


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Abbreviation or 
specialist term 
Explanation 
EQ-5D 
European Quality of Life – 5 Dimensions 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
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 
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 
LTS 
Long-Term Safety 
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 
M/P ratios 
Metabolite to parent ratio of AUC and Cmax 
MRT 
mean residence time 
MMSE 
Mini-mental State Examination 
OH 
Orthostatic Hypotension 
PD 
Parkinson’s disease 
PDQ-39 
Parkinson’s Disease Questionnaire 
PGI 
Patient Global Impression 


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Abbreviation or 
specialist term 
Explanation 
PK 
pharmacokinetic 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale 
RBC 
red blood cell 
REB 
Research Ethics Board 
Rollover Patients 
patients who have previously completed any of the following studies: CTH-201, 
CTH-203, CTH-300, or CTH-302 
RR 
respiratory rate 
SAE 
serious adverse event 
s.c. 
subcutaneous 
SD 
standard deviation 
SOP 
Standard Operating Procedure 
t½ 
Terminal-phase half-life 
TEAE 
treatment emergent adverse events 
Temp 
temperature 
t.i.d. 
three times daily 
tmax 
observed time of the maximum concentration 
US 
United States 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
ZBI 
Zarit Burden Interview 
 


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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 (Tanner, 1996). 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 (Hornykiewicz, 2008). 
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 patients 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 (Mouradian, 1989; Stocchi, 2005). 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 patients with PD experience motor fluctuations and/or 
dyskinesias after 4 to 6 years of L-Dopa therapy, with close to 90% of patients experiencing 
these symptoms after 9 or more years of treatment (Ahlskog, 2001). 
Predictable motor fluctuations (ie wearing "OFF") can be treated by increasing the dose or 
frequency of L-Dopa or by adding adjunctive Parkinson’s disease medications (Catechol 
O-methyltransferase [COMT] inhibitors, MAO-B inhibitors, dopamine agonists). However, over 
time this becomes less effective. Treatment of unpredictable motor fluctuations (ie delayed 
"ON", Sudden "OFF", "ON"/"OFF" fluctuations) is limited. Some patients 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 the United States is 
apomorphine dosed by subcutaneous (s.c.) injection. 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 patients. 
APL-130277, sublingually administered apomorphine, provides a more patient-friendly, easy to 
administer medication for the management of both predictable and unpredictable "OFF" 
episodes. 
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 


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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 
(APOMORPHINE, 1949; Cotzias, 1970; Corsini, 1979; Millan, MJ; Schwab, 1951). 
APOKYN®/APO-go® (apomorphine hydrochloride injection, see Section 19.1) are prescription 
medicines that reverses "OFF" episodes (end-of-dose wearing-"OFF" and unpredictable 
"ON"-"OFF" episodes) associated with advancing PD. APOKYN®/APO-go®, which are 
indicated for the acute, intermittent treatment of hypomobility, "OFF" episodes associated with 
advanced PD, have 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 to 
20 minutes of injection, apomorphine demonstrates a magnitude of effect (ability to convert the 
patients with PD to the "ON" state) that is comparable to L-Dopa. The effects of a single 
s.c. injection last for approximately 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 (APOMORPHINE, 1949; Cotzias, 1970; Corsini, 1979; Millan, MJ; 
Schwab, 1951). 
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 of 
s.c. apomorphine 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. Patients 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. 
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 minute, 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-Chemie. Apomorphine hydrochloride is manufactured from morphine monohydrate in the 
presence of orthophosphoric acid, ethyl acetate and hydrochloric acid. Purification is performed 
in the presence of water, sodium chloride, sodium sulfite, ethyl acetate and silica gel. 
A summary of physico-chemical data are provided in Table 8. 


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Table 8: 
Summary of Apomorphine Physico-Chemical Data 
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 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. APL-130277 can be administered without regard to 
food status (ie, either fed or fasted). The product is intended to be an alternative to the injectable 
form of apomorphine hydrochloride, which is marketed as APOKYN® and as APO-go®. 
APL-130277 is manufactured for clinical studies as a bilayer 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 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 sublingual film. 


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Table 9: 
Physical APL-130277 Characteristics 
APL-130277 Dose 
(mg) 
Length 
(mm) 
Width  
(mm) 
Area 
(mm2) 
Identifying 
Mark 
10 
22 
8.8 
193.6 
C1 or 10 
15 
22 
13.2 
290.4 
C2 or 15 
20 
22 
17.6 
387.2 
C3 or 20 
25 
22 
22 
484.0 
C4 or 25 
30 
22 
26.4 
580.8 
C5 or 30 
The 35 mg dose will be administered by dosing with the 20 mg sublingual film, and after 
3 minutes have elapsed, followed by dosing with a 15 mg sublingual film. 
The APL-130277 drug product will be manufactured and packaged at ARx, LLC facilities at: 
400 Seaks Run Road, Glen Rock, PA 17327, USA and Tapemark Company facilities at: 1685 
Marthaler Lane, West St. Paul, MN 55118, 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 color additives for patient 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 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. 
Summary of Potential Risks and Benefits 
Given that APL-130277 uses the same active pharmaceutical ingredient (API) as 
APOKYN®/APO-go®, and that the pharmacokinetic profile is comparable between the 
sublingual film and the s.c. injection, the risks associated with the drug will be similar to those 
seen in the APOKYN®/APO-go® prescribing information (see Section 19.1), except for the 
significant injection site reactions, which are associated with the mode of administration for 
APOKYN®/APO-go®. It is assumed that the bioavailability of APL-130277 will be consistent in 
CTH-301 with that found in previous experience with APL-130277 compared with 
APOKYN®/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 but in clinical studies with 
APL-130277, adverse event reports of irritation of the oral mucosa have been observed. The 
current study will closely monitor for this potential AE. 
The goal of this development program, however, is to formulate a medication that provides the 
PD patient with an easier delivery system. It is hypothesized that a sublingually administered 
formulation may be easier to use, allow more effective and safer control over predicted "OFF" 


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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. 
7.5. 
Rationale 
This multi-center, Phase 3 study is designed to evaluate the long-term efficacy, safety and 
tolerability of APL-130277 in subjects with PD who experience motor fluctuations ("OFF" 
episodes). "OFF" episodes are frequently seen in PD patients who receive chronic treatment with 
L-Dopa, and can be a source of disability. Additional doses of L-Dopa may not be effective 
because of a long-duration to benefit, or no response at all. A treatment that rapidly and reliably 
turns patients "ON" is an important unmet medical need in PD. 
Single doses of APL-130277 for the treatment of "OFF" episodes experienced by subjects with 
PD have been previously investigated in both a healthy and PD population, however, a long-term 
study testing multiple treatments of APL-130277 in both an in-clinic and outpatient setting has 
not been performed. Such a study will provide long-term information on the effect of 
APL-130277 on "OFF" episodes based on physician and subject assessment in a controlled 
clinical setting, and based on subject evaluations in an outpatient setting. This study will provide 
information on treating "OFF" episodes in a PD subject population, assessing the drug in a 
manner in which it will be recommended for regular clinical use. The study is thus designed to 
primarily investigate the long-term safety and tolerability of APL-130277 in acutely treating 
"OFF" episodes (eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF"). 
 


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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. It 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 long-term safety and tolerability of APL-130277 in 
subjects with Parkinson’s disease (PD). 
9.2. 
Study Endpoints 
9.2.1. 
Primary Endpoint 
1. Evaluation of safety and tolerability data collected, based on incidence of adverse events 
in the LTS phase. 
9.2.2. 
Secondary Efficacy Endpoints 
1. Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS-UPDRS 
MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and 
Week 48 visits (LTS V4, V5, and V6) of the LTS Phase. 
2. Percentage of subjects with a subject-rated full "ON" response within 30 minutes at 
Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase. 
3. The percentage of instances where a full "ON" response was achieved within 30 minutes 
after self-administration of study medication at Week 24, Week 36, and Week 48 visits 
(LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries. 
9.2.3. 
Other Efficacy Endpoints 
1. CGI-I post dosing. 
2. PGI-I post dosing. 
3. Change from baseline in the PDQ-39. 
4. Change from baseline in the MDS-UPDRS – Part II: Motor Aspects of Experiences of 
Daily Living. 
5.  Percentage of subjects with Investigator-rated full “ON” response within 30 minutes 
during the titration period. 
6. Change from baseline in the Epworth Sleepiness Scale (ESS) 
9.2.4. 
Safety Endpoints 
1. Observed Values and Change in 12 lead ECGs,  
2. Incidence of oropharyngeal and dopaminergic AEs,  
3. C-SSRS, and Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease 
Rating Scale (QUIP RS) 


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10. 
STUDY DESIGN 
This is a multi-center, open-label, Phase 3 study in L-Dopa responsive PD subjects with motor 
fluctuations, designed to evaluate the long-term safety, tolerability, and efficacy of APL-130277. 
10.1. 
General Overview 
This study will be an open-label, long-term safety study of APL-130277 for the treatment of up 
to 5 "OFF" episodes per day. Subjects will return to the clinic at regular intervals for assessments 
as defined in the schedule of assessments (see Tables 2-7). Subjects may participate in the study 
until the Sponsor terminates the study, or until commercial availability of APL-130277 in the 
subject’s country. 
10.1.1. 
Screening Visits 
10.1.1.1. Screening Procedures for De Novo Subjects 
De Novo subjects are defined as subjects who have not previously participated in a study with 
APL-130277. 
Before any study procedures are performed on any subject, informed consent must be obtained at 
an initial Screening Visit (SV1). If required by the Investigator, and following receipt of patient 
consent, the Investigator may review the subject’s medical history, BMI, height, weight, vital 
signs, 12-Lead ECG (in triplicate) and perform a complete physical examination at SV1 to 
determine if the patient may be eligible for study participation and continuation onto the second 
Screening Visit (SV2). Subjects recruited to participate in the study, and who have provided full 
consent to participate, will be asked to attend the second Screening Visit (SV2), and will be 
instructed to arrive at the clinic after their usual morning dose of PD medications; but before 
taking their next dose of medication. Their normal morning dose of L-Dopa (without adjunctive 
PD medication) will be administered in the clinic approximately two hours after their normally 
scheduled second dose of PD medication, following confirmation of an "OFF" episode by the 
Investigator, to ensure that they experience a full "ON" response. Eligibility criteria will be 
assessed and subject "ON" /"OFF" training will be performed (see Section 12.11.3.1). 
Subjects who fail the screening process will be allowed to rescreen once if agreed by the Medical 
Monitor. 
10.1.1.2. Screening Procedures for Rollover Subjects 
Rollover subjects are defined as subjects who have previously completed any of the following 
studies: CTH-201, CTH-203, CTH-300, or CTH-302. 
Rollover Subjects will be required to attend the Screening Visit and applicable eligibility 
assessments will be performed. This visit will occur up to up to 14 days after the final visit of the 
previous study. Subjects will present to clinic following their normal PD medication regimen and 
should not withhold any of their normal PD medications. Screening assessments will be 
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Eligibility criteria will be assessed and eligible subjects will be asked to return to the clinic in the 
morning of Long-term Safety Visit 1 (LTS V1). 
Subjects will begin treatment at the last APL-130277 dose level they were taking in the previous 
study. These subjects will not undergo titration. If during the screening visit (prior to LTS V1), 
the Investigator determines a dose adjustment is necessary, the subject will have dose adjustment 
visits. 
Subjects who fail the screening process will be allowed to rescreen once if agreed by the Medical 
Monitor. 
Evaluation of subjects who choose to withdraw from the study at any time will be conducted in 
accordance with Section 12.8, Early Terminations. 
10.1.1.3. Screening Procedures for CTH-301 Completer Subjects 
CTH-301 Completer subjects are defined as subjects who have previously completed the 
CTH-301 study under protocol version 3.00. 
Subjects who previously completed the CTH-301 study and are re-enrolling into CTH-301 will 
be required to attend the Screening Visit Phase 2 (SVP2) and applicable eligibility assessments 
will be performed. Re-enrolling patients will present to clinic following their normal PD 
medication regimen and should not withhold any of their normal PD medications. 
Eligibility criteria will be assessed and once a subject is deemed eligible, the site will contact the 
subject to have them return to the clinic 5 to 28 days later and follow study procedures beginning 
at LTS Visit 7. These subjects will resume treatment with APL-130277 at the dose he/she was 
administered prior to completing CTH-301. If this dose is no longer considered tolerable or 
effective, the subject will return to the clinic for dose adjustment visits until a new tolerable or 
effective dose is established. 
Subjects who fail the screening process will be allowed to rescreen once if agreed by the Medical 
Monitor. 
10.1.2. 
Dose Titration Phase - De Novo Subjects Only 
On Titration Visit 1 (TV1), 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. Subjects will be 
required to wait approximately two hours after their normally scheduled dose of PD medications 
and following confirmation by both the Investigator and patient that they are in the "OFF" state, 
subjects will be treated with 10 mg APL-130277. Efficacy (MDS-UPDRS Part III) will be 
performed prior to dosing, and at 15, 30, 60, and 90 minutes after dosing. Safety assessments 
(AE, vital signs [including supine and standing BP to assess OH]) will be performed prior to 
dosing, and immediately after the 60 minute MDS-UPDRS Part III assessment. 
Electrocardiograms (ECGs) will be obtained prior to dosing and approximately 50 minutes after 
dosing. 
Subjects who respond to the APL-130277 10 mg dose with a full "ON" response within 
45 minutes at TV1, as assessed by both the patient and Investigator, will be considered complete 
from a Dose Titration Phase perspective, and can proceed to the LTS Phase of the study. These 
subjects will be asked to return to the clinic for LTS V1. A full "ON", as assessed by the subject, 


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is 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; AND 
the response is comparable to or better than their normal response to PD medications prior to 
enrolling in the study (refer to Section 12.11.3.1). A full "ON", as determined by the Investigator 
is defined as: per clinical judgement, 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 (refer to 
Section 12.11.3.1). 
Subjects who develop symptoms such as nausea and/or vomiting which warrant treatment may 
receive anti-emetic therapy (US sites – Tigan® [trimethobenzamide hydrochloride; 300 mg t.i.d.]; 
non US sites – domperidone [10 mg b.i.d.]). If initiated, anti-emetic therapy should be stopped 
when clinically indicated. Anti-emetic medication should not be administered prophylactically. 
Subjects who do not achieve a full "ON" response (as defined in Section 12.11.3.1) within 
45 minutes with their 10 mg APL-130277 dose will restart their normal PD medications and will 
be asked to return to the clinic within the next 3 days for Titration Visit 2 (TV2), to assess the 
next highest dose (ie, 15 mg) in a manner identical to that on Titration Visit 1 (TV1), with 
identical evaluations.  
All 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. Subjects will be required to wait 
approximately two hours after their normally scheduled second dose of PD medications before 
being dosed with 15 mg APL-130277. Subjects who achieve a full "ON" (as defined in 
Section 12.11.3.1) within 45 minutes of receiving the 15 mg dose will be considered complete 
from a Dose Titration Phase perspective, and can proceed to the LTS Phase. Subjects who do not 
achieve a full "ON" response (as defined in Section 12.11.3.1) within 45 minutes of dosing at 
TV2 will restart their standard PD medications and be asked to return to the clinic within the 
next 3 days to assess the next higher dose of APL-130277 (20 mg [TV3], 25 mg [TV4], 30 mg 
[TV5], or 35 mg [TV6], as appropriate). For subjects dosed with 35 mg, the first sublingual film 
(ie, 20 mg) will be placed under the tongue for 3 minutes before placing the second sublingual 
film (ie, 15 mg) under the tongue immediately after and without delay. 
For each visit in the Dose Titration Phase, the site will arrange subject transfers, if needed. 
Alternatively, subjects may be monitored in the clinic overnight if such facilities exist and the 
subject consents. These occurrences will not be considered a SAE. Safety and efficacy 
assessments will be performed at each visit exactly as described above. Subjects who achieve a 
full "ON" response at any titration visit may proceed to the LTS Phase. 
At all titration visits, at the discretion of the subject and/or Investigator, the next highest dose 
may be evaluated at a subsequent titration visit following a full "ON" response in order to assess 
the potential for the next highest dose in inducing an improved full "ON" response. If this dose 
produces an improved "ON" response relative to the lower dose without impacting subject safety 
and tolerability, the higher dose will be used during the LTS Phase of the study. If the "ON" 
response is the same or worse, or this higher dose is not well-tolerated, the previous dose will be 
used during the LTS Phase of the study. 
During the Dose Titration Phase visits, if in the opinion of the Investigator the subject can no 
longer tolerate the "OFF" state at any point during the Visit, the patient may receive rescue 


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L-Dopa (± other adjunctive PD medication) at a dosage considered appropriate by the 
Investigator to achieve a full "ON" state. If this occurs, subjects can return to the clinic on 
another day to resume the titration with the next highest dose. If a dose of APL-130277 cannot 
be found that provided a full "ON" response, the subject will be terminated from the study. 
In this study, the minimum titration dose is 10 mg APL-130277 and the maximum titration dose 
is 35 mg APL-130277. Any subjects who reach 35 mg at Titration Visit 6 (TV6) and do not 
exhibit a full "ON" response (as defined in Section 12.11.3.1) within 45 minutes will be 
terminated from the study and will have the applicable procedures outlined in the Early 
Termination Visit performed. 
Dosing days in the Dose Titration Phase are not required to occur consecutively, but the Dose 
Titration Phase must be completed within 21 days. Following completion of the titration phase, 
subjects will return to clinic for LTS V1 where they will be given their open-label study 
medication (APL-130277) and appropriate training for self-administration.  
Titration in this study may be modified following a review of the Dose Titration Phase data from 
CTH-300 by a Data Safety Monitoring Board (DSMB). If, after review of the data from 
CTH-300, the DSMB determines that in-clinic titration is not necessary and that dose titration 
can be safely accomplished in an outpatient setting, the Dose Titration Phase paradigm may be 
modified. 
Evaluation of subjects who choose to withdraw from the study at any time will be conducted in 
accordance with Section 12.8, Early Terminations. 
10.1.3. 
Long-Term Safety Phase Year 1 – In-clinic Visits – De Novo and Rollover 
Subjects Only 
De novo subjects who successfully completed the Dose Titration Phase of the study will be 
asked to return to the clinic on LTS V1 where they will be given their dose of APL-130277. This 
visit will occur between up to 21 days after the final visit in the Dose Titration Phase of the 
study. The dose given will be the same as that determined during the Dose Titration Phase of the 
study. 
Rollover subjects who successfully completed the Screening visit (SV1) will return to the clinic 
on LTS Day 1 up to 21 days after SV1. These subjects will receive the same dose they received 
in the previous study. 
All 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. Subjects will be required to wait 
approximately two hours after their normally scheduled second dose of PD medications. 
Following a confirmed "OFF" state by both the subject and the Investigator, subjects will be 
dosed with their study medication and assessments of efficacy and safety will be performed for 
up to 90 minutes after dosing. During this visit, subjects will be trained by clinic staff on how to 
remove study medication from its packaging and how to self-administer their dose using placebo 
treatment sublingual films supplied to the site. Subjects should not self-administer the placebo 
sublingual films. Subjects cannot be discharged from clinic until satisfactorily completing the 
training. 
At the in-clinic visits, staff will dose subjects with APL-130277 by placing the sublingual 
film under the subject’s tongue (see Section 14.2 for full dosing details). Subjects will be 


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asked to follow the same process of study drug administration during the at-home portions 
of the study. 
During LTS Phase Year 1 of the study, subjects will return to the clinic at 4 weeks for LTS 
Visit 2 (LTS V2), 12 weeks for LTS Visit 3 (LTS V3), 24 weeks for LTS Visit 4 (LTS V4), 
36 weeks for LTS Visit 5 (LTS V5), and 48 weeks for LTS Visit 6 (LTS V6). At LTS V3, 
LTS V4, LTS V5, and LTS V6, subjects will be dosed with APL-130277 and the procedures 
performed at these visits will be similar to those performed on LTS V1. LTS V2 will be a safety 
visit only. 
At the LTS in-clinic visits where the subject is dosed with APL-130277, 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 90 minute efficacy assessments are complete. 
Following LTS V6, subject will be asked to return to the clinic approximately 4 months 
(16 weeks ± 1 week) later for LTS Visit 7 (LTS V7). 
Evaluation of subjects who choose to withdraw from the study at any time will be conducted in 
accordance with Section 12.8, Early Terminations. 
All PD medications must remain stable during LTS Phase Year 1, and any changes should be 
avoided unless absolutely necessary and approved by the Medical Monitor. Changes in 
medications for the treatment of other medical disorders are allowed with permission from the 
Medical Monitor. 
10.1.4. 
Long-Term Safety Phase Year 1 – At Home Assessments – De Novo and Rollover 
Subjects Only 
During LTS Phase Year 1, subjects will be instructed to continue with their regular PD 
medication regimen(s), but they should dose themselves with their study treatment 
(APL-130277) if they experience an "OFF" episode (eg, morning akinesia, wearing "OFF", dose 
failure, sudden "OFF", etc.) while on their current treatment regimen. Subjects will be instructed 
to dose up to 5 "OFF" episodes per day. Subjects will be instructed to wait a minimum of 2 hours 
between doses taken at home. 
For 2 days prior the in-clinic visits, subjects will be requested to complete a home dosing diary 
that captures: 
• Time of randomized treatment self-administration; 
• Subject "ON"/"OFF" state at 30 minutes after dosing. 
• The type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; 
no "ON"; or sudden "OFF"). 
Between each in-clinic visit, subjects will be contacted at the midpoint between visits by the site 
to assess subject well-being and safety. If required due to safety concerns or lack of efficacy, 
subjects will be asked to return to the clinic for additional evaluations at an unscheduled Dose 
Adjustment Visit. These visits will be classified as unscheduled visits. 


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10.1.5. 
Long-Term Safety Phase Years 2, 3, 4, and 5 – In-clinic Visits - All Patients 
During LTS Phase Years 2 to 5, subjects will return to the clinic every 4 months (16 weeks). 
These visits will be safety visits only.  
Subjects will return to the clinic to have safety assessed and receive additional study drug 
(APL-130277). 
Subjects may continue to participate in the study until the Sponsor terminates the study, or until 
commercial availability of APL-130277 in the subject’s country. If a subject continues in the 
study beyond LTS Phase Year 5, the protocol will be amended to accommodate additional in 
clinic visits every 4 months (16 weeks). 
Evaluation of subjects who choose to withdraw from the study at any time will be conducted in 
accordance with Section 12.8, Early Terminations. 
All PD medications should remain stable during LTS Phase Years 2 to 5, and any changes 
should be avoided unless approved by the Medical Monitor. Changes in medications for the 
treatment of other medical disorders are allowed with permission from the Medical Monitor. 
10.1.6. 
LTS Phase Years 2, 3, 4, and 5 – At Home Assessments – All Subjects 
During LTS Phase Years 2 to 5, subjects will be instructed to continue with their regular PD 
medication regimen(s), but they should dose themselves with their study treatment 
(APL-130277) if they experience an "OFF" episode (eg, morning akinesia, wearing "OFF", dose 
failure, sudden "OFF", etc.) while on their current treatment regimen. Subjects will be instructed 
to dose up to 5 "OFF" episodes per day. Subjects will be instructed to wait a minimum of 2 hours 
between doses taken at home. 
For 2 days prior the in-clinic visits, subjects will be requested to complete a home dosing diary 
that captures: 
•
Time of randomized treatment self-administration;
•
Subject "ON"/"OFF" state at 30 minutes after dosing.
•
The type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF";
no "ON"; or sudden "OFF").
Between each in-clinic visit, subjects will be contacted at the midpoint between visits by the site 
to assess subject well-being and safety. If required due to safety concerns or lack of efficacy, 
subjects will be asked to return to the clinic for additional evaluations at an unscheduled Dose 
Adjustment Visit. These visits will be classified as unscheduled visits. 
10.2. 
Blinding 
This is an open-label study; there will be no blinding. 
10.3. 
Data Safety Monitoring Board 
A formal DSMB will be convened during the course of the study in order to: 
•
On a regular basis, review the safety data including SAEs;


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• Respond to special requests from regulatory authorities and/or IRB/IEC/REBs; 
The full responsibilities and purview of the DSMB will be outlined in the DSMB Charter, which 
will be approved by the Sponsor prior to the implementation of any DSMB review. 


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11. 
SUBJECT POPULATION 
11.1. 
Selection of Study Population 
A screening log of potential study candidates and an enrollment log of enrolled patients must be 
maintained at each study site. 
The overall number of subjects is not pre-specified as this is an extension study. 
11.1.1. 
Criteria for De Novo Subjects 
De Novo Subjects are defined as subjects who have not previously participated in a study with 
APL-130277. 
11.1.1.1. Inclusion Criteria – De Novo Subjects 
A subject will be eligible for study entry if all of the following inclusion criteria are met: 
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) (see Section 19.14). 
3. Clinically meaningful response to L-Dopa as determined by the Investigator. 
4. Receiving stable doses of L-Dopa/carbidopa (immediate or CR) administered at least 
4 times per day OR Rytary™ administered at least 3 times per day, for at least 4 weeks 
before the initial Screening Visit (SV1). Adjunctive PD medication 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. Subject must experience at least one well defined "OFF" episode per day with a total 
daily "OFF" time duration of ≥ 2 hours during the waking day, based on patient self-
assessment. 
7. Subject and/or caregiver must be trained in performing home dosing diary assessments of 
the motor state and must be able to recognize "ON" and "OFF" states. 
8. Stage III or less on the modified Hoehn and Yahr scale in the "ON" state. 
9. MMSE score > 25. 
10. If female and of childbearing potential, must agree to be sexually abstinent or use one of 
the following highly effective methods of birth control: 
• Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, 
injectables, and implants); 
• Intrauterine contraceptive system; 


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• Surgical sterilization or partner sterile (must have documented proof); AND 
One of the following effective methods of birth control: 
• Male/female condom; 
• Cervical cap with spermicide; 
• Diaphragm with spermicide; 
• Contraceptive sponge. 
11. Male subjects must be either surgically sterile, agree to be sexually inactive or use a 
double-barrier method of birth control (eg, condom and diaphragm with spermicide, 
condom with cervical cap and spermicide) from first study drug administration until 
90 days after final drug administration. 
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study-related procedures. 
13. Able to understand the consent form, and to provide written informed consent. 
11.1.1.2. Exclusion Criteria – De Novo Subjects 
A subject will not be eligible for study entry if any of the following exclusion criteria are met: 
1. Atypical or secondary parkinsonism. 
2. Previous treatment with any of the following: a neurosurgical procedure for PD; 
continuous s.c. apomorphine infusion; Duodopa/Duopa; or APL-130277. 
3. Treatment with any form of s.c. apomorphine within 7 days prior to the second Screening 
Visit (SV2). Patients that stopped s.c. apomorphine for any reason other than systemic 
safety concerns or lack of efficacy may be considered. 
4. Contraindications to APOKYN®, or hypersensitivity to apomorphine hydrochloride or 
any of the ingredients of APOKYN® (notably sodium metabisulfite). 
5. Female who is pregnant or lactating. 
6. Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1). 
7. Receipt of any investigational (ie, unapproved) medication within 30 days prior to the 
initial Screening Visit (SV1). 
8. Currently taking selective 5HT3 antagonists (ie, ondansetron, granisetron, dolasetron, 
palonosetron, alosetron), dopamine antagonists (excluding quetiapine or clozapine) or 
dopamine depleting agents. 
9. Drug or alcohol dependency in the past 12 months. 
10. Subject has a history of malignancy within 5 years prior to the Screening visit, except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. 
Pituitary tumors of any duration are excluded. 
11. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the 
Investigator. 


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12. Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, 
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. 
13. History of clinically significant hallucinations during the past 6 months. 
14. History of clinically significant impulse control disorder(s). 
15. Dementia that precludes providing informed consent or would interfere with participation 
in the study. 
16. 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 
C-SSRS or attempted suicide within the last 5 years. 
17. Donation of blood or plasma in the 30 days prior to first dosing. 
18. Presence of canker or mouth sores in the 30 days prior to the initial Screening Visit 
(SV1), or other clinically significant oral pathology in the opinion of the Investigator. 
The Investigator should follow-up with an appropriate specialist on any finding, if 
indicated, before enrolling a patient into the study. 
11.1.2. 
Criteria for Rollover Subjects 
Rollover Subjects are defined as subjects who have previously completed any of the following 
studies: CTH-201, CTH-203, CTH-300, or CTH-302. 
11.1.2.1. Inclusion Criteria - Rollover Subjects 
Subjects who meet each of the following criteria will be eligible for participation in the study: 
1. Completion of any of the following studies: CTH-201, CTH-203, CTH-300, or CTH-302; 
and, in the opinion of the Investigator, would benefit from continued treatment with 
APL-130277. 
2. No major changes in concomitant PD medications since completion of any of the 
following studies: CTH-201, CTH-203, CTH-300, or CTH-302. Any change in PD 
medications since the previous study should be discussed with the Medical Monitor to 
determine subject eligibility in the current study. 
3. If female and of childbearing potential, must agree to be sexually abstinent or use one of 
the following highly effective methods of birth control: 
• Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, 
injectables, and implants); 
• Intrauterine contraceptive system; 
• Surgical sterilization or partner sterile (must have documented proof); AND 
One of the following effective methods of birth control: 
• Male/female condom; 
• Cervical cap with spermicide; 


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• Diaphragm with spermicide; 
• Contraceptive sponge. 
4. Male subjects must be either surgically sterile, agree to be sexually inactive or use a 
double-barrier method of birth control (eg, condom and diaphragm with spermicide, 
condom with cervical cap and spermicide) from first study drug administration until 
90 days after final drug administration. 
5. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study-related procedures. 
6. Able to understand the consent form, and to provide written informed consent. 
11.1.2.2. Exclusion Criteria – Rollover Subjects 
Subjects will be excluded from participation in the study for any of the following reasons: 
1. Female who is pregnant or lactating. 
2. Presence of any major psychiatric disorder including, but not limited to, dementia, 
bipolar disorder, psychosis (including clinically significant hallucinations during the past 
6 months) or any disorder that, in the opinion of the Investigator, requires ongoing 
treatment that would make study participation unsafe or make treatment compliance 
difficult. 
3. Presence of any clinically significant medical (including but not limited to CNS, 
cardiovascular, hepatic, pulmonary, metabolic, or renal events), surgical, or laboratory 
abnormality that would make study participation unsafe or make treatment compliance 
difficult. Clinical significance to be determined by the Investigator. 
4. Receipt of any investigational (ie, unapproved) medication or participation in any clinical 
trial of an investigational product since completing a previous study using APL-130277. 
5. Development of canker or mouth sores within 14 days of completing a previous study 
using APL-130277. For other clinically significant oral pathology, the Investigator should 
follow-up with an appropriate specialist on any finding, if indicated, before enrolling 
such a subject into the study. Clinical significance to be determined by the Investigator. 
The eligibility of subjects who have experienced AEs related to the oral cavity during the 
previous study using APL-130277, should be reviewed with the medical monitor and 
approval obtained. 
6. Current suicidal ideation within one year of the screening visit, as evidenced by 
answering "yes" to Question 4 or 5 on the suicidal ideation portion of the C-SSRS at 
Screening or attempted suicide within 5 years. 
11.1.3. 
Criteria for CTH-301 Completer Subjects 
CTH-301 Completer Patients are defined as patients who have previously completed the 
CTH-301 study under protocol version 3.00. 
11.1.3.1. Inclusion Criteria - CTH-301 Completer Subjects 
Subjects who meet each of the following criteria will be eligible for participation in the study: 


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1. Completion of the CTH-301 study under protocol version 3.00, and in the opinion of the 
Investigator, would benefit from continued treatment with APL-130277. 
2. If female and of childbearing potential, must agree to be sexually abstinent or use one of 
the following highly effective methods of birth control: 
• Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, 
injectables, and implants); 
• Intrauterine contraceptive system; 
• Surgical sterilization or partner sterile (must have documented proof); AND 
One of the following effective methods of birth control: 
• Male/female condom; 
• Cervical cap with spermicide; 
• Diaphragm with spermicide; 
• Contraceptive sponge. 
3. Male subjects must be either surgically sterile, agree to be sexually inactive or use a 
double-barrier method of birth control (eg, condom and diaphragm with spermicide, 
condom with cervical cap and spermicide) from first study drug administration until 
90 days after final drug administration. 
4. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study-related procedures. 
5. Able to understand the consent form, and to provide written informed consent. 
11.1.3.2. Exclusion Criteria – CTH-301 Completer Subjects 
Subjects will be excluded from participation in the study for any of the following reasons: 
1. Female who is pregnant or lactating. 
2. Presence of any major psychiatric disorder including, but not limited to, dementia, 
bipolar disorder, psychosis (including clinically significant hallucinations during the past 
6 months) or any disorder that, in the opinion of the Investigator, requires ongoing 
treatment that would make study participation unsafe or make treatment compliance 
difficult. 
3. Presence of any clinically significant medical (including but not limited to CNS, 
cardiovascular, hepatic, pulmonary, metabolic, or renal events), surgical, or laboratory 
abnormality that would make study participation unsafe or make treatment compliance 
difficult. Clinical significance to be determined by the Investigator. 
4. Receipt of any investigational (ie, unapproved) medication or participation in any clinical 
trial since completing the CTH-301 study. 
5. Development of canker or mouth sores since completing the CTH-301 study. For other 
clinically significant oral pathology, the Investigator should follow-up with an 


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appropriate specialist on any finding, if indicated, before enrolling such a patient into the 
study. Clinical significance to be determined by the Investigator. 
6. Current suicidal ideation as evidenced by answering "yes" to Question 4 or 5 on the 
suicidal ideation portion of the C-SSRS at the Screening Visit Phase 2 (SVP2). 
11.2. 
Prior and Concomitant Treatments 
11.2.1. 
Prohibited Treatments 
The following prior and/or concomitant treatments will not be allowed during the course of this study: 
• Treatment with any form of s.c. apomorphine is prohibited as follows:  
− from 7 days prior to the second Screening Visit (SV2) until study completion for 
De Novo subjects 
− from the time of the Screening Visit for Rollover subjects, until study completion 
− from the Screening Visit Period 2 (SVP2) for CTH-301 Completer subjects until 
study completion. 
• Any selective 5HT3 antagonist (eg, ondansetron, granisetron, dolasetron, 
palonosetron, alosetron) are prohibited as follows: 
− from 30 days prior to the initial Screening Visit (SV1) for De Novo subjects until 
study completion 
− from 14 days prior to the Screening Visit for Rollover subjects until study 
completion 
− from the Screening Visit Period 2 (SVP2) for CTH-301 Completer subjects until 
study completion. 
• Any dopamine antagonists or dopamine depleting drugs excluding anticholinergics 
and/or antihistamines with anticholinergic effects. Examples include, but are not 
limited to: 
− Antipsychotics - Both typical and atypical antipsychotics (except quetiapine and 
clozapine), including but not limited to: aripiprazole, fluphenazine, haloperidol, 
perphenazine, pimozide, thiothixene, trifluoperazine, loxapine, molindone, 
chlorpromazine, mesoridazine, thioridazine, olanzapine, risperidone, ziprasidone, 
depot neuroleptics; 
− Cinnarizine; 
− Flunarizine; 
− Prochlorperazine; 
− Promethazine; 
− Tetrabenazine; 
− Lithium; 


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− Metoclopropamide; 
− Reserpine. 
• Deep brain stimulation or other neurosurgical procedure for the treatment of PD. 
• Continuous s.c. apomorphine infusion. 
• Duodopa/Duopa. 
• Cisapride. 
• Dronedarone. 
• Any sublingual medicinal product, including Vitamin B6. 
• Any other preparation of Vitamin B6. 
• Medicinal/recreational marijuana. 
11.2.2. 
Permitted Treatments 
Anti-emetic medication is optional and can be initiated at the Investigator's discretion if 
clinically warranted. If initiated, anti-emetic therapy should be stopped when clinically indicated. 
Anti-emetic medication should not be administered prophylactically. 
The following concomitant treatments will be allowed during the course of the study: 
• Domperidone (10 mg b.i.d.; non-US sites) or Tigan® (trimethobenzamide 
hydrochloride; 300 mg t.i.d.; US sites) to overcome the potential nausea associated 
with apomorphine administration. NOTE: Domperidone is not indicated for longer 
than 7 continuous days of use. Extended use beyond 7 days should be discussed with 
the Medical Monitor. 
• Stable doses of an L-Dopa formulation with or without other stable adjunctive PD 
therapies is permitted with no planned medication changes during the study as 
follows: 
o from at least 4 weeks prior to the initial Screening Visit (SV1) for De Novo 
subjects 
o within 14 days of completing the previous study for Rollover subjects 
o from the Screening Visit Period 2 (SVP2) for CTH-301 Completer subjects  
• MAO-B inhibitors will be allowed but must be stable as follows: 
o for at least 8 weeks prior to the initial Screening Visit (SV1) for De Novo subjects  
o for at least 14 days after completion of the previous study for Rollover subjects  
o from the Screening Visit Period 2 (SVP2) for CTH-301 Completer subjects. 
• Any other medication other than those identified as Prohibited Treatments are 
allowed, provided they are stable (within 14 days after completing the previous study 
for Rollover subjects or within 4 weeks for De novo subjects). 


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Other therapies should only be administered as necessary for the treatment of the patient, at the 
discretion of the Investigator. All concomitant medications must be recorded in the appropriate 
Case Report Form (CRF) for the patient. 
11.3. 
Subject Withdrawal from the Study 
Subjects may be withdrawn from participating in this study for the following: 
1. In order to protect their safety and/or well-being; 
2. If they, or their caregiver, are unwilling or unable to comply with required study 
procedures; 
3. If they withdraw their consent to participate in the study; 
4. If the study is prematurely terminated by the Sponsor or Regulatory Authorities; 
5. 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 ET Visit will 
be performed, where possible. Subjects withdrawn/terminated during the Dose Titration Phase 
will have fewer assessments performed than those withdrawn/terminated during the LTS Phase 
(refer to Section 4 and Section 12.8 for additional details on the procedures to be performed). 
 


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12. 
STUDY PROCEDURES 
This study will consist of the following: 
1. Screening Visits (SV1 and SV2; De Novo subjects only); OR 
Screening Visit (SV; Rollover subjects only) 
Screening Visit (SVP2; CTH-301 Completer subjects only) 
2. Dose Titration Phase (De Novo Subjects only) 
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) 
3. Long-Term Safety (LTS) Phase Year 1 (De Novo and Rollover Subjects only) 
a. Long-Term Safety Visit 1 (LTS V1) 
b. Long-Term Safety Visit 2 (LTS V2) 
c. Long-Term Safety Visit 3 (LTS V3) 
d. Long-Term Safety Visit 4 (LTS V4) 
e. Long-Term Safety Visit 5 (LTS V5) 
f. Long-Term Safety Visit 6 (LTS V6) 
g. Telephone Call (T1 to T5) 
h. Unscheduled Dose Adjustment Visits 
4. Long-Term Safety (LTS) Phase Year 2 (All Subjects) 
a. Long-Term Safety Visit 7 (LTS V7) 
b. Long-Term Safety Visit 8 (LTS V8) 
c. Long-Term Safety Visit 9 (LTS V9) 
d. Telephone Call (T6 to T8) 
e. Unscheduled Dose Adjustment Visits 
5. Long-Term Safety (LTS) Phase Year 3 (All Subjects) 
a. Long-Term Safety Visit 10 (LTS V10) 
b. Long-Term Safety Visit 11 (LTS V11) 
c. Long-Term Safety Visit 12 (LTS V12) 
d. Telephone Call (T9 to T11) 
e. Unscheduled Dose Adjustment Visits 
6. Long-Term Safety (LTS) Phase Year 4 (All Patients) 
a. Long-Term Safety Visit 13 (LTS V13) 
b. Long-Term Safety Visit 14 (LTS V14) 
c. Long-Term Safety Visit 15 (LTS V15) 
d. Telephone Call (T12 to T14) 
e. Unscheduled Dose Adjustment Visits 


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7. Long-Term Safety (LTS) Phase Year 5 (All Patients) 
a. Long-Term Safety Visit 16 (LTS V16) 
b. Long-Term Safety Visit 17 (LTS V17) 
c. Long-Term Safety Visit 18 (LTS V18) 
d. Telephone Call (T15 to T17) 
e. Unscheduled Dose Adjustment Visits 
Note: If a patient continues in the study beyond LTS Phase Year 5, the protocol will be 
amended to accommodate additional in clinic visits every 4 months (16 weeks). 
8. Early Termination Visit (All subjects) 
12.1. 
Screening Visits  
12.1.1. 
Screening Procedures for De Novo Subjects  
De Novo Patients are defined as patients who have not previously participated in a study with 
APL-130277. 
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 28 days 
before Titration Visit 1 (TV1). 
If required by the Investigator, and following receipt of subject consent, the Investigator may 
review the patient’s 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. 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: 
• Register the visit in the IWRS to obtain the subject screening number. 
• Review inclusion/exclusion criteria. 
• Review restriction 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. 


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• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG in triplicate. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry, 
urinalysis and serology). Serum pregnancy for females of child-bearing potential 
only. The total volume of blood collected will not exceed 25 mL. 
• Perform a MMSE. 
• Assess subject using the Modified Hoehn and Yahr scale (for a sample, see 
Section 19.3). 
• Assess subject using MDS-UPDRS Parts I, II and IV (for a sample, see Section 19.4). 
• Assess subject motor function using MDS-UPDRS Part III at t = 0 (just prior to 
L-Dopa administration), 15, 30, 60 and 90 minutes after L-Dopa administration (for a 
sample, see Section 19.4). If the subject does not experience an "ON" within 
90 minutes of dosing, the site should record the time when the subject turns "ON" and 
perform an additional MDS-UPDRS Part III assessment at this time. 
• Confirm L-Dopa responsiveness. Subjects will take their normal dose of L-Dopa 
without their normal adjunctive PD medication. 
• Investigator confirmation of "OFF" or "ON". 
• Perform subject training in order to distinguish "OFF" versus "ON" episodes (see 
Section 12.11.3.1). 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). The 
"Screening" scale should be used at this visit. 
• Provide the subject with the PDQ-39 to complete (for a sample, see Section 19.7). 
• Provide the subject with the EQ-5D (for a sample, see Section 19.13). 
• Assess using the ESS (for a sample, see Section 19.10). 
• Assess caregiver burden using the ZBI (for a sample, see Section 19.11). 
• Complete the QUIP-RS (for a sample, see Section 19.12). 
• Begin adverse event recording and serious adverse event reporting when the subject 
signs the ICF. 
• Begin recording of any new concomitant medications and/or changes to current 
concomitant medications being used by the subject. 


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The Investigator will review all information obtained from the screening procedures. If the 
subject is not eligible, the patient 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. 
12.1.2. 
Screening Procedures for Rollover Subjects 
Rollover Subjects are defined as subjects who have previously completed any of the following 
studies: CTH-201, CTH-203, CTH-300, or CTH-302. 
Rollover Subjects must sign an ICF before any screening-related procedures are performed at the 
Screening Visit. Following receipt of subject consent, applicable assessments will be performed 
to ensure eligibility before continuing to the LTS Phase. Screening assessments will be 
performed while subjects are in the “ON” state. Subjects will be trained to assess their “OFF” 
and “ON” states during Screening visits. 
All screening assessments must be performed up to 21 days before Long-term Safety Visit 1 
(LTS V1). 
The following procedures will be performed by study staff at Screening: 
• Register the visit in the IWRS to obtain the subject screening number. 
• Review inclusion/exclusion criteria. 
• Review restriction criteria. 
• Record demographics and detailed medical history, including review of medications 
taken within 6 months prior to the initial Screening Visit, 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. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG in triplicate. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry, 
urinalysis and serology). Serum pregnancy for females of child-bearing potential 
only. The total volume of blood collected will not exceed 25 mL. 
• Assess subject using MDS-UPDRS Parts I, II and IV (for a sample, see Section 19.4). 


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• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). The 
"Screening" scale should be used at this visit. 
• Provide the subject with the PDQ-39 to complete (for a sample, see Section 19.7). 
• Assess using the ESS (for a sample, see Section 19.10). 
• Assess caregiver burden using the ZBI (for a sample, see Section 19.11). 
• Complete the QUIP-RS (for a sample, see Section 19.12). 
• Begin recording concomitant medications. 
• Begin adverse event recording and serious adverse event reporting when the subject 
signs the ICF. 
• Begin recording of any new concomitant medications and/or changes to current 
concomitant medications being used by the subject. 
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 study and an 
appointment for LTS V1 will be made. 
12.1.3. 
Screening Procedures for CTH-301 Completer Subjects 
CTH-301 Completer Subjects are defined as subjects who have previously completed the 
CTH-301 study under protocol version 3.00. 
Subjects who have previously completed the CTH-301 study under protocol version 3.00 and are 
re-enrolling into CTH-301 must sign an ICF before any screening-related procedures are 
performed at the Screening Visit Phase 2 (SVP2). Following receipt of subject consent, 
applicable assessments will be performed. All screening assessments must be performed within 
28 days. 
The following procedures will be performed by study staff at SVP2: 
• Register the visit in the IWRS to obtain the subject screening number.  
• Review inclusion/exclusion criteria. 
• Review restriction criteria. 
• Record any new medical history and medications taken since completion of the 
CTH-301 study. 
• 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. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 


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4 minutes. 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. 
• Perform a standard 12-lead ECG in triplicate. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry, 
urinalysis and serology). Serum pregnancy for females of child-bearing potential 
only. The total volume of blood collected will not exceed 25 mL. 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). The 
"Screening" scale should be used at this visit. 
• Begin adverse event recording and serious adverse event reporting when the patient 
signs the ICF. 
• Begin recording of any new concomitant medications and/or changes to current 
concomitant medications being used by the patient. 
The Investigator will review all information obtained from the screening procedures. If the 
subject is not eligible, the subject will be a screening failure from SVP2 and will not attend any 
other visits. Subjects who fulfill all entry criteria and found eligible to participate in the study 
will be asked to return to clinic 5 to 28 days later and follow study procedures beginning at LTS 
Visit 7. These subjects will resume treatment with APL-130277 at the dose he/she was 
administered prior to completing CTH-301. If this dose is no longer considered tolerable or 
effective, the subject will return to the clinic for dose adjustment visits until a new tolerable or 
effective dose is established. 
12.2. 
Dose Titration Phase (TV1 to TV6) - De Novo Subjects Only 
12.2.1. 
TV1 to TV6 
On the day of these visits, subjects will be asked to come to the clinic having taken their usual 
morning PD medication; but before taking their next dose of PD medications. The subjects will 
be required to wait approximately two hours after their normally scheduled second dose of PD 
medications. If needed, the site will arrange subject transfers.  
Doses of APL-130277 will be administered as follows during the Dose Titration Phase: 
• Titration Visit 1 (TV1) – 10 mg APL-130277; 
• Titration Visit 2 (TV2) – 15 mg APL-130277; 
• Titration Visit 3 (TV3) – 20 mg APL-130277; 
• Titration Visit 4 (TV4) – 25 mg APL-130277; 
• Titration Visit 5 (TV5) – 30 mg APL-130277; 
• Titration Visit 6 (TV6) – 35 mg APL-130277 (administered as a 20 mg sublingual 
film and 15 mg sublingual film, sequentially). 


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Subjects who develop symptoms such as nausea and/or vomiting which warrant treatment may 
receive anti-emetic therapy (US sites – Tigan® [trimethobenzamide hydrochloride; 300 mg 
t.i.d.]; non-US sites – domperidone [10 mg b.i.d.]). If initiated, anti-emetic therapy should be 
stopped when clinically indicated. Anti-emetic medication should not be administered 
prophylactically. 
Site staff will perform the following procedures on each Titration Visit: 
• Register the visit in IWRS to enroll the subject in the Titration Phase and obtain the 
Titration kit number (TV1 only). 
• Review restriction criteria. 
• Perform an abbreviated physical examination, including oropharyngeal examination, 
prior to dosing and 2 hours post 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. A window of 
+/- 10 minutes is given for post-dose abbreviated physical and oropharyngeal 
examinations during TV1 to TV6. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG prior to dosing and approximately 50 minutes after 
dosing. 
• Assess subject motor function using MDS-UPDRS Part III at t = 0 (just prior to 
dosing), 15, 30, 60, and 90 minutes after dosing (for a sample, see Section 19.4). 
During the Dose Titration Phase only, these assessments may cease if the patient does 
not experience a full "ON" response within 45 minutes of dosing. 
• If subjects are in the "OFF" state, dose with APL-130277. 
• Investigator confirmation of "OFF" or "ON". Investigator will assess "OFF"/"ON" 
state as part of the MDS-UPDRS Part III assessments, except at 45 minutes, which 
will be assessed independent of the MDS-UPDRS Part III. The subject must be in an 
"OFF" state prior to dosing in order to proceed with dosing. During the Dose 
Titration Phase only, these assessments may cease if the subject does not experience a 
full "ON" response within 45 minutes of dosing. 
• Subject confirmation of "OFF" or "ON". Subject should report: "OFF"/"ON" state at 
t = 0, 15, 30, 45, 60, and 90 minutes after dosing.  
• Subject should also report time to when the study medication is starting to have an 
effect (if applicable), and time to "OFF" following dosing (if it occurs within 
90 minutes of dosing). Note: The timing of this should begin when the study 


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medication sublingual film has fully dissolved, and can be recorded using a stopwatch 
or other suitable timing device. 
• Provide subject with a home dosing diary (TV1 only; see Section 19.5). Diary will be 
provided for training purposes only. If needed, subject will be retrained at LTS V1 in 
the use of the home dosing diary. 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). "Since Last 
Visit" version should be used at these visits. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
Subjects who respond to an APL-130277 dose with a full "ON" response within 45 minutes of 
dosing at any Titration Visit, will be considered complete from a Dose Titration Phase 
perspective and may proceed to the LTS Phase. This dose will be used in the LTS Phase of the 
study. Sites should enter all titration MDS-UPDRS Part III data for the patient into the CRF 
within 48 hours of the last titration visit for review by the Medical Monitor. NOTE: At all 
titration visits, at the discretion of the subject and/or Investigator, the next highest dose may be 
evaluated at a subsequent titration visit following a full "ON" response in order to assess the 
potential for the next highest dose in inducing an improved full "ON" response. If this dose 
produces an improved "ON" response relative the lower dose without impacting subject safety 
and tolerability, the higher dose will be used during the LTS Phase of the study. If the "ON" 
response is the same or worse, or this higher dose is not well-tolerated, the previous dose will be 
used during the LTS Phase of the study. 
A full "ON" is defined in Section 12.11.3.1. 
Subjects who do not achieve a complete and full "ON" response within 45 minutes with the 
APL-130277 dose given will be asked to return to clinic within the next 3 days for their 
subsequent Titration Visit, to assess the next highest dose in a manner identical to that on 
Titration Visit 1 (TV1). 
At any point in the visit, subjects in the "OFF" state who, in the opinion of the Investigator, can no 
longer tolerate their "OFF" state may receive rescue L-Dopa (± other adjunctive PD medication) 
at a dosage considered appropriate by the Investigator to achieve an "ON" state. If this occurs, 
subjects can return to the clinic on another day to resume the titration with the next highest dose. 
If a dose of APL-130277 cannot be found that provides a full "ON" response, the subject will be 
terminated from the study. 
12.3. 
Long-Term Safety (LTS) Treatment Phase Year 1 – De Novo and 
Rollover Subjects Only 
The long-term safety phase year 1 of the study will consist of 2 parts –in-clinic assessments and 
at-home assessments. The former will consist of 6 in-clinic visits where formal assessments of 
efficacy and/or safety will be performed. The latter will be an at-home self-administration, where 
all subjects will be instructed to self-administer their doses of APL-130277 in order to treat up to 
5 "OFF" episodes (ie, morning akinesia; delayed "ON"; wearing "OFF"; no "ON"; or sudden 


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"OFF") per day. Subjects will be instructed to wait a minimum of 2 hours between each dose 
taken at home. 
De novo Subjects who have successfully completed the Dose Titration Phase of the study will 
receive their dose of open-label study treatment on LTS V1. The dose given will be the same as 
that determined during the Dose Titration Phase of the study. 
 
Rollover subjects will receive treatment with the same dose they were on in the previous study. 
12.3.1. 
LTS V1, LTS V3, LTS V4, LTS V5, and LTS V6: In-Clinic Assessments 
Long-Term Safety Visit 1 (LTS V1) may occur no later than 21 days after the last Dose Titration 
Phase visit for De novo subjects, or no later than 21 days after Screening for Rollover subjects.  
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. Subjects will be required to wait approximately 
two hours after their normally scheduled second dose of PD medications. 
The following procedures will take place at these visits except where explicitly noted: 
• Review restriction criteria. 
• Perform a complete physical examination, including oropharyngeal examination prior 
to 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 weight. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG prior to dosing and approximately 50 minutes after 
dosing. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry 
and urinalysis). Serum pregnancy for females of child-bearing potential only. Blood 
collected for this evaluation will not exceed 20 mL (LTS V3, LTS V4, LTS V5, and 
LTS V6 only). 
• Assess subject using MDS-UPDRS Parts I, II and IV (LTS V3, LTS V4, LTS V5, and 
LTS V6 only; for a sample, see Section 19.4). 
• Assess subject motor function using MDS-UPDRS Part III at t = 0 (just prior to 
dosing), 15, 30, 60, and 90 minutes after dosing (for a sample, see Section 19.4). 
• If subjects are in the "OFF" state, dose with study treatment assigned by the IWRS. 


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• Investigator confirmation of "OFF" or "ON". Investigator will assess "OFF"/"ON" 
state as part of the MDS-UPDRS Part III assessments, except at 45 minutes, which 
will be assessed independent of the MDS-UPDRS Part III. The subject must be in an 
"OFF" state prior to dosing in order to proceed with dosing. 
• Subject confirmation of "OFF" or "ON". Subject should report: "OFF"/"ON" state at 
t = 0, 15, 30, 45, 60, and 90 minutes after dosing. 
• Subject should also report time to when the study medication is starting to have an 
effect (if applicable), and time to "OFF" following dosing (if it occurs within 
90 minutes of dosing). Note: The timing of this should begin when the study 
medication sublingual film has fully dissolved, and can be recorded using a stopwatch 
or other suitable timing device. 
• Dispense Study Medication assigned by the IWRS for Outpatient Dosing. 
• Collect Study Medication (excluding LTS V1). 
• Collect Subject Dosing Diary (De novo Subjects only). 
• Provide Subject Dosing Diary (see Section 19.5) and provide subject training on 
proper completion of the diary (at LTS V1). At all other visits, collect subject diary 
and ensure it was properly completed, and provide retraining on diary completion as 
necessary. 
• Perform IP accountability and assess treatment compliance (excluding LTS V1). 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). "Since Last 
Visit" version should be used at these visits. 
• Provide the subject with the PDQ-39 to complete (LTS V1, LTS V4, LTS V5, and 
LTS V6 only; for a sample, see Section 19.7). 
• Ask subject to complete the PGI (LTS V1, LTS V4, LTS V5, and LTS V6 only; for a 
sample, see Section 19.9). PGI–S to be used at the first visit, PGI-I to be used at all 
subsequent visits. 
• Complete the CGI (LTS V1, LTS V4, LTS V5, and LTS V6 only; for a sample, see 
Section 19.8). CGI–S to be used at the first visit, CGI-I to be used at all subsequent 
visits. 
• Assess using the ESS (LTS V1, LTS V4, LTS V5, and LTS V6 only; for a sample, 
see Section 19.10). 
• Assess caregiver burden using the ZBI (LTS V1, LTS V4, LTS V5, and LTS V6 
only; for a sample, see Section 19.11). 
• Complete the QUIP-RS (LTS V1, LTS V4, LTS V5, and LTS V6 only; for a sample, 
see Section 19.12). 
• Outpatient self-administration training (LTS V1 for De novo Subjects only). Subjects 
will be trained by clinic staff on how to remove study medication from its packaging, 
and how to handle the sublingual films using placebo sublingual films supplied to the 


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site. Subjects should not self-administer the placebo sublingual films. Subjects 
cannot be discharged from clinic until satisfactorily completing the training. 
• Blood sampling for PK analysis (for applicable sites participating in the PK 
sub-study). Samples will be taken at t = 0 (just prior to dosing) and at t = 10, 20, 30, 
60, 90, 120, 180 and 240 minutes post dosing. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last 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 after the 90 minute efficacy assessments are complete. 
12.3.2. 
LTS V2: In-Clinic Assessment 
Subjects will be asked to return to the clinic having taken their usual morning PD medications. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Perform a complete physical examination, including oropharyngeal examination prior 
to 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 weight. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG. 
• Register the visit in the IWRS to obtain the study medication kit numbers. 
• Dispense Study Medication assigned by the IWRS for Outpatient Dosing. 
• Collect Study Medication. 
• Collect subject's previous home dosing diary. Verify that the diary has been 
appropriately completed and retrain subject on diary completion as necessary. 
• Provide subject with a dosing diary. 
• Perform IP accountability and assess treatment compliance. 


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• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). "Since Last 
Visit" version should be used at this visit. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.3.3. 
LTS Phase Year 1 – At Home Assessments 
During the LTS Phase, subjects will be instructed to continue with their regular PD medication 
regimen(s), but should dose themselves with their APL-130277 treatment if they experience an 
"OFF" episode (eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF", etc.) while on 
their current treatment regimen. Subjects will be instructed to dose up to 5 "OFF" episodes per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 
For 2 days prior to in-clinic visits, subjects will be requested to complete a dosing diary (for a 
sample, see Section 19.5) that captures: 
• Time of APL-130277 treatment self-administration; 
• Subject "ON"/"OFF" state at 30 minutes after dosing. 
• The type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; 
no "ON"; or sudden "OFF"). 
Subjects will complete this diary for every self-administration they perform on each of these 
2 days. Clinic staff will call each subject approximately 3 days prior to the in-clinic visits in 
order to remind subjects to complete their home dosing diary. Subjects should be reminded to 
document when they dose themselves and to accurately report their "ON"/"OFF" status at 
30 minutes after dosing. 
12.3.4. 
LTS Phase Year 1 – Telephone Contacts 
Sites will follow-up with subjects at the mid-point between each in-clinic visit in order to assess 
study medication compliance, subject safety and well-being. If needed, an unscheduled Dose 
Adjustment Visit will be scheduled with the subject in order to further assess safety and 
well-being. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.4. 
Long-Term Safety (LTS) Treatment Phase Year 2 - All Subjects 
The long-term safety phase year 2 of the study will consist of 2 parts –in-clinic assessments and 
at-home assessments. The former will consist of 3 in-clinic visits where formal assessments of 
safety will be performed. The latter will be an at-home self-administration, where all subjects 
will be instructed to self-administer their doses of APL-130277 in order to treat up to 5 "OFF" 


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episodes (ie, morning akinesia; delayed "ON"; wearing "OFF"; no "ON"; or sudden "OFF") per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 
12.4.1. 
LTS V7, LTS V8, and LTS V9: In-Clinic Assessment 
Subjects will be asked to return to the clinic having taken their usual morning PD medications. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Perform a complete physical examination, including 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 weight. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG (excluding LTS V7 for CTH-301 Completer 
Subjects). 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry 
and urinalysis). Serum pregnancy for females of child-bearing potential only. Blood 
collected for this evaluation will not exceed 20 mL (excluding LTS V7 for CTH-301 
Completer Subjects). 
• Register the visit in the IWRS to obtain the study medication kit numbers. 
• Dispense Study Medication assigned by the IWRS for Outpatient Dosing. 
• Collect Study Medication (excluding LTS V7 for CTH-301 Completer Subjects). 
• Dispense Study Medication for Outpatient Dosing. 
• Provide subject with a dosing diary (see Section 19.5). 
• Collect subject's previous dosing diary, excluding TLS V7 for CTH-301 Completer 
Subjects (see Section 19.5). Verify that the diary has been appropriately completed 
and retrain subject on diary completion as necessary. 
• Perform IP accountability and assess treatment compliance (excluding LTS V7 for 
CTH-301 Completer Subjects).  
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). "Since Last 
Visit" version should be used at this visit. 
• Record any AEs/SAEs that have occurred since the last subject visit. 


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• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.4.2. 
LTS Phase Year 2 – At Home Assessments 
During the LTS Phase, subjects will be instructed to continue with their regular PD medication 
regimen(s), but should dose themselves with their APL-130277 treatment if they experience an 
"OFF" episode (eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF", etc.) while on 
their current treatment regimen. Subjects will be instructed to dose up to 5 "OFF" episodes per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 
For 2 days prior to in-clinic visits, subjects will be requested to complete a dosing diary (for a 
sample, see Section 19.5) that captures: 
• Time of APL-130277 treatment self-administration; 
• Subject "ON"/"OFF" state at 30 minutes after dosing; 
• The type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; 
no "ON"; or sudden "OFF"). 
Subjects will complete this diary for every self-administration they perform on each of these 
2 days. Clinic staff will call each subject approximately 3 days prior to the in-clinic visits in 
order to remind subjects to complete their home dosing diary. Subjects should be reminded to 
document when they dose themselves and to accurately report their "ON"/"OFF" status at 
30 minutes after dosing. 
12.4.3. 
LTS Phase Year 2 – Telephone Contacts 
Sites will follow-up with subjects at the mid-point between each in-clinic visit in order to assess 
study medication compliance, subject safety and well-being. If needed, an unscheduled Dose 
Adjustment Visit will be scheduled with the subject in order to further assess safety and 
well-being. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.5. 
Long-Term Safety (LTS) Treatment Phase Year 3 - All Subjects 
The long-term safety phase year 3 of the study will consist of 2 parts –in-clinic assessments and 
at-home assessments. The former will consist of 3 in-clinic visits where formal assessments of 
safety will be performed. The latter will be an at-home self-administration, where all subjects 
will be instructed to self-administer their doses of APL-130277 in order to treat up to 5 "OFF" 
episodes (ie, morning akinesia; delayed "ON"; wearing "OFF"; no "ON"; or sudden "OFF") per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 


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12.5.1. 
LTS V10, LTS V11, and LTS V12: In-Clinic Assessment 
Subjects will be asked to return to the clinic having taken their usual morning PD medications. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Perform a complete physical examination, including oropharyngeal examination prior 
to 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 weight. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry 
and urinalysis). Serum pregnancy for females of child-bearing potential only. Blood 
collected for this evaluation will not exceed 20 mL. 
• Register the visit in the IWRS to obtain the study medication kit numbers. 
• Dispense Study Medication assigned by the IWRS for Outpatient Dosing. 
• Collect Study Medication. 
• Provide subject with a home dosing diary (see Section 19.5). 
• Collect subject's previous home dosing diary (see Section 19.5). Verify that the diary 
has been appropriately completed and retrain subject on diary completion as 
necessary. 
• Perform IP accountability and assess treatment compliance. 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). "Since Last 
Visit" version should be used at this visit. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
• Provide the subject with the PDQ-39 to complete (LTS V12 only; for a sample, see 
Section 19.7). 
• Ask subject to complete the PGI-I (LTS V12 only; for a sample, see Section 19.9). 
• Complete the CGI-I (LTS V12 only; for a sample, see Section 19.8). 


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• Assess using the ESS (LTS V12 only; for a sample, see Section 19.10). 
• Assess caregiver burden using the ZBI (LTS V12 only; for a sample, see 
Section 19.11). 
• Complete the QUIP-RS (LTS V12 only; for a sample, see Section 19.12). 
12.5.2. 
LTS Phase Year 3 – At Home Assessments 
During the LTS Phase, subjects will be instructed to continue with their regular PD medication 
regimen(s), but should dose themselves with their APL-130277 treatment if they experience an 
"OFF" episode (eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF", etc.) while on 
their current treatment regimen. Subjects will be instructed to dose up to 5 "OFF" episodes per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 
For 2 days prior to in-clinic visits, subjects will be requested to complete a dosing diary (for a 
sample, see Section 19.5) that captures: 
• Time of APL-130277 treatment self-administration; 
• Subject "ON"/"OFF" state at 30 minutes after dosing. 
• The type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; 
no "ON"; or sudden "OFF"). 
Subjects will complete this diary for every self-administration they perform on each of these 
2 days. Clinic staff will call each subject approximately 3 days prior to the in-clinic visits in 
order to remind subjects to complete their home dosing diary. Subjects should be reminded to 
document when they dose themselves and to accurately report their "ON"/"OFF" status at 
30 minutes after dosing. 
12.5.3. 
LTS Phase Year 3 – Telephone Contacts 
Sites will follow-up with subjects at the mid-point between each in-clinic visit in order to assess 
study medication compliance, subject safety and well-being. If needed, an unscheduled Dose 
Adjustment Visit will be scheduled with the subject in order to further assess safety and 
well-being. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.6. 
Long-Term Safety (LTS) Treatment Phase Year 4 - All Subjects 
The long-term safety phase year 4 of the study will consist of 2 parts –in-clinic assessments and 
at-home assessments. The former will consist of 3 in-clinic visits where formal assessments of 
safety will be performed. The latter will be an at-home self-administration, where all subjects 
will be instructed to self-administer their doses of APL-130277 in order to treat up to 5 "OFF" 


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episodes (ie, morning akinesia; delayed "ON"; wearing "OFF"; no "ON"; or sudden "OFF") per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 
12.6.1. 
LTS V13, LTS V14, and LTS V15: In-Clinic Assessment 
Subjects will be asked to return to the clinic having taken their usual morning PD medications. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Perform a complete physical examination, including oropharyngeal examination prior 
to 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 weight. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry 
and urinalysis). Serum pregnancy for females of child-bearing potential only. Blood 
collected for this evaluation will not exceed 20 mL. 
• Register the visit in the IWRS to obtain the study medication kit numbers. 
• Dispense Study Medication assigned by the IWRS for Outpatient Dosing. 
• Collect Study Medication. 
• Provide subject with a home dosing diary (see Section 19.5). 
• Collect subject's previous home dosing diary (see Section 19.5). Verify that the diary 
has been appropriately completed and retrain subject on diary completion as 
necessary. 
• Perform IP accountability and assess treatment compliance. 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). "Since Last 
Visit" version should be used at this visit. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 


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12.6.2. 
LTS Phase Year 4 – At Home Assessments 
During the LTS Phase, subjects will be instructed to continue with their regular PD medication 
regimen(s), but should dose themselves with their APL-130277 treatment if they experience an 
"OFF" episode (eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF", etc.) while on 
their current treatment regimen. Subjects will be instructed to dose up to 5 "OFF" episodes per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 
For 2 days prior to in-clinic visits, subjects will be requested to complete a dosing diary (for a 
sample, see Section 19.5) that captures: 
• Time of APL-130277 treatment self-administration; 
• Subject "ON"/"OFF" state at 30 minutes after dosing; 
• The type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; 
no "ON"; or sudden "OFF"). 
Subjects will complete this diary for every self-administration they perform on each of these 
2 days. Clinic staff will call each subject approximately 3 days prior to the in-clinic visits in 
order to remind subjects to complete their home dosing diary. Subjects should be reminded to 
document when they dose themselves and to accurately report their "ON"/"OFF" status at 
30 minutes after dosing. 
12.6.3. 
LTS Phase Year 4 – Telephone Contacts 
Sites will follow-up with subjects at the mid-point between each in-clinic visit in order to assess 
study medication compliance, subject safety and well-being. If needed, an unscheduled Dose 
Adjustment Visit will be scheduled with the subject in order to further assess safety and 
well-being. 
The following safety assessments will be conducted: 
• Review restriction criteria. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.7. 
Long-Term Safety (LTS) Treatment Phase Year 5 - All Subjects 
The long-term safety phase year 4 of the study will consist of 2 parts –in-clinic assessments and 
at-home assessments. The former will consist of 3 in-clinic visits where formal assessments of 
safety will be performed. The latter will be an at-home self-administration, where all subjects 
will be instructed to self-administer their doses of APL-130277 in order to treat up to 5 "OFF" 
episodes (ie, morning akinesia; delayed "ON"; wearing "OFF"; no "ON"; or sudden "OFF") per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 
12.7.1. 
LTS V16, LTS V17, and LTS V18: In-Clinic Assessment 
Subjects will be asked to return to the clinic having taken their usual morning PD medications. 
The following safety assessments will be conducted: 


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• Review restriction criteria. 
• Perform a complete physical examination, including oropharyngeal examination prior 
to 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 weight. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Perform a standard 12-lead ECG. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry 
and urinalysis). Serum pregnancy for females of child-bearing potential only. Blood 
collected for this evaluation will not exceed 20 mL. 
• Register the visit in the IWRS to obtain the study medication kit numbers. 
• Dispense Study Medication assigned by the IWRS for Outpatient Dosing. 
• Collect Study Medication. 
• Provide subject with a home dosing diary (see Section 19.5). 
• Collect subject's previous home dosing diary (see Section 19.5). Verify that the diary 
has been appropriately completed and retrain subject on diary completion as 
necessary. 
• Perform IP accountability and assess treatment compliance. 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). "Since Last 
Visit" version should be used at this visit. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
12.7.2. 
LTS Phase Year 5 – At Home Assessments 
During the LTS Phase, subjects will be instructed to continue with their regular PD medication 
regimen(s), but should dose themselves with their APL-130277 treatment if they experience an 
"OFF" episode (eg, morning akinesia, wearing "OFF", dose failure, sudden "OFF", etc.) while on 
their current treatment regimen. Subjects will be instructed to dose up to 5 "OFF" episodes per 
day. Subjects will be instructed to wait a minimum of 2 hours between each dose taken at home. 


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For 2 days prior to in-clinic visits, subjects will be requested to complete a dosing diary (for a 
sample, see Section 19.5) that captures: 
• Time of APL-130277 treatment self-administration; 
• Subject "ON"/"OFF" state at 30 minutes after dosing; 
• The type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; 
no "ON"; or sudden "OFF"). 
Subjects will complete this diary for every self-administration they perform on each of these 
2 days. Clinic staff will call each subject approximately 3 days prior to the in-clinic visits in 
order to remind subjects to complete their home dosing diary. Subjects should be reminded to 
document when they dose themselves and to accurately report their "ON"/"OFF" status at 
30 minutes after dosing. 
12.7.3. 
LTS Phase Year 5 – Telephone Contacts 
Sites will follow-up with subjects at the mid-point between each in-clinic visit in order to assess 
study medication compliance, subject safety and well-being. If needed, an unscheduled Dose 
Adjustment Visit will be scheduled with the subject in order to further assess safety and 
well-being. 
The following safety assessments will be conducted: 
• Reconfirm consent. 
• Review restriction criteria. 
• Record any AEs/SAEs that have occurred since the last patient visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the patient since the last visit. 
12.8. 
Early Termination Visit 
 
Every effort should be made to have subjects complete all study visits. The following 
assessments will be conducted when an individual subject discontinues: 
• Perform a complete physical examination, including oropharyngeal examination, 
prior to 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 weight. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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, 


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dizziness, or changes in sensorium upon standing, every attempt should be made to 
obtain BP and HR in the sitting position. 
• Perform a standard 12-lead ECG. 
• Collect blood and urine samples for clinical laboratory tests (hematology, chemistry 
and urinalysis). Serum pregnancy for females of child-bearing potential only. Blood 
collected for this evaluation will not exceed 20 mL. 
• Assess suicidal ideation using C-SSRS (for a sample, see Section 19.6). 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
Subjects who discontinue the study during the LTS Phase will also have the following 
assessments performed: 
• Collect outpatient supplies (if applicable). 
• Collect Subject Dosing Diary (if applicable). 
• Assess treatment compliance (if applicable). 
• Provide the subject with the PDQ-39 to complete (for a sample, see Section 19.7). 
• Ask subject to complete the PGI-I (for a sample, see Section 19.9). 
• Complete the CGI-I (for a sample, see Section 19.8). 
• Assess using the ESS (for a sample, see Section 19.10). 
• Assess caregiver burden using the ZBI (for a sample, see Section 19.11). 
• Complete the QUIP-RS (for a sample, see Section 19.12). 
• Complete Ease of Use Questionnaire (for a sample, see Section 19.15). 
• Register the visit in the IWRS. 
 
12.9. 
Unscheduled Dose Adjustment Visits 
If at any time during the LTS Phase of this study it is determined that a dose adjustment is 
required, where possible the medical monitor should be contacted to discuss the dose adjustment. 
Once agreed, “Unscheduled Dose Adjustment” should be registered in IWRS, indicating whether 
the dose adjustment should happen at the next LTS visit or at an unscheduled visit, to obtain the 
new dose of APL-130277 for the subject. Once IP is at site, subject will return for an 
unscheduled Dose Adjustment Visit (or this could be combined with the next scheduled LTS 
visit). 
At the investigator’s discretion, the subject may receive the adjusted dose in-clinic and undergo 
efficacy (MDS-UPDRS part III and ON/OFF assessments up to 90 minutes), and additional 
safety assessments as deemed appropriate. 


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Subjects will be contacted by telephone within 3 days after dose adjustment visits for assessment 
of effect of the dose adjustment and safety. 
The following will be performed: 
• Review restriction criteria. 
• Record vital signs (BP, HR, RR and body temperature). Vital signs should be 
measured after the subject has been resting in the supine position for at least 
3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
• Collect remaining study medication provided at the last visit (if required). 
• Provide subject home dosing diary (see Section 19.5) and instruct subjects to 
complete it 2 days before their subsequent in-clinic visit (if applicable). 
• Collect subject diaries completed since the last visit (if applicable; see Section 19.5). 
Verify that the diary has been appropriately completed and retrain subject on diary 
completion as necessary. 
• Assess treatment compliance. 
• Record any AEs/SAEs that have occurred since the last subject visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
• Record reason for the dose adjustment. 
• Dispense new study medication for outpatient dosing (Only after all safety 
assessments have been completed and deemed safe by the investigator to dispense the 
new dose to the subject). 
This visit may occur over multiple days to accommodate receipt of the new dose of study drug 
(if necessary). 
If, in the opinion of the Investigator, dose adjustments are necessary for subject safety, 
tolerability or lack of efficacy, the Investigator may adjust the scheduled dose of study drug to 
the next dose (eg, to the 10 mg dose if the subject is receiving 15 mg, or up to 20 mg dose if 
subject is receiving 15 mg). The Investigator should make all attempts to maintain subjects on a 
stable dose. 
Any subject whose dose has been reduced or increased at a Dose Adjustment Visit will 
self-administer study drug using the new dosage at home and at all in-clinic visits for the 
remainder of the LTS Phase of the study. If, in the opinion of the Investigator, the dose is no 
longer optimal for the subject, after discussions/approval from the medical monitor, additional 
dose adjustments could be performed. 


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12.10. 
Duration of Treatment 
Subjects may participate in the study until the Sponsor terminates the study, or until commercial 
availability of APL-130277 in the subject’s country. 
12.11. 
Assessments 
12.11.1. 
Order of Assessments 
The following summarizes the suggested sequence of assessments prior to dosing during SV2 
(de novo patients only), Dose Titration Phase and the in-clinic visits during the LTS Phase: 
ECG – Vitals – Subject "OFF"/"ON" status - MDS-UPDRS Part III 
The following summarizes the suggested sequence of assessments after dosing during SV2 
(de novo subjects only), Dose Titration Phase and the in-clinic visits during the LTS Phase: 
MDS-UPDRS Part III - Subject "OFF"/"ON" status - ECG – 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.  
12.11.2. 
Clinical Safety Assessments 
12.11.2.1. 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; musculoskeletal system; central and peripheral nervous system; 
and skin. 
Abbreviated physical examinations at all scheduled timepoints must include head-eyes-ears-nose 
and throat; cardiovascular system; respiratory system; abdomen; and skin; to be done at t = 0 
(just prior to dosing) and 120 minutes post dosing at visits at TV1 to TV6 (De novo subjects 
only). A window of +/- 10 minutes is given for post-dose abbreviated physical examinations 
during TV1 to TV6. 
All examinations performed in this study 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 
• None 
• Focal reddening 
• Multiple foci of reddening 
• Edema 


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• Ulceration 
Grade 
• Mild 
• Moderate 
• 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). 
Any subject who presents with an adverse event involving the oral cavity must be seen by a 
qualified dermatologist (or specialist in a related field) within 24 hours. The dermatologist (or 
specialist in a related field) must examine the subject, and provide a consultation report including 
photographs of the oral cavity (see Section 13.1.7). 
12.11.2.2. Vital Signs 
Vital signs (HR, RR, BP and body temperature) will be measured at various timepoints during 
the study. Vital signs should be measured after the subject has been resting in the supine position 
for at least 3 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. 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. 
During the Dose Titration Phase (De novo subjects only), if the 60 minute MDS-UPDRS Part III 
assessment is not performed since the subject did not experience a full "ON" response within 
45 minutes of dosing, the vital signs assessment will be performed at the approximate time it 
would have been scheduled if the MDS-UPDRS Part III assessment were performed (ie 
70 minutes). 
Study personnel will carefully monitor patients 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. 
12.11.2.3. 12-Lead ECGs 
A standard 12-lead ECG will be performed at all timepoints outlined in the protocol. A triplicate 
12-lead ECG will be performed at the second Screening Visit (SV2) for De Novo subjects, at 
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CTH-301 Completer subjects. If required by the Investigator to assess De Novo Patient 
eligibility, a triplicate ECG may be performed at SV1, but will not be repeated at SV2. 
ECGs will be performed in a semi-recumbent position and after 5 minutes of rest. 
The following parameters will be collected: 
• Heart rate 
• PR interval 
• QRS interval 
• RR interval 
• QT interval 
• QTc Interval (Fridericia’s correction) 
• QTc Interval (Bazett’s correction) 
All ECGs should be assessed by the Investigator and deemed "Normal", "Abnormal, not 
clinically significant" and "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. 
ECG assessments will be centralized and performed by a suitable vendor contracted by the 
Sponsor and/or designate. 
12.11.2.4. Modified Hoehn and Yahr 
The Modified Hoehn and Yahr scale will be administered at the second Screening Visit (SV2) to 
verify that De Novo subjects meet the eligibility criteria for this study. This will be conducted in 
the "ON" state. 
No Modified Hoehn and Yahr scale will be performed on Rollover subjects during Screening 
Visit (SV1) or on CTH-301 Completer subjects at Screening Visit Period 2 (SVP2). 
12.11.2.5. 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 will be performed on all females of child-bearing 
potential only. 
Urinalysis: 
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Serology (at the Screening 
Visit only): 
Human immunodeficiency virus (HIV), Hepatitis B surface antigen, 
Hepatitis C antibodies. 
12.11.2.6. 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. 
12.11.2.7. C-SSRS 
At the Screening Visit (SV2 for De Novo subjects, SV1 for Rollover subjects, or SVP2 for 
CTH-301 Completer Patients), 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. 
Formal assessments of subject suicidal ideation and behavior will be assessed all in-clinic visits 
during the Dose Titration Phase and LTS Phase of the study. A final assessment will be 
performed at the time of early termination. 
The Investigator or designate should closely monitor the responses of subjects during the 
interview and watch for signs that suggest current suicidal ideation or intent. 
12.11.2.8. Other Safety and Quality of Life Assessments 
The following assessments will be performed in this study at the timepoints indicated in the 
Schedule of Events: 
• PDQ-39 
• PGI 
• CGI 
• ESS 
• ZBI – Optional; to be completed if caregiver is present and consent is provided. 
• QUIP-RS 
• EQ-5D 


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These assessments will be performed at any point during the scheduled visit in accordance with 
the guidelines for each (see applicable Appendices). 
12.11.2.9. Medical History 
At the Screening Visits, 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 patient’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 subject’s 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 (eg, 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: 
− dopamine agonists; 
− MAO-B inhibitors; 
− COMT inhibitors; 
− Amantadine; 
− Anti-cholinergics. 
12.11.3. 
Efficacy Assessments 
12.11.3.1. Confirmation of "OFF" or "ON" Episodes "OFF" and "ON" Training of 
Subjects at SV2 
"OFF" and "ON" Training 
Training will only be performed with De Novo subjects only. Rollover subjects and CTH-301 
Completer subjects will not be required to undergo "OFF"/"ON" training during the Screening 
Visit. 
At Screening Visit 2 (SV2), De Novo subjects will present to the clinic having taken their usual 
morning dose of L-Dopa and any other adjunctive PD medication; but before taking their next 
dose of medication. Their normal dose of L-Dopa (without adjunctive PD medication) will be 
administered in the clinic approximately two hours after their normally scheduled second dose of 
PD medication. 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 


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Investigator will educate the subject that this is an "OFF" period or "OFF" 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 normal 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 patient 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 eCRF. 
Any subject who cannot differentiate between an "ON" and "OFF" state will be deemed a screen 
failure. 
A window of ± 5 minutes is allowed for both the subject and the Investigator assessments at each 
post-dose timepoint. 
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". 
** Not applicable for at-home assessments using the subject dosing diary. 
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; De Novo subjects 
only]). 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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At each Dose Titration and LTS Phase Year 1 Visit (except LTS V2), the Investigator will assess 
"OFF"/"ON" state as part of the MDS-UPDRS Part III assessments except at 45 minutes, which 
will be assessed independent of the MDS-UPDRS Part III. 
At each Dose Titration and LTS Phase Year 1 Visit (except LTS V2), the subject should report: 
"OFF"/"ON" state at 0, 15, 30, 45, 60, and 90 minutes after dosing (site staff should prompt the 
patient). Subjects should also report: time to when the study medication is starting to have an 
effect (if applicable), and time to "OFF" following dosing (if it occurs within 60 minutes of 
dosing). The timing of this should begin when the study medication sublingual film has fully 
dissolved, and can be recorded using a stopwatch or other suitable timing device. These times 
should be documented on the appropriate form of the CRF. 
During the Dose Titration Phase only (De novo subjects only), subject and Investigator 
assessments of "OFF" and "ON" state may cease if the patient does not experience a full "ON" 
state within 45 minutes of dosing. 
12.11.3.2. MDS-UPDRS Parts I, II and IV 
Investigators will administer Part I (Non-Motor Aspects of Experiences of Daily Living), Part II 
(Motor Aspects of Experiences of Daily Living) and Part IV (Motor Complications) at the 
Screening Visit (SV2 for De Novo subjects and SV1 for Rollover subjects; CTH-301 Completer 
subjects will not be required to undergo this assessment at Screening) and at LTS V3, LTS V4, 
LTS 5, and LTS 6). 
12.11.3.3. MDS-UPDRS Part III 
The Motor Function section (Part III) of the MDS-UPDRS will be administered at all visits 
where it is indicated. 
At SV2 (De Novo subjects only), administration will be performed at t = 0 (just prior to dosing) 
and at 15, 30, 60 and 90 minutes after L-Dopa administration. If the subject does not experience 
an "ON" within 90 minutes, the site should record the time when the subject turns "ON" and 
perform an additional MDS-UPDRS Part III assessment at this time. 
At all other visits, administration will be performed at t = 0 (just prior to dosing) and at 15, 30, 
60, and 90 minutes after dose administration. The same assessor should be utilized for each 
subject throughout the study.  
A window of ± 5 minutes is allowed for post-dose assessments at each timepoint. 
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 – De 
Novo Patients only). 
During the Dose Titration Phase only, Investigator assessments may cease if the subject does not 
experience a full "ON" state within 45 minutes of dosing. 
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 site staff member can perform the assessment if approved by the Sponsor. 


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12.11.3.4. Subject Dosing Diary 
De novo Subjects (only) will be given a home dosing diary on TV1 of the Dose Titration Phase. 
All subjects will be given a dosing diary at all LTS Visits. The diary will collect the following 
information: 
• Date; 
• Subject Number; 
• Time study treatment is self-administered; 
• Subject "ON"/"OFF" status at 30 minutes following dosing; 
• Type of "OFF" experienced (ie, morning akinesia; delayed "ON"; wearing "OFF"; no 
"ON"; or sudden "OFF"). 
The diary provided on TV1 (De novo Subjects only) will be used for training purposes only and 
the information collected will not be included in the CRF. Subjects will be asked to complete the 
diary using their normal dose of L-Dopa and other adjunctive PD medication as the self-
administration timepoint, and return this diary on LTS V1. Subjects will also be instructed on the 
different types of "OFF" episodes experienced and how to differentiate between each. 
Staff should review the completed diary returned at LTS V1 and re train subjects on diary 
completion, as necessary. Site staff should remind subjects at this visit that moving forward, the 
diary must be completed only when the subject self-administers their intended study treatment, 
not their other standard PD medication. 
During the LTS Phase of the study, subjects will complete the dosing diary on the 2 days prior to 
their scheduled in-clinic visits. Site staff will call all subjects approximately 3 days before the 
scheduled in-clinic visit in order to confirm the next visit and remind them to complete the 
dosing diary as part of their procedures in the study. Subjects should bring their completed 
dosing diary with them at their scheduled visit. 
12.11.3.5. Optional Pharmacokinetic (PK) Evaluation 
Blood draws for APL-130277 PK analyses will occur during LTS Phase Year 1, where indicated, 
at t = 0 (just prior to dosing) and at t = 10, 20, 30, 60, 90, 120, 180 and 240 minutes. A window 
of ± 5 minutes is allowed for post-dose assessments at each timepoint. PK assessments will be 
performed at select participating sites, and subjects must consent in order to participate in 
optional PK sub-study. Approximately 6 sites will be chosen, and 4 subjects from each of these 
are estimated to take part in the sub-study. Dosing date and time as well as PK sampling date and 
time must be recorded in the CRF. Actual elapse time from dosing will be used in all PK 
parameter estimations. 
Instructions specific to PK draws will be outlined in the PK lab manual. 
12.12. 
Assessment of Treatment Compliance 
Treatment compliance will be assessed by counting the number of used and unused study 
medication pouches returned by subjects at each in-clinic visit during the LTS Phase of this 
study relative to the amount given at the preceding visit. Discrepancies in the amount previously 


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dispensed and returned by the subject will be queried by the Investigator and documented in the 
appropriate CRF. Significant non-compliance, as assessed by the Investigator, may lead to 
subject dismissal from the study. 
The responsible monitors will verify the data being reported in the CRF versus the study 
medication returned by each subject. 


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13. 
ADVERSE EVENTS 
Adverse event recording and serious adverse event reporting will begin when the subject signs 
the ICF. AEs will be recorded in the CRFs until 7 to 10 days after the last dose of study drug, 
and SAEs will be reported through 14 days after the last dose of study drug. 
13.1.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject (or subject) or clinical investigation 
subject (or subject) 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 subject) 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 
the investigational drug during pregnancy is an SAE. 


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Due to the nature of subjects being enrolled in this study, and the given study objectives, 
subjects who are admitted for their titration and/or LTS Phase "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 because of 
the AE. 
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 


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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 the oral cavity requires 
reporting to the Sponsor or designate. These AESIs include, but are not limited to: 
• Stomatitis; 
• Oral irritation/oral inflammation/oral pain, including redness 
• Oral swelling; edema 
• Oral ulcers, including blisters 
• Oral infections, including candidiasis 
• Oral paresthesia, hypoesthesia, 
• Oral sensation alterations such as dysgeusia, ageusia 
• Salivary complaints 
All AESIs should be reported to the Sponsor or designate, as appropriate, for processing. 
Instructions for reporting AESIs and their processing will be outlined in a separate study 
document. 
Any subject who presents with an adverse event involving the oral cavity must be seen by a 
qualified dermatologist (or specialist in a related field) within 24 hours (if it is not possible to 
report within 24 hours, the Medical Monitor should be consulted immediately to discuss the 
evaluation plan including timeline). The dermatologist (or specialist in a related field) must 
examine the subject, and provide a consultation report including photographs of the oral cavity.  
Subjects should be instructed to notify the clinical site within 24 hours if they develop any one or 
more of the oral events noted above. 
For all AESIs, if the event meets seriousness criteria, the Investigator will report the event to the 
Sponsor or designate within 24 hours of the site being made aware of the event, as outlined in 
Section 13.1.14. All AESIs which do not meet the seriousness criteria will be reported by the 
Investigator to the Sponsor or designate within 7 days of site awareness (Section 13.1.14). 
 
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: 


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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 (eg, 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; 
• 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"; 


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• 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) (ie, 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 
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. 
Unblinding procedures are not applicable for this study as it is being conducted as an open-label 
study. 
13.1.13. 
Notification of Serious Adverse Events 
If the Investigator or study center staff becomes aware of a SAE that occurs in a study subject 
from signing informed consent through 14 days following the last dose of the study medication, 
this must be reported immediately to the Sponsor whether considered related or unrelated to the 
study drug. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 
An initial / follow-up SAE form as applicable must be completed and signed and sent via fax or 
email (see Table 1) to PPD-PVG within 1 business day of the Investigator or study center staff 
becoming aware of the event. The SAE form must be signed by the Investigator or appropriate 
designee. The Sponsor will provide the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers 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 
Investigator or the appropriate person at the study center if required per IRB/REB/IEC 
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13.1.14. 
Notification of Oral Adverse Events of Special Interest 
Oral AESIs (Section 13.1.7) that do not meet seriousness criteria (Section 13.1.2) must be 
reported by the Investigator to the Sponsor within 7 business days of the Investigator or study 
center staff awareness of the event. 


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14. 
TREATMENTS 
14.1. 
Treatments Administered (APL-130277 and Matching Placebo) 
APL-130277 is a rectangular 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. 
Each package of investigational drug product will be labeled with study specific information 
meeting all the applicable regulatory requirements, including specifying the dose of 
apomorphine. 
Individual sublingual films of APL-130277 will be supplied packed into unit dose pouches. 
Buffer layer will be on the side of the sublingual film that has an alphanumeric or numeric 
printing. 
APL-130277 sublingual films will be provided in 5 strengths: 10 mg, 15 mg, 20 mg, 25 mg and 
30 mg. Two sublingual films will be administered sequentially to form the 35 mg dose (a 20 mg 
dose first followed immediately by the 15 mg dose). In this study, placebo sublingual films will 
also be prepared for training purposes only, which will be identical in appearance, size and color, 
but contain no active ingredient (ie, apomorphine).  
14.2. 
Administration of Study Medication (APL-130277 and Placebo 
APL--130277) 
During Dose Titration (De novo Subjects only) and applicable visits in the LTS Phase, dosing 
will occur in the clinic administered by clinic staff. Time of dosing will be the time when the 
sublingual film is placed underneath the tongue. 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 towards the tongue (ie, 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 three minute mark, the film is 
not completely dissolved, subjects should be instructed to close their mouth and hold the 
study medication under their tongue for another minute (ie, maximum of 4 minutes in 
total). 
If the subject feels the film has fully dissolved prior to the three minute mark, they should 
indicate this to site 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. 


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At LTS V1, De novo subjects (only) will undergo outpatient self-administration training with 
clinic staff using placebo sublingual films. This training is performed in order to familiarize 
subjects with the self-administration process during the LTS Phase. Staff should demonstrate to 
subjects the process of opening the individual dose pouches and handling the individual 
sublingual films. Subjects should not self-administer the placebo sublingual films. Subjects will 
not be dismissed until they have adequately been trained and site staff feel confident they 
understand the full process. 
Prior to each self-administration, subjects will be instructed to consume a glass of water 
immediately prior to dosing, and ensure the sublingual space is free of excess water. Using their 
hands, subjects (or their caregivers) should place the product beneath the tongue, with the drug 
side facing up towards the tongue (ie, the side of the film that does not have an alphanumeric 
printing), and close their mouth naturally. Subjects should not swallow the medication and 
should also try not to swallow their saliva for at least 3 minutes, or until they feel the film 
has fully dissolved. 
The 35 mg dose will be administered by dosing with the 20 mg sublingual film, and after 
3 minutes have elapsed, followed by dosing with a 15 mg sublingual film. 
During the in-clinic visits of the Dose Titration Phase (De novo subjects only), subjects will be 
dosed by clinic staff. The time of dosing (t = 0) will be the time when the sublingual film is 
placed underneath the tongue. 
At each outpatient visit, subjects will be provided sufficient study medication in order to 
self-administer for up to 5 "OFF" episodes per day until their next scheduled visit. Subjects will 
be instructed to wait a minimum of 2 hours between doses taken at home. Unused study 
medication will be collected by each site and inventoried. 
14.3. 
Storage 
The Investigator is responsible for ensuring the proper storage of study medication according to 
procedures agreed in advance. Unit dose pouches should be stored at a controlled room 
temperature: 68-77°F (20-25°C). The study drug should be stored in a limited-access location 
with appropriate environmental controls (e.g., for temperature) and a mechanism for 
documenting that required conditions were maintained during the entire storage timeframe. 
Temperature excursions between 15°C (59°F) and 30°C (86°F) do not need to be reported to the 
sponsor, unless the duration exceeds 7 consecutive days. 
If the storage conditions fall below 15°C (59°F), reach above 30°C (86°F), or if there is an event 
where temperatures reach above 25 °C (77°F) up to 30°C (86°F) for at least 7 consecutive days, 
the excursions should be reported to the sponsor. Please refer to the Pharmacy Manual for 
additional details and reporting instructions. 
Subjects will be instructed to store the study medication at room temperature. 
The Investigator must maintain accurate and adequate records including expiry dates, lot 
number, 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. At the time of 
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have been returned by the subject and that no remaining supplies are in the Investigator's 
possession. Certificates of delivery and returns must be signed and filed in the Study Site File. 
Refer to Study Pharmacy Manual for additional information. 
14.4. 
Packaging and Labeling 
During the Dose Titration Phase, open-label titration kits containining 12 dose level pouches will 
be supplied to sites. The kits and the individual pouches will be labeled with all applicable 
information.   
Kits of sublingual films of Placebo APL-130277, containing 3 individual dose peelable foil 
laminate pouches will be supplied for training purposes. The kits and Individual pouches will be 
labelled with all applicable information. 
During the LTS Phase, treatment kits of APL-130277, containing 150 individual dose peelable 
foil laminate pouches, will be labeled with study specific information meeting all the applicable 
regulatory requirements, including specifying the dose of apomorphine. Investigational drug 
product will be administered both in clinic and at home during the LTS Phase. 
Refer to the pharmacy manual (or equivalent) for more details. 
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 
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 study site 
personnel may supply or administer the investigational drug. 
Refer to Study Pharmacy Manual for additional information. 
14.6. 
Method of Assigning Subjects to Treatment Groups 
Subjects will be assigned open-label APL-130277 treatment using an IWRS system. 
The strength (ie, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 35 mg) to be given will be determined 
during the Dose Titration Phase of the study for De novo subjects. 


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The strength to be given for Rollover subjects will be the dose they were on in the previous 
study. 
The strength to be given for Completer subjects will be the dose they previously received in 
study CTH-301 (under protocol version 3.00). 
Doses may be adjusted in the LTS Phase of the study based on safety/tolerability and efficacy 
assessed during unscheduled Dose Adjustment Visits. 
14.7. 
Randomization and Blinding 
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 by the IWRS within each site. 
There will be no blinding of treatment and no randomization performed. 
When the Dose Titration Phase for a subject is complete (De novo subjects only), sites should 
enter all titration MDS-UPDRS Part III date for that patient into the appropriate CRF within 48 
hours of the last titration visit for review by the Medical Monitor. 
 


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15. 
STATISTICAL ANALYSES 
15.1. 
Statistical Analysis Plan 
Full statistical considerations, table mock-ups and final analysis of safety and efficacy data 
collected in this study will be outlined in a formal Statistical Analysis Plan. This plan will be 
finalized prior to locking the database. 
15.2. 
Analysis Sets 
15.2.1. 
Titration Full Analysis Set 
All subjects who are enrolled in this study and receive one dose of study medication during the 
dose titration phase will be included in the titration full analysis set. This analysis set will be 
used for safety and efficacy analysis of titration phase data. 
15.2.2. 
LTS Full Analysis Set 
All subjects who are enrolled and receive at least one dose of study medication during the LTS 
phase will comprise the LTS full analysis set. This set will be used for safety and efficacy 
analysis of LTS phase data.  
15.3. 
Sample Size Calculation. 
The sample size of this safety study is not based on any power calculations.  
15.4. 
Efficacy Analysis 
The efficacy endpoints will be analyzed by time point for the LTS Full Analysis set and 
separately for De Novo Subjects and Rollover Subjects. 
The changes from baseline in the continuous efficacy endpoints will be summarized 
descriptively. The categorical endpoints will be analyzed using subject counts and percentages. 
15.5. 
Safety Analysis 
The analysis of the safety data will focus on data collected during the LTS Phase. In addition, all 
safety data will be reported separately for the Dose Titration Phase. The safety data will be 
primarily analyzed for the full analysis set, but additional summaries will be done separately for 
De Novo Subjects and Rollover Subjects (based on initial enrollment status). Adverse events will 
be tabulated according to the MedDRA. Treatment-emergent adverse events will be summarized 
by body system and preferred term. The AE analysis will focus on the dopaminergic TEAEs. 
Descriptive statistics will be used to summarize the overall incidence of TEAEs.  
15.6. 
Pharmacokinetic Analysis 
For plasma PK samples, apomorphine levels and metabolites (norapomorphine and apomorphine 
sulphate) will be measured in plasma using a validated liquid chromatography-tandem mass 


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spectrometry (LC-MS/MS) method developed by Info Kinetics. Apomorphine-glucuronide and 
norapomorphine-glucuronide levels will be measured using a qualified LC-MS/MS method. 
Pharmacokinetic parameters will be derived using noncompartmental methods employing 
WinNonlin® Phoenix version 6.3 or higher (Pharsight, St Louis, MO). Pharmacokinetic analysis 
will be conducted using concentration-time data for apomorphine and metabolites. 
For pharmacokinetic analysis concentrations that are below the limit of quantification (BLQ) will 
be assigned a value of zero when they precede quantifiable samples in the initial portion of the 
profile. Following Cmax, BLQ values embedded between two quantifiable data points will be 
treated as missing when calculating area under the curve. BLQ values occurring at the end of the 
collection interval (after the last quantifiable concentration) will be treated as missing data. 
When consecutive BLQ concentrations are followed by quantifiable concentrations in the 
terminal portion of the concentration curve, these quantified values will be excluded from the PK 
analysis by assigning them a value of missing, unless otherwise warranted by the 
concentration-time profile. 
The following PK parameters if appropriate for the particular analyte will be estimated by 
noncompartmental methods from plasma samples (Table 10). Additional parameters may be 
calculated as necessary. Actual elapsed time from dosing will be used to determine all individual 
PK parameters. A detailed PK analysis plan will be developed prior to conducting analysis. 
Table 10: 
Pharmacokinetic Parameters to be Estimated 
Parameter 
Definition 
Cmax  
Maximum observed plasma concentration 
Tmax  
The observed time of the maximum concentration 
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. 
AUC∞ 
Area under the concentration-time curve from time zero extrapolated to infinity using 
the linear up log down trapezoidal rule. 
λz 
Terminal-phase rate constant 
t½ 
Terminal-phase half-life 
MRT 
Mean residence time 
M/P ratios 
Metabolite to parent ratio of AUC and Cmax 
The individual subject concentration-time data will be listed and displayed graphically on linear 
and semi-log scales. The concentration-time data will be summarized descriptively in tabular and 
graphical formats (linear and semi-log scales) overlaid by dose level. Individual PK parameters 
from the noncompartmental PK analysis will be tabulated, where calculable, and summarized 
descriptively. The following summary statistics will be presented for PK parameters: N, 
arithmetic mean, CV%, SD of the arithmetic mean, median, minimum, maximum, geometric 
mean and CV% of the geometric mean. Tmax will be presented as N, median, minimum and 
maximum. 


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Figures illustrating the time course of mean drug concentration vs. time for each regimen will be 
overlaid and presented for relevant comparisons on linear and semi-logarithmic scales, as 
appropriate. Other analyses such as exploring the relationship between PK parameters and dose 
will be conducted, as appropriate. A standalone PK report will be produced. 
 


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16. 
STUDY CONDUCT 
Steps to assure the accuracy and reliability of data include the selection of qualified Investigators 
and appropriate study 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 (eg, 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 Section 19.2 for additional information. 
16.2. 
Study Initiation 
Clinical site 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 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. 
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 


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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. 
Table 11: 
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/REB/IEC Approvals 
Signed Financial Disclosure 
IRB/REB/IEC Membership List / Assurance Statement  
Regulatory Agency Approval  
Approved Informed Consent Template(s) 
 
PI signed FDA Form 1572 / Qualified Investigator 
Undertaking 
Additional documentation requirements may be communicated by Sunovion staff (or 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. 
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. 


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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. 
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. 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, EDC data 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 patient’s eligibility for the 
study. 
Original versions of the laboratory reports and ECG tracings will be retained at the clinical site 
with the patient’s source documents, and anonymized copies provided to Sunovion with the CRF 
copies. 
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 its 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. 


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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. 
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. 


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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 
not limited to the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines; 
• Inadequate subject enrollment; 
• Administrative reasons. 
16.4.7. 
Data Safety Monitoring Board 
A DSMB will be utilized in this study in order to monitor subject safety independently from the 
Sponsor. 
The DSMB will be composed of members who are not participating in the trial, led by a Chair. 
The DSMB will be responsible for monitoring subject safety, and with the support of an 
independent statistician, review safety data collected for a planned analysis or other analysis as 
required by the DSMB. The DSMB, under specific circumstances, may suggest revisions to the 
current protocol if these improve patient safety and potential outcomes. 
The independent statistician will have access to regular database transfers. For each safety 
meeting, the statistician will prepare summary tables, listings and figures, as appropriate, in order 
to aid the DSMB in making a decision on patient safety. Data used will be as presented in the 
study database, whether it has undergone quality control and cleaning. Safety data reviewed and 
analyzed will, at a minimum, include SAEs, AEs that are related to the oropharyngeal 
examinations, and any other safety data required by the DSMB to make an assessment. 
The composition, responsibility and general overview of procedures will be outlined in the 
DSMB Charter and finalized prior to implementation of any DSMB review. 


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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. Abstracts, manuscripts, and presentation 
materials should be provided to Sunovion for review at least 30 days prior to the relevant 
submission deadline. 
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. 
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 patient. 


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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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25 February 2019 
18. 
REFERENCES 
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. 
APOMORPHINE treatment for morphine addiction. Br J Addict Alcohol Other Drugs. 
1949;46(2):93-101. 
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. 
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. 
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. 
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. 
Mouradian MM, Heuser IJ, Baronti F, et al. Pathogenesis of dyskinesias in Parkinson's disease. 
Ann Neurol. 1989;25(5):523-6. 
Schwab RS, Amador LV, Lettvin JY. Apomorphine in Parkinson's disease. Trans Am Neurol 
Assoc. 1951;56: 251–3. 
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. 
Tanner CM, Goldman SM. Epidemiology of Parkinson's disease. Neurol Clin. 1996;14:317-35. 
 


Protocol CTH-301, Version 5.00 
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Confidential and Proprietary 
 
 
25 February 2019 
19. 
APPENDICES 
19.1. 
APPENDIX I: APOKYN® Prescribing Information and APO-go® 
Summary of Product Characteristics 
For the most current APOKYN® PI, see 
https://www.apokyn.com/sites/all/themes/apokyn/content/resources/Apokyn_PI.pdf 
 
For the most current APO-go® SmPC, see https://www.medicines.org.uk/emc/medicine/12941 


Protocol CTH-301, Version 5.00 
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Confidential and Proprietary 
 
 
25 February 2019 
19.2. 
APPENDIX II: Regulations and Guidelines 
19.2.1. 
Declaration of Helsinki 
The Policy of the World Medical Association is available at URL: 
http://www.wma.net/en/30publications/10policies/b3/ 
19.2.2. 
Approval by an IRB/REB/IEC 
For Investigational New Drug (IND) studies, the minimum standards of conduct and 
requirements for informed consent are defined in the FDA regulations or the applicable 
regulations of the country in which the study is conducted. 
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. 
FDA Regulations 
Refer to the following United States Code of Federal Regulations (CFR):  
FDA Regulations 21 CFR Parts 50.20 - 50.27 
Subpart B - Informed Consent of Human Subjects 
FDA Regulations 21 CFR Parts 56.107 - 56.115 
Part 56-Institutional Review Boards 
Subpart B - Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records 
FDA Regulations 21 CFR Parts 312.50 - 312.70 
Subpart D - Responsibilities of Sponsors and Investigators 
 
 


Protocol CTH-301, Version 5.00 
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Confidential and Proprietary 
 
 
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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. 
 
 
 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
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


Page 3 
 
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  


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.5. 
APPENDIX V: Home Dosing Diary (Sample) 
 
CTH-301 Dosing Diary 
Date: _______________________ 
 
Instructions: Complete this diary on the 2 days prior to your next study visit. During these two days you will need 
to write down some information every time you treat an "OFF" episode with study medication  
• 
Write down the time you take the study medication. 
• 
Place a checkmark in the appropriate box if you are in a full "ON" state or are still in an "OFF" state 
exactly 30 minutes after taking the study medication. 
• 
Place a checkmark in the appropriate box describing the type of "OFF" you experienced prior to taking the 
study medication. 
• 
If you did not use your study medication on one of the diary days, please mark the date and check off N/A 
below. 
Full "ON" means a period of time where your medication is providing benefit with regard to mobility, stiffness and 
slowness and where you feel you can perform normal daily activities. This "ON" should feel the same or better than 
what you felt like when taking your normal Parkinson’s disease medications before starting the study. 
"OFF" means a period of time when medication has worn off and is no longer providing benefit with regard to 
mobility, slowness, and stiffness. 
 N/A – did not use study medication. 
Dosing Time 
"ON"/"OFF" 
Status 30 minutes 
after Dosing 
Type of "OFF" Experienced Prior to Dosing 
Date:  __________ 
Time: __________ 
 AM 
 PM 
 "ON" 
 "OFF" 
 You woke up feeling "OFF" 
 Your normal PD medication took too long to work 
 Your normal PD medication stopped working too early 
 Your normal PD medication didn’t work at all 
 Your normal PD medication suddenly stopped working 
Date:  __________ 
Time: __________ 
 AM 
 PM 
 "ON" 
 "OFF" 
 You woke up feeling "OFF" 
 Your normal PD medication took too long to work 
 Your normal PD medication stopped working too early 
 Your normal PD medication didn’t work at all 
 Your normal PD medication suddenly stopped working 
Date:  __________ 
Time: __________ 
 AM 
 PM 
 "ON" 
 "OFF" 
 You woke up feeling "OFF" 
 Your normal PD medication took too long to work 
 Your normal PD medication stopped working too early 
 Your normal PD medication didn’t work at all 
 Your normal PD medication suddenly stopped working 
Date:  __________ 
Time: __________ 
 AM 
 PM 
 "ON" 
 "OFF" 
 You woke up feeling "OFF" 
 Your normal PD medication took too long to work 
 Your normal PD medication stopped working too early 
 Your normal PD medication didn’t work at all 
 Your normal PD medication suddenly stopped working 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
 
19.6. 
APPENDIX VI: 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  
12 
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) 
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                  


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.7. 
APPENDIX VII: Parkinson’s Disease Questionnaire (PDQ-39) 
 
 
 


 
PDQ-39 © Copyright, Isis Innovation Limited 1993. All Rights Reserved. 
The authors, being Professor Crispin Jenkinson, Professor Ray Fitzpatrick and Ms Viv Peto, have asserted their moral rights. 
Parkinson’s Disease Quality of Life Questionnaire  
(PDQ-39) 
Due to having Parkinson’s disease,  
how often during the last month have you… 
Please tick one box for each question 
 
Never 
Occasionally Sometimes 
Often 
Always  
or cannot  
do at all 
1. 
Had difficulty doing the leisure 
activities which you would like  
to do? 
 
 
 
 
 
 
2. 
Had difficulty looking after your home, 
e.g. DIY, housework, cooking? 
 
 
 
 
 
 
3. 
Had difficulty carrying bags of 
shopping? 
 
 
 
 
 
 
4. 
Had problems walking half a mile? 
 
 
 
 
 
 
5. 
Had problems walking 100 yards? 
 
 
 
 
 
 
6. 
Had problems getting around the 
house as easily as you would like? 
 
 
 
 
 
 
7. 
Had difficulty getting around in 
public? 
 
 
 
 
 
 
8. 
Needed someone else to accompany 
you when you went out? 
 
 
 
 
 
 
 
 
Please check that you have ticked one box for each question before going onto the next page. 


 
PDQ-39 © Copyright, Isis Innovation Limited 1993. All Rights Reserved. 
The authors, being Professor Crispin Jenkinson, Professor Ray Fitzpatrick and Ms Viv Peto, have asserted their moral rights. 
 
Due to having Parkinson’s disease,  
how often during the last month have you… 
Please tick one box for each question 
 
Never 
Occasionally Sometimes 
Often 
Always  
or cannot  
do at all 
9. 
Felt frightened or worried about 
falling over in public? 
 
 
 
 
 
 
10. Been confined to the house more 
than you would like? 
 
 
 
 
 
 
11. Had difficulty washing yourself? 
 
 
 
 
 
 
12. Had difficulty dressing yourself? 
 
 
 
 
 
 
13. Had problems doing up buttons  
or shoe laces? 
 
 
 
 
 
 
14. Had problems writing clearly? 
 
 
 
 
 
 
15. Had difficulty cutting up your food?  
 
 
 
 
 
16. Had difficulty holding a drink 
without spilling it? 
 
 
 
 
 
 
17. Felt depressed? 
 
 
 
 
 
 
18. Felt isolated and lonely? 
 
 
 
 
 
 
 
 
Please check that you have ticked one box for each question  
before going onto the next page. 


 
PDQ-39 © Copyright, Isis Innovation Limited 1993. All Rights Reserved. 
The authors, being Professor Crispin Jenkinson, Professor Ray Fitzpatrick and Ms Viv Peto, have asserted their moral rights. 
 
Due to having Parkinson’s disease,  
how often during the last month have you… 
Please tick one box for each question 
 
Never 
Occasionally Sometimes 
Often 
Always 
19. Felt weepy or tearful? 
 
 
 
 
 
 
20. Felt angry or bitter? 
 
 
 
 
 
 
21. Felt anxious? 
 
 
 
 
 
 
22. Felt worried about your future? 
 
 
 
 
 
 
23. Felt you had to conceal your 
Parkinson’s from people? 
 
 
 
 
 
 
24. Avoided situations which involve 
eating or drinking in public? 
 
 
 
 
 
 
25. Felt embarrassed in public due to 
having Parkinson’s disease? 
 
 
 
 
 
 
26. Felt worried by other people’s 
reaction to you? 
 
 
 
 
 
 
27. Had problems with your close 
personal relationships? 
 
 
 
 
 
 
 
 
Please check that you have ticked one box for each question  
before going onto the next page. 


 
PDQ-39 © Copyright, Isis Innovation Limited 1993. All Rights Reserved. 
The authors, being Professor Crispin Jenkinson, Professor Ray Fitzpatrick and Ms Viv Peto, have asserted their moral rights. 
 
Due to having Parkinson’s disease,  
how often during the last month have you… 
Please tick one box for each question 
 
Never 
Occasionally Sometimes 
Often 
Always 
28. 
Lacked support in the ways you 
need from your spouse or partner? 
If you do not have a spouse  
or partner, please tick here  
 
 
 
 
 
 
 
29. 
Lacked support in the ways you 
need from your family or close 
friends? 
 
 
 
 
 
 
30. Unexpectedly fallen asleep during 
the day? 
 
 
 
 
 
 
31. 
Had problems with your 
concentration, e.g. when reading  
or watching TV? 
 
 
 
 
 
 
32. Felt your memory was bad? 
 
 
 
 
 
 
33. Had distressing dreams or 
hallucinations? 
 
 
 
 
 
 
34. Had difficulty with your speech? 
 
 
 
 
 
 
35. Felt unable to communicate with 
people properly? 
 
 
 
 
 
 
 
 
Please check that you have ticked one box for each question  
before going onto the next page. 


 
PDQ-39 © Copyright, Isis Innovation Limited 1993. All Rights Reserved. 
The authors, being Professor Crispin Jenkinson, Professor Ray Fitzpatrick and Ms Viv Peto, have asserted their moral rights. 
 
Due to having Parkinson’s disease,  
how often during the last month have you… 
Please tick one box for each question 
 
Never 
Occasionally Sometimes 
Often 
Always 
36. Felt ignored by people? 
 
 
 
 
 
 
37. Had painful muscle cramps or 
spasms? 
 
 
 
 
 
 
38. Had aches and pains in your joints 
or body? 
 
 
 
 
 
 
39. Felt unpleasantly hot or cold? 
 
 
 
 
 
 
 
 
Please check that you have ticked one box for each question. 
 
Thank you for completing the questionnaire. 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.8. 
APPENDIX VIII: Clinical Global Impression (CGI) 
 
Screening # _____________ Site #_________ Investigator: _______________ 
 
CGI - Severity (baseline assessment) 
Considering your total clinical experience with this particular population, how ill is the patient at 
this time? 
1 = normal/not at all ill 
2 = borderline ill 
3 = mildly ill 
4 = moderately ill 
5 = markedly ill 
6 = severely ill 
7 = among the most extremely ill of patients 
 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
 
Screening # _____________ Site #_________ Investigator: _______________ 
 
CGI - Improvement (subsequent assessments) 
Compared to his/her condition on baseline, how much has he/she changed? 
1 = very much improved 
2 = much improved 
3 = minimally improved 
4 = no change 
5 = minimally worse 
6 = much worse 
7 = very much worse 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.9. 
APPENDIX IX: Patient Global Impression (PGI) 
 
Screening # _____________ Site #_________ Investigator: _______________ 
 
PGI – Severity (baseline assessment) 
Ask the patient: “How would you rate your illness at this time”. 
1 = normal/not at all ill 
2 = borderline ill 
3 = mildly ill 
4 = moderately ill 
5 = markedly ill 
6 = severely ill 
7 = among the most extremely ill of patients 
 
 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
 
Screening # _____________ Site #_________ Investigator: _______________ 
 
PGI – Change/Improvement (subsequent assessments) 
Ask the patient: “Since starting study medication, how has your illness changed?”  
1 = very much improved 
2 = much improved 
3 = minimally improved 
4 = No change 
5 = minimally worse 
6 = much worse 
7 = very much worse 
 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.10. 
APPENDIX X: Epworth Sleepiness Scale (ESS) 
 
 


Epworth Sleepiness Scale 
 
 
Name: ______________________________________________ Today’s date: _________________ 
 
Your age (Yrs): _______________ Your  sex (Male = M, Female = F): ________ 
 
 
How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just 
tired? 
 
This refers to your usual way of life in recent times. 
 
Even if you haven’t done some of these things recently try to work out how they would have affected 
you. 
 
Use the following scale to choose the most appropriate number for each situation: 
           
0  =  would never doze 
1  =  slight chance of dozing 
2  =  moderate chance of dozing 
3  =  high chance of dozing 
 
It is important that you answer each question as best you can. 
 
Situation 
 
 
 
 
 
 
 
Chance of Dozing (0-3) 
 
 
 
Sitting and reading        ________________________________________ 
  
 
Watching TV                ________________________________________ 
 
 
Sitting, inactive in a public place (e.g. a theatre or a meeting)    _________ 
 
 
As a passenger in a car for an hour without a break    _________________  
 
Lying down to rest in the afternoon when circumstances permit   ________  
 
Sitting and talking to someone   __________________________________ 
 
 
Sitting quietly after a lunch without alcohol   ________________________  
 
In a car, while stopped for a few minutes in the traffic  ________________ 
 
 
 
 
THANK YOU FOR YOUR COOPERATION 
 
 
¤ M.W. Johns  1990-97 
 
 
___ 
 
___ 
 
___ 
 
___ 
 
___ 
 
___ 
 
___ 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.11. 
APPENDIX XI: Zarit Burden Interview (ZBI) 
 
 
 


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Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.12. 
APPENDIX XII: Questionnaire for Impulsive-Compulsive Disorders 
in Parkinson’s Disease – Rating Scale (QUIP-RS) 
 
 


QUIP-RATING SCALE 
Version 1.0 (7/01/09) 
Copyright © University of Pennsylvania 2009 
 
1
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale 
(QUIP-RS) 
 
Reported by:  
_____ Patient  
_____ Informant 
 
_____ Patient and Informant 
  
Patient / Subject: 
__________________________________________ 
Date:  
 
__________________________________________ 
 
 
 
 
 
1. How much do you think about the following behaviors (such as having trouble keeping thoughts out of your mind or 
feeling guilty)? 
Gambling?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
 
2. Do you have urges or desires for the following behaviors that you feel are excessive or cause you distress (including 
becoming restless or irritable when unable to participate in them)?  
 
Gambling?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
 
3. Do you have difficulty controlling the following behaviors (such as increasing them over time, or having trouble cutting 
down or stopping them)?  
Gambling?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
 
 
4. Do you engage in activities specifically to continue the following behaviors (such as hiding what you are doing, lying, 
hoarding things, borrowing from others, accumulating debt, stealing, or being involved in illegal acts)?   
Gambling?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
 
 


QUIP-RATING SCALE 
Version 1.0 (7/01/09) 
Copyright © University of Pennsylvania 2009 
 
2
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale 
(QUIP-RS) 
 
Subject: 
 
__________________________________________ 
Date:  
 
__________________________________________ 
 
 
SCORING SHEET 
 
A.  Gambling  
 
 
______ 
(0-16) 
B.  Sex 
 
 
 
______ 
(0-16) 
C.  Buying  
 
 
 
______ 
(0-16) 
D.  Eating 
 
 
 
______ 
(0-16)  
E.  Hobbyism-Punding 
 
______ 
(0-32)  
F.  PD Medication Use 
 
______ 
(0-16) 
 
 
Total ICD Score (A-D) 
 
______ 
(0-64) 
 
Total QUIP-RS Score (A-F)  
______ 
(0-112) 
 
 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.13. 
APPENDIX XIII: European Quality of Life – 5 Dimensions (EQ-5D) 
 
 
 
 
 




 
Page | 8 
 
 
 
 
 
We would like to know how good or bad your health is TODAY. 
 
This scale is numbered from 0 to 100. 
 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
Mark an X on the scale to indicate how your health is TODAY.  
 
Now, please write the number you marked on the scale in the box below.  
                     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAMPLE
YOUR HEALTH TODAY=


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.14. 
APPENDIX XIV: United Kingdom Parkinson’s Disease Brain Bank 
Clinical Diagnostic Criteria 
Step 1 - Diagnosis of Parkinsonian Syndrome 
• Bradykinesia 
• At least one of the following: 
− Muscular rigidity 
− 4-6 Hz rest tremor 
− 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 
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 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
• 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. 


Protocol CTH-301, Version 5.00 
APL-130277 
Confidential and Proprietary 
 
 
25 February 2019 
19.15. 
APPENDIX XV: Ease of Use Questionnaire  
CTH-301 Ease of Use Questionnaire 
Date: _______________________ 
Instructions:  
Please base your response on your experience over your entire time in the study.  
Under each heading, please tick the ONE box that best describes your assessment of the 
medication and its use. 
OPENING THE PACKAGE 
Very easy to open 
 
Easy to open 
 
Neither easy nor difficult to open 
 
Difficult to open 
 
Very difficult to open 
 
 
HANDLING 
Very easy to handle 
 
Easy to handle 
 
Neither easy nor difficult to handle 
 
Difficult to handle 
 
Very difficult to handle 
 
 
DOSING 
Very easy to dose myself 
 
Easy to dose myself 
 
Neither easy nor difficult to dose myself 
 
Difficult to dose myself 
 
Very difficult to dose myself 
 
 
 

SAP_001.pdf: 
This document is confidential. 
SAP Version:Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 1 of 60 
Statistical Analysis Plan 
Sponsor Name: Sunovion Pharmaceuticals Inc. 
Protocol Number: CTH-301 
Protocol Title: An Open-Label, Phase 3 Study Examining the Long-Term Safety, Tolerability and 
Efficacy of APL-130277 in Levodopa Responsive Patients with Parkinson’s Disease 
Complicated by Motor Fluctuations (“OFF” Episodes) 
Protocol Version and Date:  
Original/Version 1.0 - All Sites (30 December 2014)  
Amendment/Version 2.0 - All Sites (18 July 2015)  
Amendment/Version 3.0 - US Specific (27 October 2015)  
Amendment/Version 3.1 - UK Specific (13 May 2016)  
Amendment/Version 4.0 - US Specific (30 May 2017)  
Amendment/Version 4.10A - UK Specific (22 September 2017)  
Amendment/Version 4.00B - Europe Specific (22 September 2017) 
Amendment/Version 5.0 - US Specific (25 February 2019)  
Amendment/Version 5.00A - UK Specific (25 February 2019)  
Amendment/Version 5.00B - Europe Specific (25 February 2019)  
Syneos Health Project Code: 1005892 
Authors: 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Sunovion Pharmaceuticals Inc. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Sunovion 
Pharmaceuticals Inc.. However, this document may be disclosed to appropriate Institutional Review Board 
and Ethics Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential. In the event of an actual or suspected breach of 
this obligation, Syneos Health should be notified promptly. 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 2 of 60 
Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
30-Sep-2021 
 
Final version 1.0 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 3 of 60 
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
 Principal 
Biostatistician 
Name, Title 
Lead  Biostatistician 
Signature 
Date (DD-Mmm-YYYY) 
Associate Director, Biostatistics 
Name, Title 
Signature 
Date (DD-Mmm-YYYY) 
Sunovion Pharmaceuticals, Inc. Approval 
Executive Director
Name, Title 
Sponsor Contact 
Signature 
Date (DD-Mmm-YYYY) 
Sr. Director, Biostatistics 
Name, Title 
Sponsor Contact 
Signature 
Date (DD-Mmm-YYYY) 
Associate Director, Biostatistics 
Name, Title 
Sponsor Contact 
Signature 
Date (DD-Mmm-YYYY) 
'
Oct 6, 2021
Oct 6, 2021


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Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 8 of 60 
Abbreviation 
Description 
LTS 
Long-Term Safety 
λz 
Terminal-Phase Rate Constant 
MAA 
Marketing Authorization Application 
MDS-UPDRS 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
M/P 
Ratios Metabolite to Parent Ratio Of AUC and Cmax 
MRT 
Mean Residence Time 
MMSE 
Mini-Mental State Examination 
OH 
Orthostatic Hypotension 
PD 
Parkinson’s Disease 
PDQ-39 
Parkinson’s Disease Questionnaire 
PGI-I 
Patient Global Impression of Improvement 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale 
Rollover Subjects 
Subjects Who Have Previously Completed Any of the Following 
Studies: CTH-201, CTH-203, CTH-300, or CTH-302 
RR 
Respiratory Rate 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SI 
International System of Units 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
t½ 
Terminal-Phase Half-Life 
TEAEs 
Treatment-Emergent Adverse Events 
TFL 
Tables, Figures, Listings 
tmax 
Observed Time Of The Maximum Concentration 
WHO-DD 
World Health Organization Drug Dictionary 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 9 of 60 
Abbreviation 
Description 
ZBI 
Zarit Burden Interview 


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Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 13 of 60 
 
    c. Long-Term Safety Visit 9 (LTS V9) 
    d. Telephone Call (T6 to T8) 
    e. Unscheduled Dose Adjustment Visits 
5. Long-Term Safety (LTS) Phase Year 3 (All Subjects) 
    a. Long-Term Safety Visit 10 (LTS V10) 
    b. Long-Term Safety Visit 11 (LTS V11) 
    c. Long-Term Safety Visit 12 (LTS V12) 
    d. Telephone Call (T9 to T11) 
    e. Unscheduled Dose Adjustment Visits 
6. Long-Term Safety (LTS) Phase Year 4 (All Subjects) 
    a. Long-Term Safety Visit 13 (LTS V13) 
    b. Long-Term Safety Visit 14 (LTS V14) 
    c. Long-Term Safety Visit 15 (LTS V15) 
    d. Telephone Call (T12 to T14) 
    e. Unscheduled Dose Adjustment Visits 
7. Long-Term Safety (LTS) Phase Year 5 (All Subjects) 
    a. Long-Term Safety Visit 16 (LTS V16) 
    b. Long-Term Safety Visit 17 (LTS V17) 
    c. Long-Term Safety Visit 18 (LTS V18) 
    d. Telephone Call (T15 to T17) 
    e. Unscheduled Dose Adjustment Visits  
Note: Subjects may participate in the study until the Sponsor terminates the study, or until 
commercial availability of APL-130277 in the subject’s country.  If a subject continues in the 
study beyond LTS Phase Year 5, the protocol will be amended to accommodate additional in 
clinic visits every 4 months (16 weeks). 
8. Early Termination Visit (All subjects) 


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Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 15 of 60 
 
For De novo subjects, at all titration visits, at the discretion of the subject and/or Investigator, the next 
highest dose may be evaluated at a subsequent titration visit following a full "ON" response in order to 
assess the potential for the next highest dose in inducing an improved full "ON" response. If this dose 
produces an improved "ON" response relative to the lower dose without impacting subject safety and 
tolerability, the higher dose will be used during the LTS Phase of the study. If the "ON" response is the 
same or worse, or this higher dose is not well-tolerated, the previous dose will be used during the LTS 
Phase of the study. 
The study procedures and flow chart differ slightly for each protocol amendment. Also, they are slightly 
different among region specific versions. Below is a summary of study procedures and flow chart 
differences comparing with protocol amendment v5.00. 
US Specific 
UK Specific 
Europe Specific 
v5.00 (25 February 2019) 
v5.00A (25 February 2019) 
v5.00B (25 February 2019) 
v4.0 (30 May 2017) 
v4.10A (22 September 2017) 
v4.00B (22 September 2017) 
v3.0 (27 October 2015) 
v3.1 (13 May 2016) 
 
v2.0 (18 July 2015) 
 
 
v1.0 (30 December 2014) 
 
 
 
V5.00 US Specific 
De Novo subjects will be required to attend 2 screening visits with informed consent obtained at the initial 
screening visit. All eligible subjects will be asked to return to the clinic in the morning of Titration Visit 1 
(TV1) for the Dose Titration Phase of the study. After the dose is selected, subjects will continue with LTS 
visits. 
Rollover subjects directly enter the LTS phase starting with LTS V1 after completing screening. 
CTH-301 completers directly enter the LTS phase starting with LTS V7 after completing screening. 
V5.00A UK Specific 
All subjects are rollover subjects who will come into the study after completing study CTH-302. After 
completing screening, subjects will go directly to the LTS phase. 
V5.00B Europe Specific 
All subjects are rollover subjects who will come into the study after completing study CTH-302. After 
completing screening, subjects will go directly to the LTS phase. 
V4.0 for US Specific 
Same as V5.00 
V4.10A UK Specific 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 16 of 60 
 
Same as V5.00. Study flow based on general design for all subjects (De Novo, rollover, and CTH-301 
completers) 
V4.00B Europe Specific 
Same as V5.00. Study flow based on general design for all subjects (De Novo, rollover, and CTH-301 
completers) 
V3.0 US  
Rollover subject specifically refers to CTH-300 rollover. 
Rollover subject required to begin with Titration phase and then proceed to LTS phase. 
V3.1 UK Specific 
Same as V3.10 UK specific.  
Rollover subject specifically refers to CTH-300 rollover. 
Rollover subject required to begin with Titration phase and then proceed to LTS phase. 
V2.0 
Same as V3.10 UK specific.  
V1.0 
Only has 1 screening visit for all subjects. 
 


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Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 31 of 60 
 
• 
TEAEs by SOC, PT and maximum severity; percentages will be calculated for the subject count out 
of total number of subjects 
• 
TEAEs by SOC, PT, and relationship as event counts, percentages will be calculated for the event 
count out of total number of events 
• 
Serious TEAEs by SOC, PT by overall and region (NA vs Europe), both as event and subject counts 
• 
TEAEs leading to drug withdrawal by SOC, PT by overall and region (NA vs Europe), both as event 
and subject counts  
• 
TEAEs leading to drug interruption by SOC and PT, both as event and subject counts 
• 
TEAEs leading to dose reduction by SOC, PT by overall and region (NA vs Europe), both as event 
and subject counts 
• 
TEAEs leading to death by SOC, PT by overall and region (NA vs Europe), both as event and subject 
counts  
The tables will be sorted by alphabetically SOC and then, within a SOC, by overall descending frequency 
of PT based on the overall subject count. If only event count is presented, the sorting will be done based 
on the event count.   
An exposure adjusted incidence rate table will be provided for TEAEs by SOC and PT. The exposure years 
censored will be computed as the time in years to first event for a subject or total exposure if no event for 
each SOC and PT. The exposure adjusted incidence rate is calculated as the number of subjects with the 
event / exposure years censored. The exposure adjusted incidence rate will also be provided for TEAEs of 
special interest. 
Separate summaries will be generated for TEAEs of special interest, tabulated by category and PT using 
the categories as specified below: 
– 
Hypotension, orthostatic hypotension: defined as all TEAEs with HLGT “decreased and non-
specific blood pressure disorders and shock” 
– 
Syncope: defined as all TEAEs  with any of the following PTs  
• 
“Hypotonic-hyporesponsive episode” (MedDRA code 10021121) 
• 
“Altered state of consciousness” (MedDRA code 10001854) 
• 
“Depressed level of consciousness” (MedDRA code 10012373) 
• 
“Hypokinesia” (MedDRA code 10021021) 
• 
“Hypokinesia neonatal” (MedDRA code 10021022) 
• 
“Hyporesponsive to stimuli” (MedDRA code 10071552) 
• 
“Loss of consciousness” (MedDRA code 10024855) 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 32 of 60 
 
• 
“Neurogenic shock” (MedDRA code 10058119) 
• 
“Presyncope” (MedDRA code 10036653) 
• 
“Shock” (MedDRA code 10040560) 
• 
“Shock symptom” (MedDRA code 10040581) 
• 
“Syncope” (MedDRA code 10042772) 
• 
“Unresponsive to stimuli” (MedDRA code 10045555) 
Or HLGT of “Seizures (incl subtypes)” 
– 
Falls & injuries: defined as all TEAEs meeting the criteria for the standardized MedDRA Query 
(SMQ) “Accidents and injuries” (narrow terms) 
– 
Dyskinesias: defined as all TEAEs meeting the criteria for the SMQ “Dyskinesia” (narrow terms) 
– 
Hallucinations and psychotic behaviors: defined as all TEAEs meeting the criteria for the SMQ 
“Psychosis & psychotic disorders” (narrow terms) 
– 
Impulse control disorders: defined as all TEAEs meeting the following criteria.  
• 
HLT “Impulse Control Disorders” 
• 
HLT “Paraphilia and paraphilic disorders” or “Sexual desire disorders” 
• 
Binge eating: PT “Binge Eating” (MedDRA code 10004716) 
• 
Gambling: PT “Gambling” (MedDRA code 10017655) or Gambling Disorder (MedDRA code 
10078070) 
• 
Compulsive shopping: PT “Compulsive shopping” (MedDRA code 10067948) or any TEAE with 
verbatim term including the text “spending” 
– 
Daytime sudden onset of sleep: defined as all TEAEs with HLGT “Sleep disorders and 
disturbances” or the PT “Sudden onset of sleep” 
– 
QT prolongation and ventricular arrhythmias: defined as all TEAEs meeting the criteria for the SMQ 
“Torsade de pointes /QT prolongation” (broad terms) 
– 
Acute Coronary Syndrome, Myocardial infarction, Angina: defined as all TEAEs meeting the criteria 
for the SMQ “Myocardial infarction” (broad terms) 
– 
Suicidal ideation & attempts: defined as all TEAEs meeting the criteria for the SMQ “Suicide/self-
injury” (narrow terms) 
– 
Melanoma: defined as all TEAEs meeting the criteria for the SMQ “Skin malignant tumors” (narrow 
terms) 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 33 of 60 
 
– 
Stomatitis, Oral ulcers, Oral irritation: defined as all TEAEs meeting the criteria for the SMQ 
“Oropharyngeal disorders” (narrow terms) 
– 
Allergic/sensitivity response to the formulation: defined as all TEAEs meeting the broad criteria for 
the SMQ “Hypersensitivity” (broad terms) 
– 
Serious TEAEs of special interest by category and PT, both as event and subject counts 
– 
TEAEs of special interest leading to drug withdrawal by category and PT, both as event and subject 
counts  
– 
TEAEs of special interest by category, PT and Actual Dose Received, both as event and subject 
counts 
Separate summaries will be also be generated for TEAEs  associated with the topics below 
− 
Withdrawal-emergent Neuroleptic Malignant Syndrome: defined as MedDRA PTs of Hyperthermia 
malignant, Neuroleptic malignant syndrome, and Serotonin syndrome. 
− 
Dopamine Agonist Withdrawal Syndrome: defined as MedDRA PTs of Drug withdrawal syndrome, 
Withdrawal syndrome, or Therapy cessation, plus at least one of the following: Agitation, Anxiety, 
Depression, Fatigue, Hyperhidrosis, Dizziness, Drug dependence, Flushing, Panic attack, 
Insomnia, Irritability, Nausea, Vomiting, Orthostatic hypotension, and Pain. 
− 
Dopamine Dysregulation Syndrome: defined using the search criteria in Appendix 15.2 
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 whether an AE is treatment-emergent:  
• 
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 same as month of first dose date of study treatment. If 
yes, impute to first dose date of study treatment; else impute first day of the month. 
• 
If the start day and month are missing: Check if year is same as the year of the first dose date of 
study treatment. If yes, impute to first dose date of study treatment; else impute to first day of the 
first month (January). 
If the AE stop date is partial, then it will be imputed as follows:  
• 
If the stop date is completely missing and the AE is not ongoing, the stop date will be equal to the 
last dose date or date of completion/withdrawal, whichever is the latest.  


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 34 of 60 
 
• 
If the stop day is missing, the last day of the month will be used. If resulted imputed stop date is after 
the latest of last dose date or date of completion/withdrawal, then the latest of last dose date or date 
of completion/withdrawal will be used.  
• 
If the stop day and month are missing, then the last day of the last month (December) will be used. 
If resulted imputed stop date is after the latest of last dose date or date of completion/withdrawal, 
then the latest of last dose date or date of completion/withdrawal will be used. 
The original date and time will be shown on all listings of AEs. Listings will be provided for all AEs, serious 
AEs, serious TEAEs, TEAEs leading to death, TEAEs leading to drug withdrawal, and TEAEs of special 
interest. The listings will display study day, calculated as the AE start date – date of first dose in the relevant 
study phase (Dose Titration or LTS 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. 
Oropharyngeal adverse event cluster analysis will be provided by enrollment group and overall. Treatment 
emergent adverse events will be tabulated by cluster and individual PT using the clusters specified in 
Appendix 15.1. TEAE cluster summaries will be presented both for the Titration Full Analysis Set and for 
the LTS Full Analysis Set, unless specified otherwise. TEAE cluster summaries will be presented by 
severity, leading to drug withdrawal, and actual dose received at AE onset. Summaries by PT and actual 
dose received at AE Onset during LTS Phase will also be provided by region (NA vs Europe).  An exposure 
adjusted incidence rate table will be provided for oropharyngeal AE clusters by PT. The exposure years 
censored will be computed as the time in years to first event for a subject or total exposure if no event for 
each cluster and PT. The exposure adjusted incidence rate is calculated as the number of subjects with the 
event / exposure years censored.  
Kaplan-Meier curves will be used to illustrate the time to first onset of each cluster event (days) with 
frequency > 10% and overall (any oral cluster event). For a given subject, the first onset date across the 
relevant individual cluster events will be used for this analysis. For censored subjects without an event at 
at the time of analysis, end of study date for the subjects who completed the study or data cut-off date for 
on-going subjects  will be used as the censoring date. These plots will be presented by enrollment group 
and will also be provided by region (NA vs Europe) for the Titration and LTS Full Analysis Sets and safety 
population. 
Prevalence plots display the percentage of the subjects who are experiencing a cluster event during a 
specific interval of time. In the plot, the time intervals (treatment weeks) are shown on the horizontal axis.  
Time zero corresponds to first dose of treatment received. On the vertical axis, the percentage of subjects 
with an adverse event cluster within each time interval is shown. The event may span multiple intervals 
depending on its duration. Ongoing events are counted in each time interval in which they occur to assess 
the prevalence of the event over time. For cluster events which are ongoing at study completion or ongoing 
at the time of analysis, end of study date for that subject or data cut-off date respectively was used to 
calculate duration of event. 
Each bar displays the total percentage of subjects with an event in each weekly time interval. The number 
of subjects at risk at the beginning of each weekly interval is shown in the bottom row of the figure and is 
the denominator for the percentage calculation. Subjects who drop-out of the study prior to a given time 
interval are removed from the risk set (denominator) for that interval. Within each bar, the different shading 


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Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 45 of 60 
 
• All footnotes will be left justified with single-line spacing immediately below the solid line underneath 
the data display. 
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footnote. Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
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footnotes are planned, then a cover page is strongly recommended to be used to display footnotes, 
and only those essential to comprehension of the data will be repeated on each page.  
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


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Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 49 of 60 
 
Cluster 
Term 
Oral pruritus 
Oral submucosal fibrosis 
Parotid gland enlargement 
PFAPA syndrome 
Pharyngeal exudate 
Sjogren's syndrome 
Tongue pruritus 
Oropharyngeal discoloration 
Gingival discolouration 
Gingival hyperpigmentation 
Leukoplakia oral 
Oral mucosal discolouration 
Oral pigmentation 
Oropharyngeal plaque 
Tongue discolouration 
Oral leukoedema 
Tongue pigmentation 
Oropharyngeal infections 
Abscess of salivary gland 
Abscess oral 
Acute postoperative sialadenitis 
Adenoiditis 
Angina gangrenous 
Aspergillosis oral 
Bacterial parotitis 
Cellulitis pharyngeal 
Chronic tonsillitis 
Foot and mouth disease 
Gingival abscess 
Hand-foot-and-mouth disease 
Herpangina 
Herpes pharyngitis 
Herpes simplex pharyngitis 
Herpes zoster pharyngitis 
Infective glossitis 
Laryngitis 
Lip infection 
Ludwig angina 
Mumps 
Necrotising ulcerative gingivostomatitis 
Necrotising ulcerative periodontitis 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 50 of 60 
 
Cluster 
Term 
Oral bacterial infection 
Oral candidiasis 
Oral fungal infection 
Oral helminthic infection 
Oral herpes 
Oral infection 
Oral pustule 
Oral tuberculosis 
Oral viral infection 
Oro-pharyngeal aspergillosis 
Oropharyngeal candidiasis 
Oropharyngeal gonococcal infection 
Oropharyngitis fungal 
Parotid abscess 
Peritonsillar abscess 
Peritonsillitis 
Pharyngeal abscess 
Pharyngeal chlamydia infection 
Pharyngitis 
Pharyngitis bacterial 
Pharyngitis mycoplasmal 
Pharyngitis streptococcal 
Pharyngoconjunctival fever of children 
Pharyngotonsillitis 
Salivary gland induration 
Staphylococcal parotitis 
Staphylococcal pharyngitis 
Strawberry tongue 
Subglottic laryngitis 
Tongue abscess 
Tongue fungal infection 
Tonsillar exudate 
Tonsillitis 
Tonsillitis bacterial 
Tonsillitis fungal 
Tonsillitis streptococcal 
Tonsillolith 
Uvulitis 
Viral parotitis 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 51 of 60 
 
Cluster 
Term 
Viral pharyngitis 
Viral tonsillitis 
Oropharyngeal mass / neoplasm 
Acinic cell carcinoma of salivary gland 
Adenocarcinoma of salivary gland 
Adenoid cystic carcinoma of salivary gland 
Benign salivary gland neoplasm 
Buccal polyp 
Carcinoma ex-pleomorphic adenoma 
Epiglottic carcinoma 
Epiglottic cyst 
Epiglottic mass 
Epulis 
Giant cell epulis 
Gingival cancer 
Gingival cyst 
Gingival polyp 
Leukoplakia 
Lip and/or oral cavity cancer 
Lip and/or oral cavity cancer recurrent 
Lip and/or oral cavity cancer stage 0 
Lip and/or oral cavity cancer stage I 
Lip and/or oral cavity cancer stage II 
Lip and/or oral cavity cancer stage III 
Lip and/or oral cavity cancer stage IV 
Malignant palate neoplasm 
Melanoplakia oral 
Metastases to mouth 
Metastases to pharynx 
Metastases to salivary gland 
Metastases to tonsils 
Metastatic salivary gland cancer 
Mouth cyst 
Mucoepidermoid carcinoma of salivary gland 
Oral cavity cancer metastatic 
Oral fibroma 
Oral haemangioma 
Oral hairy leukoplakia 
Oral neoplasm 
Oral neoplasm benign 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 52 of 60 
 
Cluster 
Term 
Oral papilloma 
Oropharyngeal cancer 
Oropharyngeal cancer recurrent 
Oropharyngeal cancer stage 0 
Oropharyngeal cancer stage I 
Oropharyngeal cancer stage II 
Oropharyngeal cancer stage III 
Oropharyngeal cancer stage IV 
Oropharyngeal lymphoepithelioma 
Oropharyngeal neoplasm 
Oropharyngeal neoplasm benign 
Oropharyngeal squamous cell carcinoma 
Papillary cystadenoma lymphomatosum 
Pharyngeal cancer 
Pharyngeal cancer metastatic 
Pharyngeal cancer recurrent 
Pharyngeal cancer stage 0 
Pharyngeal cancer stage I 
Pharyngeal cancer stage II 
Pharyngeal cancer stage III 
Pharyngeal cancer stage IV 
Pharyngeal cyst 
Pharyngeal leukoplakia 
Pharyngeal mass 
Pharyngeal neoplasm 
Pharyngeal neoplasm benign 
Pharyngeal polyp 
Pleomorphic adenoma 
Salivary gland adenoma 
Salivary gland cancer 
Salivary gland cancer recurrent 
Salivary gland cancer stage 0 
Salivary gland cancer stage I 
Salivary gland cancer stage II 
Salivary gland cancer stage III 
Salivary gland cancer stage IV 
Salivary gland neoplasm 
Squamous cell carcinoma of pharynx 
Squamous cell carcinoma of the oral cavity 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 53 of 60 
 
Cluster 
Term 
Squamous cell carcinoma of the tongue 
Throat cancer 
Tongue cancer metastatic 
Tongue cancer recurrent 
Tongue carcinoma stage 0 
Tongue carcinoma stage I 
Tongue carcinoma stage II 
Tongue carcinoma stage III 
Tongue carcinoma stage IV 
Tongue cyst 
Tongue dysplasia 
Tongue neoplasm 
Tongue neoplasm benign 
Tongue neoplasm malignant stage unspecified 
Tongue polyp 
Tonsil cancer 
Tonsil cancer metastatic 
Tonsillar cyst 
Tonsillar neoplasm 
Tonsillar neoplasm benign 
Oropharyngeal numbness / 
changes in sensation 
Dysaesthesia pharynx 
Hypoaesthesia oral 
Oral dysaesthesia 
Oral hyperaesthesia 
Paraesthesia oral 
Pharyngeal hypoaesthesia 
Pharyngeal paraesthesia 
Oropharyngeal pain 
Burn oral cavity 
Burning mouth syndrome 
Burning sensation 
Gingival discomfort 
Gingival pain 
Glossodynia 
Lip pain 
Odynophagia 
Oropharyngeal discomfort 
Oral discomfort 
Oral pain 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 54 of 60 
 
Cluster 
Term 
Oropharyngeal pain 
Tongue discomfort 
Throat irritation 
Oropharyngeal ulcerations 
Angina bullosa haemorrhagica 
Angular cheilitis 
Aphthous ulcer 
Chapped lips 
Cheilitis 
Contact stomatitis 
Epiglottis ulcer 
Gingival erosion 
Gingival blister 
Gingival ulceration 
Lip blister 
Lip exfoliation 
Lip ulceration 
MAGIC syndrome 
Mouth ulceration 
Nicotinic stomatitis 
Oral mucosal blistering 
Oral mucosal eruption 
Palatal ulcer 
Pharyngeal enanthema 
Pharyngeal erosion 
Pharyngeal lesion 
Pharyngeal ulceration 
Oropharyngeal blistering 
Tongue blistering 
Tongue ulceration 
Tonsillar ulcer 
Stomatitis 
Stomatitis haemorrhagic 
Stomatitis necrotising 
Stomatitis radiation 
Oral mucosa erosion 
Oral mucosal exfoliation 
Sialometaplasia 
Alterations in taste 
Ageusia 
Dysgeusia 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 55 of 60 
 
Cluster 
Term 
Hypogeusia 
Salivary complaints and oral 
Aptyalism 
Dry mouth 
Dry throat 
Lip dry 
Noninfective sialoadenitis 
Ranula 
Saliva altered 
Saliva discolouration 
Salivary duct inflammation 
Salivary duct obstruction 
Salivary duct stenosis 
Salivary gland atrophy 
Salivary gland calculus 
Salivary gland cyst 
Salivary gland disorder 
Salivary gland enlargement 
Salivary gland fistula 
Salivary gland mass 
Salivary gland mucocoele 
Salivary gland pain 
Salivary hypersecretion 
Sialoadenitis 
Tongue dry 
Foaming at mouth 
Sordes 
Tongue coated 
Dental complaints 
Dental caries 
Periodontal destruction 
Periodontal disease 
Periodontal inflammation 
Pulpitis dental 
Sensitivity of teeth 
Tooth abscess 
Tooth discolouration 
Tooth fracture 
Tooth infection 
Tooth loss 
Trauma 
Chronic cheek biting 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 56 of 60 
 
Cluster 
Term 
Corrosive oropharyngeal injury 
Gingival bleeding 
Gingival injury 
Lip injury 
Mouth injury 
Mouth haemorrhage 
Oral contusion 
Oral mucosa haematoma 
Pharyngeal injury 
Pharynx radiation injury 
Radiation salivary gland injury 
Tongue biting 
Tongue injury 
Traumatic ulcerative granuloma with stromal eosinophilia 
Other 
Acquired macroglossia 
Adenoidal disorder 
Adenoidal hypertrophy 
Ankyloglossia acquired 
Atrophic glossitis 
Auriculotemporal syndrome 
Buccoglossal syndrome 
Chronic throat clearing 
Coating in mouth 
Cobble stone tongue 
Exposed bone in jaw 
Gingival atrophy 
Gingival disorder 
Gingival hypertrophy 
Gingival hypoplasia 
Gingival pruritus 
Gingival recession 
Glossoptosis 
Hypertrophy of tongue papillae 
Mikulicz's disease 
Mikulicz's syndrome 
Oral allergy syndrome 
Oral cavity fistula 
Oral disorder 
Oral mucosa atrophy 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 57 of 60 
Cluster 
Term 
Oral mucosal hypertrophy 
Oral papule 
Oral toxicity 
Oropharyngeal cobble stone mucosa 
Oropharyngeal scar 
Palatal disorder 
Palatal dysplasia 
Palatal palsy 
Parotid duct obstruction 
Parotid gland haemorrhage 
Parotid lipomatosis 
Pharyngeal disorder 
Pharyngeal dyskinesia 
Pharyngeal fistula 
Pharyngeal haematoma 
Pharyngeal haemorrhage 
Pharyngeal hypertrophy 
Pharyngeal mucosa atrophy 
Pharyngeal necrosis 
Pharyngeal pouch 
Pharyngeal stenosis 
Plicated tongue 
Protrusion tongue 
Pyostomatitis vegetans 
Scalloped tongue 
Sialectasia 
Sialocele 
Sialogram abnormal 
Submaxillary gland enlargement 
Swallow study abnormal 
Throat lesion 
Tongue atrophy 
Tongue disorder 
Tongue eruption 
Tongue geographic 
Tongue haematoma 
Tongue haemorrhage 
Tongue infarction 
Tongue movement disturbance 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 58 of 60 
Cluster 
Term 
Tongue necrosis 
Tongue paralysis 
Tongue spasm 
Tonsillar atrophy 
Tonsillar disorder 
Tonsillar haemorrhage 
Tonsillar hypertrophy 
Velopharyngeal incompetence 
Appendix 15.2: Dopamine Dysregulation Syndrome Search Criteria 
1. MedDRA PT: Dopamine dysregulation syndrome OR
2. Any combination of the any selected PTs from the SMQ drug abuse and dependence PLUS
at least one of the PTs from group a, b, or c below.
Selected MedDRA PTs from the SMQ Drug abuse and dependence (broad): 
Drug abuse 
Drug abuser 
Drug dependence 
Drug use disorder 
Intentional overdose 
Intentional product misuse 
Substance abuse 
Substance abuser 
Substance dependence 
Substance use disorder 
Accidental overdose 
Dependence 
Disturbance in social behaviour 
Drug level above therapeutic 
Drug level increased 
Intentional product use issue 
Overdose 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 59 of 60 
Substance use 
Substance-induced mood disorder 
Substance-induced psychotic disorder 
PLUS one of the below: 
a.
Impulse control/compulsive behavior: MedDRA terms: MedDRA High Level Term
of “Impulse control disorders”, “Paraphilias and paraphilic disorders”, or “Sexual
desire disorders”. MedDRA Preferred Terms of Stereotypy, Binge eating, Gambling,
Gambling disorder, Compulsive shopping; or any TEAE with a verbatim term that
included the text “spending.”
b. Behavioral changes: selected MedDRA PTs from SMQ Hostility/Aggression:
Aggression 
Anger 
Borderline personality disorder 
Defiant behaviour 
Intermittent explosive disorder 
Psychopathic personality 
Abnormal behaviour 
Agitated depression 
Agitation 
Attention-seeking behaviour 
Behaviour disorder 
Disturbance in social behaviour 
Hypomania 
Impatience 
Irritability 
Mania 
Manic symptom 
Personality change 
Personality disorder 
Psychotic behaviour 
Psychotic disorder 


Statistical Analysis Plan 
Sponsor: Sunovion Pharmaceuticals Inc.; Protocol No.: CTH-301 
 
This document is confidential. 
SAP Version: Final 1.0/30-Sep-2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 60 of 60 
Pyromania 
Substance-induced psychotic disorder 
c.
Dyskinesia: selected MedDRA PTs from MedDRA SMQ Dyskinesia
Athetosis 
Ballismus 
Buccoglossal syndrome 
Chorea  
Choreoathetosis 
Dyskinesia 
Dyskinesia oesophageal 
Grimacing 
Oculogyric crisis 
Pharyngeal dyskinesia 
Rabbit syndrome 
Tardive dyskinesia 
Abnormal involuntary movement scale 
Chronic tic disorder 
Complex tic 
Drooling 
Extrapyramidal disorder 
Motor dysfunction 
Movement disorder 
Muscle twitching 
Provisional tic disorder 
Tic