Clinical trial NCT02469090
Conditions: Parkinson Disease, Off Episodes
Keywords: Parkinson Disease, off episodes
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2015-06-18; Completion date: 2017-12-11
Enrollment: 141 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A 12-week, prospective, multi-center, randomized, double-blind, placebo controlled, Phase 3 study in L-Dopa responsive PD patients with motor fluctuations ("OFF" episodes), designed to determine the efficacy, safety and tolerability of APL-130277.

Detailed description:

Arms: arm 1: APL-130277 sublingual thin film (10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg) arm 2: Matching placebo for APL-130277 sublingual thin film (10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg)
Interventions: intervention 1: APL-130277 intervention 2: Placebo
Intervention descriptions: intervention 1: Use to treat up to 5 "OFF" episodes per day intervention 2: placebo

Protocol documents:
Prot_001.pdf: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Examine the Efficacy, Safety and Tolerability of APL-130277 in Levodopa Responsive 
Patients with Parkinson’s Disease Complicated by Motor Fluctuations (“OFF” Episodes) 
PROTOCOL 
NUMBER: 
CTH-300 
IND: 
110955 
PROTOCOL DATE: 
06 May 2015 
SPONSORED BY: 
Cynapsus Therapeutics Inc. 
Information contained and may not be used, divulged, published, or otherwise disclosed to others 
except to the extent necessary to obtain approval of the Institutional Review Board or Research 
Ethics Board, or as required by law. Persons to whom this information is disclosed should be 
informed that this information is confidential and may not be further disclosed without the express 
permission of Cynapsus Therapeutics Inc. 
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2 
EMERGENCY CONTACT INFORMATION 
 Medical Monitor 
Vice President, Medical Affairs 
Cynapsus Therapeutics Inc. 
 
 
  
Clinical Project Leader 
Cynapsus Therapeutics Inc., 
 
 
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3 
INVESTIGATOR APPROVAL STATEMENT 
I have read this protocol and agree to conduct this clinical trial as outlined herein. I will ensure 
that all Sub-Investigators and other study staff members have read and understand all aspects of 
this protocol. I agree to cooperate fully with Cynapsus Therapeutics Inc. (Cynapsus) during the 
study. I will adhere to all Food and Drug Administration (FDA), International Conference on 
Harmonisation (ICH), and other applicable regulations and guidelines regarding clinical trials on 
a study drug during and after study completion. 
Principal Investigator 
Printed Name: 
Signature: 
Date: 
PROTOCOL 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Examine the Efficacy, Safety and Tolerability of APL-130277 in Levodopa Responsive 
Patients with Parkinson’s Disease Complicated by Motor Fluctuations (“OFF” Episodes) 
Protocol: 06 May 2015 
Version: 2.0 FINAL 
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last dose of L-Dopa and any other adjunctive PD medication no later than 
midnight the evening prior to the visit. Their normal morning dose of L-Dopa 
(without adjunctive PD medication) will be administered in the clinic 
following confirmation of an “OFF” episode by the Investigator, to ensure 
that they experience an “ON” response. Eligibility criteria will be assessed, 
and patient “ON”/”OFF” training will be performed. Eligible patients will be 
supplied with anti-nausea medication (US sites – Tigan® [trimethobenzamide 
hydrochloride; 300 mg t.i.d.]; non-US sites – domperidone [10 mg b.i.d.]), to 
be taken daily starting on Day -3. 
Patients will be asked to return to the clinic in the morning of Titration Visit 1 
(TV1) for the Dose Titration Phase of the study, and will be instructed to take 
their last dose of L-Dopa and any other adjunctive PD medication no later 
than midnight on the evening prior. 
Dose Titration Phase 
On Titration Visit 1 (TV1), all patients will not take their regular morning 
dose of L-Dopa or any other adjunctive PD medications. Patients will present 
to the clinic in an “OFF” state and will be treated with 10 mg APL-130277. 
Efficacy (MDS-UPDRS Part III) will be performed prior to dosing, and at 
15, 30, 45, 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 50 minutes 
after dosing.  
Patients who respond to the 10 mg APL-130277 dose with a full “ON” 
response within 45 minutes at TV1, as assessed by the patient and 
Investigator, will be considered complete from a Dose Titration Phase 
perspective, and can proceed to randomization and the Maintenance 
Treatment Phase of the study at this dose. A full “ON”, as assessed by the 
patient, is defined as: a period of time where medication is providing benefit 
with regard to mobility, stiffness and slowness and where a patient 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 patient has adequate motor function to allow them to 
perform their normal daily activities.  
Patients who do not achieve a complete and full “ON” response (as defined 
above) within 45 minutes with the 10 mg APL-130277 dose at TV1 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 (i.e., 15 mg) in a manner identical to that on Titration Visit 1 (TV1), 
with identical evaluations. All patients will be asked to take their last dose of 
L-Dopa and any other adjunctive PD medication no later than midnight the 
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evening prior to the visit, and come to the clinic without taking their normal 
morning PD medications. Patients who achieve a full “ON” (as defined 
above) within 45 minutes of receiving the 15 mg dose will considered 
complete from a Dose Titration Phase perspective, and can proceed to the 
Maintenance Treatment Phase of the study. Patients 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 higher dose of APL-130277. This 
will sequentially be 20 mg [TV3], 25 mg [TV4], 30 mg [TV5] and 35 mg 
[TV6], as appropriate. In each of these cases, patients will be asked to take 
their last dose of L-Dopa (and any other adjunctive PD medication) no later 
than midnight the evening prior to each visit, and come to the clinic without 
taking their normal morning medication. Safety and efficacy assessments will 
be performed at each visit exactly as described above. Patients who achieve 
a full “ON” response within 45 minutes at any titration visit may proceed to 
randomization and the Maintenance Treatment Phase of the study.  
At all titration visits, at the discretion of the patient 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 patient 
safety and tolerability, the higher dose will be used during the Maintenance 
Treatment 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 Maintenance Treatment Phase of the study. 
During the Dose Titration Phase visits, if in the opinion of the Investigator 
the patient can no longer tolerate the “OFF” state at any point during the 
Visit, the patient may receive rescue L-Dopa (+/- other adjunctive PD 
medication) at their standard dosage, or at a dosage considered appropriate 
by the Investigator to achieve a full “ON” state. If this occurs, patients can 
return to the clinic on another day to resume the titration with the next highest 
dose.  However, if the patient cannot tolerate the “OFF” state and does not 
respond efficaciously to a dose of APL-130277, they 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 patients 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 End of Study Visit (EOS) 
performed. 
Dosing days in the Dose Titration Phase are not required to occur daily but 
must be completed within 21 days. Following completion of the titration 
phase, patients will return to clinic and be randomized to treatment with APL-
130277 at the dose determined in the Dose Titration Phase, or matching 
placebo.  
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The Data Safety Monitoring Board (DSMB) will review data on a regular 
basis during the study and, when 50% of patients have completed the Dose 
Titration Phase of the study, the DSMB will evaluate whether potential 
changes to the safety assessment schedule during the Dose Titration Phase 
can be implemented. Any changes will be outlined in a formal amendment to 
the study Protocol. 
Maintenance Treatment Phase – In-clinic Visits 
Patients who successfully completed the Dose Titration Phase of the study 
will be asked to return to the clinic in an untreated state on Maintenance 
Visit 1 (MV1). They will be randomized via the Interactive Web Response 
System (IWRS) to treatment with either APL-130277 or placebo (ratio 1:1) 
in a double-blind fashion. This visit will occur between 7 and 30 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 
(or matching placebo). Patients will be asked to take their last dose of L-Dopa 
(and any other adjunctive PD medications) no later than midnight the evening 
prior to the visit, and attend the clinic without taking their normal morning 
PD medications. Assessments of efficacy and safety will be performed for up 
to 90 minutes after dosing. Patients will be trained by clinic staff on how to 
remove study medication from its packaging, and how to handle the 
sublingual thin films using placebo sublingual thin films supplied to the site. 
Patients should not self-administer the placebo sublingual thin films. Patients 
cannot be discharged from the clinic until satisfactorily completing the 
training. 
During the Maintenance Treatment Phase of the study, patients will return to 
the clinic at monthly intervals (Maintenance Visit 2 [MV2], Maintenance 
Visit 3 [MV3], and Maintenance Visit 4 [MV4]), to be dosed with their 
randomized treatment (APL-130277 or placebo). Safety and efficacy 
performed at these visits will be similar to that performed on Maintenance 
Visit 1 (MV1). 
Maintenance Treatment Phase – At Home Assessments 
During the 12-week Maintenance Treatment Phase, patients will be 
instructed to continue with their regular PD medication regimen(s), but 
should dose themselves with their randomized treatment (APL-130277 or 
placebo) if they experience an “OFF” episode (e.g., morning akinesia, 
wearing “OFF”, dose failure, sudden “OFF”, etc.) during the day while on 
their current PD treatment regimen. Patients will be instructed to dose up to 
5 “OFF” episodes per day.  
 For 2 days prior to each of these in-clinic visits, patients will be requested to 
complete a home dosing diary that captures: 
• 
Time of randomized treatment self-administration; 
• 
Patient “ON”/”OFF” state at 30 minutes after dosing. 
Between each in-clinic visit, patients will be contacted at two week intervals 
by the site to assess patient well-being and safety. If required, patients will 
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be asked to return to the clinic for additional evaluations at an unscheduled 
Dose Adjustment Visit. 
During the Maintenance Treatment Phase of the study, anti-nausea 
medication (i.e., Tigan® [trimethobenzamide hydrochloride] or domperidone 
for patients from US and non-US sites, respectively) may be discontinued at 
the discretion of the Investigator. 
INVESTIGATIONAL DRUG 
APL-130277 (10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg [given as 2 
sublingual thin films consisting of 15 mg and 20 mg]) 
For patients dosed with 35 mg, instructions will be given to place the first 
sublingual thin film (i.e., 20 mg) under the tongue for 3 minutes before 
placing the second sublingual thin film (i.e., 15 mg) under the tongue 
immediately and without delay. 
REFERENCE PRODUCT 
N/A 
TREATMENT REGIMENS 
Dose titration from 10 mg up to 35 mg APL-130277 in 5 mg increments, and 
long term outpatient treatment with dose reductions based on safety and 
tolerability. 
CONCOMITANT AND CO- 
ANALGESIC TREATMENT 
Patients at US-sites: Tigan® (trimethobenzamide hydrochloride; 300 mg t.i.d. 
orally) to overcome the potential nausea associated with administration of 
APL-130277. 
Patients at non-US sites: domperidone (10 mg b.i.d.) to overcome the 
potential nausea associated with administration of APL-130277. 
All patients: stable doses of a L-Dopa formulation and other stable adjunctive 
PD medications. 
PROHIBITED 
TREATMENT 
- Treatment with any form of apomorphine other than study medication. 
- Any selective 5HT3 antagonist (i.e., ondansetron, granisetron, dolasetron, 
palonosetron, alosetron). 
- Dopamine antagonists (excluding quetiapine or clozapine) or depleting 
drugs. 
- Deep brain stimulation or other neurosurgical PD treatment, continuous s.c. 
apomorphine infusion or Duodopa/Duopa. 
STUDY DURATION 
Participation is anticipated to be approximately 135 days. 
INVESTIGATIVE SITES OR 
COUNTRIES 
This is a multicenter trial run at approximately 35 sites in North America. 
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UPDRS MOTOR score after 30 minutes at 12 weeks (Maintenance Visit 4, 
MV4). The difference between APL-130277 and placebo at MV4 will be 
estimated using a Mixed Model for Repeated Measurements (MMRM). The 
model will include the observed change from pre-dose MDS-UPDRS 
MOTOR score values after 30 minutes at Maintenance Visit 1 (MV1), 
Maintenance Visit 2 (MV2), Maintenance Visit 3 (MV3) and Maintenance 
Visit 4 (MV4) as the response values, i.e. no imputation will be done. The 
treatment difference at 12 weeks will be estimated using contrasts. The 
MMRM model will include the treatment group (APL-130277 or placebo), 
visit (MV1, MV2, MV3 and MV4), the stratification variables (if any) and 
the interaction between the treatment group and visit as fixed factors. The 
change from pre-dose in MDS-UPDRS MOTOR score after 30 minutes at 
the final Titration visit will be used as a covariate in the model. 
The sensitivity analyses of the primary endpoint will be specified in the 
Statistical Analysis Plan. Sensitivity analysis will include a method to handle 
missing data (e.g., Analysis of Covariance with last observation carried 
forward or pattern mixture models using multiple imputation), definition of 
analysis population (e.g., patients completing the study) and statistical 
method (e.g., Analysis of Covariance models separately for each visit). 
The primary and secondary endpoints will be tested using a hierarchical 
approach. The primary endpoint will be tested first and the difference will be 
declared statistically significant if the nominal two-sided p-value is less than 
0.05.  In case the primary objective is statistically significant, the secondary 
endpoint ranked first will be tested using a nominal significance level of 0.05 
based on two-sided tests. The testing will continue in a hierarchical manner 
as long as the previously ranked endpoint was statistically significant. 
The continuous secondary endpoints will be analyzed using a MMRM model 
similar to the one used for the primary endpoint. The categorical endpoints 
will be analyzed using Cochran-Mantel-Haenszel test stratified by the 
stratification variables, if any. The time-to-event endpoints will be described 
using the Kaplan-Meier method along with group comparisons analyzed 
using the Cox proportional hazards model. For categorical and time-to-event 
endpoints, each visit will be tested separately. In case of missing data, the last 
value will be carried forward for the categorical and time-to-event endpoints. 
Safety Analyses 
The analysis of the safety data will focus on the comparison of APL-130277 
and placebo during the Maintenance Treatment Phase. In addition, all safety 
data will be reported separately for the Dose Titration Phase. 
Adverse events will be tabulated by treatment group according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
adverse events (TEAEs) will be summarized by body system and preferred 
term.  Descriptive statistics will be used to compare the overall incidence of 
TEAEs between the treatment groups. For vital signs and ECG parameters, 
the changes from pre-dose to post-dose assessments of the corresponding day 
will be calculated and compared between the treatment groups using 
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descriptive statistics. In addition, the changes from baseline in the pre-dose 
values will be compared between the treatment groups. The changes in 
laboratory values and C-SSRS from baseline to subsequent visits will be 
compared as well. 
SAMPLE SIZE 
CALCULATION 
The study intends to show the superiority of sublingual apomorphine 
compared with placebo. Assuming a treatment difference of 7 points and 
standard deviation of 10 points, a sample size of 44 patients per group or 
88 patients for two groups will provide ≥ 90% power to detect a statistically 
significant difference at the 0.05 level (2-sided), using a two-sample t-test. 
Taking into consideration a 10% dropout rate during the titration phase and 
a 15% dropout rate during the maintenance phase, the study plans to enroll 
approximately 126 patients into the Dose Titration Phase and to randomize 
approximately 114 patients into the Maintenance Treatment Phase. 
 
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Dose Titration Phase1 
Maintenance Treatment Phase 
Procedures 
Screening Visits2 
Telephone Call3 
Titration Visit 1 
Titration Visit 2 
Titration Visit 3 
Titration Visit 4 
Titration Visit 5 
Titration Visit 6 
Maintenance 
Visit 11 
Telephone Call 
Maintenance 
Visit 2 
Telephone Call 
Maintenance 
Visit 3 
Telephone Call 
Maintenance 
Visit 4 
End of Study  
Visit20 
Dose Adjustment 
Visit 
Study Visit 
SV1 
SV2 
T1 
TV1 
TV2 
TV3 
TV4 
TV5 
TV6 
MV1 
T2 
MV2 
T3 
MV3 
T4 
MV4 
EOS 
N/A 
Day (+/- 2 days) 
-28 to -3 
-4 
1 
4 
7 
10 
13 
16 
23 
37 
51 
55 
79 
93 
100 
107 
N/A 
Outpatient Visit4 
X 
X4 
 
X4 
X4 
X4 
X4 
X4 
X4 
X 
 
X 
 
X 
 
X 
X 
X 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reconfirmation of Consent 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Entry Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Restriction Criteria 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Medical 
History/Demographics 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam, 
including Oropharyngeal 
Exam5 
 
X2 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Abbreviated Physical Exam, 
including Oropharyngeal 
Exam6 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Anti-nausea Medication (starts 
on Day-3)7 
 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
BMI, weight and height8 
 
X2 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital Signs (BP, HR, RR and 
Temp) 9, 10 
 
X2 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECG10, 11 
 
X2 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Clinical Laboratory Tests 
 
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 
X 
 
X 
 
X 
 
X 
 
 
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Dose Titration Phase1 
Maintenance Treatment Phase 
Procedures 
Screening Visits2 
Telephone Call3 
Titration Visit 1 
Titration Visit 2 
Titration Visit 3 
Titration Visit 4 
Titration Visit 5 
Titration Visit 6 
Maintenance 
Visit 11 
Telephone Call 
Maintenance 
Visit 2 
Telephone Call 
Maintenance 
Visit 3 
Telephone Call 
Maintenance 
Visit 4 
End of Study  
Visit20 
Dose Adjustment 
Visit 
Study Visit 
SV1 
SV2 
T1 
TV1 
TV2 
TV3 
TV4 
TV5 
TV6 
MV1 
T2 
MV2 
T3 
MV3 
T4 
MV4 
EOS 
N/A 
Day (+/- 2 days) 
-28 to -3 
-4 
1 
4 
7 
10 
13 
16 
23 
37 
51 
55 
79 
93 
100 
107 
N/A 
Confirmation of L-Dopa 
Responsiveness 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Confirmation of 
“OFF” or full “ON”13 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Patient Confirmation of “OFF” 
or full “ON”13 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
In-Clinic Dosing14 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Dispense Study Medication for 
Outpatient Dosing 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Collect Study Medication 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X21 
X 
Provide Patient Dosing Diary15 
 
 
 
X16 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Collect Patient Dosing Diary15 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient “OFF” versus “ON” 
Training 
 
X17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Compliance 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X21 
X 
C-SSRS18 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
PDQ-39 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X21 
 
PGI19 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X21 
 
CGI19 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X21 
 
Epworth Sleepiness Scale 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X21 
 
Caregiver Burden (Zarit 
Burden Interview [ZBI])22 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X21 
 
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Dose Titration Phase1 
Maintenance Treatment Phase 
Procedures 
Screening Visits2 
Telephone Call3 
Titration Visit 1 
Titration Visit 2 
Titration Visit 3 
Titration Visit 4 
Titration Visit 5 
Titration Visit 6 
Maintenance 
Visit 11 
Telephone Call 
Maintenance 
Visit 2 
Telephone Call 
Maintenance 
Visit 3 
Telephone Call 
Maintenance 
Visit 4 
End of Study  
Visit20 
Dose Adjustment 
Visit 
Study Visit 
SV1 
SV2 
T1 
TV1 
TV2 
TV3 
TV4 
TV5 
TV6 
MV1 
T2 
MV2 
T3 
MV3 
T4 
MV4 
EOS 
N/A 
Day (+/- 2 days) 
-28 to -3 
-4 
1 
4 
7 
10 
13 
16 
23 
37 
51 
55 
79 
93 
100 
107 
N/A 
Questionnaire for Impulsive-
Compulsive Disorders in 
Parkinson’s Disease Rating 
Scale (QUIP-RS) 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X21 
 
European Quality of Life – 5 
Dimensions (EQ-5D) 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X21 
 
Outpatient  
Self-Administration Training 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
AEs/Serious AEs (SAEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/Current Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Reason(s) for Dose 
Adjustment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1 Dosing during the Titration Phase must be completed within 21 days. The initial Maintenance Visit (MV1) must occur between 7 and 30 days after the final Dose 
Titration Phase visit. 
2 All screening procedures to be conducted within 28 days prior to Titration Visit 1 (TV1). If required by the Investigator, and following receipt of patient consent, 
the Investigator may review the patients’ 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. Procedures performed on SV1 will not be repeated at SV2. 
3 Reminder phone call to patient to start their anti-nausea medication on the morning of Day -3. 
4 Patients may be monitored in the clinic overnight before Dose Titration Visits if such facilities exist and the patient 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. 
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6 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. 
7 May be discontinued in the Maintenance Treatment Phase, at the discretion of the Investigator. 
8 Both height and weight captured at the Screening Visit (SV2) to calculate BMI; only weight captured at all other visits. 
9 Vital signs will be assessed at the Screening Visit (SV2), all Dose Adjustment Visits and EOS; TV1 to TV6 and MV1 to MV4 at t = 0 minutes (just prior to 
dosing) and immediately after the 60 minute MDS-UPDRS Part III assessment. Blood pressure to be measured supine and standing (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 
Suggested Sequence of Assessments Post-Dose where conflict arises: MDS-UPDRS Part III - Patient “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); single ECGs at t = 0 (just prior to dosing) and 50 minutes post dosing at TV1 to TV6 and MV1 to MV4; 
single ECG at EOS. 
12 MDS-UPDRS Part III (Motor Function) to be assessed at t = 0 (just prior to dosing), 15, 30, 45, 60 and 90 minutes post dosing at the Screening Visit (SV2), TV1 
to TV6, and MV1 to MV4. These assessments will exclude the “Dyskinesia Impact on Part III Ratings” and the Hoehn and Yahr staging. 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. 
13 Investigator/patient confirmation of “OFF” or “ON” at SV2. 
At TV1 to TV6 and MV1 to MV4, the Investigator will assess “OFF/”ON” state as part of the MDS-UPDRS Part III assessments. During the Dose Titration 
Phase, these assessments may cease if the patient does not experience a full “ON” response within 45 minutes of dosing. 
At TV1 to TV6 and MV1 to MV4, the patient should report: “OFF”/”ON” state at 0, 15, 30, 45, 60 and 90 minutes after dosing, 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). Patients will also be asked if they 
attained a full “ON” state anytime within 30 minutes of dosing. 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. 
14 Dosing in clinic from outpatient supplies (excluding MV4). 
15 Sites will call each patient 3 days before an in-clinic visit during the Maintenance Treatment Phase to remind patients to complete the Patient Dosing Diary. 
Diary will record: time when patient self-administers a dose; patient “ON”/”OFF” status at 30 minutes following dosing. 
16 Patient Dosing Diary provided on TV1 will be provided for training purposes only. During this phase, patients should be instructed to use their scheduled PD 
medication administration as the reference point. If needed, patients will be retrained on MV1 in the use of the home dosing diary. 
17 Patient “OFF” versus “ON” Training will occur as part of the L-Dopa challenge at SV2.  
18 “Screening” scale to be used at the Screening Visit (SV2); “Since Last Visit” to be used at all other visits. 
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19  –S to be used at first visit, -I to be used at all subsequent visits. 
20 Patients whose participation is terminated during the Dose Titration Phase or Maintenance Treatment Phase will have the procedures/assessments outlined in the 
EOS visit completed. 
21 Assessments will not be performed on patients whose participation is terminated during the Dose Titration Phase of the study. 
22 Assessment optional; to be completed if caregiver is present and consent is provided. 
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21 of 181
06 May 2015
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Cynapsus Therapeutics Inc. 
CTH-300
22 of 181
06 May 2015
CONFIDENTIAL
Version 2.0 FINAL


 
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Cynapsus Therapeutics Inc. 
CTH-300
23 of 181
06 May 2015
CONFIDENTIAL
Version 2.0 FINAL


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17.4.7 
Data Safety Monitoring Board .................................................................................83 
18 
GENERAL CONSIDERATIONS .......................................................................84 
19 
REFERENCES .....................................................................................................86 
20 
APPENDICES ......................................................................................................87 
20.2.1 
Declaration of Helsinki ........................................................................................106 
20.2.2 
Approval by an IRB/REB/IEC .............................................................................106 
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7 
LIST OF ABBREVIATIONS 
5HT3 
5-hydroxy tryptophan (serotonin) 
AE 
adverse event 
ALT 
alanine aminotransferase 
APOKYN® 
apomorphine hydrochloride injection 
API 
active pharmaceutical ingredients 
AST 
aspartate aminotransferase 
b.i.d. 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
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 
Cynapsus 
Cynapsus Therapeutics Inc. 
DSMB 
Data Safety Monitoring Board 
EAC 
enrollment adjudication committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
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 
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L-Dopa 
L-3,4-dihydroxyphenylalanine or Levodopa 
MCH 
mean corpuscular hemoglobin 
MCHC 
MCH concentration 
MDS-UPDRS 
Movement Disorders Society Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measurements 
MMSE 
Mini-mental State Examination 
OH 
Orthostatic Hypotension 
PD 
Parkinson’s disease 
PDQ-39 
Parkinson’s Disease Questionnaire 
PGI 
Patient Global Impression 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale 
RBC 
red blood cell 
REB 
Research Ethics Board 
RR 
respiratory rate 
SAE 
serious adverse event 
s.c. 
subcutaneous 
SOP 
Standard Operating Procedure 
TEAE 
treatment emergent adverse events 
Temp 
temperature 
t.i.d. 
three times daily 
US 
United States 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
ZBI 
Zarit Burden Interview 
 
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multiple treatments of APL-130277 in patients 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 patients with PD 
have been previously investigated in both a healthy and PD population, however, a well powered 
study testing multiple treatments of APL-130277 in both an in-clinic and outpatient setting has not 
been performed. Such a study will provide information on the effect of APL-130277 on “OFF” 
episodes based on physician and patient assessment in a controlled clinical setting, and based on 
patient evaluations in an outpatient setting. This study will provide information on treating “OFF” 
episodes in a PD patient 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 
efficacy of APL-130277 in treating “OFF” episodes (e.g., morning akinesia, wearing “OFF”, dose 
failure, sudden “OFF”) when compared with placebo over a 3 month treatment period in both an 
in-clinic and at-home environment.  
 
 
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9 
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 patient information and recruitment materials before 
the start of the study. 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 patients 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 patient before any study activity or procedure is undertaken. 
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11.1.2 
Dose Titration Phase 
On Titration Visit 1 (TV1), patients will arrive at the clinic in the practically defined “OFF” state 
having not taken their regular morning dose of L-Dopa or any other adjunctive PD medications, 
as well as having taken their last dose of L-Dopa and any other adjunctive PD medications no later 
than midnight the night before. Patients in an “OFF” state, as determined by both the Investigator 
and patient, will be treated with 10 mg APL-130277. Efficacy (MDS-UPDRS Part III) will be 
performed prior to dosing, and at 15, 30, 45, 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 50 minutes after dosing.  
Patients who respond to the APL-130277 10 mg dose with a full “ON” response within 45 minutes 
at TV1, as assessed by the patient and Investigator, will be considered complete from a Dose 
Titration Phase perspective, and can proceed to randomization and the Maintenance Treatment 
Phase of the study at this dose. A full “ON”, as assessed by the patient, is defined as: a period of 
time where medication is providing benefit with regard to mobility, stiffness and slowness and 
where a patient 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 13.6.3.1). A full “ON”, as determined by the Investigator is defined as: the period of time 
where the Investigator feels the medication is providing benefit with regard to mobility, stiffness 
and slowness and the patient has adequate motor function to allow them to perform their normal 
daily activities (refer to Section 13.6.3.1).  
Patients who do not achieve a complete and full “ON” response (as defined in Section 13.6.3.1) 
within 45 minutes with the 10 mg APL-130277 dose at TV1 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 (i.e., 15 mg) in a manner identical to that on Titration Visit 1 
(TV1), with identical evaluations. All patients will be asked to take their last dose of L-Dopa and 
any other adjunctive PD medication no later than midnight the evening prior to the visit, and come 
to the clinic without taking their normal morning PD medications. Patients who achieve a full 
“ON” (as defined in Section 13.6.3.1) within 45 minutes of receiving the 15 mg dose will be 
considered complete from a Dose Titration Phase perspective, and can proceed to randomization 
and the Maintenance Treatment Phase of the study. Patients who do not achieve a full “ON” 
response (as defined in Section 13.6.3.1) 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. This will sequentially be 20 mg [TV3], 25 mg [TV4], 30 mg 
[TV5] and 35 mg [TV6], as appropriate. In each of these cases, patients will be asked to take their 
last dose of L-Dopa (and any other adjunctive PD medication) no later than midnight the evening 
prior to each visit, and come to the clinic without taking their normal morning PD medications. 
For patients dosed with 35 mg, instructions will be given to place the first sublingual thin film (i.e., 
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20 mg) under the tongue for 3 minutes before placing the second sublingual thin film (i.e., 15 mg) 
under the tongue immediately after and without delay. For each visit in the Dose Titration Phase, 
the site will arrange patient transfers, if needed. Alternatively, patients may be monitored in the 
clinic overnight if such facilities exist and the patient consents. These occurrences will not be 
considered a SAE. Safety and efficacy assessments will be performed at each visit exactly as 
described above. Patients who achieve a full “ON” response within 45 minutes at any titration visit 
may proceed to randomization and the Maintenance Treatment Phase of the study. 
At all titration visits, at the discretion of the patient 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 patient safety 
and tolerability, the higher dose will be used during the Maintenance Treatment 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 Maintenance Treatment Phase of the study. 
During the Dose Titration Phase visits, if in the opinion of the Investigator the patient can no longer 
tolerate the “OFF” state at any point during the Visit, the patient may receive rescue L-Dopa 
(+/- other adjunctive PD medication) at their standard dosage, or at a dosage considered 
appropriate by the Investigator to achieve a full “ON” state. If this occurs, patients can return to 
the clinic on another day to resume the titration with the next highest dose.  However, if the patient 
cannot tolerate the “OFF” state and does not respond efficaciously to a dose of APL-130277, they 
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 patients who reach 35 mg at Titration Visit 6 (TV6) and do not exhibit 
a full “ON” response (as defined in Section 13.6.3.1) within 45 minutes will be terminated from 
the study and will have the applicable procedures outlined in the EOS Visit performed. 
Dosing days in the Dose Titration Phase are not required to occur daily, but must be completed 
within 21 days. Following completion of the titration phase, patients will return to clinic and be 
randomized to treatment with APL-130277 at the dose determined in the Dose Titration Phase, or 
matching placebo.  
The DSMB will review data on a regular basis during the study and, when 50% of patients have 
completed the Dose Titration Phase of the study, the DSMB will evaluate whether potential 
changes to the safety assessment schedule during the Dose Titration Phase can be implemented. 
Any changes will be outlined in a formal amendment to the study Protocol. 
11.1.3 
Maintenance Treatment Phase – In-clinic Visits 
Patients who successfully completed the Dose Titration Phase of the study will be asked to return 
to the clinic on Maintenance Visit 1 (MV1). They will be randomized via the IWRS to treatment 
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with either APL-130277 or placebo (ratio 1:1) in a double-blind fashion. This visit will occur 
between 7 and 30 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 (or matching 
placebo). Patients will be asked to take their last dose of L-Dopa (and any other adjunctive PD 
medications) no later than midnight the evening prior to the visit, and attend the clinic without 
taking their normal morning PD medications. Assessments of efficacy and safety will be 
performed for up to 90 minutes after dosing. Patients will be trained by clinic staff on how to 
remove study medication from its packaging, and how to handle the sublingual thin films using 
placebo sublingual thin films supplied to the site. Patients should not self-administer the placebo 
sublingual thin films. Patients cannot be discharged from the clinic until satisfactorily completing 
the training. 
At the in-clinic visits, patients will be instructed to place the sublingual thin film under their 
tongue (see Section 15.2 for full dosing details).  Patients will be asked to follow the same 
process of study drug administration (excluding staff confirmation) during the at-home 
portion of the study. 
During the Maintenance Treatment Phase of the study, patients will return to the clinic at monthly 
intervals (Maintenance Visit 2 [MV2], Maintenance Visit 3 [MV3], and Maintenance Visit 4 
[MV4]), to be dosed with their randomized treatment (APL-130277 or placebo). Safety and 
efficacy performed at these visits will be similar to that performed on Maintenance Visit 1 (MV1). 
11.1.4 
Maintenance Treatment Phase – At Home Assessments 
For the duration of the Maintenance Treatment Phase, patients will be instructed that for the next 
12 weeks, they should continue with their regular PD medication regimen(s), but should dose 
themselves with their randomized treatment (APL-130277 or placebo) if they experience an “OFF” 
episode (e.g., morning akinesia, wearing “OFF”, dose failure, sudden “OFF”, etc.) during the day 
while on their current treatment regimen. Patients will be instructed to dose up to 5 “OFF” episodes 
per day.  
 For 2 days prior to each of these in-clinic visits, patients will be requested to complete a home 
dosing diary that captures: 
• Time of randomized treatment self-administration; 
• Patient “ON”/”OFF” state at 30 minutes after dosing. 
Between each in-clinic visit, patients will be contacted at two week intervals by the site to assess 
patient well-being and safety. If required, patients 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. 
During the Maintenance Treatment Phase of the study, anti-nausea medication (i.e., Tigan® 
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The EAC will be comprised of a committee of two neurologists who will determine the patient’s 
appropriateness for inclusion in the study, independent of the entry criteria (see APPENDIX XV: 
Enrollment Adjudication Committee Form).  The EAC will consult with the Medical Monitor, and 
the Investigator as appropriate, to address and resolve any outstanding questions or issues.  
The EAC review should be completed within 48 hours of submitting a request, and the Investigator 
will be informed in writing (e.g., via e-mail) of the decision.  Following EAC approval, the final 
determination of eligibility for enrollment in the study will be made by the Investigator, who will 
then submit a request via the IWRS for enrollment into the Dose Titration Phase of the study. In 
case of refusal, the decision will be accompanied by a rationale.   
A dedicated charter will be developed in order to address the mode of operations of the EAC to 
ensure the integrity of the study will be protected.  The communication from the EAC, 
documenting review and approval of the patient, will serve as EAC documentation for inclusion 
into the study and must be stored in the site study file. 
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• Contraceptive patch; 
• Barrier (diaphragm, sponge or condom) plus spermicidal preparations; 
• Intrauterine contraceptive system; 
• Levonorgestrel implant; 
• Medroxyprogesterone acetate contraceptive injection; 
• Complete abstinence from sexual intercourse; 
• Hormonal vaginal contraceptive ring; or 
• Surgical sterilization or partner sterile (must have documented proof). 
11) Male subjects must be either surgically sterile, agree to be sexually abstinent or use a barrier 
method of birth control (e.g., condom) from first study drug administration until 30 days 
after final drug administration. 
12) Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
study-related procedures to complete the study. 
13) Able to understand the consent form, and to provide written informed consent. 
14) Must be approved as a satisfactory candidate by an EAC. 
12.1.2 
Exclusion Criteria 
A patient 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; or Duodopa/Duopa. 
3) Treatment with any form of s.c. apomorphine within 7 days prior to the initial Screening 
Visit (SV1). 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); 
Tigan® 
(trimethobenzamide hydrochloride; patients from US sites only); or domperidone (patients 
from non-US sites only). 
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 (i.e., unapproved) medication within 30 days prior to the 
initial Screening Visit (SV1). 
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• 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; 
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. 
12.2.2 
Permitted Treatments 
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. Use of anti-nausea medication will be required 
during the Dose Titration Phase of the study, however may be discontinued during 
the Maintenance Treatment Phase, at the discretion of the Investigator. 
• Stable doses of an L-Dopa formulation with or without other stable adjunctive PD 
therapies (from at least 4 weeks prior to the initial Screening Visit (SV1), with no 
planned medication changes during the study). MAO-B inhibitors will be allowed but 
must be stable for at least 8 weeks prior to the initial Screening Visit (SV1). 
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• Review inclusion/exclusion criteria. 
• Record demographics and detailed medical history, including review of medications 
taken within 6 months prior to the initial Screening Visit (SV1), current treatment 
regimens, drug, alcohol and smoking history. 
• Perform a complete physical examination, including an oropharyngeal examination. 
The oropharyngeal cavity examination should include a visual inspection of the 
inside of each cheek, the inside of the lower lip, the surface of the tongue, and under 
the tongue. 
• Provide patient with anti-nausea medication (to begin on Day -3). 
• Measure height and weight; calculate BMI. 
• Record vital signs (BP, HR, RR and Temp), after the patient has been in a supine 
position for 5 minutes. Patient BP to be measured both supine and standing (within 3 
minutes of standing). 
• 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 patient using the Modified Hoehn and Yahr scale (see APPENDIX III: 
Modified Hoehn and Yahr Scale). 
• Assess patient using MDS-UPDRS Parts I, II and IV (see APPENDIX IV: Movement 
Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)). 
• Assess patient motor function using MDS-UPDRS Part III at t = 0 (just prior to L-
Dopa administration), 15, 30, 45, 60 and 90 minutes after L-Dopa administration (see 
APPENDIX IV: Movement Disorder Society - Unified Parkinson’s Disease Rating 
Scale (MDS-UPDRS)). 
• Confirm L-Dopa responsiveness. Patients will take their normal morning dose of L-
Dopa without their normal adjunctive PD medication. 
• Investigator confirmation of “OFF” or “ON”. 
• Patient confirmation of “OFF” or “ON”. 
• Perform patient training in order to distinguish “OFF” versus “ON” episodes (see 
Section 13.6.3.1).  
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• 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 
thin film and 15 mg sublingual thin film, sequentially). 
Site staff will perform the following procedures on each Titration Visit: 
• Reconfirm consent. 
• 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. 
• Record supine vital signs (BP, HR, RR and Temp) prior to dosing and after the 
60 minute MDS-UPDRS Part III assessment. Blood pressure to be measured both 
supine and standing (measured within 3 minutes of standing). 
• Perform a standard 12-lead ECG prior to dosing and 50 minutes after dosing. 
• Assess patient motor function using MDS-UPDRS Part III at t = 0 (just prior to 
dosing), 15, 30, 45, 60 and 90 minutes after dosing (see APPENDIX IV: Movement 
Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)). 
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 patients 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. The patient 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 patient does not experience a full 
“ON” response within 45 minutes of dosing. 
• Patient confirmation of “OFF” or “ON”. Patient should report: “OFF”/“ON” state at 
t = 0, 15, 30, 45, 60 and 90 minutes after dosing, 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). Patients will also be asked if they attained a full 
“ON” state anytime within 30 minutes. During the Dose Titration Phase only, these 
assessments may cease if the patient does not experience a full “ON” response within 
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45 minutes of dosing. The patient must be in an “OFF” state prior to dosing in order 
to proceed with dosing. 
• Provide patient with a home dosing diary (TV1 only; see APPENDIX V: Patient 
Home Dosing Diary). Diary will be provided for training purposes only. If needed, 
patients will be retrained at MV1 in the use of the home dosing diary. 
• Assess suicidal ideation using C-SSRS (see APPENDIX VI: Columbia Suicide 
Severity Rating Scale (C-SSRS)). “Since Last Visit” version should be used at these 
visits. 
• 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. 
• Provide patient with anti-nausea medication. 
Patients 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 perspective and 
may proceed to the Maintenance Treatment Phase of the study. This dose will be used in the 
Maintenance Treatment 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 patient 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 
patient safety and tolerability, the higher dose will be used during the Maintenance Treatment 
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 Maintenance Treatment Phase of the study. 
A full “ON” is defined in Section 13.6.3.1.  
Patients 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, patients 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 their standard dosage, or at a dosage considered appropriate by the Investigator to achieve an 
“ON” state. If this occurs, patients can return to the clinic on another day to resume the titration 
with the next highest dose.  However, if the patient cannot tolerate the “OFF” state and does not 
respond efficaciously to a dose of APL-130277, they will be terminated from the study. 
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• Assess patient using MDS-UPDRS Parts I, II and IV (MV4 only; see APPENDIX 
IV: Movement Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS)). 
• Assess patient motor function using MDS-UPDRS Part III at t = 0 (just prior to 
dosing), 15, 30, 45, 60 and 90 minutes after dosing (see APPENDIX IV: Movement 
Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)). 
• If patients are in the “OFF” state, dose with randomized treatment. 
• Investigator confirmation of “OFF” or “ON”. Investigator will assess “OFF”/“ON” 
state as part of the MDS-UPDRS Part III assessments. The patient must be in an 
“OFF” state prior to dosing in order to proceed with dosing. 
• Patient confirmation of “OFF” or “ON”. Patient should report: “OFF”/“ON” state at 
t = 0, 15, 30, 45, 60 and 90 minutes after dosing, 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). Patients will also be asked if they attained a full 
“ON” state anytime within 30 minutes of dosing. The patient must be in an “OFF” 
state prior to dosing in order to proceed with dosing. 
• Dispense outpatient supplies (excluding MV4). 
• Collect outpatient supplies (excluding MV1). 
• Provide patient with a home dosing diary (excluding MV4).  
• Collect patient home dosing diary. 
• Assess treatment compliance (excluding MV1). 
• Assess suicidal ideation using C-SSRS (see APPENDIX VI: Columbia Suicide 
Severity Rating Scale (C-SSRS)). “Since Last Visit” version should be used at these 
visits. 
• Provide the patient with the PDQ-39 to complete (see APPENDIX VII: PDQ-39). 
• Ask patient to complete the PGI (see APPENDIX IX: PGI). –S to be used at the first 
visit, -I to be used at all subsequent visits. 
• Complete the CGI (see APPENDIX VIII: CGI). –S to be used at the first visit, -I to 
be used at all subsequent visits. 
• Assess using the ESS (see APPENDIX X: ESS). 
• Assess caregiver burden using the ZBI (see APPENDIX XI: ZBI). 
• Complete the QUIP-RS (see APPENDIX XII: QUIP-RS). 
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• Provide the patient with the EQ-5D (see APPENDIX XIII: EQ-5D). 
• Outpatient self-administration training (MV1 only). Patients will be trained by clinic 
staff on how to remove study medication from its packaging, and how to handle the 
sublingual thin films using placebo sublingual thin films supplied to the site. Patients 
should not self-administer the placebo sublingual thin films. Patients cannot be 
discharged from clinic until satisfactorily completing the training. 
• 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. 
• Provide patient with anti-nausea medication, if applicable (excluding MV4). 
13.4.2 
At-Home Assessments 
During the 12-week Maintenance Treatment Phase, patients will be instructed to continue with 
their regular PD medication regimen(s), but should dose themselves with their randomized 
treatment (APL-130277 or placebo) if they experience an “OFF” episode (e.g., morning akinesia, 
wearing “OFF”, dose failure, sudden “OFF”, etc.) during the day while on their current treatment 
regimen. Patients will be instructed to dose up to 5 “OFF” episodes per day.  
 Prior to each in-clinic visit during the Maintenance Treatment Phase of the study, patients will be 
requested to complete a home dosing diary that captures: 
• Time of randomized treatment self-administration; 
• Patient “ON”/”OFF” state at 30 minutes after dosing. 
Patients will complete this diary for every self-administration they perform on each of these 2 days. 
Clinic staff will call each patient approximately 3 days prior to a scheduled in-clinic visit in order 
to remind patients to complete their home dosing diary. Patients should be reminded to document 
when they dose themselves and to accurately report their “ON”/”OFF” status at 30 minutes after 
dosing. 
13.4.3 
Telephone Contacts (T2 to T4) 
Sites will follow-up with patients at the mid-point between each in-clinic visit in order to assess 
study medication compliance, patient safety and well-being. If needed, an unscheduled Dose 
Adjustment Visit will be scheduled with the patient in order to further assess safety and well-being. 
Staff should enquire and record any AEs/SAEs that have occurred since the last patient visit, and 
any new concomitant medications and/or changes to current concomitant medications being used 
by the patient since the last visit.  
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13.4.4 
End of Study Visit 
Approximately 1 week following the completion of the study, patients will be asked to return for 
a final safety assessment visit. The following procedures will take place at this visit: 
• Reconfirm consent. 
• 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 supine vital signs (BP, HR, RR and Temp). Blood pressure to be measured 
both supine and standing (measured within 3 minutes of standing). 
• 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. 
• Collect outpatient supplies (if applicable). 
• Assess treatment compliance (if applicable). 
• Assess suicidal ideation using C-SSRS (see APPENDIX VI: Columbia Suicide 
Severity Rating Scale (C-SSRS)). 
• Provide the patient with the PDQ-39 to complete (see APPENDIX VII: PDQ-39). 
• Ask patient to complete the PGI-I (see APPENDIX IX: PGI). 
• Complete the CGI-I (see APPENDIX VIII: CGI). 
• Assess using the ESS (see APPENDIX X: ESS). 
• Assess caregiver burden using the ZBI (see APPENDIX XI: ZBI). 
• Complete the QUIP-RS (see APPENDIX XII: QUIP-RS). 
• Provide the patient with the EQ-5D (see APPENDIX XIII: EQ-5D). 
• 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. 
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13.4.5 
Early Terminations 
Every effort should be made to have patients complete all study visits. All patients who are 
terminated early in either the Dose Titration Phase or Maintenance Treatment Phase will all 
undergo the following assessments: 
• Reconfirm consent. 
• 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 supine vital signs (BP, HR, RR and Temp). Blood pressure to be measured 
both supine and standing (measured within 3 minutes of standing). 
• 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 (see APPENDIX VI: Columbia Suicide 
Severity Rating Scale (C-SSRS)). 
• 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. 
Patients whose participation is terminated early in the Maintenance Treatment Phase will also 
undergo the following assessments in addition to those listed above: 
• Collect outpatient supplies (if applicable). 
• Assess treatment compliance (if applicable). 
• Provide the patient with the PDQ-39 to complete (see APPENDIX VII: PDQ-39). 
• Ask patient to complete the PGI-I (see APPENDIX IX: PGI). 
• Complete the CGI-I (see APPENDIX VIII: CGI). 
• Assess using the ESS (see APPENDIX X: ESS). 
• Assess caregiver burden using the ZBI (see APPENDIX XI: ZBI). 
• Complete the QUIP-RS (see APPENDIX XII: QUIP-RS). 
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• Provide the patient with the EQ-5D (see APPENDIX XIII: EQ-5D). 
13.4.6 
Unscheduled Dose Adjustment Visits 
If at any time during the Maintenance Treatment Phase of this study, it is determined that a dose 
adjustment is required, the patient will return for an unscheduled Dose Adjustment Visit. The 
following will be performed: 
• Reconfirm consent. 
• Review restriction criteria. 
• Record supine vital signs (BP, HR, RR and Temp). Blood pressure to be measured 
both supine and standing (measured within 3 minutes of standing). 
• IWRS system transaction in order to obtain the proper new dose (if required). 
• Dispense new study medication for outpatient dosing (if required). 
• Collect remaining study medication provided at the last visit (if required). 
• Provide patient home dosing diary and instruct patients to complete it 2 days before 
their subsequent in-clinic visit. 
• Collect patient diaries completed since the last visit. 
• Assess treatment compliance. 
• 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. 
• Record reason for the dose adjustment. 
This visit may occur over multiple days to accommodate receipt of the new dose of study drug (if 
necessary).  
Dosage adjustments, if in the opinion of the Investigator are necessary for patient safety and 
tolerability, may reduce the scheduled dose of study drug the next lowest dose (e.g., to the 10 mg 
dose if the patient is receiving 15 mg). Increases in dosage in this study will not be allowed. The 
Investigator should make all attempts to maintain patients on a stable dose.  
Any patient whose dose has been reduced at a Dose Adjustment Visit will self-administer study 
drug using the lower dosage at home however, all in-clinic visits during the Maintenance 
Treatment Phase of the study will be assessed using the dose identified during the Dose Titration 
Phase as inducing a full “ON” response. If, in the opinion of the Investigator, use of this dose 
cannot be tolerated by the patient, they should be discontinued from the study. 
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o Multiple foci of reddening 
o Edema 
o Ulceration 
• Grade 
o Mild 
o Moderate 
o Severe 
All abnormal findings at baseline will be recorded on the Medical History/Concomitant Diagnoses 
page (or equivalent) of the CRF. New abnormal findings or a worsening of baseline conditions 
detected at follow-up physical examinations will be recorded as AEs on the CRF. 
The Investigator (or designate) should evaluate each finding against AE criteria and complete the 
AE CRF, as appropriate. Photographs for reference may be taken by the Investigator (or designate) 
provided the patient provides consent to do so. 
13.6.2.2 
Vital Signs 
Vital signs (HR, RR, BP and body temperature) will be measured at various timepoints after the 
patient has been in a supine position for 5 minutes. Vital signs will be measured at all scheduled 
study visits. Vital signs (BP only) will also be measured within three minutes of standing at all 
timepoints. 
During the Dose Titration Phase, if the 60 minute MDS-UPDRS Part III assessment is not 
performed since the patient 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.  
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. 
13.6.2.3 
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) only. If required by the 
Investigator to assess patient eligibility, a triplicate ECG may be performed at SV1 instead, but 
will not be repeated at SV2.  
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ECGs will be performed in a semi-recumbent position and after 5 minutes of rest.  
The following parameters will be reported in the CRF: 
• 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 contractor by the 
Sponsor. 
13.6.2.4 
Modified Hoehn and Yahr 
The Modified Hoehn and Yahr scale will be administered at the second Screening Visit (SV2) to 
verify patients meet the eligibility criteria for this study. This will be conducted in the “OFF” and 
“ON” state. 
13.6.2.5 
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. 
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Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones  
Serology (at the 
Screening Visit only): 
Human immunodeficiency virus (HIV), Hepatitis B surface 
antigen, Hepatitis C antibodies 
13.6.2.6 
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 patient 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. 
13.6.2.7 
C-SSRS 
Formal assessments of patient suicidal ideation and behavior will be assessed at the second 
Screening Visit (SV2) and all in-clinic visits during the Dose Titration Phase and Maintenance 
Treatment Phase of the study. A final assessment will be performed at the time of termination, 
regardless if it is scheduled (i.e., at EOS visit) or an early termination/withdrawal. 
At the Screening Visit (SV2), the C-SSRS ‘Screening’ assessment tool will be used. Patients 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. 
The Investigator should closely monitor the responses of patients during the interview and watch 
for signs that suggest current suicidal ideation or intent. 
13.6.2.8 
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 
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• ZBI – Optional; to be completed if caregiver is present and consent is provided. 
• QUIP-RS 
• EQ-5D 
These assessments will be performed at any point during the scheduled visit in accordance with 
the guidelines for each (see applicable Appendices). 
13.6.2.9 
Medical History 
At the Screening Visits, the Investigator (or designate) will review the patient’s medical history in 
order to ascertain the patient’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 patients PD history, 
including, but not limited to: 
• Year of Diagnosis; 
• Presence of a rest tremor at the time of diagnosis; 
• Year when motor fluctuations began; 
• Type of “OFF” episodes experienced (e.g., morning akinesia, wearing “OFF, delayed 
“ON”, dose failure, sudden “OFF”); 
• Number of “OFF” episodes per day; 
• Typical length of “OFF” episodes. 
• PD medications previously or currently taken, including: 
o dopamine agonists; 
o MAO-B inhibitors; 
o COMT inhibitors; 
o Amantadine; 
o Anti-cholinergics. 
13.6.3 
Efficacy Assessments 
13.6.3.1 
Confirmation of “OFF” or “ON” Episodes 
“OFF” and “ON” Training of Patients at SV2 
At Screening Visit 2 (SV2), patients will present to the clinic having taken their last dose of L-
Dopa and any other adjunctive PD medication no later than midnight the evening prior to the visit. 
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Their normal morning dose of L-Dopa (without adjunctive PD medication) will be administered 
in the clinic. Prior to administration of their L-Dopa dose, patients will be examined by the 
Investigator in order to verify that they are in the “OFF” state.  If they are in the “OFF” state, the 
Investigator will educate the patient that this is an “OFF” period or “OFF” episode.  The 
Investigator should clearly explain to the patient that this “OFF” time is when their medication has 
worn off, and does not provide benefits in terms of mobility, slowness and stiffness. 
Patients will then take their normal morning dose of L-Dopa. Once the Investigator determines 
that the patient is experiencing an “ON” state, they should educate the patient that this is an “ON” 
state. The Investigator should clearly explain to the patient 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 patient who cannot differentiate between an “ON” and “OFF” state will be deemed a screen 
failure.  
Definitions of Full “ON” and “OFF” 
The following definitions will be used in this study: 
 “OFF” – defined as: 
• A period of time when medication has worn off and is no longer providing benefit 
with regard to mobility, slowness, and stiffness; 
• Confirmed by the Investigator using their clinical judgement as “OFF”**; 
• Confirmed by the patient as “OFF”. 
** Not applicable for at-home assessments using the patient dosing diary. 
Full “ON” as assessed by the patient – defined as: 
• A period of time where medication is providing benefit with regard to mobility, 
stiffness and slowness and where a patient 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 patient has adequate motor function to allow them to perform their normal daily 
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activities.  
Clinical confirmation of the “OFF” state must occur prior to dosing a patient with study medication 
(or their standard L-Dopa dose at the second Screening Visit (SV2)). The same assessor should be 
utilized for each patient throughout the study. 
Patients must confirm they are in an “OFF” state prior to dosing with study medication (or their 
standard L-Dopa dose at the second Screening Visit (SV2)). 
At each Dose Titration and Maintenance Treatment Visit, the Investigator will assess “OFF/”ON” 
state as part of the MDS-UPDRS Part III assessments.  
At each Dose Titration and Maintenance Treatment Visit, the patient should report: “OFF”/”ON” 
state at 0, 15, 30, 45, 60 and 90 minutes after dosing (site staff should prompt the patient). Patients 
will also be asked if they attained a full “ON” state anytime within 30 minutes of dosing. Patients 
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). The timing of this 
should begin when the study medication sublingual thin 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, patient 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.  
13.6.3.2 
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 second 
Screening Visit (SV2) and at Maintenance Visit 4 (MV4). 
13.6.3.3 
MDS-UPDRS Part III 
The Motor Function section (Part III) of the MDS-UPDRS will be administered at all visits where 
it is indicated. Administration will be performed at t = 0 (just prior to dosing) and at 15, 30, 45, 60 
and 90 minutes after dose administration (or L-Dopa administration at the second Screening Visit 
(SV2)). The same assessor should be utilized for each patient throughout the study.  
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 SV2. 
During the Dose Titration Phase only, Investigator assessments may cease if the patient 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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14 
ADVERSE EVENTS 
Adverse events will be recorded from the time of signing of the ICF by the patient through to study 
completion or earlier, if warranted by a patient discontinuation. 
14.1.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject (or patient) or clinical investigation subject 
(or patient) administered a pharmaceutical product that does not necessarily have a causal 
relationship with the product. An AE can therefore be any unfavorable and unintended sign 
(including a new, clinically important abnormal laboratory finding), symptom, or disease, 
temporally associated with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. 
14.1.2 
Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening; 
• Requires in-subject hospitalization (being admitted) or prolongation of existing 
hospitalization; 
• Results in permanent (persistent) disability/incapacity; 
• Is a congenital anomaly; 
• Is an important medical event. 
Medical and scientific judgment should be exercised in deciding whether it is appropriate to 
consider other situations serious, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject (or patient) or 
may require intervention to prevent another of the outcomes listed in the definition above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the investigational 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition 
or event as an SAE. 
A spontaneous abortion or congenital anomaly in an infant born to a mother who was exposed to the 
investigational drug during pregnancy is an SAE. 
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Due to the nature of patients being enrolled in this study, and the given study objectives, 
patients who are admitted for their titration and maintenance “OFF” exam will not be 
considered a SAE. 
14.1.3 
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 
 
14.1.4 
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.) 
 
14.1.5 
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. 
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14.1.6 
Definition of Expectedness 
An expected AE is an AE for which the nature or severity is consistent with the known AE profile 
of the product. For an investigational drug, the known information is contained in the IB. For a 
marketed product, the known information is contained in the current package insert for the product. 
An unexpected AE is an AE for which the specificity or severity is not consistent with the current 
IB. For example, hepatic necrosis would be unexpected (greater severity) if the IB only listed 
elevated hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (greater specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. Examples would be (a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
and (b) hepatitis with a first occurrence of fulminate hepatitis. 
14.1.7 
Definition of Relationship to Investigational Drug(s) 
The categories for classifying the Investigator’s opinion regarding the relationship of an AE to 
investigational drug(s) are listed below: 
Certain: 
An AE occurring in a plausible time relationship to 
investigational drug administration and which cannot be 
explained by a concurrent disease or other drugs or events. 
The response to withdrawal of the drug (dechallenge) is 
clinically reasonable. 
Probable (likely): 
An AE with a reasonable time sequence to administration of 
the investigational drug and which is unlikely to be attributed 
to concurrent disease or other drugs or events. The response to 
withdrawal of the drug (dechallenge) is clinically reasonable. 
Possible: 
An AE with a reasonable time sequence to administration of 
the investigational drug, but which could also be explained by 
concurrent disease or other drugs or events. Information on 
drug withdrawal may be lacking or unclear. 
Unlikely: 
An AE, including laboratory test abnormality, with a temporal 
relationship to investigational drug administration that makes a 
causal relationship improbable and in which other drugs, 
events, or underlying disease provide plausible explanations. 
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Not related: 
An AE with sufficient evidence to accept that there is no 
causal relationship to investigational drug administration (e.g., 
no temporal relationship to drug administration, because the 
drug was administered after onset of event; investigation 
shows that the drug was not administered; another cause was 
proven; etc.). 
 
14.1.8 
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 patient’s death, the outcome of death should be indicated for the AE 
attributed as the cause of death in the death certificate or summary. 
14.1.9 
Documentation of Adverse Events 
The Investigator will monitor and/or ask about or evaluate AEs using non-leading questions at 
each visit or evaluation. The occurrence of all AEs will be documented in the CRF with the 
following information, where appropriate: 
• AE name or term; 
• When the AE first occurred (start date); 
• When the AE stopped (stop date), or an indication of “ongoing”; 
• How long the AE persisted (optional); 
• Severity of the AE; 
• Seriousness; 
• Actions taken; 
• Outcome; 
• Investigator opinion regarding the relationship of AE to the investigational drug(s). 
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14.1.10 
Follow-up of Patients With an Adverse Event 
Any AE will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by another known cause(s) (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. All findings relevant to the final 
outcome of an AE must be reported in the patient’s medical record. 
14.1.11 
Special Procedures for Managing AEs/SAEs and Need for Unblinding 
If AEs occur in a patient 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 patient. Patient 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. 
When a patient has an AE that requires that the Investigator be unblinded, the Investigator can 
obtain the treatment assignment from the IWRS system. The site is expected to notify the Study 
Medical Monitor before breaking the study blind, unless it is in the patient’s best interest if the 
blind is broken immediately. Note: in most circumstances it is not necessary to unblind a patient, 
even if an SAE has occurred. For many drugs there is no specific therapy for AEs. The appropriate 
course of action is to stop the investigational drug, and treat the signs and symptoms resulting from 
the AE. 
14.1.12 
Notification of Serious Adverse Events 
The Investigator must report all SAEs and pregnancies promptly to Cynapsus or its designee, by 
completing an SAE form (which will be provided) and fax within 24 hours of first becoming aware 
of the event. Fax: 1-877-464-7787. 
In the event of an issue with the fax line; the Investigator should forward the SAE form via email 
to INCDrugSafety@INCresearch.com. 
The Investigator will be able to contact Dr. Jordan Dubow, the study Medical Monitor, at +1 (224) 
213-2114.  
If a SAE is reported via telephone, the Investigator must follow up the initial telephone notification 
by completing a SAE form and faxing it to 1-877-464-7787.   
At the time of the first notification of an SAE, the study site should provide the following 
information to the Cynapsus contact person, if available: 
• Patient’s study number and initials 
• Patient’s date of birth 
• Patient’s gender 
• Date of first dose of investigational drug(s) 
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• Date of last dose of investigational drug(s), if applicable 
• AE term 
• Time and date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to investigational drug(s). (“Is there a 
reasonable possibility that the investigational drug caused the SAE? Yes or No?”) 
• Whether and when the Investigator was unblinded as to the patient’s treatment 
assignment 
Any missing or additional relevant information concerning the serious (or unexpected) AE should 
be provided in a written follow-up report. 
The Investigator is required to comply with applicable regulations regarding the notification of 
his/her IRB/ REB/IEC. 
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Cynapsus will authorize shipment of investigational drug to the clinical site. Copies of the 
Investigator’s regulatory documents must be retained at the clinical site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the APL-
130277 IB, copies of regulatory references, copies of IRB/REB/IEC correspondence, and 
investigational drug accountability records must be retained as part of the Investigator’s regulatory 
documents. It is the Investigator’s responsibility to ensure that copies of all required regulatory 
documents are organized, current, and available for inspection. 
Documents Required for Regulatory Packet: 
Confidentiality Agreement 
Signed Clinical Trial Agreement 
Final Protocol 
PI CV 
Final Protocol Amendments (if any) 
PI Medical License 
Protocol Signature Pages 
Sub-Investigator CV 
Protocol Amendment  Signature Pages  
(if any) 
Sub-Investigator License 
APL-130277 IB 
IRB Approvals 
Signed Financial Disclosure 
IRB Membership List / Assurance Statement  
Regulatory Agency Approval  
Approved Informed Consent Template(s) 
 
PI signed FDA Form 1572 / Qualified 
Investigator Undertaking 
 
Additional documentation requirements may be communicated by Cynapsus staff (or its 
designate). 
17.3.2 
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 patients who 
sign an ICF. 
The vendor selected to perform CRF design will be responsible for drafting CRFs for the study, 
which Cynapsus 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. 
Cynapsus 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. 
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that it sponsors. Cynapsus, 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. 
17.4.1 
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 Cynapsus personnel access. The 
clinical site will be monitored by Cynapsus and/or its designate to ensure compliance with the 
protocol, GCP, and applicable regulations and guidelines. As representatives of Cynapsus, CRAs 
are responsible for following the study protocol closely and notifying project management of any 
noted deviations. The assigned CRA(s) will visit the Investigator and clinical site at periodic 
intervals and maintain periodic communication. The CRA(s) will maintain current knowledge of 
the study through observation, review of study records and source documentation, and discussion 
of the conduct of the study with the Investigator and staff. While on site, the CRA(s) will review 
regulatory documents, compare entries in the source documents, and review investigational drug 
accountability records. The CRA will ask for clarification and/or correction of any noted 
inconsistencies. 
By signing the protocol, the Investigator agrees to meet with the CRA during clinical site visits, to 
ensure that study staff is available to the CRA(s) as needed, to provide the CRA(s) access to all 
study documentation, 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. 
17.4.2 
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 Cynapsus. 
Should an EDC system be implemented, the CRA will verify data with source documents. If the 
CRA’s comparison of the original EDC module data with source documents reveals data 
discrepancies or omissions that require study staff to make corrections, the corrections will be 
made as outlined in the Study Monitoring Plan. After the EDC module data have been monitored 
and all corrections have been made, the Investigator must appropriately document within the data 
system his/her agreement with the data contained therein. If corrections are required subsequent 
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to the Investigator’s signature, the Investigator must document his/her agreement with the EDC 
module data to confirm the accuracy of the changed data. A copy of all EDC module data will be 
retained at the clinical site. If corrections are required after all data have been electronically 
transferred, the corrections must be made as instructed in site training. 
17.4.3 
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 Cynapsus. 
17.4.4 
Data Management 
A vendor contracted by Cynapsus 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. 
17.4.5 
Study Termination 
The study may be terminated at Cynapsus’ discretion at any time for any reason. If Cynapsus 
discovers conditions that warrant early termination of the study, the Investigator will be notified 
by Cynapsus 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 patients enrolled 
in the study; and 
• The decision on the part of Cynapsus to suspend or discontinue testing, evaluation, 
or development of the investigational product. 
17.4.6 
Clinical Site Closure 
On termination of the study, all screening and ongoing study related procedures conducted at the 
clinical site will be closed. Cynapsus 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 patient enrollment; 
• Administrative reasons. 
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17.4.7 
Data Safety Monitoring Board 
A DSMB will be utilized in this study in order to monitor patient 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 patient 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 our potential outcomes. 
The independent statistician will have access to the randomization code, and will receive 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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19 
REFERENCES 
1) Tanner CM, Goldman SM.  Epidemiology of Parkinson's disease.  Neurol 
Clin.  1996;14:317-35. 
2) Hornykiewicz O.  Basic research on dopamine in Parkinson's disease and the discovery of 
the nigrostriatal dopamine pathway:  the view of an eyewitness.  Neurodegener 
Dis.  2008;5:114–7. 
3) Mouradian MM, Heuser IJ, Baronti F, et al.  Pathogenesis of dyskinesias in Parkinson's 
disease.  Ann Neurol.  1989;25(5):523-6. 
4) Stocchi F, Vacca L, Ruggieri S, et al.  Intermittent vs. continuous levodopa administration 
in patients with advanced Parkinson disease.  Arch Neurol.  2005;62(6):905-10). 
5) Ahlskog JE, Muenter MD.  Frequency of levopdopa-related dyskinesias and motor 
fluctuations as estimated from the cumulative literature.  Mov Disord.  2001;16(3):448-
58). 
6) Dent JY (1949). “Apomorphine Treatment of Addiction.” British Journal of Addiction to 
Alcohol & Other Drugs 46 (1); 15-210. 
7) Cotzias G, Papavasiliou P, Fehling C, Kaufman B, Mena I (1970). "Similarities between 
neurologic effects of L-dopa and of apomorphine.". N Engl J Med 2102 (1): 31–33. 
8) Corsini G, Del Zompo M, Gessa G, Mangoni A (1979). "Therapeutic efficacy of 
apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson's 
disease.". Lancet 1 (10123): 954–56. 
9) 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." The Journal of Pharmacology and Experimental Therapeutics 303 (2): 
791–1004. 
10) Schwab R, Amador L, Lettvin J (1951). "Apomorphine in Parkinson's disease." 
11) Trans Am Neurol Assoc 56: 251–253. 
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_____________________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________________________ 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
APOKYN® safely and effectively.  See full prescribing information for 
APOKYN®.
APOKYN® (apomorphine hydrochloride injection)
For Subcutaneous Use Only
Initial U.S. Approval: 2004 
---------------------------RECENT MAJOR CHANGES---------------------------
Warnings and Precautions 
Impulse Control/Compulsive Behaviors (5.9) 
07/2014 
----------------------------INDICATIONS AND USAGE---------------------------
APOKYN is a non-ergoline dopamine agonist indicated for the acute, 
intermittent treatment of hypomobility, “off” episodes (“end-of-dose wearing 
off” and unpredictable “on/off” episodes) associated with advanced 
Parkinson’s disease (1) 
----------------------DOSAGE AND ADMINISTRATION-----------------------
x For subcutaneous use only (2.1) 
x Always express APOKYN dose in mL to minimize dosing errors (2.1) 
x The starting dose of APOKYN is 0.2 mL (2 mg); give the first dose under 
medical supervision; titrate the dose to effect and tolerance; the maximum 
recommended dose is 0.6 mL (2.3) 
x Treatment with a concomitant antiemetic, e.g., trimethobenzamide, is 
recommended, starting 3 days prior to the first dose of APOKYN, and for 
at least the first two months of therapy (2.2, 5.2) 
x APOKYN doses must be separated by at least 2 hours (2.6) 
x Renal impairment: reduce test dose, and reduce starting dose to 0.1 mL 
(1 mg) (2.4, 8.6, 12.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Multi-dose glass cartridges, 30 mg/3 mL (10 mg/mL) for use with a multiple-
dose pen injector (APOKYN Pen) (3, 16)
-------------------------------CONTRAINDICATIONS------------------------------
x Concomitant use of APOKYN with 5HT3 antagonists, including 
antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and 
alosetron, is contraindicated (4) 
x Hypersensitivity to apomorphine, its excipients or sodium metabisulfite (4) 
-----------------------WARNINGS AND PRECAUTIONS------------------------
x For subcutaneous use only; thrombus formation and pulmonary embolism 
have followed intravenous administration of APOKYN (5.1) 
x Falling asleep during activities of daily living, and daytime somnolence 
may occur (5.3) 
x Syncope and hypotension/orthostatic hypotension may occur (5.4, 5.5) 
x Falls may occur, or increase (5.6) 
x May cause hallucinations and psychotic-like behavior (5.7) 
x May cause dyskinesia or exacerbate pre-existing dyskinesia (5.8)
x May cause problems with impulse control and impulsive behaviors (5.9) 
x May cause coronary events (5.10) 
x May prolong QTc and cause torsades de pointes or sudden death (5.11)
------------------------------ADVERSE REACTIONS-------------------------------
Most common adverse reactions (incidence at least 10% greater on APOKYN 
than on placebo) were yawning, drowsiness/somnolence, dyskinesias, 
dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, 
hallucination/confusion, and edema/swelling of extremities (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact US
WorldMeds at -1-877-727-6596 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
x Concomitant use of antihypertensive medications and vasodilators:
increased risk for hypotension, myocardial infarction, pneumonia, falls, and 
injuries (7.2)
x Dopamine antagonists such as neuroleptics or metoclopramide, may 
diminish the effectiveness of APOKYN (7.3) 
-----------------------USE IN SPECIFIC POPULATIONS------------------------
x Pregnancy: Based on animal data, may cause fetal harm (8.1) 
x Geriatric Use: In clinical trials, patients 65 years of age and older were 
more likely to experience certain adverse events (8.5) 
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling. 
Revised: 07/2014
FULL PRESCRIBING INFORMATION: CONTENTS* 
1
INDICATIONS AND USAGE 
2
DOSAGE AND ADMINISTRATION 
2.1 
Important Administration Instructions 
2.2 
Premedication and Concomitant Medication 
2.3 
Dosing Information 
2.4 
Dosing in Patients with Renal Impairment 
2.5 
Dosing in Patients with Hepatic Impairment 
2.6 
Re-treatment and Interruption in Therapy 
3
DOSAGE FORMS AND STRENGTHS 
4
CONTRAINDICATIONS 
5
WARNINGS AND PRECAUTIONS 
5.1 
Serious Adverse Reactions after Intravenous Administration 
5.2 
Nausea and Vomiting 
5.3 
Falling Asleep During Activities of Daily Living and 
Somnolence 
5.4 
Syncope 
5.5 
Hypotension/Orthostatic Hypotension 
5.6 
Falls 
5.7 
Hallucinations/Psychotic-Like Behavior 
5.8 
Dyskinesias 
5.9 
Impulse Control/Compulsive Behaviors 
5.10 
Coronary Events 
5.11 
QTc Prolongation and Potential for Proarrhythymic Effects 
5.12 
Withdrawal-Emergent Hyperpyrexia and Confusion 
5.13 
Melanoma 
5.14 
Fibrotic Complications 
5.15 
Priapism 
5.16 
Retinal Pathology in Albino Rats 
6
ADVERSE REACTIONS 
6.1 
Clinical Trial Experience 
7
DRUG INTERACTIONS 
7.1 
5HT3 Antagonists 
7.2 
Antihypertensive Medications and Vasodilators 
7.3 
Dopamine Antagonists 
7.4 
Drugs Prolonging the QT/QTc Interval 
8
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.3 
Nursing Mothers 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
8.6 
Renal Impairment
8.7 
Hepatic Impairment 
9
DRUG ABUSE AND DEPENDENCE 
9.2 
Abuse 
10 OVERDOSAGE 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.2 
Pharmacodynamics 
12.3 
Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
14  CLINICAL STUDIES 
16  HOW SUPPLIED/STORAGE AND HANDLING 
17  PATIENT COUNSELING INFORMATION 
*Sections or subsections omitted from the Full Prescribing Information are not 
listed 
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FULL PRESCRIBING INFORMATION 
1
INDICATIONS AND USAGE 
APOKYN® (apomorphine hydrochloride injection) is indicated for the acute, intermittent treatment of 
hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes) in 
patients with advanced Parkinson’s disease. APOKYN has been studied as an adjunct to other 
medications [see Clinical Studies (14)].
2
DOSAGE AND ADMINISTRATION 
2.1
Important Administration Instructions 
APOKYN is indicated for subcutaneous administration only [see Warnings and Precautions (5.1)] and 
only by a multiple-dose APOKYN Pen with supplied cartridges.  The initial dose and dose titrations 
should be performed by a healthcare provider. Blood pressure and pulse should be measured in the 
supine and standing position before and after dosing. 
A caregiver or patient may administer APOKYN if a healthcare provider determines that it is 
appropriate. Instruct patients to follow the directions provided in the Patients Instructions For Use. 
Because the APOKYN Pen has markings in milliliters (mL), the prescribed dose of APOKYN should be 
expressed in mL to avoid confusion.  
Visually inspect the APOKYN drug product through the viewing window for particulate matter and 
discoloration prior to administration. The solution should not be used if discolored (it should be 
colorless), or cloudy, or if foreign particles are present. Rotate the injection site and use proper aseptic 
technique [see How Supplied/Storage and Handling (16) and Patient Counseling Information (17)].
2.2
Premedication and Concomitant Medication 
APOKYN should be initiated with the use of a concomitant antiemetic [see Warnings and Precautions 
(5.2)]. Oral trimethobenzamide (300 mg three times a day) should be started 3 days prior to the initial 
dose of APOKYN and continued at least during the first two months of therapy. 
Based on reports of profound hypotension and loss of consciousness when apomorphine was 
administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist 
class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and 
alosetron are contraindicated [see Contraindications (4)]. 
2.3
Dosing Information 
The recommended starting dose of APOKYN is 0.2 mL (2 mg).  Titrate on the basis of effectiveness and 
tolerance, up to a maximum recommended dose of 0.6 mL (6 mg) [see Clinical Studies (14)].
There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased 
effect and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average 
frequency of dosing in the development program was 3 times per day. There is limited experience with 
single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses 
greater than 2 mL (20 mg). 
Begin dosing when patients are in an “off” state.  The initial dose should be a 0.2 mL (2 mg) test dose in 
a setting where medical personnel can closely monitor blood pressure and pulse. Both supine and 
standing blood pressure and pulse should be checked pre-dose and at 20 minutes, 40 minutes, and 60 
minutes post-dose (and after 60 minutes, if there is significant hypotension at 60 minutes). Patients who 
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develop clinically significant orthostatic hypotension in response to this test dose of APOKYN should 
not be considered candidates for treatment with APOKYN. 
If the patient tolerates the 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be 
0.2 mL (2 mg), used on an as needed basis to treat recurring “off” episodes. If needed, the dose can be 
increased in 0.1 mL (1 mg) increments every few days on an outpatient basis. 
The general principle guiding subsequent dosing (described in detail below) is to determine that the 
patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under 
close medical supervision. A trial of outpatient dosing may follow (periodically assessing both efficacy 
and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose. 
If the patient tolerates the 0.2 mL (2 mg) test dose but does not respond adequately, a dose of 
0.4 mL (4 mg) may be administered under medical supervision, at least 2-hours after the initial test dose, 
at the next observed “off” period. If the patient tolerates and responds to a test dose of 0.4 mL (4 mg),
the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring “off” 
episodes as an outpatient. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few 
days on an outpatient basis. 
If the patient does not tolerate a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be 
administered during a separate “off” period under medical supervision, at least 2-hours after the 
previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should 
be 0.2 mL (2 mg) used on an as needed basis to treat existing “off” episodes. If needed, and the 
0.2 mL (2 mg) dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days. In such a 
patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an out-patient basis. 
2.4 
Dosing in Patients with Renal Impairment 
For patients with mild and moderate renal impairment, the test dose and starting dose should be reduced 
to 0.1 mL (1 mg) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].
2.5. 
Dosing in Patients with Hepatic Impairment 
Closely monitor patients with mild and moderate hepatic impairment [see Clinical Pharmacology (12.3) 
and Use in Specific Populations (8.7)].
2.6 
Re-treatment and Interruption in Therapy 
If a single dose of APOKYN is ineffective for a particular “off” period, a second dose should not be 
given for that “off” episode. The efficacy of the safety of administering a second dose for a single “off” 
episode has not been studied systematically. Do not administer a repeat dose of APOKYN sooner than 2 
hours after the last dose. 
Patients who have an interruption in therapy of more than a week should be restarted on a 0.2 mL (2 mg) 
dose and gradually titrated to effect and tolerability.
3 
DOSAGE FORMS AND STRENGTHS 
APOKYN 30 mg/3 mL (10 mg/mL) containing apomorphine hydrochloride (as apomorphine 
hydrochloride hemihydrate), USP is supplied as a clear, colorless, sterile, solution in a 3 mL (30 mg) 
cartridge. The 3 mL (30 mg) glass cartridge is used with a manual reusable, multiple-dose pen injector 
(APOKYN Pen). A single cartridge, pen and needle can deliver doses up to 1 mL (10 mg) in 
0.02 mL (0.2 mg) increments. The multiple-dose pen injector is provided in a package with six needles. 
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4
5
5.1
5.2
5.3
CONTRAINDICATIONS 
APOKYN is contraindicated in patients:
x Using concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, 
granisetron, dolasetron, palonosetron) and alosetron [see Drug Interactions (7.1)]. There have been 
reports of profound hypotension and loss of consciousness when APOKYN was administered with 
ondansetron. 
x With hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or various 
manifestations of angioedema to apomorphine or to any of the excipients including a sulfite (i.e., 
sodium metabisulfite). Patients with a sulfite sensitivity may experience various allergic-type 
reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. Patients who 
experience any hypersensitivity/allergic reaction to APOKYN should avoid taking APOKYN again. 
WARNINGS AND PRECAUTIONS 
Serious Adverse Reactions After Intravenous Administration 
Following intravenous administration of APOKYN, serious adverse reactions including thrombus 
formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred.  
Consequently, APOKYN should not be administered intravenously. 
Nausea and Vomiting 
APOKYN causes severe nausea and vomiting when it is administered at recommended doses. Because 
of this, in domestic clinical studies, 98% of all patients were pre-medicated with trimethobenzamide, an 
antiemetic, for three days prior to study enrollment, and were then encouraged to continue 
trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical 
studies, 31% and 11% of the APOKYN-treated patients had nausea and vomiting, respectively, and 3% 
and 2% of the patients discontinued APOKYN due to nausea and vomiting, respectively. Among 522 
patients treated, 262 (50%) discontinued trimethobenzamide while continuing APOKYN. The average 
time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 
262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without 
trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years). 
The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) to reduce 
the incidence of nausea and/or vomiting in APOKYN-treated patients has not been studied. Antiemetics 
with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, 
metaclopramide) have the potential to worsen the symptoms in patients with Parkinson’s disease and 
should be avoided. 
Falling Asleep During Activities of Daily Living and Somnolence 
There have been reports in the literature of patients treated with APOKYN subcutaneous injections who 
suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. 
Somnolence is commonly associated with APOKYN, and it is reported that falling asleep while engaged 
in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not 
give such a history. Somnolence was reported in 35% of patients treated with APOKYN and in none of 
the patients in the placebo group. Prescribers should reassess patients for drowsiness or sleepiness, 
especially since some of the events occur well after the start of treatment. Prescribers should also be 
aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about 
drowsiness or sleepiness during specific activities. 
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5.4
5.5
5.6
5.7
Before initiating treatment with APOKYN, advise patients of the risk of drowsiness and ask them about 
factors that could increase the risk with APOKYN, such as concomitant sedating medications and the 
presence of sleep disorders. If a patient develops significant daytime sleepiness or falls asleep during 
activities that require active participation (e.g., conversations, eating, etc.), APOKYN should ordinarily 
be discontinued. If a decision is made to continue APOKYN, patients should be advised not to drive and 
to avoid other potentially dangerous activities. There is insufficient information to determine whether 
dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 
Syncope 
In clinical studies, approximately 2% of APOKYN-treated patients experienced syncope. 
Hypotension / Orthostatic Hypotension
Dopamine agonists, including APOKYN, may cause orthostatic hypotension at any time but especially 
during dose escalation. Patients with Parkinson’s disease may also have an impaired capacity to respond 
to an orthostatic challenge. For these reasons, Parkinson’s disease patients being treated with 
dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic 
hypotension, especially during dose escalation, and should be informed of this risk. 
Patients undergoing titration of APOKYN showed an increased incidence (from 4% pre-dose to 18% 
post-dose) of systolic orthostatic hypotension (≥ 20 mmHg decrease) when evaluated at various times 
after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension 
(≥ 30 mmHg decrease and systolic BP ≤ 90 mmHg) after subcutaneous apomorphine injection. In 
clinical trials of APOKYN in patients with advanced Parkinson’s disease, 59 of 550 patients (11%) had 
orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in 
4 patients (< 1%) and resulted in withdrawal of APOKYN in 10 patients (2%). These events occurred 
both with initial dosing and during long-term treatment. Whether or not hypotension contributed to other 
significant adverse events seen (e.g., falls), is unknown. APOKYN causes dose-related decreases in 
systolic (SBP) and diastolic blood pressure (DBP) [see Clinical Pharmacology (12.2)].
The hypotensive effects of APOKYN may be increased by the concomitant use of alcohol, 
antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid alcohol when 
using APOKYN. Check blood pressure for hypotension and orthostatic hypotension in patients 
APOKYN with concomitant antihypertensive medications and/or vasodilators [see Drug Interactions 
(7.2)]. 
Falls 
Patients with Parkinson’s disease (PD) are at risk of falling due to underlying postural instability, 
possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs 
used to treat PD. Subcutaneous APOKYN might increase the risk of falling by simultaneously lowering 
blood pressure and altering mobility [see Clinical Pharmacology (12.2)].
In clinical trials, 30% of patients had events that could reasonably be considered falls and about 5% of 
patients had falls that were considered serious. 
Hallucinations / Psychotic-Like Behavior 
In clinical studies, hallucinations were reported by 14% of the APOKYN-treated patients. In one 
randomized, double-blind, placebo-controlled study, hallucinations or confusion occurred in 10% of 
patients treated with APOKYN and 0% of patients treated with placebo. Hallucinations resulted in 
discontinuation of APOKYN in 1% of patients. 
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Post marketing reports indicate that patients may experience new or worsening mental status and 
behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing 
the dose of APOKYN.  Other drugs prescribed to improve the symptoms of Parkinson’s disease can 
have similar effects on thinking and behavior.  This abnormal thinking and behavior can consist of one 
or more of a variety of manifestations, including paranoid ideation, delusions, hallucinations, confusion, 
disorientation, aggressive behavior, agitation, and delirium. 
Patients with a major psychotic disorder should ordinarily not be treated with APOKYN because of the 
risk of exacerbating psychosis.  In addition, certain medications used to treat psychosis may exacerbate 
the symptoms of Parkinson’s disease and may decrease the effectiveness of APOKYN [see Drug 
Interactions (7.3)].
5.8 
Dyskinesias 
APOKYN may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical studies, dyskinesia or 
worsening of dyskinesia was reported in 24% of patients. Overall, 2% of APOKYN-treated patients 
withdrew from studies due to dyskinesias. 
5.9 
Impulse Control/Compulsive Behaviors 
Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, 
intense urges to spend money uncontrollably, and other intense urges and the inability to control these 
urges while taking one or more of the medications, including APOKYN, that increase central 
dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, 
although not all, these urges were reported to have stopped when the dose was reduced or the medication 
was discontinued. Because patients may not recognize these behaviors as abnormal it is important for 
prescribers to specifically ask patients or their caregivers about the development of new or increased 
gambling urges, sexual urges, uncontrolled spending or other urges while being treated with APOKYN. 
Physicians should consider dose reduction or stopping the medication if a patient develops such urges 
while taking APOKYN. 
5.10 
Coronary Events 
In clinical studies, 4% of patients treated with APOKYN experienced angina, myocardial infarction, 
cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close 
proximity to APOKYN dosing (within 2 hours), while other cases of cardiac arrest and sudden death 
were observed at times unrelated to dosing. APOKYN has been shown to reduce resting systolic and 
diastolic blood pressure and may have the potential to exacerbate coronary (and cerebral) ischemia in
patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms 
of coronary or cerebral ischemia, prescribers should re-evaluate the continued use of APOKYN.
5.11 
QTc Prolongation and Potential for Proarrhythymic Effects 
There is a small dose related prolongation of QTc interval with doses of APOKYN greater than 6 mg
[See Clinical Pharmacology (12.2)]. Doses greater than 6 mg do not provide additional clinical benefit 
and are not recommended. 
Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. 
The relationship of QTc prolongation to torsades de pointes is clearest for larger increases (20 msec and 
greater), but it is possible that smaller QTc prolongations may also increase risk, or increase it in 
susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant 
use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation 
of the QT interval). Although torsades de pointes has not been observed in association with the use of 
APOKYN at recommended doses in clinical studies, experience is too limited to rule out an increased 
risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes. 
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The risks and benefits of APOKYN treatment should be considered prior to initiating treatment with 
APOKYN in patients with risk factors for prolonged QTc. 
5.12 
Withdrawal-Emergent Hyperpyrexia and Confusion 
A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated 
temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious 
etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in 
antiparkinsonian therapy. 
5.13 
Melanoma 
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to 
approximately 6-fold higher) of developing melanoma than the general population. Whether the 
increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat 
Parkinson’s disease, is unclear. 
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently 
and on a regular basis when using APOKYN for any indication. Ideally, periodic skin examinations 
should be performed by appropriately qualified individuals (e.g., dermatologists). 
5.14 
Fibrotic Complications 
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac 
valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While 
these complications may resolve when the drug is discontinued, complete resolution does not always 
occur. Although these adverse reactions are believed to be related to the ergoline structure of these 
dopamine agonists, whether other, nonergot derived dopamine agonists, such as APOKYN, can cause 
these reactions is unknown. 
5.15 
Priapism 
APOKYN may cause prolonged painful erections in some patients. In clinical studies, painful erections 
were reported by 3 of 361 APOKYN-treated men, and one patient withdrew from APOKYN therapy 
because of priapism. Although no patients in the clinical studies required surgical intervention, severe 
priapism may require surgical intervention. 
5.16 
Retinal Pathology in Albino Rats 
In a 2-year carcinogenicity study of apomorphine in albino rat, retinal atrophy was detected at all
subcutaneous doses tested (up to 0.8 mg/kg/day or 2 mg/kg/day in males or females, respectively; less 
than the maximum recommended human dose of 20 mg/day on a body surface area (mg/m2) basis). 
Retinal atrophy/degeneration has been observed in albino rats treated with other dopamine agonists for 
prolonged periods (generally during 2-year carcinogenicity studies). Retinal findings were not observed 
in a 39-week subcutaneous toxicity study of apomorphine in monkey at doses up to 1.5 mg/kg/day, a 
dose similar to the MRHD on a mg/m2 basis. The clinical significance of the finding in rat has not been 
established but cannot be disregarded because disruption of a mechanism that is universally present in 
vertebrates (e.g., disk shedding) may be involved. 
ADVERSE REACTIONS 
The following adverse reactions are discussed in more detail in the Warnings and Precautions section of 
labeling:
x
Nausea and Vomiting [see Warnings and Precautions (5.2)] 
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x
Syncope [see Warnings and Precautions (5.4)] 
x
Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.5)] 
x
Falls [see Warnings and Precautions (5.6)] 
x
Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.7)] 
x
Dyskinesias [see Warnings and Precautions (5.8)] 
x
Coronary Events [see Warnings and Precautions (5.10)] 
x
Priapism [see Warnings and Precautions (5.15)] 
6.1  
Clinical Trial Experience 
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions
(number of unique patients experiencing an adverse reaction associated with treatment per total number 
of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence 
of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse 
reactions observed in practice. 
In placebo-controlled trials, most patients received only one subcutaneous dose of APOKYN. All 
patients received concomitant levodopa and 86% received a concomitant dopamine agonist. All patients 
had some degree of spontaneously occurring periods of hypomobility (“off episodes”) at baseline. 
The most common adverse reactions (APOKYN incidence at least 10% greater than placebo incidence)
observed in a placebo-controlled trial were yawning, drowsiness/somnolence, dyskinesias, 
dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and 
edema/swelling of extremities. 
Table 1 presents the most common adverse reactions reported by APOKYN-naïve Parkinson’s disease 
patients who were enrolled in a randomized placebo-controlled, parallel group trial and who were 
treated for up to 4 weeks (Study 1) [see Clinical Studies (14)]. Individual APOKYN doses in this trial 
ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms. 
Table 1: Adverse Reactions Occurring in Two or More APOKYN-Treated Patients in Study 1 
APOKYN (n = 20)
PLACEBO (n = 9)
%
%
Yawning 
40
0
Dyskinesias 
35
11
Drowsiness or Somnolence 
35
0
Nausea and/or Vomiting
30
11
Dizziness or Postural Hypotension 
20
0
Rhinorrhea 
20
0
Chest Pain/Pressure/Angina 
15
11
Hallucination or Confusion 
10
0
Edema/Swelling of Extremities 
10
0
Other Adverse Reactions 
Injection Site Reactions 
Patients treated with APOKYN subcutaneous injections during clinical studies, 26% of patients had 
injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). 
In addition to those in Table 1, the most common adverse reactions in pooled APOKYN trials (occurring 
in at least 5% of the patients) in descending order were injection site reaction, fall, arthralgia, insomnia, 
headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, 
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7
7.1
7.2
7.3
7.4
8
8.1
Parkinson’s disease aggravated, pneumonia, confusion, sweating increased, dyspnea, fatigue, 
ecchymosis, constipation, diarrhea, weakness, and dehydration. 
DRUG INTERACTIONS 
5HT3 Antagonists 
Based on reports of profound hypotension and loss of consciousness when APOKYN was administered 
with ondansetron, the concomitant use of APOKYN with 5HT3 antagonists,s including antiemetics (for 
example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated. 
Antihypertensive Medications and Vasodilators 
The following adverse events were experienced more commonly in patients receiving concomitant 
antihypertensive medications or vasodilators (n = 94) compared to patients not receiving these 
concomitant drugs (n = 456): hypotension 10% vs 4%, myocardial infarction 3% vs 1%, serious 
pneumonia 5% vs 3%, serious falls 9% vs 3%, and bone and joint injuries 6% vs 2%. The mechanism 
underlying many of these events is unknown, but may represent increased hypotension [see Warnings 
and Precautions (5.5, 5.6)].
Dopamine Antagonists
Since APOKYN is a dopamine agonist, it is possible that concomitant use of dopamine antagonists, such 
as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish 
the effectiveness of APOKYN. Patients with major psychotic disorders, treated with neuroleptics, 
should be treated with dopamine agonists only if the potential benefits outweigh the risks. 
Drugs Prolonging the QT/QTc Interval 
Caution should be exercised when prescribing APOKYN concomitantly with drugs that prolong the 
QT/QTc interval [see Warnings and Precautions (5.11)].
USE IN SPECIFIC POPULATIONS 
Pregnancy 
Pregnancy Category C 
There are no adequate and well-controlled studies in pregnant women. APOKYN has been shown to be 
teratogenic in rabbits and embryolethal in rats when given at clinically relevant doses.  APOKYN should 
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 
No adverse developmental effects were observed when apomorphine (0.3 mg/kg/day, 1 mg/kg/day,
3 mg/kg/day) was administered by subcutaneous injection to pregnant rat throughout organogenesis; the 
highest dose tested (3 mg/kg/day) is 1.5 times the MRHD (20 mg/day) on a mg/m2 basis. Administration 
of apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day) by subcutaneous injection to pregnant 
rabbits throughout organogenesis resulted in an increased incidence of malformations of the heart and/or 
great vessels at the mid and high doses tested; the no-effect dose is less than the MRHD on a mg/m2
basis.
Apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day), administered by subcutaneous injection to 
females throughout gestation and lactation, resulted in increased offspring mortality at the highest dose 
tested. There were no effects on developmental parameters or reproductive performance in surviving 
offspring. The no-effect dose for developmental toxicity (1 mg/kg/day) is less than the MRHD on a 
mg/m2 basis. 
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8.3
Nursing Mothers 
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human 
milk and because of the potential for serious adverse reactions in nursing infants from APOKYN, a 
decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into 
account the importance of the drug to the mother. 
8.4
Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
8.5
Geriatric Use 
In the APOKYN clinical development program, there were 239 patients less than age 65 treated with 
APOKYN and 311 patients who were age 65 years of age or older. Confusion and hallucinations were 
reported more frequently with patients age 65 and older compared to patients with less than age 65.
Serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased 
disability) were also more common in patients age 65 and older. Patients age 65 and older were more 
likely to fall (experiencing bone and joint injuries), have cardiovascular events, develop respiratory 
disorders, and have gastrointestinal events. Patients age 65 and above were also more likely to 
discontinue APOKYN treatment as a result of one or more adverse reactions.
8.6
Renal Impairment 
The starting APOKYN dose should be reduced in patients with mild or moderate renal impairment 
because the concentration and exposure (Cmax and AUC) are increased in these patients. Studies in 
subjects with severe renal impairment have not been conducted [see Dosage and Administration (2.4) 
and Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment 
Caution should be exercised when administrating APOKYN to patients with mild and moderate hepatic 
impairment due to the increased Cmax and AUC in these patients. Studies of subjects with severe hepatic 
impairment have not been conducted [see Dosage and Administration (2.5) and Clinical Pharmacology 
(12.3)].
9
DRUG ABUSE AND DEPENDENCE 
9.2
Abuse 
In premarketing clinical experience, APOKYN did not reveal any tendency for a withdrawal syndrome or 
any drug-seeking behavior. However, there are rare postmarketing reports of abuse of medications 
containing APOKYN or levodopa. In general, these reports consist of patients taking increasing doses of 
medication in order to achieve a euphoric state. 
10
OVERDOSAGE 
A 62-year-old man accidentally injected 25 mg of APOKYN subcutaneously. After 3 minutes, the 
patient felt nauseated and lost consciousness for 20 minutes. Afterwards, he was alert with a heart rate 
40/minute and a supine blood pressure of 90/50. He recovered completely within an hour. 
11
DESCRIPTION 
APOKYN (apomorphine hydrochloride injection) contains apomorphine hydrochloride, a non-ergoline 
dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol 
hydrochloride hemihydrate with a molecular formula of C17H17NO2 • HCL • ½ H2O. Its structural 
formula and molecular weight are: 
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M.W. 312.79 
Figure 1: Structural Formula and Molecular Weight of Apomorphine 
Apomorphine hydrochloride appears as minute, white or grayish-white glistening crystals or as white 
powder that is soluble in water at 80°C. 
APOKYN is a clear, colorless, sterile solution for subcutaneous injection and is available in 
3 mL (30 mg) multi-dose cartridges. Each mL of solution contains 10 mg of apomorphine 
hydrochloride, USP as apomorphine hydrochloride hemihydrate, 1 mg of sodium metabisulfite, NF and 
5 mg of benzyl alcohol, NF (preservative) in water for injection, USP. In addition, each mL of solution 
may contain sodium hydroxide, NF and/or hydrochloric acid, NF to adjust the pH of the solution. 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
APOKYN is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4
receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C
receptors. The precise mechanism of action of APOKYN as a treatment for Parkinson’s disease is 
unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2-type receptors 
within the caudate-putamen in the brain. 
12.2 
Pharmacodynamics 
Prolongation of the QTc Interval: In a placebo-controlled study in which patients received increasing 
single doses of APOKYN from 2 mg to up to 10 mg, the mean difference in QTc (measured by Holter 
monitor) between APOKYN and placebo was 0 msec at 4 mg, 1 msec at 6 mg, and 7 msec at 8 mg. Too 
few patients received a 10 mg dose to be able to adequately characterize the change in QTc interval at 
that dose. 
In a controlled trial in which patients were administered placebo or a single dose of APOKYN (mean 
dose of 5.2 mg; range of 2 mg to 10 mg), the mean difference between APOKYN and placebo in the 
change in QTc was about 3 msec at 20 minutes and 90 minutes. In the entire database, 2 patients (one at 
2 mg and 6 mg, one at 6 mg) exhibited large QTc increments (> 60 msecs from pre-dose) and had QTc 
intervals greater than 500 msecs acutely after dosing. Doses of 6 mg or less thus are associated with 
minimal increases in QTc. 
Decreases in blood pressure 
Dose-dependent mean decrements in systolic blood pressure ranged from 5 mmHg after 2 mg to 
16 mmHg after 10 mg. Dose-dependent mean decrements in diastolic blood pressure ranged from 
3 mmHg after 2 mg to 8 mmHg after 10 mg. These changes were observed at 20 minutes, and were 
maximal between 20 and 40 minutes after dosing. Lesser, but still noteworthy blood pressure 
decrements persisted up to at least 90 minutes after dosing. 
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12.3
Pharmacokinetics 
Absorption 
Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak 
concentration ranges from 10 minutes to 60 minutes) following subcutaneous administration into the 
abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal 
to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose 
range of 2 mg to 8 mg following a single subcutaneous injection of APOKYN into the abdominal wall in 
patients with idiopathic Parkinson’s disease. 
Distribution 
The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent 
volume of distribution was 218 L (123 L to 404 L). Maximum concentrations in cerebrospinal fluid 
(CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes later. 
Metabolism and Elimination 
The mean apparent clearance (range) is 223 L/hr (125 L/hr to 401 L/hr) and the mean terminal 
elimination half-life is about 40 minutes (range about 30 minutes to 60 minutes). 
The route of metabolism in humans is not known. Potential routes of metabolism in humans include 
sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid 
autooxidation. 
Special Populations 
The clearance of apomorphine does not appear to be influenced by age, gender, weight, duration of 
Parkinson’s disease, levodopa dose or duration of therapy. 
Renal Impairment 
In a study comparing renally-impaired subjects (moderately impaired as determined by estimated 
creatinine clearance) to healthy matched volunteers, the AUC0-∞ and Cmax values were increased by 
approximately 16% and 50%, respectively, following a single subcutaneous administration of APOKYN 
into the abdominal wall. The mean time to peak concentrations and the mean terminal half-life of 
apomorphine were unaffected by the renal status of the individual. Studies in subjects with severe renal 
impairment have not been conducted. The starting dose for patients with mild or moderate renal
impairment should be reduced [see Dosage and Administration (2.4) and Use in Specific Populations 
(8.6)].
Hepatic Impairment 
In a study comparing subjects with hepatic impairment (moderately impaired as determined by the 
Child-Pugh classification method) to healthy matched volunteers, the AUC0-∞ and Cmax values were 
increased by approximately 10% and 25%, respectively, following a single subcutaneous administration 
of APOKYN into the abdominal wall. Studies in subjects with severe hepatic impairment have not been 
conducted [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].
Drug-Drug Interactions 
Carbidopa/levodopa: Levodopa pharmacokinetics were unchanged when subcutaneous APOKYN and 
levodopa were co-administrated in patients. However, motor response differences were significant. The 
threshold levodopa concentration necessary for an improved motor response was reduced significantly, 
leading to an increased duration of effect without a change in the maximal response to levodopa therapy. 
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Other Drugs Eliminated Via Hepatic Metabolism 
Based upon an in vitro study, cytochrome P450 enzymes play a minor role in the metabolism of 
apomorphine. In vitro studies have also demonstrated that drug interactions are unlikely due to 
apomorphine acting as a substrate, an inhibitor, or an inducer of cytochrome P450 enzymes. 
COMT Interactions 
A pharmacokinetic interaction of APOKYN with catechol-O-methyl transferase (COMT) inhibitors or 
drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT. 
13  
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenesis 
Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1 mg/kg/day,
0.3 mg/kg/day, 0.8 mg/kg/day) and female (0.3 mg/kg/day, 0.8 mg/kg/day, 2 mg/kg/day) rats. 
Apomorphine was administered by subcutaneous injection for 22 months or 23 months, respectively. In 
males, there was an increase in Leydig cell tumors at the highest dose tested, which is less than the 
MRHD (20 mg) on a mg/m2 basis. This finding is of questionable significance because the endocrine 
mechanisms believed to be involved in the production of Leydig cell tumors in rats are not relevant to 
humans. No drug-related tumors were observed in females; the highest dose tested is similar to the 
MRHD on a mg/m2 basis. 
In a 26-week carcinogenicity study in P53-knockout transgenic mice, there was no evidence of 
carcinogenic potential when apomorphine was administered by subcutaneous injection at doses up to 
20 mg/kg/day (male) or 40 mg/kg/day (female).
Mutagenesis 
Apomorphine was mutagenic in the in vitro bacterial reverse mutation (Ames) and the in vitro mouse 
lymphoma tk assays. Apomorphine was clastogenic in the in vitro chromosomal aberration assay in 
human lymphocytes and in the in vitro mouse lymphoma tk assay. Apomorphine was negative in the in 
vivo micronucleus assay in mice. 
Impairment of Fertility 
Apomorphine was administered subcutaneously at doses up to 3 mg/kg/day (approximately 1.5 times the 
MRHD on a mg/m2 basis) to male and female rats prior to and throughout the mating period and 
continuing in females through gestation day 6. There was no evidence of adverse effects on fertility or 
on early fetal viability. A significant decrease in testis weight was observed in a 39-week study in 
cynomolgus monkey at all subcutaneous dose tested (0.3 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day); the 
lowest dose tested is less than the MRHD on a mg/m2 basis. 
In a published fertility study, apomorphine was administered to male rats at subcutaneous doses of 
0.2 mg/kg, 0.8 mg/kg, and 2 mg/kg prior to and throughout the mating period. Fertility was reduced at 
the highest dose tested. 
14  
CLINICAL STUDIES 
The effectiveness of APOKYN in the acute symptomatic treatment of the recurring episodes of 
hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes), in 
patients with advanced Parkinson’s disease was established in three randomized, controlled trials of 
APOKYN given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of 
Parkinson’s disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at
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baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a 
concomitant catechol-ortho-methyl transferase COMT) inhibitor, and 10% were using a concomitant 
monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to 
APOKYN (i.e., APOKYN naïve) and Studies 2 and 3 were conducted in patients with at least 3 months 
of APOKYN use immediately prior to study enrollment. Almost all patients without prior exposure to 
APOKYN began taking an antiemetic (trimethobenzamide) three days prior to starting APOKYN and 
50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after 
initiating APOKYN.
The change from baseline in Part III (Motor Examination) of the Unified Parkinson’s Disease Rating 
Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the 
UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, 
rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson’s disease. 
Study 1 
Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with 
advanced Parkinson’s disease who had at least 2 hours of “off” time per day despite an optimized oral 
regimen for Parkinson’s disease including levodopa and an oral dopaminergic agonist. Patients with 
atypical Parkinson’s disease, psychosis, dementia, hypotension, or those taking dopamine antagonists 
were excluded from participation.  In an office setting, hypomobility was allowed to occur by 
withholding the patients’ Parkinson’s disease medications overnight. The following morning, patients 
(in a hypomobile state) were started on study treatment in a 2:1 ratio (2 mg of APOKYN or placebo 
given subcutaneously).  At least 2 hours after the first dose, patients were given additional doses of 
study medication until they achieved a “therapeutic response” (defined as a response similar to the 
patient’s response to their usual dose of levodopa) or until 10 mg of APOKYN or placebo equivalent 
was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 
mg, 6 mg, 8 mg, 10 mg of APOKYN) or placebo equivalent. 
Of the 20 patients randomized to APOKYN, 18 achieved a “therapeutic response” at about 20 minutes. 
The mean APOKYN dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg, 
3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached 
a “therapeutic response.” The mean change-from-baseline for UPDRS Part III score for APOKYN group 
(highest dose) was statistically significant compared to that for the placebo group (Table 2). 
Table 2: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 1 
Treatment 
Baseline UPDRS Motor 
Score 
Mean Change from Baseline 
Difference from placebo 
Placebo 
36.3 
- 0.1 
NA
APOKYN 
39.7 
- 23.9 
- 23.8 
Study 2 
Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson’s disease 
who had been using APOKYN for at least 3 months. Patients received their usual morning doses of 
Parkinson’s disease medications and were followed until hypomobility occurred, at which time they 
received either a single dose of subcutaneous APOKYN (at their usual dose) and placebo on different 
days in random order. UPDRS Part III scores were evaluated over time. The mean dose of APOKYN 
was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg, 
5 mg, 8 mg, and 10 mg). The mean change-from-baseline UPDRS Part III score for the APOKYN group 
was statistically significant compared to that for the placebo group (Table 3).
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Table 3: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 2 
Treatment 
Baseline UPDRS Motor 
Score 
Mean Change from Baseline 
Difference from placebo 
Placebo 
40.1 
- 3.0
NA
APOKYN 
41.3 
- 20.0
- 17.0
Study 3 
Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (APOKYN-35; 
Placebo-27) with Parkinson’s disease who had been using APOKYN for at least 3 months. Patients were 
randomized to one of the following 4 treatments dosed once by subcutaneous administration: APOKYN 
at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual APOKYN dose, 
APOKYN at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the 
usual APOKYN dose + 0.2 mL. Patients received their usual morning doses of Parkinson’s disease 
medications and were followed until hypomobility occurred, at which time they received the randomized 
treatment. APOKYN doses ranged between 2 mg – 10 mg. The mean change-from-baseline for the 
APOKYN group for UPDRS Part III scores at 20 minutes post dosing was statistically significant 
compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in 
UPDRS Motor Scores over time for pooled APOKYN and placebo administration.  
Table 4: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 4 
Treatment 
Baseline UPDRS Motor 
Score 
Mean Change from Baseline 
Difference from placebo
Placebo (Pooled) 
40.6 
- 7.4 
NA
APOKYN (Pooled) 
42.0 
- 24.2 
- 16.8 
Figure 2: Mean Change from Baseline in UPDRS Motor Scores of Pooled APOKYN Groups and Placebo Group in  
Study 3 
In Study 3, the mean changes-from-baseline for UPDRS Part III scores at 20 minutes post dosing for the 
APOKYN and higher dose APOKYN groups were 24 and 25, respectively. This result suggests that 
patients chronically treated at a dose of 4 mg might derive little additional benefit from a dose increment 
of 2 mg. There was also an increased incidence of adverse reactions in patients randomized to higher 
APOKYN dose. 
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16
HOW SUPPLIED/STORAGE AND HANDLING 
APOKYN is supplied as a 10 mg/mL clear, colorless, sterile, solution in 3 mL (30 mg) glass cartridges. 
NDC 27505-004-05 
Cartons of five 3 mL cartridges 
APOKYN Pen 
The pen injector is provided in a package with six needles and a carrying case. 
Store at 25°C (77°F).  Excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room 
Temperature] 
17
PATIENT COUNSELING INFORMATION 
See FDA-approved patient labeling (Patient Information and Instructions for Use) 
Administration with the APOKYN Pen 
Instruct patients and caregivers to read the “Patient Information and Instructions for Use for APOKYN 
and the dosing pen. Instruct patients to use APOKYN only as prescribed [See Dosage and 
Administration (2)].
Instruct patients and caregivers that the APOKYN Pen is dosed in milliliters, not milligrams. 
Inform patients and caregivers that it is possible to dial in their usual dose of APOKYN even though the 
cartridge may contain less than that amount of drug. In this case, they will receive only a partial dose 
with the injection, and the amount left to inject will appear in the dosing window. To complete the 
correct dose, patients/caregivers will need to “re-arm” the device and dial in the correct amount of the 
remaining dose. Patients and caregivers should be alerted to the fact that there may be insufficient drug 
left in the cartridge to deliver a complete dose (for example, patients and caregivers should be urged to 
keep records of how many doses they have delivered for each cartridge, so that they can replace any 
cartridge that has an inadequate amount of drug remaining). 
Instruct patients to rotate the injection site and to observe proper aseptic technique. 
Advise patients that APOKYN is intended only for subcutaneous injection and must not be given 
intravenously because of the risk of serious complications such as thrombus formation and pulmonary 
embolism due to crystallization [see Warnings and Precautions (5.1)]. 
Avoidance of Concomitant Antiemetic Drugs of 5HT3 Antagonist Class 
Advise patients that they should not use concomitant drugs of the 5HT3 antagonist class including 
antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron with APOKYN. Use 
of APOKYN with concomitant antiemetic drugs of the 5HT3 antagonist class is contraindicated because 
there have been reports of profound hypotension and loss of consciousness when APOKYN was 
administered with ondansetron [see Contraindications (4)]. 
Hypersensitivity / Allergic Reactions 
Advise patients that hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or 
various manifestations of angioedema may occur because of APOKYN or any of its excipients including 
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a sulfite (i.e., sodium metabisulfite). Inform patients with a sulfite sensitivity that they may experience 
various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. 
Advise patients who experience any hypersensitivity/allergic reaction to APOKYN that they should 
avoid taking APOKYN again [see Contraindications (4)]. 
Nausea and Vomiting 
Advise patients that they may experience severe nausea and/or vomiting and that they should begin 
taking trimethobenzamide 300 mg tablets orally 3 times per day for three days prior to starting 
APOKYN injections and continue taking it until told by a healthcare provider that trimethobenzamide 
can be discontinued [see Warnings and Precautions (5.2)]. 
Falling Asleep Suddenly and Sedation / Sleepiness 
Alert patients to the potential sedating effects of APOKYN, including somnolence and falling asleep 
while engaged in activities of daily living. Instruct patients not to drive a car or engage in other 
potentially dangerous activities until they have gained sufficient experience with APOKYN to gauge 
whether or not it affects their mental and/or motor performance adversely. Advise patients that if 
increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching 
television, passenger in a car, etc.) occur, they should not drive or participate in potentially dangerous 
activities until they have contacted their physician. Because of possible additive effects of alcohol use, 
advise patients to limit their alcohol intake [see Warnings and Precautions (5.3)]. 
Syncope 
Advise patients that APOKYN may cause syncope [see Warnings and Precautions (5.4)]. 
Hypotension / Orthostatic Hypotension 
Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such 
as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may 
occur more frequently during initial therapy or with an increase in dose at any time (cases have been 
seen after months of treatment). Instruct patients to rise slowly after sitting or lying down after taking 
APOKYN. Instruct patients to limit their alcohol intake because it may potentiate the hypotensive effect 
of APOKYN [see Warnings and Precautions (5.5)]. 
Falls 
Alert patients that they may have increased risk for falling when using APOKYN [see Warnings and 
Precautions (5.6)].
Hallucinations and/or Psychotic-Like Behavior 
Inform patients that hallucinations or other manifestations of psychotic-like behavior can occur.  Tell 
patients if they have a major psychotic disorder, ordinarily they should not use APOKYN because of the 
risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that 
many treatments for psychosis may decrease the effectiveness of APOKYN [see Warnings and 
Precautions (5.7)].
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Dyskinesia 
Inform patients that APOKYN may cause and/or exacerbate pre-existing dyskinesias [see Warnings and 
Precautions (5.8)]. 
Impulse Control / Compulsive Behaviors 
Patients and their caregivers should be alerted to the possibility that they may experience intense urges 
to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or 
other intense urges and the inability to control these urges while taking APOKYN [see  Warnings and 
Precautions (5.9)].
Coronary Events 
Inform patients that APOKYN may cause coronary events including angina and myocardial infarction 
and these outcomes could possibly be related to significant hypotension/orthostatic hypotension [see 
Warnings and Precautions (5.10)]. 
QTc Prolongation and Potential for Proarrhythymic Effects 
Alert patients that APOKYN may cause QTc prolongation and might produce proarrhythmic effects that 
could cause torsades de pointes and sudden death. Palpitations and syncope may signal the occurrence of 
an episode of torsades de pointes [see Warnings and Precautions (5.11)]. 
Withdrawal-Emergent Hyperpyrexia and Confusion 
Advise patients to contact their healthcare provider if they wish to discontinue APOKYN or decrease the 
dose of APOKYN [see Warnings and Precautions (5.12)]. 
Melanoma 
Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma. Advise 
patients to have a qualified healthcare provider examine that patient’s skin periodically for melanomas 
on a regular basis when using APOKYN [see Warnings and Precautions (5.13)]. 
Priapism 
Advise patients that APOKYN may cause prolonged painful erections and that if this occurs that they 
should seek medical attention immediately [see Warnings and Precautions (5.15)]. 
Injection Site Reactions 
Inform patients that injections of APOKYN may result in injection site reactions including bruising, 
granuloma, and pruritus [see Adverse Reactions (6.1)]. 
Distributed by: 
US WorldMeds, LLC
4010 Dupont Circle, Suite L-07 
Louisville, KY 40207
US WorldMeds, LLC is the exclusive licensee and distributor of APOKYN in the United States and Its territories. 
© 2014 Britannia Pharmaceuticals Limited. APOKYN is a registered trademark of Britannia Pharmaceuticals Limited. 
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Modified Hoehn & Yahr  
 
0: Asymptomatic.  
1: Unilateral involvement only.  
1.5: Unilateral and axial involvement 
2: Bilateral involvement without impairment of balance.  
2.5: Mild bilateral disease with recovery on pull test. 
3: Mild to moderate involvement; some postural instability but physically independent; needs assistance 
to recover from pull test.  
4: Severe disability; still able to walk or stand unassisted.  
5: Wheelchair bound or bedridden unless aided.  
 
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MDS-UPDRS Permissions  
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Continue to p. 2 to view the MDS-UPDRS  
________________________________________________________________________ 
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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
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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’. 
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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 
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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.  

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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. 

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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 
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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:
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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.  

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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.    

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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.   

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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) 
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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 
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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.  

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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.  

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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.  

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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.    
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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:  _____________
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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.  

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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 
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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 
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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 
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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.  
 
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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.  
 
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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
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Page 25 
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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 
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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. 
 
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  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):
 _____ 
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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):     _____
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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%).  
 
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Page 30 
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C. “OFF” DYSTONIA
4.6  PAINFUL OFF-STATE DYSTONIA
Instructions to examiner:  For patients who have motor fluctuations, determine what proportion of the 
OFF episodes usually includes painful dystonia? You have already determined the number of hours of 
“OFF” time (4.3). Of these hours, determine how many are associated with dystonia and calculate the 
percentage.  If there is no OFF time, mark 0. 
Instructions to patient [and caregiver]:    In one of the questions I asked earlier, you said you generally 
have ___ hours of low or “OFF” time when your Parkinson's disease is under poor control.  During these 
low or “OFF” periods, do you usually have painful cramps or spasms?  Out of the total ____ hrs of this 
low time, if you add up all the time in a day when these painful cramps come, how many hours would 
this make?  
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):
    _____
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_________________________ 
___ ___ ___ 
___ ___ - ___ ___  - ___ ___ ___ ___ 
___ ___ ___ 
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  
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Screening # _____________ 
Site #_________ 
Investigator: ________________ 
Randomization # _____________ 
CTH-300 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 (up to 5 times a day).
x
Write down the time you take the study medication.
x
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.
x
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
Time: __________ 
 AM
 PM
 “ON”
 “OFF”
Time: __________ 
 AM
 PM
 “ON”
 “OFF”
Time: __________ 
 AM
 PM
 “ON”
 “OFF”
Time: __________ 
 AM
 PM
 “ON”
 “OFF”
Time: __________ 
 AM
 PM
 “ON”
 “OFF”
Page ___ of ___
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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. 
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Past  
X Months 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
 
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Past X Years 
or 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy, 
or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck 
but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did 
anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal         
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Screening (Version 1/14/09)    
 
 
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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. 
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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)    
 
 
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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)    
 
 
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Final English (US) PDQ-39 1996 
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 check one box for each question 
Never 
Occasionally
Sometimes 
Often 
Always  
or cannot 
do at all
1. 
had difficulty doing the leisure 
activities you would like to do? 
2. 
had difficulty looking after your 
home, for example, housework, 
cooking or yardwork? 
3. 
had difficulty carrying grocery bags?
4. 
had problems walking half a mile? 
5. 
had problems walking 100 yards 
(approximately 1 block)? 
6. 
had problems getting around the 
house as easily as you would like? 
7. 
had difficulty getting around  
in public places? 
8. 
needed someone else to 
accompany you when you went out?
Please verify that you have checked one box for each question
before going on to the next page.
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Final English (US) PDQ-39 1996 
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 check one box for each question 
Never 
Occasionally
Sometimes 
Often 
Always  
or cannot 
do at all
9. 
felt frightened or worried about 
falling in public? 
10. been confined to the house more 
than you would like? 
11. had difficulty showering and 
bathing? 
12. had difficulty dressing? 
13. had difficulty with buttons or 
shoelaces? 
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 verify that you have checked one box for each question
before going on to the next page.
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Final English (US) PDQ-39 1996 
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 check 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 hide 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 about other people's 
reaction to you? 
27. had problems with your close 
personal relationships? 
Please verify that you have checked one box for each question
before going on to the next page.
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Final English (US) PDQ-39 1996 
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 check one box for each question 
Never 
Occasionally
Sometimes 
Often 
Always 
28. 
lacked the support you needed  
from your spouse or partner? 
If you do not have a spouse  
or Partner, please check here
29. lacked the support you needed  
from your family or close friends? 
30. unexpectedly fallen asleep during 
the day? 
31. 
had problems with your 
concentration, for example  
when reading or watching TV? 
32. felt your memory was failing? 
33. had distressing dreams or 
hallucinations? 
34. had difficulty speaking? 
35. felt unable to communicate 
effectively? 
36. felt ignored by people? 
Please verify that you have checked one box for each question
before going on to the next page.
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Final English (US) PDQ-39 1996 
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 check one box for each question 
Never 
Occasionally
Sometimes 
Often 
Always 
37. had painful muscle cramps or 
spasms? 
38. had aches and pains in your joints 
or body? 
39. felt uncomfortably hot or cold? 
Please verify that you have checked one box for each question. 
Thank you for completing the questionnaire. 
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Screening # _____________ Site #_________ Investigator: _______________ 
Rand. # ________________ 
 
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 
 
 
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Screening # _____________ Site #_________ Investigator: _______________ 
Rand. # ________________ 
 
 
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 
 
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Screening # _____________ Site #_________ Investigator: _______________ 
Rand. # ________________ 
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 
 
 
 
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Screening # _____________ Site #_________ Investigator: _______________ 
Rand. # ________________ 
 
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 
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$33(1',;;(66
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ESS - United States/English - Version of 16 Jan 15 - Mapi. 
ID037309 / ESS_AU1.0_eng-US1.doc 
Epworth Sleepiness Scale 
 
 
Name: _______________________________________________  Today’s date: ___________________  
 
Your age (yrs): ____________  Your gender (Male = M, Female = F): ___________  
 
 
How likely are you to doze off or fall asleep in the following situations, in contrast to just feeling tired? 
 
This refers to your usual way of life recently. 
 
Even if you haven’t done some of these things recently, try to figure out how they would have affected you. 
 
Use the following scale to choose the most appropriate number for each situation: 
 
0  =  no chance of dozing  
1  =  slight chance of dozing 
2  =  moderate chance of dozing 
3  =  high chance of dozing 
 
It is important that you answer each item as best as you can. 
 
Situation 
Chance of Dozing (0-3) 
 
 
 
 
Sitting and reading   ___________________________________________  
___ 
 
 
Watching TV   ________________________________________________  
___ 
 
 
Sitting inactive in a public place (e.g., a theater 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 or bus, while stopped for a few minutes in traffic   _____________ 
___ 
 
 
 
 
 
THANK YOU FOR YOUR COOPERATION 
 
 
¤ M.W. Johns  1990-97. Used under License 
 
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ZBI – USA/English – Original version 
ZBI-22_AU1.0_eng-USori.doc 
 
BURDEN INTERVIEW 
 
 
INSTRUCTIONS: The following is a list of statements, which reflect how people sometimes feel 
when taking care of another person.  After each statement, indicate how often you feel that way; 
never, rarely, sometimes, quite frequently, or nearly always.  There are no right or wrong 
answers. 
 
1. 
Do you feel that your relative asks for more help than he/she needs? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
2. 
Do you feel that because of the time you spend with your relative that you don’t have 
enough time for yourself? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
3. 
Do you feel stressed between caring for your relative and trying to meet other 
responsibilities for your family or work? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
4. 
Do you feel embarrassed over your relative’s behavior? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
5. 
Do you feel angry when you are around your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
6. 
Do you feel that your relative currently affects your relationship with other family 
members or friends in a negative way? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
7. 
Are you afraid what the future holds for your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
8. 
Do you feel your relative is dependent upon you? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
9. 
Do you feel strained when you are around your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
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ZBI – USA/English – Original version 
ZBI-22_AU1.0_eng-USori.doc 
 
10. 
Do you feel your health has suffered because of your involvement with your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
11. 
Do you feel that you don’t have as much privacy as you would like, because of your 
relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
12. 
Do you feel that your social life has suffered because you are caring for your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
13. 
Do you feel uncomfortable about having friends over, because of your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
14. 
Do you feel that your relative seems to expect you to take care of him/her, as if you were 
the only one he/she could depend on? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
15. 
Do you feel that you don’t have enough money to care for your relative, in addition to the 
rest of your expenses? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
16. 
Do you feel that you will be unable to take care of your relative much longer? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
17. 
Do you feel you have lost control of your life since your relative’s illness? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
18. 
Do you wish you could just leave the care of your relative to someone else? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
19. 
Do you feel uncertain about what to do about your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
20. 
Do you feel you should be doing more for your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
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ZBI – USA/English – Original version 
ZBI-22_AU1.0_eng-USori.doc 
 
21. 
Do you feel you could do a better job in caring for your relative? 
 
0.  Never 1.  Rarely 2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
22. 
Overall, how burdened do you feel in caring for your relative? 
 
0.  Not at all 
1.  A little 2.  Moderately 3.  Quite a bit 4.  Extremely 
 
 
 
 
Copyright 1983, 1990, Steven H. Zarit and Judy M. Zarit 
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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) 
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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) 
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$33(1',;;,,,(4'
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USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the USA 
 
 
 
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2 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 
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3 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
The worst health 
you can imagine 
 
 
 
 
 
x We would like to know how good or bad your health is TODAY. 
x This scale is numbered from 0 to 100. 
x 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
x Mark an X on the scale to indicate how your health is TODAY. 
x Now, please write the number you marked on the scale in the box 
below. 
 
  
The best health 
you can imagine 
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100 
5
15
25
35
45
55
75
65
85
95
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• Rest tremor present 
• Progressive disorder 
• Persistent asymmetry affecting side of onset most 
• Excellent response (70-100%) to L-Dopa 
• Severe L-Dopa-induced chorea 
• L-Dopa response for 5 years or more 
• Clinical course of ten years or more 
 
 
Reference: Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP 1992;55:181-184. 
 
 
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Enrollment Adjudication Committee Form
Cynapsus Protocol Number: CTH-300
____________________________________________________________________________________
Version 1: April 10, 2015 
 
Page 1 of 3 
 
ENROLLMENT ADJUDICATION COMMITTEE FORM 
Site Investigator and Subject Information
Site Number: Click here to enter text.
Patient Screening Number: Click here to enter 
text.
Date of Form Completion:Click here to enter a 
date.
Gender:
M        
F
Site Contact Phone Number: Click here to enter 
text.
Age: Click here to enter text.
Site Investigator Name: Click here to enter text.
Screening Date: Click here to enter a date.
Name of Person Completing the Form:
Click here to enter text.
Contact Phone Number of Person Completing 
the form: Click here to enter text.
Parkinson’s Disease History
1. Duration of PD from Time of Diagnosis:
Click here to enter text.
months
2. Hoehn & Yahr Stage in the “ON” state:
Click here to enter text.
(0-5 in half point increments)
3. Hoehn & Yahr Stage in the “OFF” state:
Click here to enter text.
(0-5 in half point increments)
4. MDS-UPDRS Part III Score in the “ON” state:
Click here to enter text.(0-56)
5. MDS-UPDRS Part III Score in the “OFF” state:
Click here to enter text.(0-56)
6. Does patient have a good response to levodopa (> 25%
in MDS-UPDRS score)?
Yes        
No
7. Does patient have ≥ 2 hours of off time per day?
Yes        
No 
8. Does patient have predictable early morning off periods?
Yes        
No 
9. Does patient have severe dyskinesias?
Yes        
No 
10. Can patient come  back to clinic in off state at regularly 
scheduled time points – describe how patient will get to 
clinic with early AM off periods
Yes        
No 
If yes, describe: Click here to 
enter text.
11. Does patient have prominent gait disturbance - describe 
Yes        
No 
If yes, describe: Click here to 
enter text.
12. Does patient have prominent non-motor features -
describe
Yes        
No 
If yes, describe: Click here to 
enter text. 
13. Does patient have prominent cognitive impairment -
describe 
Yes        
No 
If yes, describe: Click here to 
enter text. 
14. Has patient had MRI in past 12 months?
Yes        
No 
If yes, describe: Click here to 
enter text.
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Enrollment Adjudication Committee Form
Cynapsus Protocol Number: CTH-300
____________________________________________________________________________________
Version 1: April 10, 2015 
 
Page 2 of 3 
 
15. Has patient had previous imaging of dopamine system?
Yes        
No 
If yes, what were the 
results? Click here to enter 
text.
16. Is there any history of significant psychiatric problems?
Yes        
No
If yes, describe: Click here to 
enter text.
17. Are there any factors that raise a question as to the 
diagnosis of PD?
Yes        
No
If yes, describe: Click here to 
enter text.
18. Any factors that would preclude patient returning for 
follow up visits?
Yes        
No
If yes, describe: Click here to 
enter text.
19. Has nausea or vomiting been a problem with the 
introduction of dopaminergic agents in the past/present?
Yes        
No
If yes, describe: Click here to 
enter text.
20. Does patient suffer from objective or symptomatic 
orthostatic hypotension? 
Yes        
No
If yes, describe and provide 
values: Click here to enter 
text.
21. Does the patient have cankers or mouth sores?
Yes        
No 
22. Has the subject had prior exposure to apomorphine?
Yes        
No 
23. Current Concomitant Medications (attach supplemental 
pages if needed):
Name of Medicine
Dose
# tabs/ caps
Frequency
Click here to enter 
text.
Click here to 
enter text.
Click here to 
enter text.
Click here to 
enter text.
Click here to enter 
text.
Click here to 
enter text.
Click here to 
enter text.
Click here to 
enter text.
Click here to enter 
text.
Click here to 
enter text.
Click here to 
enter text.
Click here to 
enter text.
Click here to enter 
text.
Click here to 
enter text.
Click here to 
enter text.
Click here to 
enter text.
Click here to enter 
text.
Click here to 
enter text.
Click here to 
enter text.
Click here to 
enter text. 
 
I have reviewed the above information and approve the subject for further evaluation
_______________________________________                      Click here to enter a date.
Investigator Signature                                                               Date
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Enrollment Adjudication Committee Form
Cynapsus Protocol Number: CTH-300
____________________________________________________________________________________
Version 1: April 10, 2015 
 
Page 3 of 3 
 
please forward to the recipient below
 
Clintrex/Cynapsus Medical Review
 
               
  
. 
Date: Click here to enter a date.
Signature: ____________________________________
 
 Approved for Enrollment 
 Not Approved for Enrollment 
Include reason:Click here to enter 
text.
 Additional information 
required (specify): Click here to 
enter text. 
Note: Site personnel must print review response and accompanying email correspondence for 
the patient file.
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SAP_000.pdf: 
 
Statistical Analysis Plan      
 
Page 1 (34) 
 
Sponsor: Sunovion Pharmaceuticals Inc.  
Final 2017-11-2 
Study: CTH-300 
 
 
 
 
 
 
 
 
 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Examine the Efficacy, Safety and Tolerability of APL-130277 in Levodopa Responsive  
Patients with Parkinson’s Disease Complicated by Motor Fluctuations (“OFF” Episodes). 
 
 
Study code: CTH-300 
 
Phase III study 
 
 
 
STATISTICAL ANALYSIS PLAN 




 
Statistical Analysis Plan      
 
Page 3 (34) 
 
Sponsor: Sunovion Pharmaceuticals Inc.  
Final 2017-11-2 
Study: CTH-300 
 
Table of Contents 
 
1 
Abbreviations ...................................................................................................................................... 5 
2 
Introduction......................................................................................................................................... 7 
3 
Study objectives .................................................................................................................................. 7 
4 
Design and type of the study ............................................................................................................... 7 
5 
Endpoints ............................................................................................................................................ 8 
5.1 
Primary endpoint .......................................................................................................................... 8 
5.2 
Key secondary endpoint ............................................................................................................... 8 
5.3 
Other secondary endpoints ........................................................................................................... 9 
5.4 
Other subject-reported secondary endpoints .............................................................................. 11 
6 
Sample size considerations ............................................................................................................... 12 
7 
Statistical hypotheses ........................................................................................................................ 12 
8 
Analysis Populations ........................................................................................................................ 13 
8.1 
All Available population ............................................................................................................ 13 
8.2 
Modified Intention-To-Treat population .................................................................................... 13 
8.3 
Intention-To-Treat population .................................................................................................... 13 
8.4 
Safety population ....................................................................................................................... 13 
8.5 
Maintenance Phase Safety population ....................................................................................... 13 
8.6 
Completer population ................................................................................................................. 14 
8.7 
Per Protocol population .............................................................................................................. 14 
9 
General statistical considerations ..................................................................................................... 14 
9.1 
Adjustment for covariates .......................................................................................................... 14 
9.2 
Handling of drop-outs or missing data ....................................................................................... 15 
9.3 
Interim analyses and data monitoring ........................................................................................ 15 
9.4 
Multiple comparison/multiplicity .............................................................................................. 15 
9.5 
Examination of subgroups ......................................................................................................... 16 
10 
Disposition .................................................................................................................................... 17 
11 
Demographic and other baseline characteristics ........................................................................... 18 
12 
Concomitant medication/treatment ............................................................................................... 19 
13 
Medical history .............................................................................................................................. 20 
14 
Analysis of efficacy ....................................................................................................................... 21 
14.1 
Primary endpoint ................................................................................................................. 21 
14.1.1 
Patient Global Sensitivity analyses of the primary endpoint ............................................... 22 
14.1.2 
Graphical summaries of the primary endpoint .................................................................... 23 
14.2 
Key Secondary endpoint ...................................................................................................... 24 
14.2.1 
Graphical summaries of percent of patients with patient-rated full “ON” .......................... 25 
14.3 
Other secondary endpoints .................................................................................................. 25 
14.4 
Other patient-reported endpoints ......................................................................................... 27 
15 
Analysis of safety and tolerability ................................................................................................. 27 


 
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15.1 
Extent of exposure ............................................................................................................... 27 
15.2 
Compliance .......................................................................................................................... 28 
15.3 
Adverse events .................................................................................................................... 28 
15.4 
Laboratory safety variables .................................................................................................. 31 
15.5 
Vital signs ............................................................................................................................ 31 
15.6 
ECG ..................................................................................................................................... 32 
15.7 
Other safety variables .......................................................................................................... 33 
16 
Other variables .............................................................................................................................. 33 
17 
Deviations from the analyses planned in the study protocol ......................................................... 33 
18 
Execution of statistical analyses .................................................................................................... 34 
19 
Hardware and software .................................................................................................................. 34 
20 
References ..................................................................................................................................... 34 
 


 
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1 
Abbreviations 
 
AAP  
All Available Population 
AE 
 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC  
Anatomical Therapeutic Chemical 
BP 
 
Blood Pressure 
CGI-S  
Clinical Global Impression of Severity 
CGI-I  
Clinical Global Impression of Improvement 
CI 
 
Confidence Interval 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSMB  
Data and Safety Monitoring Board 
EOS 
 
End Of Study 
EQ-5D             European Quality of Life – 5 Dimensions 
ESS 
 
Epworth Sleepiness Scale 
HR 
 
Heart Rate 
ITT 
 
Intention-To-Treat 
L-Dopa 
Levodopa 
LOCF  
Last Observation Carried Forward 
LS 
 
Least Square 
MAR  
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MDS  
Movement Disorders Society 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
 
Multiple Imputation 
mITT  
Modified Intention-To-Treat 
MMRM 
Mixed Model for Repeated Measures 
MMSE    
Mini–Mental State Examination 
MV 
 
Maintenance Visit 
PD 
 
Parkinson’s Disease 


 
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PDQ-39 
Parkinson’s Disease Questionnaire-39 
PGI-I  
Patient Global Impression of Improvement 
PGI-S  
Patient Global Impression of Severity 
PMM  
Pattern Mixture Model 
PT 
 
Preferred Term 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease – Rating 
Scale 
RR 
 
Respiratory Rate 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SD 
 
Standard Deviation 
SEM  
Standard Error of the Mean 
SI 
 
International System of Units 
SOC  
System Organ Class 
SV 
 
Screening Visit 
TEAE  
Treatment-Emergent Adverse Event 
TV 
 
Titration Visit 
UPDRS 
Unified Parkinson’s disease Rating Scale 
VAS  
Visual Analog Scale 
WHO-DD  
World Health Organization Drug Dictionary 


 
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2 
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analysis for study CTH-300 and was 
finalized prior to unblinding of the study.  The SAP will serve as a compliment to the study protocol 
and supersedes it in case of differences.  In case of major differences between the study protocol and 
SAP (e.g. changes in the analysis related to the primary endpoint), a protocol amendment will be 
considered.   
3 
Study objectives 
The primary objective of this study is to evaluate the efficacy and safety of APL-130277 versus placebo 
in patients with Parkinson’s disease (PD) over a 12 week period. 
4 
Design and type of the study 
This is a 12-week, prospective, multi-center, randomized, double-blind, placebo-controlled, Phase 3 
study in levodopa (L-Dopa) responsive PD patients with motor fluctuations, designed to determine the 
efficacy, safety and tolerability of APL-130277. 
The study includes initial Screening Visits, followed by an initial Dose Titration Phase in which 
individual responses to single doses of APL-130277 are evaluated in order to determine the optimal 
dose of APL-130277 for treating “OFF” episodes to be used in the maintenance phase of the study. 
Once complete, patients will be randomized to either the APL-130277 or placebo (ratio 1:1) and begin 
the Maintenance Treatment Phase of the study, where they will self-administer study medication in up 
to 5 doses per day to treat “OFF” episodes over the course of 12 week study in the at-home portion of 
the study. Patients will return to the clinic at regular intervals for safety and efficacy assessments 
(including in-office assessments of the primary endpoint). Overall duration of participation will be 
approximately 135 days. 
The following visits will be performed: 
 Screening Visits (SV1 and SV2) 
 Telephone Call (T1) 
 Dose Titration Phase 
o Titration Visit 1 (TV1) 
o Titration Visit 2 (TV2) 
o Titration Visit 3 (TV3) 
o Titration Visit 4 (TV4) 
o Titration Visit 5 (TV5) 


 
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o Titration Visit 6 (TV6) 
 Maintenance Treatment Phase 
o Maintenance Visit 1 (MV1) 
o Maintenance Visit 2 (MV2) 
o Maintenance Visit 3 (MV3) 
o Maintenance Visit 4 (MV4) 
o Telephone Call (T2, T3, T4) 
o End of Study Visit (EOS) 
o Unscheduled Dose Adjustment Visits. 
The patients will be randomized centrally at a study level using a computer-generated randomization 
code. No stratification factors will be used. 
5 
Endpoints 
5.1 
Primary endpoint 
The primary endpoint of the study is the mean change from pre-dose in MDS-UPDRS MOTOR score at 
30 minutes after dosing at the 12 week visit (MV4) of the Maintenance Treatment Phase. 
The MDS-UPDRS MOTOR score will be calculated as the sum of the individual items of the MDS-
UPDRS Part III questionnaire (items 3.1 – 3.18) and will be obtained separately at each assessment 
time point. Missing individual items will be imputed using the 2 non-missing values at time points 
adjacent to the missing item on the same date. The maximum of the 2 adjacent values will be assigned 
as the score for the missing individual item. However, pre-dose values will not be assigned as post-dose 
values and if one of the adjacent values for a post-dose value is a pre-dose value, only 1 adjacent value 
will be used. If a pre-dose value is missing, the pre-dose value at the prior visit will be used. The 
maximum of the 2 adjacent values represents the worse outcome out of these potential values and may 
be seen as a conservative imputation. If there are more than three individual missing items at a given 
time point, no imputation will be performed and MDS-UPDRS MOTOR score will be assigned as 
missing. The MDS-UPDRS MOTOR score will be calculated after imputation of the missing item(s) as 
described above. 
5.2 
Key secondary endpoint 
The key secondary endpoint of the study is the percentage of patients with a patient-rated full “ON” 
response within 30 minutes after dosing at the 12 week visit (MV4) of the Maintenance Treatment 
Phase.  


 
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A full “ON” response is defined as a period of time where in the judgment of the patient the medication 
is providing full benefit with regard to mobility, stiffness, slowness and other PD features comparable 
to or better than that obtained with their standard dose of oral levodopa and other anti-parkinsonian 
medications prior to beginning the study. 
An assessment of the “OFF”/”ON” state will be performed at 0, 15, 30, 45, 60 and 90 minutes after 
dosing at each visit. Patients will also be asked if they attained a full “ON” state anytime within 30 
minutes of dosing. This endpoint will be based on the latter question (did the patient attain a full “ON” 
state anytime within 30 minutes of dosing). However, if this question has not been completed but the 
patient reported the “OFF”/”ON” state at 15 and/or 30 minutes, the 15 and 30 minute assessments will 
be used to derive the endpoint. In this case, if the patient has reported an ”ON” state at either of the two 
time points the patient will be considered as having the full “ON” response within 30 minutes after 
dosing. The visits at which there is no 15 or 30 minute assessment of the “OFF”/”ON” state and the 
question about attaining a full “ON” state anytime within 30 minutes of dosing is missing will be set as 
having a missing value. 
5.3 
Other secondary endpoints 
1. The percentage of instances where a full “ON” response was achieved at 30 minutes after self-
administration of study medication based on the home dosing diary entries during the 2 days 
prior to the 12 week visit (MV4).  
During the Maintenance Treatment Phase of the study, patients will complete the home dosing 
diary on the 2 days prior to their next scheduled in-clinic visit. The patients will self-administer 
their doses of randomized treatment (APL-130277 or placebo; 1:1 ratio) in order to treat up to 5 
“OFF” episodes per day. The patients will fill in the time when study treatment is self-
administered and the “ON”/”OFF” status at 30 minutes following dosing. In total, each patient 
can record up to 10 episodes at 3 visits after the randomization (MV2, MV3 and MV4), i.e. a 
total of up to 30 episodes. For each patient, the percentage of episodes in which the full “ON” 
response was achieved at 30 minutes out of all recorded episodes will be calculated. In case the 
time of self-administration has been recorded but the corresponding “ON”/”OFF” status is 
missing, the status will be classified as “OFF”. The percentages calculated separately for each 
patient will be used as response variables in the statistical analysis. For patients who did not 
record any episodes during the Maintenance Treatment Phase, the endpoint will be set as 
missing. 
2. Mean change from pre-dose in MDS-UPDRS MOTOR score at 15, 45, 60 and 90 minutes at the 
12 week visit (MV4) of the Maintenance Treatment Phase.  
These variable will be defined using rules similar to the primary endpoint. 
3. Time (in minutes) from dosing to when study medication is starting to provide an “ON” effect 
at the 12 week visit (MV4) of the Maintenance Treatment Phase.  


 
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The time from dosing until the patient reports to have an effect will be used as the endpoint. For 
patients who do not report an effect during the follow-up period, the data will be censored at 90 
minutes.  
4. Percent of patients with a patient-rated full “ON” response within 30 minutes, whose duration 
from time when study medication begins to have an effect until their “OFF” (if applicable) lasts 
for at least 30 minutes at the 12 week visit (MV4) of the Maintenance Treatment Phase. 
The identification of patients who experienced a full “ON” response within 30 minutes will be 
defined as identical to that for the key secondary endpoint. Duration of the response will be 
calculated by evaluating the difference in time from the “Time to when study treatment started 
to have an effect as per subject assessments” and the “Time to OFF” per patient assessment. If 
the latter question is left blank or marked as “N/A”, time “OFF” will be identified as per the 
Patient confirmation of “OFF” and “ON” following dosing at 15, 30, 45, 60 and 90 minutes 
after dosing. If the patient did not turn “OFF” after dosing, duration will be assumed to have 
ended at 90 minutes after dosing. For a blank value or “N/A” ticked for the question “Time to 
when study medication started to have an effect as per subject assessment”, the data will be 
treated as having a missing value.  Patients who do not turn “ON” or who turn “ON”, but with a 
duration less than 30 minutes will be considered non-responders in this analysis.  
5. Clinical Global Impression of Improvement (CGI-I) post dosing. 
The non-missing values will be categorized as improvements (very much improved, much 
improved, minimally improved) or non-improvements (no change, minimally worse, much 
worse, very much worse). The missing values will be considered as non-improvements.  CGI 
severity (CGI-S) will also be assessed. 
6. Patient Global Impression of Improvement (PGI-I) post dosing. 
The non-missing values will be categorized as improvements (very much improved, much 
improved, minimally improved) or non-improvements (no change, minimally worse, much 
worse, very much worse). The missing values will be considered as non-improvements.  PGI 
severity (PGI-S) will also be assessed. 
7. Mean change from baseline in Parkinson’s Disease Questionnaire-39 (PDQ-39) summary index 
score. 
Change from SV to MV4 in PDQ-39 sub-scores (mobility score, activities of daily living, bodily 
discomfort score, emotional wellbeing score, social support score, communication score, 
cognitive impairment score, and stigma score) and summary index score will be calculated. The 
questionnaire provides scores on eight dimensions as outlined below: 
 mobility (10 items, #1 to 10)  
 activities of daily living (6 items, #11 to 16)  
 emotional well-being (6 items, #17 to 22)  


 
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 stigma (4 items, #23 to 26) 
 social support (3 items, #27 to 29)  
 cognitions (4 items, #30 to 33)  
 communication (3 items, #34 to 36)  
 bodily discomfort (3 items, #37 to 39). 
Items are scored from 0 (never) to 4 (always).  Dimension scores are obtained by dividing the 
sum of the item scores by the maximum possible score for any given dimension and expressing 
this as a percentage.  For example: 
 mobility = (sum of scores of #1 to 10)/(4 x 10) x 100 
 activities of daily living = (sum of scores of #11 to 16)/(4 x 6) x 100. 
For social support, if the response indicates that a patient does not have a spouse or partner for 
#28, social support can be calculated as [(sum of scores of #27 and 29)/(4 x 2) x 100]. 
A summary index is then calculated as the sum of the total score of the dimensions divided by 
the number of dimensions, i.e. (sum of dimension scores / 8). If any item score is missing, the 
relevant dimension score and the summary index will be missing. 
8. Change from baseline in MDS-UPDRS – Part II: Motor Aspects of Experiences of Daily Living. 
The change from SV to MV4 in MDS-UPDRS Part II score will be evaluated. The MDS-
UPDRS Part II score will be calculated as the sum of the individual items of the MDS-UPDRS 
Part II questionnaire (items 2.1 – 2.13). Missing individual items will not be imputed. If there is 
at least 1 missing item, the corresponding MDS-UPDRS Part II score will be set as missing. 
9. Evaluation of safety and tolerability data collected, including 12-lead ECGs, orthostatic 
hypotension, oropharyngeal and dopaminergic AEs. 
The evaluation of the safety and tolerability data is described in section 15 of this document. 
5.4 
Other subject-reported secondary endpoints 
1. Change in sleep measures on the Epworth Sleepiness Scale (ESS).  
The ESS is used to determine the level of daytime sleepiness and evaluated as change from SV 
to MV4.  There are 8 situations listed for which patients rate their likelihood of dozing or 
sleeping (0=no chance of dozing, 1=slight chance of dozing, 2=moderate chance of dozing, and 
3=high chance of dozing ). The total score is the sum of 8 item scores and can range between 0 
and 24. In case of missing item scores, the missing value will be replaced by the average of non-
missing scores at the same visit from the same patient. In case all item scores are missing, the 
total score will be set as missing. The higher total score indicates the higher level of daytime 
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2. Change in European Quality of Life – 5 Dimensions (EQ-5D).  
The EQ-5D is a utility scale consisting of three components: health state dimensions, health 
state thermometer scale and health state index. 
The health state dimensions will be described by the 5 dimensions of the EQ-5D (mobility, self-
care, usual activities, pain/discomfort and anxiety/depression). Each dimension has 5 response 
choices, listed in order of increasing severity. The health state dimensions will be evaluated by 
presenting the distribution of responses separately for each of the 5 dimensions. 
The health state thermometer scale asks respondents to rate their present health status on a 0 to 
100 visual analog scale (VAS). The change from SV to MV4 on the VAS scores will be 
evaluated. 
The health state index score will be calculated based on EQ-5D-5L Crosswalk Index Value Calculator - 
EuroQol, using the dimension scores from the 5 dimensions, ranging between 1.0 (best imaginable 
health) and -0.594 (worst imaginable health).  
6 
Sample size considerations 
The study intends to show the superiority of APL-130277 compared with placebo. Assuming a 
treatment difference of 7 points and standard deviation of 10 points, a sample size of 44 subjects per 
group or 88 patients for two groups will provide ≥ 90% power to detect a statistically significant 
difference at the 0.05 level (2-sided), using a two-sample t-test. Taking into consideration a 10% 
dropout rate during the titration phase and a 15% dropout rate during the maintenance phase, the study 
plans to enroll approximately 126 patients into the Dose Titration Phase and to randomize 
approximately 114 patients into the Maintenance Treatment Phase. 
7 
Statistical hypotheses 
The primary objective of this study is to show that APL-130277 is superior to placebo in improving the 
motor function, assessed as the mean change from pre-dose in Movement Disorders Society (MDS) 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part III Motor Examination (MDS-UPDRS 
MOTOR) score at 30 minutes after dosing at the 12 week visit (MV4) of the Maintenance Treatment 
Phase. That is, the null-hypothesis to be tested is 
H0:  
APL-130277 is the same as placebo in its effect on the motor function 
against the two-sided alternative 
H1:  
Either of the treatment groups is superior to the other in its effect on the motor function. 


 
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8 
Analysis Populations 
The following analysis populations will be used for the analysis of the disposition and efficacy and 
safety data. 
8.1 
All Available population 
The All Available Population (AAP) will include all patients who have consented for the study, 
including screening failures. Unless specified otherwise, the AAP will be used for patient listings and 
for the summary of patient disposition. 
8.2 
Modified Intention-To-Treat population 
All patients who are randomized and receive at least one post-randomization dose of study medication 
(APL-130277 or placebo) will comprise the modified Intention-To-Treat (mITT) population. The mITT 
population will be used for the efficacy analysis, and patients will be grouped according to the 
randomized treatment group. 
8.3 
Intention-To-Treat population 
All patients who are randomized will comprise the Intention-To-Treat (ITT) population and patients 
will be grouped according to the randomized treatment group. 
8.4 
Safety population 
All patients who are enrolled and receive at least one dose of APL-130277 during the Dose Titration 
Phase will be included in the safety population. The Safety population will be used for the analysis of 
the safety endpoints from the Dose Titration Phase and for the pooled data from Dose Titration Phase 
and Maintenance Treatment Phase.  
8.5 
Maintenance Phase Safety population 
All patients who receive at least one dose of study medication (APL-130277 or placebo) during the 
Maintenance Treatment Phase will comprise the Maintenance Phase Safety population. The 
Maintenance Phase Safety population will be used for the analysis of the safety endpoints from the 
Maintenance Treatment Phase. The patients will be grouped according to the medication actually 
received (APL-130277 or placebo) during the Maintenance Phase.  In cases where the patient received 
at least one dose of both APL-130277 and placebo, they will be grouped into the APL-130277 arm for 
safety analysis. 


 
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8.6 
Completer population 
All mITT patients who have a valid MDS-UPDRS MOTOR score at pre-dose and after 30 minutes 
post-dose at baseline and MV4. 
8.7 
Per Protocol population 
All mITT patients who complete the study with no major protocol deviation. 
9 
General statistical considerations 
All data from all patients entered into the database will be included in patient data listings. The listings 
will be generally sorted by center and patient number (and by visit and by time point, if applicable), 
unless specified otherwise.  
All applicable data will be summarized separately for the Dose Titration Phase, Maintenance Treatment 
Phase and for the pooled data from the Dose Titration Phase and Maintenance Treatment Phase. The 
Maintenance Treatment Phase data will be summarized by treatment group (APL-130277 or placebo). 
Selected analyses will be performed based on the dose required to achieve a full “ON” response (see 
Section 9.5 for more details). Where appropriate, data will be summarized by visit and/or time point. 
Screening visit (SV) assessments may be performed at either SV1 or SV2.  If performed at both visits, 
the latter assessment will be used as the SV assessment for the purposes of analysis. Unscheduled or 
repeat assessments will not be included in summary tables, but will be included in listings.  
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Standard error of the mean (SEM) will also be 
provided for summaries of efficacy data, if relevant.  
Descriptive statistics for categorical data will include frequency counts and percents. The total number 
of patients in the treatment group (N) will be used as the denominator for percent calculations, unless 
stated otherwise.  
Significance testing will be 2-sided using α = 0.05, unless otherwise specified.  
All statistical analyses and summaries will be produced using SAS version 9.3 or higher. Deviations 
from the statistical plan will be reported in the clinical study report, including the rationale for use. 
9.1 
Adjustment for covariates 
For the analysis of efficacy endpoints, the baseline value of the endpoint in question will generally be 
included as a baseline covariate (for continuous endpoints) or as a stratification factor (for categorical 
endpoints), if available.  Use of covariates for statistical adjustment is discussed below where relevant. 
 


 
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9.2 
Handling of drop-outs or missing data 
 
Several different methods to handle the missing data in efficacy assessments will be used. 
 For the primary efficacy analysis, likelihood-based modeling approach will be used to handle 
incomplete data. For this purpose, Mixed Model for Repeated Measures (MMRM) will be 
applied, see Section 14.1. 
 Sensitivity analysis for primary efficacy data will be conducted using the Multiple Imputation 
(MI) approach, i.e. by replacing each missing value with a set of plausible values that represent 
the uncertainty about the right value to impute.  LOCF will also be used for sensitivity analysis 
(see Section 14.1). 
Safety data will not be subject to any imputation and will be summarized on an observed case basis. 
9.3 
Interim analyses and data monitoring 
No interim analyses of the efficacy data are foreseen. The safety data will be monitored during the study 
conduct by an independent Data and Safety Monitoring Board (DSMB) to determine if safety 
monitoring can be modified. The responsibilities of the DSMB include: 
 Monitor safety and study conduct; 
 On a regular basis, review unblinded summaries of demographic, patient disposition, study 
conduct and safety data (provided by an independent statistician); 
 Evaluate results of an analysis performed after 50% patients have completed the Dose Titration 
Phase to determine if it is safe and appropriate to reduce the extent of safety evaluations during 
titration, and to make recommendations for amending the protocol. 
The full responsibilities and purview of the DSMB are outlined in the DSMB Charter , which was 
approved by the Sponsor prior to the implementation of any DSMB review (see Section 17.4.7 of the 
Protocol).  
9.4 
Multiple comparison/multiplicity 
The multiplicity due to multiple efficacy endpoints will be addressed by using a hierarchical testing 
approach.  
The primary and secondary endpoints will be tested in a fixed sequential manner.  The order of the 
testing is outlined below.  See Section 5 for the definition of the primary and secondary endpoints. 
1. Primary endpoint: Mean change from pre-dose in MDS-UPDRS MOTOR score after 30 minutes at 
MV4 
2. Key secondary endpoint: percentage of patients with a patient-rated full “ON” response within 30 
minutes at MV4 


 
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3. Percent of patients with a patient-rated full “ON” response within 30 minutes, whose duration from 
time when study medication begins to have an effect until their “OFF” (if applicable) lasts for at 
least 30 minutes at MV4 
4. Patient Global Impression of Improvement (PGI): The percentage of patients improved (ie, very 
much improved, much improved or minimally improved) at MV4 
5. Clinician Global Impression of Improvement (CGI): The percentage of patients improved (i.e., very 
much improved, much improved or minimally improved) at MV4 
6. Mean change from SV to MV4 in MDS-UPDRS – Part II: Motor Aspects of Experiences of Daily 
Living 
7. The percentage of instances where a full “ON” response was achieved at 30 minutes after self-
administration of study treatment in the outpatient setting based on the home dosing diary entries 
during the 2 days prior to MV4 
8. Mean change from SV to MV4 in PDQ-39 summary index score 
9. Mean change from pre-dose in MDS-UPDRS MOTOR score at 15 minutes at MV4 
10. Time (in minutes) to when study medication is starting to have an effect at MV4 
 
First, the endpoint ranked as first will be tested and the difference will be declared statistically 
significant if the nominal p-value is less than 0.05.  Second, in case that the difference for the first 
endpoint is statistically significant, the endpoint ranked as second will be tested, and the difference will 
be declared statistically significant if the nominal p-value is less than 0.05.  The testing will continue as 
long as the previously ranked endpoint was statistically significant.  
In case all endpoints are not evaluated as a part of the hierarchical testing procedure, the statistical tests 
will be reported in any case and interpreted in a descriptive manner 
9.5 
Examination of subgroups 
At least the following subgroup analyses have been pre-planned.  The subgroup analyses are considered 
exploratory and will be performed for selected efficacy endpoints (at least the primary endpoint) and for 
adverse events (except the subgroups based on MDS-UPDRS Motor scores). Selected baseline data will 
be presented for the subgroups as well.  Subgroups with too few patients per treatment arm (e.g. less 
than 4) may not be analysed. 
 Patients with the baseline MDS-UPDRS MOTOR score  (at the last titration visit at which the 
randomized dose is given up through TV6) less than or equal to the median versus the patients with 
the baseline score above the median   
 Patients with the change from pre-dose to 30 minutes post-dose in MDS-UPDRS MOTOR score at 
baseline less than or equal to the median versus the patients with the change score above the median   
 Non-elderly (< 65 years) versus elderly (≥ 65 years) patients 


 
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 Male versus female patients 
 Race (any race category with less than 4 patients will be combined into an “Other” category for 
analysis) patient 
 Dose level required to achieve a full “ON” response (10, 15, 20, 25, 30 or 35 mg) 
o For the purpose of efficacy analyses, this dose level is defined as the randomized dose level 
o For the purpose of the safety analysis using the Safety population, this dose level is defined 
as the highest dose level of APL- 130277 received during the Dose Titration Phase or 
Maintenance Treatment Phase. 
o  For the purpose of the safety analysis using the Maintenance Phase Safety population, this 
dose level is defined as the highest dose level of study medication (APL- 130277 or 
placebo) received during the Maintenance Treatment Phase.  
The following subset will be analyzed separately for demographic and disease history characteristics, 
and key safety outcomes during the dose titration phase:  
 Enrichment failures defined as patients in the Safety population who were not randomized into 
the maintenance phase. 
In addition, the following subsets will be analyzed separately for demographic characteristics and 
primary and key secondary efficacy endpoints: 
 The subset excluding patients with a high baseline MDS-UPDRS MOTOR pre-dose assessment 
score, defined as a score > 55 points 
 The subset including patients who were randomized to dose levels of 30 mg or less will be 
analyzed separately for demographic characteristics and primary and key secondary efficacy 
endpoints.  
10 Disposition 
The patient disposition will be summarized as follows and presented for each treatment group, as 
applicable, and overall. The percentages will be calculated based on the number of enrolled patients 
(i.e. patients who have signed the informed consent), unless otherwise specified. 
 The number of patients screened (i.e. the number of patients in the AAP) 
 The number (%) of patients who failed screening (% calculated from the AAP), including the 
distribution of reasons for failing the screening. If a patient failed screening multiple times, then 
all reasons for screen failures will be displayed. Percentages for these reasons will be calculated 
based on the total number of screen failure events 
 The number (%) of patients enrolled into the study (% calculated from the AAP) 
 The number (%) of patients who received at least one dose of study medication (Safety 
Population) 


 
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 The number (%) of patients who discontinued the study prematurely before Randomization, 
presented by highest dose level received during the Dose Titration Phase (10 mg, 15 mg, 20 mg, 
25 mg, 30 mg or 35 mg and total), including the distribution of reasons for discontinuations 
 The number (%) of patients randomized to the Maintenance Treatment Phase (ITT population) 
 The patients who were randomized to the Maintenance Treatment Phase will be presented as a 
cross-tabulation of the highest dose level received during the Dose Titration Phase and the 
randomized dose level (10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 35 mg) (% calculated from the 
ITT Population) 
 The number (%) of patients who received at least one dose of study medication during the 
Maintenance Treatment Phase, i.e. Maintenance Phase Safety Population (% calculated from the 
ITT Population) 
 The number (%) of patients in the mITT Population (% calculated from ITT Population) 
 The number (%) of patients in the Completer Population (% calculated from ITT Population) 
 The number (%) of patients in the Per Protocol Population (% calculated from ITT Population) 
 The number (%) of patients who completed the study (% calculated from ITT Population) 
 The number (%) of patients who discontinued the study prematurely after Randomization 
including the distribution of reasons for premature discontinuations after Randomization (% 
calculated from ITT Population) 
Patient completion will also be summarized by visit and presented for each treatment group.  
11 Demographic and other baseline characteristics 
Demographics and screening/baseline characteristics will be summarized descriptively for the mITT, 
maintenance phase safety and Safety populations, by treatment group and/or overall. The following 
variables will be summarized: 
 Demographics: (age (continuous), age categorized as <65 years versus ≥65 years, gender, 
ethnicity, race, height, weight, BMI, country) 
 Smoking history 
 Cognitive status: Mini–Mental State Examination (MMSE) total score (as categorical, % of 
patients with a score of 30, 29, 28, 27, 26 or <26) 
 Modified Hoehn and Yahr scale in “ON” state 
 MDS-UPDRS Total Score: Sum of MDS-UPDRS Part I (Non-Motor Aspects of Experiences of 
Daily Living), Part II (Motor Aspects of Experiences of Daily Living) and Part III (Motor 
Examination) assessed in an “OFF” state prior to L-Dopa administration at SV 
 Baseline (SV) MDS-UPDRS Part I Score 


 
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 Baseline (SV) MDS-UPDRS Part II Score  
 MDS-UPDRS Part III Score assessed in an “OFF” state prior to L-Dopa administration at SV  
 MDS-UPDRS part III (Motor Examination ) score at baseline pre-dose 
 MDS-UPDRS part III (Motor Examination ) score at baseline: 15, 30, 45, 60, 90 minutes post-
dose  
 Change in MDS-UPDRS part III (Motor Examination ) score at baseline from pre-dose to: 15, 
30, 45, 60, and 90 minutes post-dose after APL-130277 administration 
 Percentage of patients with a patient-rated full “ON” response within 30 minutes at baseline 
after APL-130277 administration 
 Total daily L-Dopa dose at baseline (PD medications reported by the patient as ongoing at first 
dose in titration phase will be added to calculate total daily dose) 
Demographic characteristics and other baseline data will also be summarized by subgroups as defined 
in section 9.5 of this document  
Baseline is defined as the last observed value before the first dose in titration phase, unless specified 
otherwise. 
12 Concomitant medication/treatment 
All medications will be classified using the Anatomical Therapeutic Chemical (ATC) classification 
codes and preferred drug names from the World Health Organization Drug Dictionary (WHO-DD).  
Medications with a stop date before the first date of study drug dosing will be considered prior 
medications. Medications with start date or stop date on or after the first date of study drug dosing will 
be considered concomitant medications. The prior and concomitant medications will be summarized 
separately. 
Summaries of prior and concomitant PD treatment medications (medications which start with ATC 
code N04) will be presented in tabular form using the ATC Level 4 and preferred term. Other prior and 
concomitant medications will be presented in tabular form using the ATC Level 1, ATC Level 2, and 
Preferred Term (PT). Frequencies and percentages of patients receiving medications will be presented 
by treatment group and overall. The tables will be sorted by overall descending frequency of ATC 
Level(s) and then, within an ATC Level, by overall descending frequency of PT. 
If the medication start date is incomplete, then it will be imputed as follows for the purpose of 
determining concomitant use:  
 If the start date is completely missing, the start date will be equal to the first dose date. 
However, if the stop date is not missing and is before the first dose date, then the stop date will 
be used instead.  


 
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 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. 
 However, if the stop date is not missing and is before the date of the first dose of study 
treatment or the imputed start date, then the stop date will be used instead. 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).  
However, if the stop date is not missing and is before the date of the first dose of study treatment or the 
imputed start date, then the stop date will be used instead. If the medication stop date is partial, then it 
will be imputed as follows for the purpose of determining concomitant use:  
 If the stop date is completely missing and the medication is not ongoing, the stop date will be 
equal to the last dose date or date of completion/withdrawal, whichever is the latest.  
 If the stop day is missing, the last day of the month will be used. If 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.  
In addition, the total daily levodopa dose (mg) will be summarized at baseline (PD medications 
reported by the patient as ongoing at first dose in titration phase will be added to calculate total daily 
dose) with descriptive statistics. 
The summary of concomitant medications will be done for the mITT and Safety population. 
13 Medical history 
Medical history data will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The medical history data will be summarized with frequencies and percentages of patients with at least 
one medical history item, and patient frequencies and percentages on the System Organ Class (SOC) 
and PT levels. The number of events will also be summarized. The table will be sorted by overall 
descending frequency of SOC and then, within a SOC, by overall descending frequency of PT.  
PD history (time since diagnosis of PD measured in years at time of first dose at TV1, presence of a rest 
tremor at the time of diagnosis, time since onset of motor fluctuations, type of OFF episodes 
experienced, number of OFF episodes/day, typical length of OFF episodes) 
The summary of medical and PD history data will be done for the mITT and Safety population. 


 
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14 Analysis of efficacy 
14.1 
Primary endpoint 
The primary endpoint of the study is the mean change from pre-dose in MDS-UPDRS MOTOR score 
after 30 minutes at 12 weeks (MV4). The difference between APL-130277 and placebo at MV4 will be 
estimated using a MMRM. The model will include the observed change from pre-dose MDS-UPDRS 
MOTOR score values after 30 minutes at MV1, MV2, MV3 and MV4 as the response values (i.e., no 
imputation will be done). The treatment difference at 12 weeks will be estimated using contrasts. The 
MMRM model will include the treatment group (APL-130277 or placebo), visit (MV1, MV2, MV3 and 
MV4) and the interaction between the treatment group and visit as fixed factors. The change from pre-
dose in MDS-UPDRS MOTOR score after 30 minutes at the last titration visit at which the randomized 
dose is given up through TV6 will be used as a baseline covariate in the model.  
An unstructured covariance structure will be applied for MMRM. In case the model will not converge 
with the unstructured covariance structure, the heterogeneous Toeplitz structure (TOEPH) will be used 
instead. In case the model will not converge with the heterogeneous Toeplitz structure, heterogeneous 
compound symmetry (CSH) will be used instead. The denominator degrees of freedom will be 
computed using the Kenward-Roger method. 
The least square (LS) mean, standard error, and LS mean difference between APL-130277 and placebo 
group at MV4 along with the 95% confidence interval (CI) will be provided. The P-value for the 
hypothesis testing will also be provided. Treatment difference will be assessed with a 2-sided alpha 
level of 0.05, unless specified otherwise.  The SAS code planned for the analysis is outlined below. 
 
proc mixed data=&data; 
class trtp avisit usubjid; 
model chgpre=basepre trtp avisit trtp*avisit / ddfm=kr; 
repeated avisit / subject=usubjid(trtp) type=un; 
lsmeans trtp*avisit / cl; 
run; 
The mITT population will be used for the primary efficacy analysis. Observed and change from pre-
dose MDS-UPDRS MOTOR scores will be summarized by visit and time point for the mITT 
population as well. 
Subgroup analyses will be performed for factors defined in section 9.5 of this document. Each subgroup 
will be analyzed separately using the same methods as in the primary analysis. In addition, for each of 
the subgroup factors, a MMRM model similar to the primary model will be used, including additional 
fixed factors for the subgroup variable and the interaction between the treatment group and subgroup 
variable. The influence of each subgroup factor will be investigated using the p-value for the interaction 
term calculated with this model.  


 
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14.1.1 Patient Global Sensitivity analyses of the primary endpoint 
The following sensitivity analyses will be performed for the primary endpoint. 
 Completer analysis: The analysis as specified above will be repeated for the Completer Population.  
 Per Protocol analysis: The analysis as specified above will be repeated for the Per Protocol 
Population. 
 MI analysis with Missing At Random assumption:  MI techniques based on Pattern Mixture Models 
(PMM) will be applied as a sensitivity analysis in the mITT population. This methodology will 
structure data based on missing data patterns. The method will be based on a missingness pattern 
having a monotone structure, i.e. if among the observations over time one data value is missing, all 
other values after this missing value will also be treated as missing.  For patients with intermittent 
missing values, before performing MI based on the PMM, it will be necessary to create a monotone 
missingness pattern.  Intermittent missing values will be imputed using the Markov Chain Monte 
Carlo (MCMC) methodology which assumes a multivariate normal distribution over all variables 
included in the imputation model. The MI procedure in SAS will be used for this purpose and this 
first MI step is planned to be repeated 100 times, creating several different datasets with a 
monotone missing data structure.  Seed value of 201507 will be used in the MI procedure.  The 
imputation is based on the missing at random (MAR) assumption, i.e. the missing data are assumed 
to follow the same model as the other patients in their respective treatment arm. 
After this, the remaining missing data can be imputed using a method for monotone missingness, 
also based on the MAR assumption. Thus, for each of the created datasets with a monotone missing 
data pattern, the MI procedure in SAS will be used to impute missing values based on a sequential 
procedure reflecting the monotone missing data pattern. Patients with the first missing value 
occurring at MV1 will have their missing MV1 value replaced by an imputed value from a 
regression model with treatment group and the change from pre-dose MDS-UPDRS MOTOR score 
at baseline as explanatory variables. In the next step, patients with their MV2 value missing will 
have their missing MV2 value replaced by an imputed value from a regression model with 
treatment group, the change from pre-dose MDS-UPDRS MOTOR score at baseline and the MV1 
value as explanatory variables.  Similar procedure will be used to replace the missing values at 
MV3 and MV4. 
The imputed datasets generated with the approach described above do contain only non-missing 
values and are used as input in the model for the sensitivity analysis of the primary endpoint. 
MMRM models similar as described above will thus be run on each of the generated imputed 
datasets and the difference between the treatment groups at MV4 will be estimated. The MMRM 
model will be similar to the primary analysis. Finally, the MIANALYZE procedure in SAS will be 
applied to combine the results from these several datasets to derive an overall estimate of the 
treatment difference at MV4. In addition to the estimates, corresponding 95% confidence intervals 
and p-values will be calculated. 


 
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 MI analysis with Missing Not At Random assumption (Placebo group based imputation):  Another 
MI analysis will be performed with the assumption that the data is not missing at random. Placebo 
group based assumption will be used, i.e. the trajectories of the patients are assumed to follow the 
placebo group after the discontinuation. Methods similar to the procedure described above will be 
used in the mITT population. However, the missing values will be imputed using Placebo based 
imputation. 
 MI analysis with Missing Not At Random assumption (Tipping point based imputation):  If the 
primary analysis significantly favors APL-130277, another MI analysis will be performed in the 
mITT population with the assumption that the data in the APL-130277 group is not missing at 
random. A tipping point based assumption will be used, i.e. the trajectories of the patients in the 
APL-130277 group after withdrawal are assumed to be worse by an amount of delta. After the MI 
using the MAR assumption, as defined above has been done, the amount of delta will be added to 
each imputed value in the APL-130277 group. Successively harsher deltas will be imposed on the 
imputed values in the APL-130277 group, starting with a UPDRS increment (worsening) of 0.5 
points. The delta is further increased in the steps of 0.5 points (1.0, 1.5, 2.0, …) until the statistical 
significance is lost, i.e. until the p-value becomes >0.05. For the placebo group, the MI using MAR 
assumption will be used. 
 Comparability of the pre-dose values:  The primary endpoint is defined as the change from the pre-
dose value of the corresponding day.  This definition is based on the assumption that the study 
treatment does not influence the pre-dose values during the study. This assumption will be 
investigated by tabulating the pre-dose values by visit and treatment group with descriptive 
statistics in the mITT population. 
 Last observation carried forward (LOCF):  In this analysis, the missing values will be replaced by 
the previous visit change values at the 30 min post-dose time point carried forward. The LOCF-
imputed values at each visit will be compared using an Analysis of Covariance (ANCOVA) model 
with treatment group as a fixed factor. The change from pre-dose in MDS-UPDRS MOTOR score 
after 30 minutes at the last titration visit at which the randomized dose is given up through TV6 will 
be used as a covariate in the model. This analysis will be performed in the mITT population. 
Similarly, the pre-dose values corresponding to the change values will be carried forward for the 
purpose of summarizing the data with descriptive statistics. 
 Responder analysis based on the MDS-UPDRS MOTOR scores. Response is defined as an 
improvement of at least 30% decrease in MDS-UPDRS MOTOR score from the pre-dose value at 
15, 30, 45, 60 and 90 minutes. The number and proportion of responders at each time point and the 
cumulative number and proportion of patients having responded at least once by each time point 
will be tabulated with descriptive statistics at each visit. 
14.1.2 Graphical summaries of the primary endpoint 
The following graphs will be generated using the estimates calculated with the MMRM: 


 
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 Estimated mean changes (with SEM) from pre-dose to 15, 30, 45, 60 and 90 minutes by treatment 
group. Separate graph will be produced for each visit (MV1, MV2, MV3 and MV4). The x-axis 
includes the time of the assessment (15, 30, 45, 60 or 90 minutes) and the y-axis the change from 
pre-dose. LS means estimates and SEMs of these estimates from the primary MMRM will be used 
for the display. 
 Estimated mean changes (with SEM) from pre-dose to 30 minutes by treatment group and visit. The 
x-axis includes the visit (MV1, MV2, MV3 or MV4) and the y-axis the change from pre-dose. 
14.2 
Key Secondary endpoint 
The key secondary endpoint, percentage of patients with a patient-rated full “ON” response within 30 
minutes at MV4 will be analyzed in the mITT population using the GLIMMIX procedure for binomial 
data with logit link.  This analysis will use the observed values from MV1, MV2, MV3 and MV4 
without any imputation as the response. The model will include the treatment group (APL-130277 or 
placebo), visit (MV1, MV2, MV3 and MV4) and the interaction between the treatment group and visit 
as fixed factors. The “ON/OFF” assessment at the last titration visit at which the randomized dose is 
given up through TV6 will be used as a covariate.  An unstructured covariance structure will be used 
for the repeated measures. In case the model will not converge with the unstructured covariance 
structure, the heterogeneous Toeplitz structure (TOEPH) will be used instead. In case the model will 
not converge with the heterogeneous Toeplitz structure, heterogeneous compound symmetry (CSH) 
will be used instead.  The odds ratio (APL-130277 vs. Placebo), 95% confidence intervals for the odds 
ratio and p-value will be provided. 
The sas code planned for this analysis is  
 
Proc glimmix data=&data; 
class treatment visit subject baseline; 
model response=treatment visit treatment*visit baseline /dist=binary link=logit ddfm=kr; 
random visit/subject=subject type=un residual;  *if the model does not converge, try a different type by 
the following order: type=UN, type=TOEPH, type=CSH*/ 
lsmeans treatment*visit/cl ilink diffs oddsratio; 
run; 
As a sensitivity analysis, a Cochran-Mantel-Haenszel test stratified by the “ON/OFF” assessment 
within 30 minutes at the last titration visit at which randomized dose given. In case of missing data at 
MV4, the patient is considered as not reaching the full “ON”. The percentage of patients with a patient-
rated full “ON” response at each visit (MV1, MV2, MV3, MV4) and time point (15, 30, 45, 60 and 90 
minutes) will also be summarized descriptively by treatment group.  The analysis will be conducted in 
the mITT population. 


 
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14.2.1 Graphical summaries of percent of patients with patient-rated full “ON” 
The following graphs will be generated for the percentage of patients with a patient-rated full “ON” 
response, as defined above: 
 Percentage of patients with a patient-rated full “ON” response at 15, 30, 45, 60 and 90 minutes by 
treatment group. Separate graph will be produced for each visit (MV1, MV2, MV3 and MV4). The 
x-axis includes the time of the assessment (15, 30, 45, 60 or 90 minutes) and the y-axis the 
proportion of patients. 
 Cumulative number of patients with a patient-rated full “ON” response within 15, 30, 45, 60 and 90 
minutes by treatment group. Separate graph will be produced for each visit (MV1, MV2, MV3 and 
MV4). The x-axis includes the time of the assessment (15, 30, 45, 60 or 90 minutes) and the y-axis 
the cumulative proportion of patients reaching the response at least once by the time point. 
 Percentage of patients with a patient-rated full “ON” response at 30 minutes by treatment group. 
The x-axis includes the visit (MV1, MV2, MV3 or MV4) and the y-axis the proportion of patients.  
14.3 
Other secondary endpoints 
All the secondary endpoints defined below will be analyzed in mITT population. 
1. The percentage of instances where a full “ON” response was achieved at 30 minutes after self-
administration of study medication based on the home dosing diary entries.  
The percentages calculated separately for each patient for each visit (2 days prior to each visit) for 
the period between MV2 and MV4 (1 value per subject per visit) will be used as response variables 
in the statistical analysis. The percentage values will be compared between APL-130277 and 
placebo using a MMRM similar to the one used for the primary endpoint.  
2. Mean change from pre-dose in MDS-UPDRS MOTOR score at 15, 45, 60 and 90 minutes at the 12 
week visit (MV4) of the Maintenance Treatment Phase.  
These endpoints will be analyzed using a model similar to the MMRM used for the primary 
endpoint with corresponding timepoint for the covariate. 
3. Time (in minutes) to when study medication is starting to have an effect at the 12 week visit (MV4) 
of the Maintenance Treatment Phase.  
This variable will be analyzed as a time-to-event endpoint. The time to effect at MV4 will be 
described using the Kaplan-Meier method, including the estimate of the median time to effect and 
corresponding 95% confidence intervals. In case the median time cannot be estimated in both 
treatment groups, the time to 25% of the patients having an effect will be estimated additionally. 
Furthermore, the Kaplan-Meier estimates at 5, 10, 15, … minutes will be summarized by 5 minute 
increments.. However, time points beyond 60 minutes will not be summarized. Cox proportional 
hazards model with treatment group as a factor will be used to compare APL-130277 and placebo. 


 
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The difference will be estimated with a hazard ratio along with a 95% CI for the hazard ratio. For 
the patients with missing data at MV4, the last available observation from visits MV1, MV2 or 
MV3 will be used instead.  If all visits, MV1 – MV4, are missing, the patient will be considered 
censored at 90 minutes for this analysis. 
4. Percent of patients with a patient-rated full “ON” response within 30 minutes, whose duration from 
time when study medication begins to have an effect until their “OFF” (if applicable) lasts for at 
least 30 minutes at the 12 week visit (MV4) of the Maintenance Treatment Phase.  
This endpoint will be analyzed using similar methods as used for the key secondary endpoint 
including the sensitivity analysis.  
5. Clinical Global Impression of Improvement (CGI-I) post dosing. 
The proportions of patients who improved (defined as very much improved, much improved or 
minimally improved) will be tabulated by treatment group and visit. This summary will be 
complemented by the distribution of each response category (very much improved, much improved, 
minimally improved, no change, minimally worse, much worse, very much worse) tabulated by the 
treatment group and visit based on the observed results. The difference between APL-130277 and 
placebo at MV4 in patients who improved versus did not improve will be analyzed using a 
Cochran-Mantel-Haenszel test stratified by the CGI-S assessment at MV1. In case the distribution 
of the CGI-S assessment at MV1 is skewed, categories will be combined (e.g. category 1-3 vs 4 vs 
5-7). 
6. Patient Global Impression of Improvement (PGI-I) post dosing. 
This endpoint will be analyzed with methods similar to those used for CGI-I and proportion of 
patients who improved will be defined in a similar way. The Cochran-Mantel-Haenszel will be 
stratified by the PGI-S assessment at MV1. The PGI-S assessment at MV1 will be used to stratify 
the Cochran-Mantel-Haenszel test and categorized, if needed using approach similar to CGI-S. 
7. Change from baseline in Parkinson’s Disease Questionnaire-39 (PDQ-39). 
The PDQ-39 summary index will be analyzed with methods similar to those used for the primary 
endpoint with the exception of using the PDQ-39 score at SV as the baseline covariate. In addition, 
the sub-scores will be summarized with descriptive statistics. 
8. Mean change from baseline in MDS-UPDRS – Part II: Motor Aspects of Experiences of Daily 
Living. 
This endpoint will be analyzed at MV4 with an ANCOVA model with treatment group as a fixed 
factor and the baseline (Screening Visit) value as a covariate. 
In addition to the part II score, each categorical question of MDS-UPDRS – Part IV (q4.1 Time 
Spent with Dyskinesias, q4.2 Functional Impact of Dyskinesias, q4.3 Time Spent in the OFF State, 
q4.4 Functional Impact of Fluctuations, q4.5 Complexity of Motor Fluctuations, q4.6 Painful OFF 
State Dystonia; each questions scored from 0 to 4) will be tabulated separately, question by 
question. Both the distribution of categories and the categorical change from baseline (Screening 


 
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Visit), categorized as improved, no change or worsened will be tabulated. In addition, the % of 
Dyskinesia time, % of OFF time and % of Dystonia time collected on the Part IV questionnaire will 
be summarized with descriptive statistics, both as absolute values and as changes from baseline. 
14.4 
Other patient-reported endpoints 
1. Change in sleep measures on the Epworth Sleepiness Scale (ESS).  
The changes from SV to MV1, MV2, MV3, and MV4 in the total ESS score will be summarized 
with descriptive statistics. In addition, the proportion of patients who are sleepy (score of 10 or 
more) or very sleepy (score of 18 or more) will be tabulated. 
2. Change in European Quality of Life – 5 Dimensions (EQ-5D).  
The distribution of responses for the health state dimensions will be tabulated. The changes from 
SV to MV1, MV2, MV3, and MV4 in health state thermometer scale and health state index score 
will be tabulated with descriptive statistics. 
15 Analysis of safety and tolerability 
The population used for safety analyses will be the Safety Population and Maintenance Phase Safety 
Population. In general, the safety data will be presented separately for the Dose Titration Phase (where 
applicable, using the Safety Population) and for the Maintenance Treatment Phase (using the 
Maintenance Phase Safety Population). The safety analysis of the Dose Titration Phase will summarize 
the safety data for the total Safety population while the analysis of the Maintenance Treatment Phase 
will focus on the comparison of the APL-130277 treated patients versus placebo. In addition, separate 
summaries will be prepared for all patients receiving APL-130277 either during the Dose Titration 
Phase or Maintenance Treatment Phase by pooling the data from the two periods during the APL-
130277 exposure (using the Safety Population). 
15.1 
Extent of exposure 
The following information will be summarized by treatment group (when applicable) and overall. In 
addition, these summaries will be broken down by the dose level of APL-130277 (10 mg, 15 mg, 20 
mg, 25 mg, 30 mg or 35 mg; see Section 9.5). 
 The number of patients exposed to study treatment, defined separately for the Dose Titration Phase 
(number of single dose exposures will be derived) and for the Maintenance Treatment Phase 
(repeated dose exposure) 
 The following summaries will be done only for the Maintenance Treatment Phase (repeated dose 
exposure) 


 
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o Duration of exposure (days): Exposure to APL-130277 and Placebo in Maintenance Phase = 
date of last dose received in Maintenance Phase – date of first dose received in Maintenance 
Phase + 1 
o Total exposure to study treatment, expressed as person years (sum of duration of exposure to 
study treatment over all patients in days divided by 365.25, classified by treatment group) 
o  Proportion of doses taken at days with 5, 4, 3, 2, 1 doses taken and average daily dose 
(during the days when the information was collected) 
o Proportion of patients using >5, 5, 4, 3, 2, 1 or 0 doses/day at least once (during the days 
when the information was collected).  
15.2 
Compliance 
Treatment compliance will be assessed by summarizing the percentage of patients taking more than 5 
doses of study medication per day at least once during the study. The data will be summarized by 
treatment group during the Maintenance Treatment Phase. 
15.3 
Adverse events 
All AEs will be coded using  MedDRA Version 19.1.. Treatment-emergent adverse events (TEAEs) are 
defined as all AEs that start after the patient receives the first dose of study treatment. Dose Titration 
Phase TEAEs are defined as all AEs that start on or after the date of the first dose of APL-130277 
during the Dose Titration Phase but before the date of the first dose of study medication (APL-130277 
or placebo) during the Maintenance Treatment Phase. Maintenance Treatment Phase TEAEs are 
defined as all AEs that start on or after the first dose of study medication (APL-130277 or placebo) 
during the Maintenance Treatment Phase.  Events will be classified as drug-related if the AE is 
classified as possibly, probably, or certainly related to study drug.  
Separate summaries will be generated for TEAEs of special interest, tabulated by category and PT using 
the categories as specified below (Narrow terms will be used for all SMQs and all preferred terms 
under the specified HLT or HLGT as defined in the MedDRA dictionary will be included): 
o Hypotension, orthostatic hypotension: defined as all TEAEs with HLGT “decreased and 
non-specific blood pressure disorders and shock” 
o 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) 
 “Neurogenic shock” (MedDRA code 10058119) 


 
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 “Presyncope” (MedDRA code 10036653) 
 “Shock” (MedDRA code 10040560) 
 “Shock symptom” (MedDRA code 10040581) 
 “Syncope” (MedDRA code 10042772) 
 “Unresponsive to stimuli” (MedDRAcode 10045555) 
 
Or HLGT of “Seizures (incl subtypes)” 
o Falls & injuries: defined as all TEAEs meeting the criteria for the standardized MedDRA 
Query (SMQ) “Accidents and injuries” 
o Dyskinesias: defined as all TEAEs meeting the criteria for the SMQ “Dyskinesia” 
o Hallucinations and psychotic behaviors: defined as all TEAEs meeting the criteria for the 
SMQ “Psychosis & psychotic disorders” 
o 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” 
o Daytime sudden onset of sleep: defined as all TEAEs with HLGT “Sleep disorders and 
disturbances” 
o QT prolongation and ventricular arrhythmias: defined as all TEAEs meeting the criteria for 
the SMQ “Torsade de pointes /QT prolongation” 
o Acute Coronary Syndrome, Myocardial infarction, Angina: defined as all TEAEs meeting 
the criteria for the SMQ “Myocardial infarction” 
o Suicidal ideation & attempts: defined as all TEAEs meeting the criteria for the SMQ 
“Suicide/self-injury” 
o Melanoma: defined as all TEAEs meeting the criteria for the SMQ “Skin malignant tumors” 
o Stomatitis, Oral ulcers, Oral irritation: defined as all TEAEs meeting the criteria for the 
SMQ “Oropharyngeal disorders” 
o Allergic/sensitivity response to the formulation: defined as all TEAEs meeting the criteria 
for the SMQ “Hypersensitivity” 
Events with a missing start time, but with a start date equal to the date of first dose of study treatment 
will be considered treatment-emergent.  If the AE start date is incomplete, it will be imputed as follows 
for the purpose of determining TEAE:  


 
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 If the start date is completely missing, the start date will be equal to the date of the first dose of 
study treatment.  However, if the stop date is not missing and is before the date of the first dose of 
study treatment, then the stop date will be used instead.  
 If the start day is missing: Check if month is 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. 
 However, if the stop date is not missing and is before the date of the first dose of study treatment or 
the imputed start date, then the stop date will be used instead. 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).  
However, if the stop date is not missing and is before the date of the first dose of study treatment or the 
imputed start date, then the stop date will be used instead.  
The original date and time will be shown on all listings of AEs.  Listings will be provided for all AEs, 
serious TEAEs, non-serious TEAEs, TEAEs leading to drug withdrawal, TEAEs leading to drug 
interruption, TEAEs leading to dose reduction, and AEs leading to deaths. The listings will display 
study day, calculated as the AE start date – date of first dose in the relevant study phase (Dose Titration 
or Maintenance Treatment) + 1 for events occurring on or after the first dose in the Dose Titration 
phase, and as AE start date – date of first dose in the Dose Titration phase for AEs occurring prior to 
the first dose in the Dose Titration Phase. 
TEAEs will be summarized by SOC and PT and by treatment group when applicable. TEAEs with 
onset after the last dose of the study treatment period are attributed to the treatment received during the 
treatment period. Both event and patient counts, where applicable, will be summarized. The counts will 
be complemented by percentages calculated for the patient counts unless otherwise specified. 
 An overall summary of the number and percentage of patients reporting TEAEs and the number of 
TEAE events,  drug-related TEAEs, severe TEAEs, serious TEAEs, non-serious TEAEs, TEAEs 
leading to drug withdrawal, TEAEs leading to drug interruption, TEAEs leading to dose reduction, 
and TEAEs leading to death 
 TEAEs by SOC and PT, both as event and patient counts 
 TEAEs by PT, both as event and patient counts 
 Drug-related TEAEs by SOC and PT, both as event and patient counts 
 Severe TEAEs by SOC and PT, both as event and patient counts 
 TEAEs by SOC, PT and severity, as event counts; percentages will be calculated for the event count 
out of total number of events 
 TEAEs by SOC, PT and relationship, as event counts; percentages will be calculated for the event 
count out of total number of events 
 Serious TEAEs by SOC and PT, both as event and patient counts  


 
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 TEAEs leading to drug withdrawal by SOC and PT, both as event and patient counts  
 TEAEs leading to death by SOC and PT, both as event and patient counts  
 TEAEs leading to drug interruption by SOC and PT, both as event and patient counts  
 TEAEs leading to dose reduction by SOC and PT, both as event and patient counts 
 TEAEs of special interest by category and  PT, both as event and patient counts 
 Non-serious TEAEs by SOC and PT, both as event and patient counts  
 Non-serious TEAEs with >3% cumulative patient incidence in any arm/group by SOC and PT, both 
as event and patient counts 
The tables will be sorted by overall descending frequency of SOC and then, within a SOC, by overall 
descending frequency of PT based on the patient count for the APL-130277 column. If only event count 
is presented, the sorting will be done based on the event count. 
Furthermore, the adverse events will also be summarized by subgroups (age, gender, race, country, dose 
level) as defined in section 9.5 of this document. In addition, the following tables will be summarized 
by dose: TEAEs, Serious TEAEs, TEAEs leading to drug withdrawal, TEAEs leading to drug 
interruption, TEAEs leading to dose reduction, TEAEs leading to death, and TEAEs of special interest.  
15.4 
Laboratory safety variables 
All clinical laboratory parameters will be converted to consistent units according to the International 
System of Units (SI) before summarization. The following will be summarized: 
 Numeric laboratory parameters: Actual values and change from baseline (SV) to EOS, if applicable, 
for each parameter, will be summarized with descriptive statistics. 
 Laboratory parameters which have an upper or lower reference range: Number and percentage of 
patients with low, normal or high (i.e., below, within or above reference range) values at each visit 
for each parameter will be summarized 
o These values will be presented as a shift table, i.e. the distribution of the three response 
categories at EOS visit will be classified by the baseline (SV) category. 
 Categorical laboratory parameters: The distribution of the categories will be summarized by visit. 
15.5 
Vital signs 
Vital sign measurements include heart rate (HR), respiratory rate (RR), blood pressure (BP) and body 
temperature. Vital signs will be measured at all scheduled study visits at various time points after the 
patient has been in a supine position for 5 minutes. BP will also be measured within three minutes of 
standing at all time points. In addition to the vital signs captured on the Case Report Form, the standing 


 
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minus supine values (standing minus supine systolic BP, standing minus supine diastolic BP) will be 
evaluated. 
The following summaries will be done: 
 Change from baseline (SV) to other visit pre-dose values for each parameter (including the standing 
minus supine values). The change from baseline to the End of Study visit values will also be 
presented. 
 Actual values and change from pre-dose to post-dose, if applicable, at each visit for each parameter 
(including the standing minus supine values). 
Orthostatic hypotension will be defined as a reduction in systolic BP of 20 mmHg or more, or a 
reduction in diastolic BP of 10 mmHg or more, for the standing measurement compared to the supine 
measurement. The proportion of patients with orthostatic hypotension will be tabulated by visit and 
time point. 
15.6 
ECG 
A standard 12-lead ECG will be performed at all time points outlined in the protocol. ECGs will be 
performed in a semi-recumbent position and after 5 minutes of rest. The following parameters will be 
captured: Heart rate, PR interval, QRS interval, RR interval, QT interval, QTc Interval (Fridericia’s 
correction) and QTc Interval (Bazett’s correction). A triplicate 12-lead ECG will be performed at 
screening and the median value will be used for summary purposes. 
The following summaries will be done: 
 Change from baseline (SV) to other visit pre-dose values for each parameter. The change from 
baseline to the End of Study visit values will also be presented.  
 Actual values and change from pre-dose to post-dose, if applicable, at each visit for each parameter. 
The ECGs will be centrally read and deemed “Normal”, “Abnormal, not clinically significant” and 
“Abnormal, clinically significant” and most severe assessment will be tabulated by visit and time point.  
In addition, the QTc Intervals fulfilling the following criteria will be tabulated separately using 
Fridericia’s correction and Bazett’s correction: 
 Values >500 msec 
 Values increasing >15% from baseline if baseline value is ≥440 msec 
 Values increasing >30% from baseline if baseline value is <440 msec 
 Values increasing >30 msec from baseline 
 Values increasing >60 msec from baseline 
 At least one of the abnormalities listed above. 


 
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15.7 
Other safety variables 
 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a measure of suicidal ideation and behavior. 
The rating scale has 4 general categories: suicidal ideation, intensity of ideation, suicidal behavior, and 
actual attempts. All C-SSRS data will be listed. The frequency and percentage of patients with each 
response for suicidal ideation, intensity of ideation, and suicidal behavior items will be summarized as 
appropriate by treatment group and visit. 
 
The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease – Rating Scale (QUIP-
RS) is an instrument used to measure the extent of impulsive and compulsive behaviors in PD patients. 
The QUIP-RS consists of four questions which have to be answered for each disorder (gambling, sex, 
buying, eating, hobbyism, punding and PD medication use) on a 5-point Likert scale. Scoring range for 
each scale (i.e. disorder) is 0–16. The frequency and percentage of patients with positive response 
(“rarely” or higher) for each disorder will be summarized by treatment group and visit. Furthermore, the 
total Impulsive Control Disorder (ICD) score and the total QUIP-RS score will be summarized with 
descriptive statistics by treatment group and visit (both absolute values and changes from baseline). 
 
The frequency and percentage of patients with physical examination findings will be summarized by 
treatment group, visit, time point (when applicable) and body system. In addition, the frequency and 
percentage of patients with each type of oropharyngeal cavity examination finding will be summarized 
by treatment group, visit, time point (when applicable) and location. 
16 Other variables 
Major protocol deviations will be tabulated including the frequency and percentage of patients with 
each type of deviation by treatment group. Deviations considered major will be identified as such prior 
to study unblinding. Summaries will be based on the Enrolled Population and provided for the 
Screening Phase and Dose Titration Phase. Summaries will also be presented for ITT population for the 
Maintenance Treatment Phase. All other data collected but not specifically mentioned including the 
Zarit Burden Interview will be listed. 
17 Deviations from the analyses planned in the study protocol 
This analysis plan presents the planned analyses in more detail and several details and additional 
endpoints have been added.  
The definition of modified intention-to-treat population was changed from “All patients who are 
randomized, receive at least one post-randomization dose of study treatment (APL-130277 or  placebo) 
and have efficacy data from at  least one post randomization evaluation will comprise the mITT 
population’ to “All patients who are randomized and receive at least one post-randomization dose of 
study treatment (APL-130277 or placebo) will comprise the modified Intention-To-Treat (mITT) 
population. 


 
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18 Execution of statistical analyses 
Statistical analyses will be performed by INC Research/inVentiv Health and supervised by Sunovion 
and CLINTREX LLC. 
19 Hardware and software 
Statistical analysis, tables and patient data listings will be performed with SAS® version 9.3 or later for 
Windows (SAS Institute Inc., Cary, NC, USA). 
20 
References 
Clinical Study Protocol: Version 2.0 (6 May, 2015), Company: Sunovion Pharmaceuticals Inc.