Clinical trial NCT03051607
Conditions: Idiopathic Parkinson Disease
Keywords: Motor Fluctuations Off time On time Dyskinesia
Sponsor: Biotie Therapies Inc.
Start date: 2017-04-10; Completion date: 2018-01-16
Enrollment: 66 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 3, international, multicenter, open-label 12 month safety study.

Detailed description:
Each patient will participate for up to 52 weeks, which includes a Screening Period, followed by a Baseline Visit and open-label treatment for 1 year with a safety Follow-up 4 weeks after the last treatment.

* Screening Period: up to 6 weeks.
* Open-Label Treatment Period: 52 weeks (1 year)
* Post-Treatment Safety Follow Up: 4 weeks.

Arms: arm 1: 120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.
Interventions: intervention 1: Tozadenant
Intervention descriptions: intervention 1: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

Protocol documents:
Prot_000.pdf: 
Confidential Material 
THIS PROTOCOL IS THE PROPERTY OF BIOTIE THERAPIES INC (COLLECTIVELY 
WITH ITS AFFILIATES AND PARENT INCLUDING BIOTIE THERAPIES AG AND 
BIOTIE THERAPIES HOLDING AG AND BIOTIE THERAPIES CORP, “COMPANY”) AND 
IS A CONFIDENTIAL COMMUNICATION. ACCEPTANCE IMPLIES AN AGREEMENT 
NOT TO DISCLOSE INFORMATION CONTAINED HEREIN THAT IS NOT OTHERWISE 
PUBLICLY AVAILABLE, EXCEPT FOR USE BY AN INSTITUTIONAL REVIEW BOARD 
(IRB)/INDEPENDENT ETHICS COMMITTEE (IEC) FOR THE PURPOSE OF OBTAINING 
APPROVAL/FAVORABLE OPINION TO CONDUCT THE STUDY. THE IRB/IEC IS 
REQUESTED AND EXPECTED TO MAINTAIN CONFIDENTIALITY. THIS DOCUMENT 
MAY NOT BE USED OR PUBLISHED IN WHOLE OR IN PART WITHOUT THE 
CONSENT OF THE COMPANY. 
Confidential 
Version 3.0 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Multicenter, Open-Label Study to Evaluate the Safety and 
Tolerability of Tozadenant as Adjunctive Therapy in Levodopa-
Treated Patients with Parkinson’s Disease Experiencing End of 
Dose “Wearing-Off” 
Protocol Number: 
TOZ-CL06 
Development Phase: 
3 
US IND Number: 
078230 
EudraCT Number: 
2016-003961-25 
Protocol Version: 
3.0  
Version Date: 
09 October 2017 
Original Date of Issue 
30 September 2016 
Sponsor 
Biotie Therapies (a wholly owned subsidiary of Acorda 
Therapeutics Inc.) 
701 Gateway Boulevard, Suite 350 
South San Francisco, CA 94080 USA 
 
 


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STUDY CONTACT INFORMATION 
Study Director 
 
 
Chief Medical Officer 
 
 
 
 
VP Clinical Development 
and Study Physician 
 
  
 
 
 
 
VP Clinical Operations 
  
 
 
 
  
 
Sr. Director, Clinical Operations 
  
 
 
 
  
 
 
 


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REPORTING OF SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: 
1. Results in death. 
2. Is life-threatening, i.e., places the patient, in the view of the investigator, at immediate 
risk of death at the time of the event. 
Note: Life-threatening does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
4. Results in persistent or significant disability/incapacity, i.e., results in a substantial 
disruption of a person’s ability to conduct normal life functions. 
5. Is a congenital anomaly or birth defect, i.e., an adverse event (AE) that occurs in the child 
or fetus of a patient exposed to a study drug prior to conception or during pregnancy. 
6. Is an important medical event, i.e., an event that may not be immediately life-threatening 
or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the patient or may require medical or surgical intervention to 
prevent one of the other serious outcomes listed above. 
Examples of important medical events include, but are not limited to, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions. Interruption, discontinuation, or adjustment of dose level of study drug 
alone will not be considered an intervention that satisfies the definition of important 
medical event. 
Although fulfilling the above listed criteria, the following events are not regarded as being 
serious for this study: 
Hospitalizations for: 
− Facilitation of assessments specific to this protocol not associated with any 
deterioration in condition (e.g., when travel time between a patient’s home and 
the study site would otherwise preclude adequate evaluation). 
− Elective or preplanned assessment or treatment for a preexisting condition that 
has not worsened since initiation of study drug administration. 
Any SAE meeting above criteria that occurs during the study or within 4 weeks after the last 
dose of study drug must be reported within 24 hours by email and/or fax and by completing the 
AE electronic case report form (eCRF) and the SAE Report Form. The SAE Report Form must 
be sent to North America –
 
E-mail: 
.  
Europe – 
: 
E-mail: 
 
Australia – 
 


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E-mail:
 
The email address and fax number used for SAE reporting is also provided on the SAE/ 
Pregnancy Reporting Form Cover Page. 
Refer to additional SAE reporting instructions in Section 9.2. 


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TOZ-CL06 
CLINICALSTUDYPROTOCOLSIGNATUREPAGE 
The undersigned have reviewed the format and content of this protocol and have approved 
Clinical Study Protocol TOZ-CL06 entitled A Multicenter, Open-Label Study to Evaluate the 
Safety and Tolerability of Tozadenant as Adjunctive Therapy In Levodopa-Treated 
Patients with Parkinson's Disease Experiencing End of Dose "Wearing-Off''. 
Any modification of the clinical study protocol must be agreed upon by the Sponsor and the 
investigator and must be documented in writing. 
Sponsor: 
Biotic Therapies (a wholly owned subsidiary of Acorda Therapeutics Inc.) 
Protocol Number: 
TOZ-CL06 
Protocol Version: 
Amendment No. 2, Version 3.0 
Date of Issue: 
09 October 2017 
Confidential 
Version 3.0 
  of 143 


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INVESTIGATOR’S STUDY ACKNOWLEDGMENT/DISCLOSURE 
By my signature, I confirm that my staff and I understand that the protocol and Investigator’s 
Brochure are the confidential and proprietary property of Biotie Therapies. Further, I/we have 
carefully read and understand this protocol and agree to comply with the conduct and terms of 
the study specified therein. In particular, I/we have agreed to: 
1. Abide by all obligations per the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines and
applicable country regulations.
2. Conduct the study according to the protocol, its amendments and study procedure
manuals and study guides.
3. Assure that written and dated approval/favorable opinion from the Institutional Review
Board (IRB)/Independent Ethics Committee (IEC) for the protocol, any amendments to
the protocol, written informed consent form (ICF), any ICF updates, and Investigator’s
Brochure is available prior to initiation of any study-related procedure, and assure
periodic review by the IRB/IEC as required per local and country regulations.
4. Obtain witnessed, written informed consent from each study participant or his/her legal
representative.
5. Report all serious adverse events (SAEs) to Biotie Therapies or its agents and to the
IRB/IEC, as required by the protocol, country and IRB/IEC regulations.
6. Assure access by study monitors to original source documents.
7. Cooperate fully with any study-related Good Clinical Practice (GCP) audit as performed
by Biotie Therapies or its agents, the US Food and Drug Administration (FDA) and/or
the Regulatory Health Authorities of the participating countries.
8. Maintain confidentiality and assure security of confidential documents such as the
protocol, informed consent, case report forms, Investigator’s Brochure, final study
reports, study data, study procedure manuals, study guides, manuscript, and/or
unpublished data and correspondence.
9. Maintain confidentiality of any supplemental information that may be added to this
document.
Protocol Number: TOZ-CL06, Amendment No.2, Version 3.0
Date of Issue: 09 October 2017
_________________________________________  _____________________________ 
Principal Investigator’s Signature 
 
 
 
 
Date 
Principal Investigator’s Name _______________________________________________ 
             (printed first and last name) 


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LIST OF ABBREVIATIONS 
6-OHDA 
6-hydroxydopamine 
A2a 
Adenosine receptor subtype 2a 
ADL 
Activities of Daily Living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase (alanine aminotransferase) 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate transaminase (aspartate aminotransferase) 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CGI-I 
Clinical Global Impression of Improvement 
CK 
Creatine phosphokinase 
CMV 
Cytomegalovirus 
COMT 
Catechol-O-methyltransferase 
CPMP 
Committee for Medicinal Products for Human Use 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
d 
Day(s) 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein Barr virus 
ECG 
Electrocardiogram 
eCRF  
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EQ-5D-5L 
EuroQol 5D-5L Health Questionnaire 
ESS 
Epworth Sleepiness Scale 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
EU 
European Union 
FDA 
US Food and Drug Administration 


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fMRI 
Functional magnetic resonance imaging 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase (gamma-glutamyl transferase) 
GMP 
Good Manufacturing Practice 
h 
Hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICD 
Impulse control disorder 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IU/L 
International units per liter 
IUD 
Intrauterine device 
IXRS 
Interactive Response System 
LDH 
Lactate dehydrogenase 
MAO-B 
Monoamine oxidase type B 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMIDI 
Modified Minnesota Impulse Disorders Interview 
MMSE 
Mini-Mental State Examination 
msec 
Millisecond 
PD 
Parkinson’s disease 
PDF 
Portable document file 
PDQ-39 
Parkinson’s Disease Quality of Life Questionnaire 39-Item 
PGI-I 
Patient’s Global Impression of Improvement 
PK 
Pharmacokinetic 
PR 
Interval from onset of P wave to start of QRS complex in ECG 
PRN 
As needed 
PT 
Preferred term 
QA 
Quality assurance 


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QRS 
Interval from onset of Q wave to end of S wave in ECG, representing time for 
ventricular depolarization  
QT 
Interval between Q and T waves in ECG 
QTcF 
Heart rate-corrected interval between Q and T waves in ECG calculated using 
Fridericia’s correction formula 
RR 
Interval between successive peaks of R wave in ECG 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedure 
SS 
Safety set 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
UK 
United Kingdom 
ULN 
Upper limit of normal 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
US/USA 
United States of America 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 


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PROTOCOL SYNOPSIS 
Title 
A Multicenter, Open-Label Study to Evaluate the Safety and Tolerability of 
Tozadenant as Adjunctive Therapy in Levodopa-Treated Patients with 
Parkinson’s Disease Experiencing End of Dose “Wearing-Off”  
Protocol Number 
TOZ-CL06 
Phase 
3 
Number of Sites/ Location Approximately 120 sites in North America, Europe and Asia/Pacific 
countries will participate. 
Test Product, Dose 
and Mode of 
Administration 
Test Product: Tozadenant tablets 
 
 
 
 
Test Product Doses: 60 mg twice daily (BID; one 60 mg tablet); 120 mg 
BID (two 60 mg tablets or one 120 mg tablet) 
Comparator: N/A 
Mode of Administration: Oral 
Indication 
Parkinson’s disease (PD) 
Study Objectives 
Primary Objective: 
• 
To evaluate the safety and tolerability of tozadenant in levodopa-treated 
PD patients experiencing motor fluctuations, based on assessment of 
treatment-emergent adverse events (TEAEs), vital signs, 
electrocardiograms (ECGs), and clinical laboratory tests. 
Secondary Objectives: 
• 
To evaluate the effects of tozadenant on the occurrence of daytime 
drowsiness, impulsive behavior, and suicidality. 
Study Population 
Male or female patients with idiopathic PD who are receiving levodopa 
treatment and experiencing end-of-dose ‘wearing-off’ (see inclusion and 
exclusion criteria). 
Study Design 
Phase 3, international, multicenter, open-label safety study. 
Number of Patients to be 
Enrolled 
Approximately 450 patients will be enrolled. 
Dose Regimen 
Eligible patients will begin dosing with investigational medicinal product 
(IMP) at a dose of 120 mg (i.e., two 60 mg tablets or one 120 mg tablet) by 
mouth BID, taken in the morning and in the evening preferably at the same 
time each day. The evening dose should be approximately 12 hours after the 
morning dose. Patients will be instructed to take each dose at least 1 hour 
before or 2 hours after a meal and to refrain from eating for at least 1 hour 
after dosing. At Week 2 or thereafter, the investigator may adjust the 


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PROTOCOL SYNOPSIS 
patient’s IMP dose as clinically indicated; doses of 60 mg BID and 120 mg 
BID will be permitted.  
Concomitant Anti-PD 
Medications 
Investigators can adjust concomitant anti-PD medications during this study 
as needed. The optimal dose of IMP for each patient will be defined 
following discussion between the patient and the investigator, taking into 
account the potential for improvement of disease symptoms and the 
tolerability profile.  
All anti-PD medications taken by a patient during the course of the study 
and the reason for their use will be recorded in the source documents and 
electronic case report form (eCRF). 
Patients are to use their own supplies of concomitant anti-PD medications. 
Study Duration 
Each patient will participate for up to 62 weeks, which includes a Screening 
Period of 1 to ≤ 6 weeks, followed by a Baseline Visit, 52 weeks of open-
label treatment, and a Safety Follow-Up Visit 4 weeks after completion of 
investigational treatment:  
• 
Screening Period: 1 to ≤ 6 weeks. 
• 
Open-Label Treatment Period: 52 weeks. 
• 
Post-Treatment Safety Follow-Up: 4 weeks. 
The end of the study is defined as the date of the last visit of the last patient 
in the study. 
Enrollment Period 
Approximately 14 months. 
Safety Endpoints 
The safety and tolerability of tozadenant will be evaluated in this study 
using the following measures: 
1. TEAEs. 
2. Physical and neurological examination. 
3. Supine and standing pulse and blood pressure (BP). 
4. Standard 12-lead ECG: RR, PR, QRS, QT and QTcF. 
5. Laboratory parameters: hematology, chemistry, thyroid function 
(thyroid stimulating hormone [TSH], free T3, and free T4), and 
urinalysis. 
6. Daytime sleepiness as measured by the Epworth Sleepiness Scale 
(ESS), including assessment of episodes of sudden onset of sleep. 
7. Modified Minnesota Impulse Disorders Interview (mMIDI). 
8. Columbia-Suicide Severity Rating Scale (C-SSRS). 


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PROTOCOL SYNOPSIS 
Other Endpoints 
The following measures will be assessed to characterize PD status during 
open-label tozadenant treatment: 
1. Unified Parkinson’s Disease Rating Scale (UPDRS) Part II (Activity of 
Daily Living [ADL] subscale) + Part III (motor subscale) total score. 
2. UPDRS Part II (ADL subscale) score. 
3. UPDRS Part III (motor subscale) score in the ON state. 
4. UPDRS Part I total score. 
5. UPDRS Part IV, including dyskinesia as measured by questions 32, 33 
and 34 and motor fluctuations as measured by question 39. 
6. Clinical Global Impression of Improvement (CGI-I). 
7. Patient’s Global Impression of Improvement (PGI-I). 
8. Parkinson’s Disease Quality of Life Questionnaire (PDQ-39; total score 
and individual domain scores). 
9. Non-motor Symptom Assessment Scale. 
10. EuroQol 5D-5L Health Questionnaire (EQ-5D-5L). 
11. Patient-completed diaries (Change from Baseline in the number of 
hours per day spent as follows: OFF time, ON time without 
troublesome dyskinesia, total ON time, ON time with troublesome 
dyskinesia and asleep time). 
12. Healthcare Resource Utilization. 
13. Fall questionnaire. 
Inclusion Criteria 
Patients must fulfill all of the following inclusion criteria in order to be 
included in the study: 
1. Patient is informed and given ample time and opportunity to think about 
his/her participation in this study and has given his/her written informed 
consent on an Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB) approved consent form. 
2. Patient is considered reliable and capable of adhering to the protocol 
(e.g., able to understand and complete diaries), visit schedule, and 
medication administration instructions according to the judgment of the 
investigator. 
3. Patient has a documented history of idiopathic Parkinson’s disease 
consistent with the UK Parkinson’s Disease Society Brain Bank 
Diagnostic criteria prior to the Screening Visit. 
4. Patient has a PD duration of at least 3 years from diagnosis. 
5. Patient has a modified Hoehn and Yahr stage 2–4 when in OFF state 
(estimated) and ≤ 3 in ON state. 
6. Patient is male or female and 30–80 years old (inclusive) at Screening. 
7. Patient must have a good response to levodopa in the opinion of the 


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investigator, be taking at least four doses of a levodopa-containing 
medication per day, and at least one other concomitant anti PD 
medication (dopamine agonists, MAO-B inhibitors, anticholinergic 
agents, amantadine or entacapone). 
8. Patient is maintained on a regimen of permitted anti-PD medications 
that has been stable for at least 4 weeks prior to Screening. 
9. Patients must have been taking a levodopa-containing anti-PD 
medication continuously for at least the previous 12 months and must 
be currently experiencing end-of-dose “wearing-off” with at least 2.5 
hours of OFF time per day as confirmed by a 3-day Baseline diary. 
10. Patient must have achieved the following results for PD diary training, 
practice diary collection, and Baseline diary recordings: 
a. During a diary concordance session with an approved PD diary 
trainer/rater (minimum 2.5 hours), patient achieved at least 80% 
overall diary concordance including at least 1 OFF interval. 
b. Returned a valid 3-day (i.e., 3 consecutive 24-hour periods) practice 
diary. 
c. Returned valid diary recordings for each of the 3 consecutive days 
preceding the Baseline Visit that indicated at least 2.5 hours of OFF 
time on each of the 3 days. 
Note: A valid diary record will not have more than 4 invalid entries 
(double or missed entries) over a given 24-hour period (defined as 
starting at 6 AM). An invalid diary entry is defined as more than one 
entry recorded in a given half-hour interval, an unreadable entry, or the 
absence of an entry in a given half-hour interval. 
Patients will be required to view the PD diary training video. Caregivers 
may assist patients in completion of the PD diary. If a caregiver 
participates in completion of the PD diary, he or she is required to 
participate in the PD diary training session, in addition to viewing the 
PD diary training video. 
Patients who do not meet the criteria for proper practice diary 
completion may be retrained within the 6-week window of the 
Screening Period, if the patients are otherwise eligible for the study. 
11. Contraception: 
a. Women of childbearing potential must use an acceptable method* 
of contraception starting 4 weeks prior to study drug administration 
and for a minimum of 1 month after study completion. Otherwise, 
women must be postmenopausal (at least 1year absence of vaginal 
bleeding or spotting, and confirmed by follicle stimulating hormone 


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[FSH] ≥ 40 mIU/mL [or ≥ 40 IU/L] if less than 2 years 
postmenopausal) or be surgically sterile. 
b. Men with a potentially fertile partner must have had a vasectomy or 
be willing to use an acceptable method* of contraception for the 
duration of the study and for 3 months after study drug 
discontinuation. 
* For men and women: Acceptable methods of contraception include 
use of a condom with spermicide; oral, implantable or injectable 
contraceptives; intrauterine device (IUD); diaphragm with 
spermicide; or, diaphragm with condom. (Note: In Germany, the 
Czech Republic and other approved local regions, acceptable methods 
of contraception include complete abstinence; single barrier 
[diaphragm or condom] combined with use of IUD or contraceptive 
[oral, implantable or injectable]; or double barrier [diaphragm with 
condom]). 
Exclusion Criteria 
Patients with any of the following characteristics will be excluded from the 
study: 
1. Patient previously participated in any study with tozadenant. 
2. Patient is currently participating in or has participated in another study 
and received an IMP (active or placebo) within 5 half-lives of the IMP.  
3. Patient has any form of secondary or atypical parkinsonism (e.g., drug-
induced, post stroke). 
4. Severe obesity defined as a body mass index (BMI) greater than 40. 
5. Patient has a QTcF interval of ≥ 500 msec at Screening (Visit 1) or the 
patient has an average QTcF interval ≥ 450 msec for males or ≥ 470 
msec for females at Baseline (Visit 2). The average at Baseline will be 
taken from 3 serial ECGs done several minutes apart. (Fridericia’s 
correction [QTcF] must be used for correction of the QT interval.) 
6. Known diagnosis of malignant melanoma. 
7. History of neurosurgical intervention for PD, except for the placement 
of deep brain stimulator electrodes at least  12 months or greater prior 
to screening; subjects with deep brain stimulation must not be 
experiencing any clinically meaningful side effects related to the 
procedure, the device, or stimulation. 
8. Patient with grade 2 hypertension (supine systolic BP ≥ 160 or diastolic 
BP ≥ 100 mmHg), treated or untreated, at Screening or at Baseline 
confirmed by at least 1 of 2 further measurements. Patients may be 
rescreened once if excluded due to this exclusion criterion, following 
appropriate treatment or treatment adjustments resulting in resolution 
of the patient’s grade 2 hypertension. 
9. Patient with a history of hypertensive crisis unless the underlying cause 


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has been removed (e.g. stenting for renal artery stenosis). 
10. Patient has a history of chronic alcohol or drug abuse within the last 
2 years. 
11. Patient is taking apomorphine, budipine, istradefylline, tolcapone, or 
 within 4 weeks prior to Screening or is likely to 
require any of these drugs during the study. 
12. Current treatment with antipsychotics; however, quetiapine 
administered at doses of ≤ 100 mg per day and pimavanserin are 
permitted if the patient has been on a stable daily dose for at least 
4 weeks before Screening. PRN (as needed) dosing is not permitted. 
13. Patient has taken digoxin within 4 weeks prior to Screening or is likely 
to require digoxin during the study. 
14. Hyperthyroidism or hypothyroidism, unless all of the following 
conditions are met: 
a. Patient has received a stable dose of thyroid medication for at least 
3 months before the Baseline Visit. 
b. TSH concentrations are in the normal range (± 10% as a window 
either side of the normal range). 
c. Patient is clinically euthyroid. 
15. Any out-of-range laboratory values at Screening that have not been 
reviewed and documented as not clinically significant by the 
investigator. Any questionable safety lab results may be repeated for 
confirmation. 
16. A score of < 26 on the Mini-Mental State Examination, Second Edition 
(MMSE-II) at the Screening Visit. If the MMSE-II is not validated in 
the requisite language, the MMSE (Original) may be used. 
17. Patients with a current episode of major depression. Patients receiving 
treatment for depression with antidepressants may be enrolled if they 
have been on a stable daily dose of the antidepressant for at least 
8 weeks before the Baseline Visit. 
18. Patient has a recent history of suicide attempt (defined as an active, 
interrupted or aborted attempt within the past 5 years), or reports 
suicidal ideation in the past 6 months as indicated by a positive 
response (‘Yes’) to either Question 4 or Question 5 of the C-SSRS 
performed at the Screening or Baseline Visit. 
19. Patient has evidence of an impulse control disorder (ICD) (i.e., one or 
more positive modules) according to the Modified Minnesota Impulse 
Disorders Interview (mMIDI) unless a structured clinical interview 
performed during Screening confirms that the patient does not have an 
ICD. 
20. Patient is currently lactating or pregnant or planning to become 


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pregnant during the duration of the study. 
21. Patient has a known hypersensitivity to any components of the IMP or 
excipients. 
22. Any other condition or clinically significant abnormal findings on the 
physical or neurological examination, psychiatric and medical history, 
at Screening or at Baseline that, in the opinion of the investigator, 
would make the patient unsuitable for the study or put the patient at 
additional risk or prejudice evaluation of safety and efficacy of the 
IMP. 
23. Patients with alanine transaminase (ALT) or aspartate transaminase 
(AST) ≥3x upper limit of normal (ULN), or total bilirubin ≥1.5x ULN, 
at Screening. 
24. Patients with a history of hepatic dysfunction secondary to viral 
infection (hepatitis B or C; Epstein Barr virus [EBV]; or 
cytomegalovirus [CMV]), or a history of diagnosed drug- or alcohol-
induced hepatic toxicity or frank hepatitis. 
25. Patients with moderate to severe hepatic or renal impairment. 
26. 
 
 
 
 
27. Patients with absolute neutrophil count less than 2000/mm3 (or 2.0 
x 10E9/L) at screening. 
Overview of Study 
Procedures 
Consenting patients will be screened for eligibility.  
During the Screening Period, the patient (and any caregiver that will assist 
the patient to complete PD diaries during the study) will complete PD diary 
training and a diary concordance session with the site’s diary trainer/rater. 
The patient (and caregiver, as applicable) will review the PD diary training 
video and receive instruction on how to complete the PD diary. The 
definitions of ON and OFF will be reviewed, including ON time according 
to dyskinesia categories “without dyskinesia”, “with non-troublesome 
dyskinesia” or “with troublesome dyskinesia”, with emphasis on the need 
for the patient to be consistent in their use of the definitions when rating 
their status in the PD diary during the study. 
When instructions appear to have been understood by the patient (and 
caregiver, as applicable), a diary concordance session will be initiated 
during which the patient and the diary trainer/rater will concurrently 
complete separate training diaries for at least 5 consecutive half-hour 
intervals (minimum 2.5 hours). During the diary concordance session, the 
patient must experience both ON and OFF. The 2.5 hour session may be 


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extended, as needed, so that the patient experiences OFF. If the patient is 
OFF at the beginning of the diary concordance session, they may be 
administered their next dose of levodopa-containing medication in order to 
experience ON. When the session is completed, the diary trainer/rater will 
review and assess the patient’s diary concordance with the trainer/rater. The 
patient is required to reach at least 80% overall diary concordance with the 
trainer/rater including at least 1 OFF interval. If the concordance criteria are 
not achieved, the trainer/rater will schedule a second PD diary training and 
diary concordance session within the 6week Screening Period, unless the 
patient declines further participation. 
Following successful completion of the PD diary training and diary 
concordance session, patients/caregivers will be required to complete 
practice PD diaries on 3 consecutive pre-specified days (24 hour periods 
starting at 6 AM each day). The trainer/rater will telephone the patient to 
remind them to start keeping the PD diary prior to the start date, to review 
the ON and OFF definitions, and to answer any questions the patient may 
have regarding completion instructions.  
Practice PD diaries will be returned to the trainer/rater and reviewed with 
patients/caregivers over the telephone or in person to ensure PD diary 
completion instructions are fully understood. Patients with invalid practice 
diaries will be asked by the trainer/rater either to complete a second PD 
diary training and diary concordance session followed by a repeat 3 day 
practice diary, or else asked to repeat the 3-day practice diary, depending on 
the patient’s understanding of the diary instructions. Patients who do not 
satisfy diary concordance criteria during a second PD diary training and/or 
who return a second set of practice diaries that are invalid, will be 
considered screen failures. 
Patients who return valid practice PD diaries and who the investigator 
considers eligible for the study will have the Baseline Visit scheduled 
within 6 weeks from the Screening Visit. They will be instructed to 
complete the Baseline PD diary on the 3 consecutive days directly 
preceding the scheduled Baseline Visit. The trainer/rater will telephone the 
patient prior to the start date to remind them to start keeping the PD diary, 
to review the ON and OFF definitions, and to answer any questions the 
patients or caregiver may have regarding completion instructions. The 
patients will be requested to bring the Baseline PD diary to the Baseline 
Visit, at which the PD diary will be assessed for validity and to confirm the 
patient’s eligibility. Patients not meeting the criteria for valid Baseline PD 
diary completion may be retrained, as described above, and may return for 
another Baseline assessment within the 6 week Screening Period. 
Eligible patients who meet all the entry criteria at Baseline will be enrolled 


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PROTOCOL SYNOPSIS 
and receive open-label IMP for 52 weeks. Patients will be assessed for 
safety and tolerability regularly throughout the study and 4 weeks after their 
last dose of IMP. Blood pressure and pulse (supine and standing) will be 
taken at each outpatient visit. 
For scheduled study visits at Weeks 2, 6, 12, 24, 36, and 52, patients will be 
instructed to have already taken their normally scheduled dose of levodopa 
and their IMP prior to arriving at the study site in order to have their 
UPDRS Part III evaluated in ON (within approximately 1 to 3 hours after 
taking their levodopa dose). UPDRS in OFF will not be evaluated. Patients 
will be asked to complete a PD diary on the 3 consecutive days directly 
preceding visits at Weeks 12, 24 and 52. Prior to each 3-day PD diary 
completion period, patients will be telephoned to be reminded to comply 
with the PD diary instructions. Patients will be requested to bring their PD 
diary to the scheduled visits. 
Please refer to the Schedule of Events/Evaluations (Table 1) for specific 
timing of assessments. 
Criteria for Patient 
Discontinuation from 
Study 
Patients are free to withdraw from the study at any time, without prejudice 
to their continued care. 
Patients may be discontinued from the study at any time if clinically 
significant out-of-range laboratory values, clinically significant abnormal 
findings on physical examination, or intolerable TEAEs put the patient at 
additional risk, as judged by the investigator. Patients experiencing TEAEs 
considered to be study drug-related and not tolerated by the patient will be 
discontinued from the study. Patients must be discontinued from the 
study if the absolute neutrophil count is less than 1000/mm3 (or 1.0 x 
10E9/L). A complete list of reasons for patient discontinuation is located in 
Section 4.3 of the protocol. 
The Study Sponsor (Biotie Therapies, Inc.) has the right to terminate the 
study at any time. 
All patients who discontinue prematurely from the study will be requested 
to return to the study site as soon as possible to complete the safety and 
efficacy evaluations outlined for an Early Termination Visit in the Schedule 
of Events/Evaluations (Table 1). The Early Termination Visit should be 
done while the patient is taking IMP, if possible. After Early Termination, 
the patient will also be asked to return for a Safety Follow-Up Visit to be 
scheduled 28 days after the last dose of IMP, unless the Early Termination 
Visit itself occurred 28 or more days after the last dose of IMP. 
All TEAEs will be followed until resolution, return to Baseline level, or 
stabilization. 


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PROTOCOL SYNOPSIS 
Sampling for Tozadenant 
Plasma Drug 
Concentrations 
Pharmacokinetic (PK) blood samples for determination of plasma 
tozadenant concentration will be collected at the Week 2 study visit. 
blood sample will be collected at the most 
convenient time during the visit (“Sparse PK Sampling”).  
 PK blood samples may 
be collected (“Expanded PK Sampling” - additional details are provided in 
Appendix 15.9). On the morning of the Week 2 visit, participating subjects 
will refrain from taking their 120 mg IMP dose until after collection of a 
predose/trough PK sample. 
 
 
  
Sample Size Justification 
Approximately 645 patients will be screened, assuming a 30% screen 
failure rate, to enroll 450 patients. 
Data and Safety 
Monitoring 
Concurrent safety monitoring is planned for this study. Responsibility for 
safety monitoring will be assigned to the independent Data and Safety 
Monitoring Board (DSMB) of study TOZ-CL05, which will also oversee 
the safety of TOZ-CL06 by reviewing relevant data on a regular basis. The 
DSMB will consist of members who are independent from Biotie Therapies, 
Inc. Study enrollment will not be halted during planned DSMB reviews of 
safety data. The objectives and procedures for the DSMB are detailed in the 
DSMB charter. 
Statistical Analysis 
Safety data, including TEAEs, vital signs, ECGs, ESS, physical 
examination, and clinical laboratory test results will be summarized 
descriptively. The descriptive statistics will be provided for the observed 
data and for the change from Baseline at each measured time point, where 
appropriate. Tables will summarize TEAE data as appropriate. Note that 
counting will be by patient, not event and patients will only be counted once 
within each system organ class or preferred term. 
Laboratory test results will be classified as below the lower limit of normal, 
within normal limits, and above the ULN. Shift tables will be used to 
summarize changes from Baseline to each visit by treatment group. 
Clinically significant physical or neurological exam findings and any 
clinically significant out-of-range laboratory tests that are TEAE will be 
recorded as TEAEs and documented in the TEAE summaries. 
Other variables will be summarized descriptively. Descriptive statistics will 
be generated for the observed and the change from Baseline. For categorical 
variables, frequency and percentages will be produced.  
 
 


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Table 1: 
Schedule of Events/Evaluations 
 
Study Period Screening a Baseline 
Predose 
Open-Label Treatment 
(52 weeks) 
Safety 
Follow-Up 
Early 
Termination w Unscheduled 
 
Study Week b 
−6 to −1 
BL 
2 
(± 3 d) 
6 
(± 3 d) 
12 
(± 3 d) 
24 
(± 7 d) 
36 
(± 7 d) 
52 
(± 14 d) 
[16 weeks] 
56 
(28 ± 3 d after 
last dose of IMP) 
 
 
Assessments 
Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History, 
including neurological and PD history 
X 
 
 
 
 
 
 
 
 
 
 
Recording of concomitant and  
anti-PD medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP c, pulse c 
X d 
X d 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
12-lead ECG f 
X 
X g 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Weight (include height at Screening) 
X 
 
 
 
X 
X 
 
X 
X 
X 
X e 
Physical and neurological examination 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X e 
PD diary training and diary concordance 
session 
X 
 
 
 
 
 
 
 
 
 
 
Modified Hoehn and Yahr staging (observed 
ON; OFF estimated per history) h 
X 
 
 
 
 
 
 
 
 
 
 
UPDRS Parts I, II, III and IV i 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
MMSE-II (in ON state) 
X 
 
 
 
 
 
 
 
 
 
 
mMIDI j 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
ESS h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PD diary collection (phone call prior to start 
of 3 consecutive 24 hour diary completion 
periods) 
X k 
X k 
 
 
X l 
X l 
 
X l 
 
X m 
 
PD diary review 
X 
X 
 
 
X 
X 
 
X m 
 
X m 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
CGI-I h 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
PGI-I h 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
PDQ-39 h 
 
X 
 
 
 
X 
 
X 
 
X 
 
Sudden onset of sleep 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fall questionnaire 
 
X 
 
 
 
X 
 
X 
 
X 
 
Healthcare Resource Utilization 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Non-motor Symptom Assessment Scaleh 
 
X 
 
 
 
X 
 
X 
 
X 
 
EQ-5D-5L h 
 
X 
 
 
 
X 
 
X 
 
X 
 
Recording of AEs 
X n 
X n 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Period Screening a Baseline 
Predose 
Open-Label Treatment 
(52 weeks) 
Safety 
Follow-Up 
Early 
Termination w Unscheduled 
 
Study Week b 
−6 to −1 
BL 
2 
(± 3 d) 
6 
(± 3 d) 
12 
(± 3 d) 
24 
(± 7 d) 
36 
(± 7 d) 
52 
(± 14 d) 
[16 weeks] 
56 
(28 ± 3 d after 
last dose of IMP) 
 
 
Assessments 
Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Laboratory tests: hematology o, chemistry p 
(including thyroid function q) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
FSH test, females who are postmenopausal 
for < 2 years 
X 
 
 
 
 
 
 
 
 
 
 
Method of contraception r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Urine pregnancy test, females of 
childbearing potential s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Urinalysis t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Review of inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Final verification of eligibility 
 
X 
 
 
 
 
 
 
 
 
 
Tozadenant blood sampling 
 
 
X u 
 
 
 
 
 
 
 
 
IMP dispensing and/or return v 
X 
X 
X 
X 
X 
X 
X 
 
X 
X e 
eCRF completion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE, adverse event; BP, blood pressure; CGI-I, Clinical Global Impression of Improvement; C-SSRS, Columbia-Suicide Severity Rating Scale; d, day; ECG, electrocardiogram; 
eCRF, electronic case report form; ESS, Epworth Sleepiness Scale; ET, Early Termination; FSH, follicle stimulating hormone; IMP, investigational medicinal product; mMIDI, 
Modified Minnesota Impulse Disorders Interview; MMSE-II, Mini-Mental State Exam – Second Edition (MMSE-II); PD, Parkinson’s disease; PDQ-39, Parkinson’s Disease 
Quality of Life Questionnaire; PGI-I, Patient’s Global Impression of Improvement; UPDRS, Unified Parkinson’s Disease Rating Scale; V, Visit. 
Footnotes 
a Screening period may not exceed 6 weeks.  
b Visit windows for scheduled visits after Baseline (V2) are in relation to the date of the Baseline Visit (V2). 
c Obtain and record BP and pulse measurements after at least 5 minutes supine rest and again after standing for approximately 1 minute and 3 minutes. 
d At Screening and Baseline (before dosing), obtain and record serial BP and pulse measurements after at least 5 minutes supine rest and again after standing for approximately 
1 and 3 minutes. Repeat these BP and pulse measurements 2 more times approximately 10 minutes apart. 
e Optional activities (e.g., additional assessments for evaluation of AEs) that may be performed at the investigator’s discretion. 
f A resting supine 12-lead ECG will be collected after the patient has been in a supine position for a minimum of 5 minutes. Ensure the ECG is collected when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
g At Baseline, obtain three 12-lead ECGs (i.e., 3 serial readings, performed several minutes apart). Ensure the ECGs are collected when the patient is not experiencing dyskinesia 
that would interfere with an adequate recording. 
h To be collected during patient’s ON state. 
i UPDRS to be measured in ON state. UPDRS Part III should be measured approximately 1 to 3 hours after patients have taken a scheduled dose of levodopa (preferably their 
morning dose of levodopa). Patients will be instructed to have already taken their normally scheduled dose of levodopa and their IMP before arriving at the study site in order to 
have their UPDRS Part III evaluated in the ON state. UPDRS in the ON state will be measured at a time representative of the ON state in that patient, not in the patient’s “best” 
ON. 


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Table 1: Schedule of Events/Evaluations (continued) 
j At Screening, send patient for structured clinical interview if one or more positive mMIDI modules. If the structured clinical interview confirms that the subject does not have an 
ICD, he/she will not be considered ineligible on that basis. After Baseline, if patient has one or more positive modules on the mMIDI, their continued participation in the study 
should be discussed with the Medical Monitor. 
k The 3-day practice diary during the Screening Period and the 3-day Baseline diary must both be valid in order to enroll a patient. The trainer/rater will call the patient before the 
scheduled start of the diary completion periods to remind him or her to keep the PD diary and to review completion instructions. The patient will also be reminded to send the 
completed practice diary to the trainer/rater and to bring their Baseline diary to the Baseline Visit. If the practice or Baseline diary is invalid, the patient may be retrained and 
complete another practice or Baseline diary within the 6-week window of the Screening Period, if the patient is otherwise eligible for the study. 
l PD diary collected over the 3 consecutive 24-hour periods before the day of the scheduled study visits on Weeks 12, 24 and 52. The PD diary trainer/rater will call the patient 
before the scheduled start of the 3-day PD diary completion period (at the latest, on the last working day before the scheduled start of the PD diary completion) and review 
completion instructions. The patient will also be reminded to bring their PD diary to the visit. The trainer/rater will instruct the patient if the PD diary contains missing and/or 
invalid entries to reinforce instructions for appropriate completion. 
m Done only if the ET date coincides with the scheduled diary collection return date. 
n Pretreatment AEs. 
o Hematology tests: Hemoglobin concentration, hematocrit, red blood cell count, total and differential white blood cell, thrombocyte (platelet) count. 
p Blood chemistry (including liver function) tests: Aspartate amino transferase (AST), alanine amino transferase, (ALT), gamma-glutamyl transpeptidase (GGT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin (conjugated and unconjugated), albumin, creatinine, urea/BUN, bicarbonate, uric acid, total protein, sodium, 
chloride, potassium, calcium, phosphate, glucose, cholesterol, creatine phosphokinase (CK). 
q TSH, free T3, and free T4. 
r For applicable patients: At Screening, document method of contraception used by patient. At subsequent visits, verify continuation of (or any change to) contraceptive method. 
s For females of childbearing potential: urine pregnancy test. 
t Urinalysis: Specific gravity, pH, ketones, blood, protein, glucose. If urine dipstick is positive for leukocytes, protein, or erythrocytes, a microscopic evaluation and culture will 
be performed. 
u A PK blood sample should be collected at the most convenient time during the Week 2 visit. Record the patient-reported date and approximate time when the patient took the 
most recent dose of IMP. Record the date and time of the PK sample collection. See Section 8.0 of the protocol. (Note: sites participating in Expanded PK Sampling should refer 
to Appendix 15.9). 
v Patients will be instructed to take the assigned dose of open-label tozadenant by mouth BID, in the morning and in the evening preferably at the same time each day. The evening 
dose should be approximately 12 hours after the morning dose. Patients will be instructed to take their morning and evening doses at least 1 hour before or 2 hours after a meal 
and to refrain from eating for at least 1 hour after dosing. 
w If patient has discontinued IMP, perform Early Termination Visit as soon as possible after the last dose of IMP. If patient took the last dose of IMP 28 or more days prior to the 
Early Termination Visit, a Safety Follow-Up Visit (Section 6.2.19) is not required. 
 
 
 


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Table 1.1: 
Schedule of Events/ Evaluations for Hematology Monitoring 
 
Study Period 
Open-Label Treatment 
(52 weeks) 
Weekly monitoring b 
(if required) 
 
Study Week 
4 
(±3 d) 
8 
(±3 d) 
10 
(±3 d) 
16 
(±3 d) 
20 
(±3 d) 
44 
(±7 d) 
 
Assessments 
Study Visit 
V3.5 
V4.3 
V4.8 
V5.3 
V5.8 
V7.5 
Laboratory test: hematology a  
X 
X 
X 
X 
X 
X 
X 
Recording of AEs 
 
 
 
 
 
 
X 
Recording of concomitant and Anti-PD medications 
 
 
 
 
 
 
X 
eCRF completion  
X 
X 
X 
X 
X 
X 
X 
aHematology tests: Hemoglobin concentration, hematocrit, red blood cell count, neutrophils, total and differential white blood cell, thrombocyte (platelet) count. 
bOnly for patients that require weekly hematology monitoring per section 4.3.2. To be captured as an unscheduled visit in EDC/RAVE. 
 


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TABLE OF CONTENTS 
STUDY CONTACT INFORMATION ...........................................................................................2 
REPORTING OF SERIOUS ADVERSE EVENTS........................................................................3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ...............................................................5 
INVESTIGATOR’S STUDY ACKNOWLEDGMENT/DISCLOSURE........................................6 
LIST OF ABBREVIATIONS ..........................................................................................................7 
PROTOCOL SYNOPSIS...............................................................................................................10 
1.0 
BACKGROUND AND RATIONALE.......................................................................30 
1.1 
Background .................................................................................................................30 
1.2 
Tozadenant Clinical Development Program in Parkinson’s Disease .........................31 
2.0 
OBJECTIVES AND ENDPOINTS ............................................................................33 
2.1 
Objectives ...................................................................................................................33 
2.1.1 
Primary Objective .......................................................................................................33 
2.1.2 
Secondary Objectives .................................................................................................33 
2.2 
Endpoints ....................................................................................................................33 
2.2.1 
Safety Endpoints .........................................................................................................33 
2.2.2 
Other Endpoints ..........................................................................................................33 
3.0 
STUDY DESIGN .......................................................................................................34 
3.1 
Study Description .......................................................................................................34 
3.1.1 
Study Duration Per Patient .........................................................................................35 
3.1.2 
Planned Number of Patients and Sites ........................................................................35 
3.1.3 
Anticipated Regions and Countries ............................................................................35 
3.2 
Schedule of Events/Evaluations..................................................................................35 
3.3 
Schematic Diagram .....................................................................................................36 
3.4 
Rationale for Dose Selection ......................................................................................36 
4.0 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................37 
4.1 
Inclusion Criteria ........................................................................................................37 
4.2 
Exclusion Criteria .......................................................................................................38 
4.3 
Criteria for Withdrawal from Study............................................................................40 
4.3.1 
Potential Criteria for Withdrawal from Study ............................................................41 
4.3.2 
Definite Criteria for Withdrawal from Study .............................................................41 
5.0 
STUDY TREATMENT(S) .........................................................................................43 


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5.1 
Description of Investigational Medicinal Product ......................................................43 
5.2 
Treatment(s) to be Administered ................................................................................43 
5.3 
Packaging ....................................................................................................................43 
5.4 
Labeling ......................................................................................................................43 
5.5 
Handling and Storage Requirements ..........................................................................44 
5.6 
Dosing Instructions .....................................................................................................44 
5.7 
Drug Accountability ...................................................................................................44 
5.8 
Procedures for Monitoring Patient Compliance .........................................................45 
5.9 
Concomitant Medications/Treatments ........................................................................45 
5.9.1 
Allowed Anti-PD Medications/Treatments ................................................................45 
5.9.2 
Prohibited Concomitant Medications/Treatments ......................................................45 
5.9.3 
Other Concomitant Medications/Treatments ..............................................................46 
5.10 
Blinding ......................................................................................................................46 
5.11 
Enrollment and Numbering of Patients ......................................................................46 
6.0 
STUDY PROCEDURES BY VISIT ..........................................................................46 
6.1 
Overview of Study Procedures ...................................................................................46 
6.2 
Detailed Study Procedures ..........................................................................................48 
6.2.1 
Recruitment and Informed Consent Process...............................................................48 
6.2.2 
Visit 1 (Week -6 to -1) Screening Period ...................................................................49 
6.2.3 
Visit 2 Baseline ...........................................................................................................52 
6.2.4 
Visit 3 (Week 2)..........................................................................................................54 
6.2.5 
Visit 3.5 (Week 4).......................................................................................................56 
6.2.6 
Visit 4 (Week 6)..........................................................................................................56 
6.2.7 
Visit 4.3 (Week 8).......................................................................................................58 
6.2.8 
Visit 4.8 (Week 10).....................................................................................................58 
6.2.9 
Telephone Call on Week 12 (to Occur Prior to PD Diary Start Date)........................59 
6.2.10 
Visit 5 (Week 12)........................................................................................................59 
6.2.11 
Visit 5.3 (Week 16).....................................................................................................61 
6.2.12 
Visit 5.8 (Week 20).....................................................................................................61 
6.2.13 
Telephone Call on Week 24 (to Occur Prior to PD Diary Start Date)........................61 
6.2.14 
Visit 6 (Week 24)........................................................................................................62 
6.2.15 
Visit 7 (Week 36)........................................................................................................63 
6.2.16 
Visit 7.5 (Week 44).....................................................................................................65 


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6.2.17 
Telephone Call on Week 52 (to Occur Prior to PD Diary Start Date)........................65 
6.2.18 
Visit 8 (Week 52)........................................................................................................66 
6.2.19 
Safety Follow-Up Visit (Visit 9, Week 56) ................................................................67 
6.2.20 
Early Termination Visit ..............................................................................................68 
6.2.21 
Unscheduled Visit .......................................................................................................70 
7.0 
ASSESSMENT OF DISEASE ACTIVITY ...............................................................71 
7.1 
Hauser Parkinson’s Disease Home Diary ...................................................................71 
7.2 
Unified Parkinson’s Disease Rating Scale (UPDRS) .................................................73 
7.3 
Fall Questionnaire .......................................................................................................74 
7.4 
Clinical/Patient Global Impression Scales (CGI-I and PGI-I)....................................74 
7.5 
Parkinson’s Disease Quality of Life Questionnaire (PDQ-39)...................................74 
7.6 
Non-Motor Symptom Assessment Scale ....................................................................74 
7.7 
EuroQol 5D-5L Health Questionnaire (EQ-5D-5L) ...................................................75 
7.8 
Healthcare Resource Utilization .................................................................................75 
8.0 
ASSESSMENT OF PLASMA DRUG CONCENTRATION ....................................75 
9.0 
ASSESSMENT OF SAFETY.....................................................................................76 
9.1 
Adverse Events ...........................................................................................................76 
9.1.1 
Definition of Adverse Event .......................................................................................76 
9.1.2 
Procedures for Reporting and Recording Adverse Events .........................................76 
9.1.3 
Description of Adverse Events ...................................................................................76 
9.1.4 
Follow Up of Adverse Events.....................................................................................76 
9.1.5 
Rule for Repetition of an Adverse Event ....................................................................77 
9.1.6 
Pregnancy....................................................................................................................77 
9.1.7 
Overdose of Investigational Medicinal Product .........................................................78 
9.1.8 
Safety Signal Detection ..............................................................................................78 
9.2 
Serious Adverse Events ..............................................................................................78 
9.2.1 
Definition of Serious Adverse Event ..........................................................................78 
9.2.2 
Procedures for Reporting Serious Adverse Events .....................................................79 
9.2.3 
Follow Up of Serious Adverse Events........................................................................80 
9.2.4 
Immediate Reporting of Adverse Events ....................................................................80 
9.3 
Laboratory Measurements ..........................................................................................80 
9.4 
Other Safety Measurements ........................................................................................82 
9.4.1 
Blood Pressure and Pulse Measurements ...................................................................82 


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9.4.2 
Twelve-lead Electrocardiogram (ECG) ......................................................................82 
9.4.3 
Epworth Sleepiness Scale (ESS).................................................................................82 
9.4.4 
Assessment for Episodes of Sudden Onset of Sleep...................................................83 
9.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS)...................................................83 
9.4.6 
Modified Minnesota Impulse Disorders Interview (mMIDI) .....................................83 
10.0 
STUDY MANAGEMENT AND ADMINISTRATION ............................................83 
10.1 
Adherence to Protocol ................................................................................................83 
10.2 
Monitoring ..................................................................................................................84 
10.2.1 
Definition of Source Data ...........................................................................................84 
10.2.2 
Source Data Verification ............................................................................................85 
10.3 
Data Handling .............................................................................................................85 
10.3.1 
Case Report Form Completion ...................................................................................85 
10.3.2 
Database Entry and Reconciliation .............................................................................85 
10.3.3 
Patient Identification Code List ..................................................................................86 
10.3.4 
Planned Safety Data Monitoring.................................................................................86 
10.4 
Termination of the Study ............................................................................................86 
10.5 
Archiving and Data Retention ....................................................................................86 
10.6 
Audit and Inspection ...................................................................................................87 
10.7 
Good Clinical Practice ................................................................................................87 
11.0 
STATISTICS ..............................................................................................................87 
11.1 
Definition of Analysis Sets .........................................................................................87 
11.2 
Study Variables ...........................................................................................................88 
11.2.1 
Safety Variables ..........................................................................................................88 
11.2.2 
Pharmacokinetic Variables .........................................................................................88 
11.2.3 
Other Variables ...........................................................................................................88 
11.3 
General Statistical Considerations ..............................................................................89 
11.4 
Planned Efficacy Analyses .........................................................................................89 
11.5 
Planned Safety Analyses.............................................................................................89 
11.6 
Other Analyses............................................................................................................90 
11.7 
Handling of Protocol Deviations ................................................................................91 
11.8 
Handling of Dropouts or Missing Data.......................................................................91 
11.9 
Determination of Sample Size ....................................................................................91 
12.0 
ETHICS AND REGULATORY REQUIREMENTS .................................................91 


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12.1 
Informed Consent .......................................................................................................91 
12.2 
Institutional Review Boards and Independent Ethics Committees.............................92 
12.3 
Patient Privacy ............................................................................................................93 
12.4 
Protocol Amendments.................................................................................................93 
13.0 
FINANCE, INSURANCE, AND PUBLICATION ....................................................93 
14.0 
REFERENCES ...........................................................................................................94 
15.0 
APPENDICES ............................................................................................................96 
15.1 
Unified Parkinson’s Disease Rating Scale (UPDRS) .................................................96 
15.2 
Epworth Sleepiness Scale .........................................................................................104 
15.3 
Assessment for Episodes of Sudden Onset of Sleep.................................................105 
15.4 
Modified Minnesota Impulse Disorders Interview (mMIDI) ...................................106 
15.5 
UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria ..............112 
15.6 
Modified Hoehn and Yahr ........................................................................................113 
15.7 
 
15.8 
Fall Questionnaire .....................................................................................................115 
15.9 
Expanded Pharmacokinetic Sampling Procedures – Applicable to Select 
Sites Only..................................................................................................................116 
15.9.1 
Baseline (Visit 2) Assignment and Dispensing and Investigational Medicinal 
Product for Subjects Participating in Expanded PK Sampling (Replacement 
Section for Section 6.2.3.4) ......................................................................................116 
15.9.2 
Visit 3 (Week 2) for Subjects Participating in Expanded PK Sampling 
(Replacement Section for Section 6.2.5) ..................................................................117 
15.10 
Clinical/Patient Global Impression Scales (CGI-I and PGI-I)..................................123 
15.11 
Parkinson’s Disease Quality of Life Questionnaire (PDQ-39).................................125 
15.12 
Non-Motor Symptom Assessment Scale for Parkinson’s Disease ...........................130 
15.13 
Hauser Parkinson’s Disease Home Diary .................................................................135 
15.14 
PD Home Diary Training, Concordance, Validation................................................136 
15.15 
Healthcare Resource Utilization Questionnaire ........................................................143 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events/Evaluations..................................................................................20 
Table 1.1:  Schedule of Events/ Evaluations for Hematology Monitoring……………………...23 
Table 2: 
Investigational Medicinal Product ..............................................................................43 
Table 3: 
Laboratory Measurements ..........................................................................................81 
Table 4: 
Schedule of Events/Evaluations for Subjects Participating in Expanded PK 
Sampling ...................................................................................................................119 
Table 4.1: Schedule of Events/ Evaluations for Hematology Monitoring……………………..122 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram of Study Design ..........................................................................36 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Background 
Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative movement disorder 
characterized clinically by resting tremor, rigidity, bradykinesia and gait disturbance with 
postural instability. Other features can include masked faces, micrographia, and non-motor 
features including hyposmia, autonomic dysfunction, mood disturbances, and cognitive 
dysfunction. Estimates of the incidence and prevalence of PD vary considerably among studies 
due to differences in study populations, case ascertainment and diagnostic criteria. However, it is 
recognized that the incidence and prevalence of PD increase with age; and it is estimated that 
1−2% of the population aged over 65 years are affected (Von Campenhausen et al, 2005). 
The characteristic pathological findings in the brains of patients with PD are loss of 
dopaminergic neurons of the substantia nigra pars compacta coupled with the presence of 
intracytoplasmic inclusions (Lewy bodies). It is now appreciated that neurodegeneration also 
involves the olfactory system, the cerebral hemispheres, the lower brain stem, the spinal cord, 
and the peripheral autonomic nervous system. Current therapy is primarily based on a dopamine 
“replacement” strategy using the dopamine precursor levodopa. Levodopa has revolutionized the 
therapy of PD, but chronic treatment is associated with the development of motor complications 
(“wearing-off” and dyskinesia) in the majority of patients. Other available pharmacologic 
treatments include dopamine agonists, monoamine oxidase type B (MAO-B) inhibitors, and 
catechol-O-methyl transferase (COMT) inhibitors. These have not been shown to be superior to 
levodopa, but have been shown to either delay the need for levodopa or reduce OFF time in 
levodopa-treated patients. Each of these agents is thought to act directly on the dopaminergic 
system. Each has shown benefit, but there remains a need for agents that can treat and prevent 
motor complications (Olanow et al, 2009). 
Adenosine A2a receptor antagonists have emerged as a potentially attractive new class of drugs 
for the treatment of PD (Pinna, 2009). A2a receptors are highly localized in the basal ganglia, 
specifically within the indirect output pathway which is important in the control of voluntary 
movement. Alterations in firing patterns in these neurons are also thought to be involved in the 
development of motor complications induced by levodopa. A2a receptor antagonists modulate 
gamma-aminobutyric acid and glutamate release in the basal ganglia along with other key 
neurotransmitters that modulate motor activity. In both rodent and primate models of PD, 
A2a receptor antagonists have been shown to produce alterations in motor behavior when 
administered alone or in combination with dopaminergic drugs, suggesting that they might be 
effective in the symptomatic treatment of PD (Bibbiani et al, 2003; Yu et al, 2006; Jenner et al, 
2009). Because of the potential of A2a antagonists to inhibit abnormal firing of overactive 
D2-bearing neurons in the indirect striato-nigral pathway, they have the potential to improve 
OFF time in patients with PD. A2a inhibition may also slow neurodegeneration (Schwarzschild 
et al, 2003). 
 
 


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nt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of tozadenant in 
levodopa-treated PD patients experiencing motor fluctuations, based on assessment of TEAEs, 
vital signs, electrocardiograms (ECGs), and clinical laboratory tests. 
2.1.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the effects of tozadenant on the occurrence 
of daytime drowsiness, impulsive behavior, and suicidality. 
2.2 
Endpoints 
2.2.1 
Safety Endpoints 
The safety and tolerability of tozadenant will be evaluated in this study using the following 
measures: 
1. TEAEs. 
2. Physical and neurological examination. 
3. Supine and standing pulse and BP. 
4. Standard 12-lead ECG: RR, PR, QRS, QT and QTcF. 
5. Laboratory parameters: hematology, chemistry, thyroid function (thyroid stimulating 
hormone [TSH], free triiodothyronine [T3], and free thyroxine [T4]), and urinalysis. 
6. Daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS), including 
assessment of episodes of sudden onset of sleep. 
7. Modified Minnesota Impulse Disorders Interview (mMIDI).  
8. Columbia-Suicide Severity Rating Scale (C-SSRS). 
2.2.2 
Other Endpoints 
The following measures will be assessed to characterize PD status during open-label tozadenant 
treatment: 
• UPDRS Part II (Activity of Daily Living [ADL] subscale) + Part III (motor 
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• UPDRS Part II (ADL subscale) score. 
• UPDRS Part III (motor subscale) score in the ON state. 
• UPDRS Part I total score. 
• UPDRS Part IV, including dyskinesia as measured by questions 32, 33 and 34 and 
motor fluctuations as measured by question 39. 
• Clinical Global Impression of Improvement (CGI-I). 
• Patient’s Global Impression of Improvement (PGI-I). 
• Parkinson’s Disease Quality of Life Questionnaire 39-Item (PDQ-39; total score 
and individual domain scores). 
• Non-motor Symptom Assessment Scale. 
• EuroQol 5D-5L Health Questionnaire (EQ-5D-5L). 
• Patient-completed diaries (Change from Baseline in the number of hours per day 
spent as follows: OFF time, ON time without troublesome dyskinesia, total ON 
time, ON time with troublesome dyskinesia and asleep time). 
• Healthcare Resource Utilization. 
• Fall Questionnaire. 
3.0 
STUDY DESIGN 
3.1 
Study Description 
This is a Phase 3, international, multicenter, open-label study in levodopa-treated patients with 
PD experiencing end-of-dose “wearing-off”. This study includes a Screening Period of up to 
6 weeks that starts with a Screening Visit, followed by a 52-week Open-Label Treatment Period 
and a Safety Follow-Up Visit 4 weeks after completion of investigational treatment. After 
providing written informed consent, patients will undergo screening evaluations. Patients must 
meet all inclusion criteria and none of the exclusion criteria and they must successfully complete 
the diary training and achieve 80% overall diary concordance with the PD diary trainer/rater 
including at least 1 OFF interval to be considered for randomization. If preliminary eligibility is 
confirmed by the investigator, patients will then be scheduled for a Baseline Visit and will be 
required to return a valid set of Baseline diaries. Final eligibility will be determined at the 
Baseline Visit. 
Patients will return to the study site for evaluation at scheduled visits at Weeks 2, 6, 12, 24, 36 
and 52. Patients will be contacted by telephone before the start of each 3-day PD diary 
completion period to be reminded to complete the diary. Patients will also be scheduled for a 
laboratory draw (hematology measurement only) at Weeks 4, 8, 10, 16, 20 and 44. A 
final Safety Follow-Up Visit (Week 56) will occur 28 ± 3 days after the patient’s last open-label 
dose of tozadenant. Upon starting study treatment, patients will receive open-label tozadenant at 
a dose of 120 mg BID. Adjustments to the open-label tozadenant dose are allowed to be made by 
the investigator starting at Week 2 and at any of the subsequent visits. Doses of 60 or 120 mg 


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BID are permitted; the investigator may adjust a patient’s dose to either level as clinically 
indicated. The Interactive Response System (IXRS) will be used to assign, track and manage the 
tozadenant inventory at each study site. 
Patients’ concomitant anti-PD medications may be adjusted as needed under the investigator’s 
supervision (see Section 5.9.1). The optimal dose of open-label tozadenant for each patient will 
be defined following discussion between the patient and the investigator, taking into account the 
potential for improvement of disease symptoms and the tolerability profile. 
Unscheduled Visits may be arranged as considered necessary by the investigator (see 
Section 6.2.21). In the event of Early Termination, patients will be asked to complete an Early 
Termination Visit as soon as possible (see Section 6.2.20) and then return 28 ± 3 days after their 
last dose of IMP for a Safety Follow-Up Visit (Section 6.2.19). 
Safety data will be provided to the Data and Safety Monitoring Board (DSMB), at a frequency 
specified by the DSMB charter, for ongoing monitoring of safety and detection of any trends. 
3.1.1 
Study Duration Per Patient 
Each patient will participate for up to 62 weeks, which includes a Screening Period of 1 to 
≤ 6 weeks, followed by a Baseline Visit, 52 weeks of open-label treatment, and a Safety 
Follow-Up Visit 4 weeks after completion of investigational treatment:  
• Screening Period: 1 to ≤ 6 weeks. 
• Open-Label Treatment Period: 52 weeks. 
• Post-Treatment Safety Follow-Up: 4 weeks. 
The total anticipated study duration for an individual patient will be a minimum of 57 weeks and 
a maximum of 62 weeks. The end of the study is defined as the date of the last visit of the last 
patient in the study. 
3.1.2 
Planned Number of Patients and Sites 
Approximately 645 patients will be screened, assuming a 30% screen failure rate, to enroll 
450 patients. 
Approximately 120 sites will participate in the study. 
3.1.3 
Anticipated Regions and Countries 
This international study will be conducted in North America, Europe, and Asia/Pacific countries. 
3.2 
Schedule of Events/Evaluations 
The Schedule of Events/Evaluations is shown in Table 1 and Table 1.1. 
 


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3.3 
Schematic Diagram 
Figure 1: 
Schematic Diagram of Study Design 
 
3.4 
Rationale for Dose Selection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OPEN-LABEL TREATMENT 
N=450 
E 
n 
r 
o 
l 
l 
m 
e 
n 
t 
Tozadenant 120 mg* 
open-label twice daily 
S 
c 
r 
e 
e 
n 
i 
n 
g 
Follow-up 
|------------------- 52 Weeks -------------------| ---- 4 Weeks ----| 
* Starting at Week 2, investigator may adjust dose 
to 60 or 120 mg BID based on individual response. 
FOLLOW-UP 
------- 6 Weeks ------| 
SCREENING 


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4.0 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
Patients must fulfill all of the following inclusion criteria in order to be included in the study: 
1. Patient is informed and given ample time and opportunity to think about his/her 
participation in this study and has given his/her written informed consent on an 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) approved 
consent form. 
2. Patient is considered reliable and capable of adhering to the protocol (e.g., able to 
understand and complete diaries), visit schedule, and medication administration 
instructions according to the judgment of the investigator. 
3. Patient has a documented history of idiopathic Parkinson’s disease consistent with the 
UK Parkinson’s Disease Society Brain Bank Diagnostic criteria prior to the Screening 
Visit. 
4. Patient has a PD duration of at least 3 years from diagnosis. 
5. Patient has a modified Hoehn and Yahr stage 2–4 when in OFF state (estimated) and ≤ 3 
in ON state. 
6. Patient is male or female and 30–80 years old (inclusive) at Screening. 
7. Patient must have a good response to levodopa in the opinion of the investigator, be 
taking at least four doses of a levodopa-containing medication per day, and at least one 
other concomitant anti-PD medication (dopamine agonists, MAO-B inhibitors, 
anticholinergic agents, amantadine or entacapone). 
8. Patient is maintained on a regimen of permitted anti-PD medications that has been stable 
for at least 4 weeks prior to Screening. 
9. Patients must have been taking a levodopa-containing anti-PD medication continuously 
for at least the previous 12 months and must be currently experiencing end-of-dose 
“wearing-off” with at least 2.5 hours of OFF time per day as confirmed by a 3-day 
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10. Patient must have achieved the following results for PD diary training, practice diary 
collection, and Baseline diary recordings: 
a. During a diary concordance session with an approved PD diary trainer/rater 
(minimum 2.5 hours), patient achieved at least 80% overall diary concordance 
including at least 1 OFF interval. 
b. Returned a valid 3-day (i.e., 3 consecutive 24-hour periods) practice diary. 
c. Returned valid diary recordings for each of the 3 consecutive days preceding the 
Baseline Visit that indicated at least 2.5 hours of OFF time on each of the 3 days. 
Note: A valid diary record will not have more than 4 invalid entries (double or missed 
entries) over a given 24-hour period (defined as starting at 6 AM). An invalid diary entry 
is defined as more than one entry recorded in a given half-hour interval, an unreadable 
entry, or the absence of an entry in a given half-hour interval. 
Patients will be required to view the PD diary training video. Caregivers may assist 
patients in completion of the PD diary. If a caregiver participates in completion of the PD 
diary, he or she is required to participate in the PD diary training session, in addition to 
viewing the PD diary training video. 
Patients who do not meet the criteria for proper practice diary completion may be 
retrained within the 6-week window of the Screening Period, if the patients are otherwise 
eligible for the study. 
11. Contraception: 
a. Women of childbearing potential must use an acceptable method* of contraception 
starting 4 weeks prior to study drug administration and for a minimum of 1 month 
after study completion. Otherwise, women must be postmenopausal (at least 1 year 
absence of vaginal bleeding or spotting, and confirmed by follicle stimulating 
hormone [FSH] ≥ 40 mIU/mL [or ≥ 40 IU/L] if less than 2 years postmenopausal) or 
be surgically sterile. 
b. Men with a potentially fertile partner must have had a vasectomy or be willing to use 
an acceptable method* of contraception for the duration of the study and for 3 months 
after study drug discontinuation. 
*For men and women: Acceptable methods of contraception include use of a condom 
with spermicide; oral, implantable or injectable contraceptives; intrauterine device (IUD); 
diaphragm with spermicide; or, diaphragm with condom. (Note: In Germany, the Czech 
Republic, and other approved local regions, acceptable methods of contraception include 
complete abstinence; single barrier [diaphragm or condom] combined with use of IUD or 
contraceptive [oral, implantable or injectable]; or double barrier [diaphragm with 
condom]). 
4.2 
Exclusion Criteria 
Patients with any of the following characteristics will be excluded from the study: 
1. Patient previously participated in any study with tozadenant. 


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2. Patient is currently participating in or has participated in another study and received an 
IMP (active or placebo) or medical device treatment within 5 half-lives of the IMP . 
3. Patient has any form of secondary or atypical parkinsonism (e.g., drug-induced, post 
stroke). 
4. Severe obesity defined as a body mass index (BMI) greater than 40. 
5. Patient has a QTcF interval of ≥ 500 msec at Screening (Visit 1) or the patient has an 
average QTcF interval ≥ 450 msec for males or ≥ 470 msec for females at Baseline (Visit 
2). The average at Baseline will be taken from 3 serial ECGs done several minutes apart. 
(Fridericia’s correction [QTcF] must be used for correction of the QT interval.) 
6. Known diagnosis of malignant melanoma. 
7. History of neurosurgical intervention for PD, except for the placement of deep brain 
stimulator electrodes at least  12 months or greater prior to screening; subjects with deep 
brain stimulation must not be experiencing any clinically meaningful side effects related 
to the procedure, the device, or stimulation. 
8. Patient with grade 2 hypertension (supine systolic BP ≥ 160 or diastolic BP 
≥ 100 mmHg), treated or untreated, at Screening or at Baseline confirmed by at least 1 of 
2 further measurements. Patients may be rescreened once if excluded due to this 
exclusion criterion, following appropriate treatment or treatment adjustment resulting in 
the resolution of the patient’s grade 2 hypertension. 
9. Patient with a history of hypertensive crisis unless the underlying cause has been 
removed (e.g. stenting for renal artery stenosis). 
10. Patient has a history of chronic alcohol or drug abuse within the last 2 years. 
11. Patient is taking apomorphine, budipine, istradefylline, tolcapone, or 
, within 4 weeks prior to Screening or is likely to require any of 
these drugs during the study. 
12. Current treatment with antipsychotics; however, quetiapine administered at doses of 
≤ 100 mg per day and pimavanserin are permitted if the patient has been on a stable daily 
dose for at least 4 weeks before Screening. PRN (as needed) dosing is not permitted. 
13. Patient has taken digoxin within 4 weeks prior to Screening or is likely to require digoxin 
during the study. 
14. Hyperthyroidism or hypothyroidism, unless all of the following conditions are met: 
a. Patient has received a stable dose of thyroid medication for at least 3 months before 
the Baseline Visit. 
b. TSH concentrations are in the normal range (± 10% as a window either side of the 
normal range). 
c. Patient is clinically euthyroid. 
15. Any out-of-range laboratory values at Screening that have not been reviewed and 
documented as not clinically significant by the investigator. Any questionable safety lab 
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16. A score of < 26 on the Mini-Mental State Examination, Second Edition (MMSE-II) at the 
Screening Visit. If the MMSE-II is not validated in the requisite language, the MMSE 
(Original) may be used. 
17. Patients with a current episode of major depression. Patients receiving treatment for 
depression with antidepressants may be enrolled if they have been on a stable daily dose 
of the antidepressant for at least 8 weeks before the Baseline Visit. 
18. Patient has a recent history of suicide attempt (defined as an active, interrupted or aborted 
attempt within the past 5 years), or reports suicidal ideation in the past 6 months as 
indicated by a positive response (‘Yes’) to either Question 4 or Question 5 of the C-SSRS 
performed at the Screening or Baseline Visit. 
19. Patient has evidence of an impulse control disorder (ICD) (i.e., one or more positive 
modules) according to the Modified Minnesota Impulse Disorders Interview (mMIDI) 
unless a structured clinical interview performed during Screening confirms that the 
patient does not have an ICD. 
20. Patient is currently lactating or pregnant or planning to become pregnant during the 
duration of the study. 
21. Patient has a known hypersensitivity to any components of the IMP or excipients. 
22. Any other condition or clinically significant abnormal findings on the physical or 
neurological examination, psychiatric and medical history, at Screening or at Baseline 
that, in the opinion of the investigator, would make the patient unsuitable for the study or 
put the patient at additional risk or prejudice evaluation of safety and efficacy of the IMP. 
23. Patients with alanine transaminase (ALT) or aspartate transaminase (AST) ≥3x upper 
limit of normal (ULN), or total bilirubin ≥1.5x ULN, at Screening. 
24. Patients with a history of hepatic dysfunction secondary to viral infection (hepatitis B or 
C; Epstein Barr virus [EBV]; or cytomegalovirus [CMV]), or a history of diagnosed 
drug- or alcohol-induced hepatic toxicity or frank hepatitis. 
25. Patients with moderate to severe hepatic or renal impairment. 
26. 
 
 
 
27. Patients with absolute neutrophil count less than 2000/mm3 (or 2.0 x 10E9/L) at 
screening. 
4.3 
Criteria for Withdrawal from Study 
Patients are free to withdraw from the study at any time, without prejudice to their continued 
care. 


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4.3.1 
Potential Criteria for Withdrawal from Study 
Investigators should contact the Medical Monitor in advance, whenever possible, to discuss the 
potential discontinuation of a patient from the study. Investigators must contact the Medical 
Monitor to discuss any of the following events that may lead to the patient being discontinued 
from the study: 
1. Patient is noncompliant with the study procedures or medications. 
2. Patient takes prohibited concomitant medications as defined in this protocol. 
3. Patient has one or more clinically significant out-of-range laboratory values or clinically 
significant abnormal findings on physical examination, or AEs that are intolerable (as 
determined by the patient) or that put the patient at additional risk as judged by the 
investigator. 
4.3.2 
Definite Criteria for Withdrawal from Study 
Patients must be discontinued from the study if any of the following events occur: 
1. Patient develops an illness that would interfere with his or her continued participation. 
2. Patient withdraws his or her consent. 
3. Confirmation of patient pregnancy during the study, as evidenced by a positive 
pregnancy test. 
4. The Sponsor/Sponsor’s designee or a regulatory agency requests withdrawal of the 
patient. 
5. The Sponsor or a regulatory agency terminates the study. 
6. Patient has active suicidality since last visit as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the C-SSRS, or reports any suicidal behavior since 
their last C-SSRS assessment. The patient should be referred immediately to a Mental 
Healthcare Professional. 
7. The patient has a QTcF interval consistently ≥ 500 msec and/or a QTcF interval 
consistently increased by ≥ 60 msec compared to the average baseline QTcF interval. The 
average baseline QTcF interval is defined as the average of the three QTcF interval 
values obtained at Visit 2. Fridericia’s method must be used for correction of QT 
intervals. 
8. Investigators must follow guidelines provided related to monitoring hepatic parameters in 
relation to investigation guidelines and stopping rules. The following necessitate 
immediate cessation of dosing with IMP: 
a. Patients with ALT or AST >8x ULN. 
b. Patients with ALT or AST ≥3x ULN and co-existing total bilirubin ≥2x ULN*. 
c. Patients with ALT or AST ≥3x ULN who exhibit a temporally associated fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever (without clear 
alternative cause), rash or eosinophilia (>5%). 


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*Patients with significant elevation of alkaline phosphatase (ALP; ALP >2x ULN) 
indicating biliary obstruction to be discussed with the Medical Monitor. 
9. Patients noted to have an elevated BP post-baseline, with a supine systolic BP ≥ 160 
mmHg and/or a diastolic BP ≥ 100 mmHg that is present at 2 consecutive post-baseline 
study visits. 
10. Patients have concomitant surgical intervention for PD, including but not limited to deep 
brain stimulation. 
11. Patients with an absolute neutrophil count less than 1000/mm3 (or 1.0 x 10E9/L).* 
Following study drug discontinuation, these patients will require weekly hematology 
measurement until the WBC and/or ANC returns to 75% of the baseline value (Visit 
2). Assess for adverse events and concomitant medication changes and record as an 
unscheduled visit. Discuss with medical monitor to assure that the patient is 
discontinued from study drug and that the appropriate follow up safety measures 
are taken. 
*Any patient experiencing a decline in absolute neutrophil count (ANC) and/or white 
blood cells (WBC) by 50% from baseline (Visit 2) will require weekly hematology 
measurement until the WBC and/or ANC returns to 75% of the baseline value. The 
patient will continue with dosing during the weekly hematology follow-up. Assess for 
adverse events and concomitant medication changes and record as an unscheduled visit. 
If the WBC and/or ANC returns to 75% of baseline, the patient should return to routine 
evaluations as outlined in the Schedule of Events/Evaluations. Discuss with medical 
monitor. 
All patients who discontinue prematurely from the study will be requested to return to the study 
site as soon as possible to complete the safety and efficacy evaluations outlined for an Early 
Termination Visit in the Schedule of Events/Evaluations (Table 1) and in Section 6.2.20. The 
Early Termination Visit should be done under IMP treatment, if possible. After Early 
Termination, the patient will also be asked to return for a Safety Follow-Up Visit to be scheduled 
28 (±3) days after their last dose of IMP, unless the Early Termination Visit itself occurred 28 or 
more days after the last dose of IMP (see Section 6.2.19). 
All TEAEs will be followed until resolution, return to Baseline level, or stabilization. 
Investigators will attempt to obtain information on patients in the case of study withdrawal or 
discontinuation. For patients considered lost to follow-up, the investigator should make an effort 
(at least one phone call and one written message to the patient) and document his or her effort 
(include the date and summary of the phone call(s) and a copy of the written message(s) in the 
source documents) to complete the final evaluation. All results of these evaluations and 
observations, together with a narrative description of the reason(s) for removing the patient, must 
be recorded in the source documents. The electronic case report form (eCRF) must document the 
primary reason for study withdrawal or discontinuation. Patients who discontinue prematurely 
from the study will not be replaced. 


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5.0 
STUDY TREATMENT(S) 
5.1 
Description of Investigational Medicinal Product 
Table 2: 
Investigational Medicinal Product 
 
Tozadenant 
Dosage Form: 
 
Route of 
Administration: 
Oral 
Batch Number: 
Will be assigned according to Good Manufacturing Practice 
(GMP) 
Retest Date: 
Will be assigned according to GMP 
 
5.2 
Treatment(s) to be Administered 
Investigational medicinal product is comprised of immediate-release, active tozadenant tablets 
for oral administration, as described above. 
5.3 
Packaging 
The IMP supplies for this study will be packaged according to current Good Manufacturing 
Practice (GMP) guidelines and applicable national laws and regulations. Supplies will be 
packaged in such a way as to protect the products from deterioration during transport and 
storage. For this study, IMP will be packaged in an open-label fashion in high-density 
polyethylene bottles containing one hundred (100) 60 mg tozadenant tablets per bottle or fifty 
(50) 120 mg tozadenant tablets per bottle. 
Sites will be supplied with an initial stock that will be monitored by the IXRS, and resupply will 
be organized throughout the duration of the study in order to ensure sufficient open-label clinical 
IMP supplies are available onsite. 
5.4 
Labeling 
Supplies of IMP will be labeled in accordance with current FDA and local regulations (and as 
applicable, International Conference on Harmonisation [ICH] guidelines) regarding Good 
Clinical Practice (GCP) and GMP, and will include any locally required statements. If necessary, 
labels will be translated into the local language. 


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5.5 
Handling and Storage Requirements 
The investigator is responsible for the safe and proper storage of IMP supplies at the site in 
accordance with labeling and written storage instructions. From receipt until final disposition 
(e.g., return shipment to Sponsor’s authorized designee), IMP stored by the investigator is to be 
kept in a secured area with limited access. 
 
Appropriate storage conditions 
must be ensured and documented by completion of a temperature log in accordance with local 
requirements on a regular basis, showing minimum and maximum temperatures reached over the 
time interval. 
In case an out-of-range temperature is noted, it must be immediately communicated to the 
Sponsor/Sponsor’s designee before further use of the IMP. The Sponsor/Sponsor’s designee will 
transmit the out-of-range temperature (copy of the temperature log and duration of the 
out-of-range temperature, if available) to the Sponsor’s Quality Assurance (QA) representative. 
Based on discussion with the Sponsor’s QA representative, the Sponsor/Sponsor’s designee will 
then provide the site with instructions regarding use of the IMP. 
The investigator or designee will instruct the patient to store the IMP according to the 
instructions on the label. 
5.6 
Dosing Instructions 
Eligible patients will be instructed to take the specified number tablets of open-label IMP by 
mouth BID, in the morning and in the evening preferably at the same time each day. 
All patients, upon start of study: 
2 tablets (2 × 60 mg tablets), BID OR  
1 tablet (1 × 120 mg tablet), BID 
If dose reduced at Week 2 or later: 
1 tablet (1 × 60 mg tablet), BID 
If dose is subsequently increased: 
2 tablets (2 × 60 mg tablets), BID OR  
1 tablet (1 × 120 mg tablet), BID 
The evening dose should be approximately 12 hours after the morning dose. Patients will be 
instructed to take their morning and evening doses at least 1 hour before or 2 hours after a meal 
and to refrain from eating for at least 1 hour after dosing. In the event of a missed dose, patients 
will be instructed to take their next dose of IMP at the normally scheduled time. 
5.7 
Drug Accountability 
A Drug Accountability Form will be used to record IMP dispensing and return information on a 
by-patient basis and will serve as source documentation during the study. Details of any IMP lost 
(due to breakage or wastage) or not used at the study site or returned to the Sponsor’s authorized 
designee must also be recorded on the appropriate forms. All clinical IMP supplies and drug 
accountability and related pharmacy documentation must be made available throughout the study 
for the Sponsor/Sponsor’s designee to review. 


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The investigator (or designee) is responsible for retaining all used, unused, and partially used 
clinical IMP supplies until they are returned to the Sponsor’s authorized designee. 
Periodically during the study and upon completion of the clinical phase of the study, all used, 
unused, and partially used clinical IMP supplies will be reconciled and returned in their original 
containers (i.e., bottles) to the Sponsor’s authorized designee. 
Clinical IMP supplies intended for this study cannot be used for any other purpose than that 
described in this protocol. The investigator must ensure that IMP is used only in accordance with 
this protocol. 
5.8 
Procedures for Monitoring Patient Compliance 
After IMP is dispensed, at each subsequent study visit patients must return all used, unused, and 
partially used clinical IMP supplies. Drug accountability must be done in the patient’s presence 
in order to obtain explanations regarding discrepancies in compliance with the dosing regimen. 
Drug accountability must be recorded on the Drug Accountability Form. Upon completion of the 
patient’s Visit 8 at Week 52 (or Early Termination Visit, whichever occurs first), the authorized 
study staff will enter the date of the last dose of IMP taken in the source documents and eCRF to 
register the end of treatment for that patient. 
If a patient is found to be persistently noncompliant (≤ 80 to ≥ 120% of the assigned dose), the 
Sponsor/Sponsor’s designee, in conjunction with the investigator, will make a decision as to 
whether the patient should be discontinued from the study. 
5.9 
Concomitant Medications/Treatments 
5.9.1 
Allowed Anti-PD Medications/Treatments 
During this study, patients’ concomitant anti-PD medications (i.e., levodopa-containing 
medication, dopamine agonists, MAO-B inhibitors, anticholinergic agents, amantadine or 
entacapone) may be adjusted as needed under the investigator’s supervision. The optimal dose of 
open-label tozadenant for each patient will be defined following discussion between the patient 
and the investigator, taking into account the potential for improvement of disease symptoms and 
the tolerability profile. 
Throughout the study, all anti-PD medications taken by a patient during the study and the reason 
for their use will be recorded in the source documents and eCRF. 
Patients will use their own supply of anti-PD medication throughout the study. 
5.9.2 
Prohibited Concomitant Medications/Treatments 
The following concomitant medications and treatments are prohibited throughout the study: 
• Digoxin. 
• Surgical intervention for PD during the study.  
• 
 


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• Apomorphine, budipine, istradefylline, tolcapone, or 
 
• Antipsychotics except quetiapine administered at doses of ≤100 mg per day and 
pimavanserin 
• Metoclopramide 
• Methyldopa 
• Amphetamines and ephedra 
5.9.3 
Other Concomitant Medications/Treatments 
During the study, patients are asked to refrain from the use of any concomitant medication 
without the specific prior approval by the investigator. All medications taken by a patient and the 
reasons for their use will be recorded in the source documents and eCRF. 
Patients taking thyroid medication for hypothyroidism or hyperthyroidism must be on a stable 
dose for at least 3 months prior to the Baseline Visit. 
5.10 Blinding 
This study will be open-label. 
5.11 Enrollment and Numbering of Patients 
During the study, the IXRS will be used for initiating the dispensing of open-label IMP as well 
as tracking the progression of patients in the open-label phase and ensuring an adequate supply 
of open-label IMP. The IXRS will also be used to dispense IMP supplies, according to the visit 
schedule and dose level assigned by the investigator. 
6.0 
STUDY PROCEDURES BY VISIT 
6.1 
Overview of Study Procedures 
An overview of the conduct of the study, including the timing of study visits and assessments 
performed, may be found in Table 1 and Table 1.1. Details of disease activity and safety 
assessment methods can be found in Section 7.0 and Section 9.0, respectively, and in the 
applicable appendices. Plasma drug concentration assessments are described in Section 8.0. 
Detailed procedures by visit are provided in Section 6.2. 
Note: Laboratory supplies that are needed for protocol-specified tests will be provided by the 
central laboratory. 
Consented patients will be screened for eligibility. During the Screening Period, the patient (and 
any caregiver that will assist the patient to complete PD diaries during the study) will complete 
PD diary training and a diary concordance session (see Section 7.1 and Appendix 15.13) with the 
site’s diary trainer/rater. The patient (and caregiver, as applicable) will review the PD diary 
training video and receive instruction on how to complete the PD diary, including the definitions 
of ON and OFF. The definitions of ON and OFF will be reviewed, including ON time according 


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to dyskinesia categories “without dyskinesia”, “with non-troublesome dyskinesia” or “with 
troublesome dyskinesia”, with emphasis on the need for the patient to be consistent in their use 
of the definitions when rating their status in the PD diary during the study. 
When instructions appear to have been understood by the patient (and caregiver, as applicable), 
a PD diary concordance session will be initiated during which the patient and diary trainer/rater 
will concurrently complete separate training diaries for at least 5 consecutive half-hour intervals 
(minimum 2.5 hours). During the diary concordance session, the patient must experience both 
ON and OFF. The 2.5 hour session may be extended, as needed, so that the patient experiences 
OFF. If the patient is OFF at the beginning of the diary concordance session, they may be 
administered their next dose of levodopa-containing medication in order to experience ON. 
When the session is completed, the trainer/rater will review and assess diary concordance 
between the patient and the trainer/rater. The patient is required to reach at least 80% overall 
concordance with the trainer/rater including at least 1 OFF interval. If the concordance criteria 
are not achieved, the trainer/rater will schedule a second PD diary training and diary 
concordance session within the 6-week Screening Period, unless the patient declines further 
participation. 
Following successful completion of the PD diary training and a diary concordance session, 
patients/caregivers will be required to complete practice PD diaries on 3 consecutive prespecified 
days (24-hour periods starting at 6 AM each day). The trainer/rater will telephone the patient to 
remind them to start keeping the PD diary prior to the start date, to review the ON and OFF 
definitions, and to answer any questions the patient may have regarding completion instructions.  
Practice PD diaries will be returned to the trainer/rater and reviewed with patients/caregivers 
over the telephone or in person to ensure PD diary completion instructions are fully understood. 
Patients with invalid practice diaries will be asked by the trainer/rater either to complete a second 
PD diary training and diary concordance session followed by a repeat 3-day practice diary, or 
else asked to repeat the 3-day practice diary, depending on the patient’s understanding of the 
diary instructions. Patients who do not satisfy diary concordance criteria during a second PD 
diary training and/or who return a second set of practice diaries that are invalid, will be 
considered screen failures. 
Patients who return valid practice PD diaries and who the investigator considers eligible for the 
study will be scheduled within 6 weeks from the Screening Visit. The patient will be instructed 
to complete the Baseline PD diary on the 3 consecutive days directly preceding the scheduled 
Baseline Visit. The trainer/rater will contact the patient prior to the start date to remind them to 
start keeping the PD diary, to review the ON and OFF definitions, and to answer any questions 
the patients or caregiver may have regarding completion instructions. The patients will be 
requested to bring the Baseline PD diary to the Baseline Visit, at which the PD diary will be 
assessed for validity and to confirm the patient’s eligibility. Patients not meeting the criteria for 
valid Baseline PD diary completion may be retrained, as described above, and may return for 
another Baseline assessment within the 6-week Screening Period. 
Patients who meet all the entry criteria at Baseline will be assigned IMP using the IXRS and will 
begin open-label treatment for 52 weeks. The first dose of IMP will be taken at home after the 
Baseline Visit. Patients will be evaluated at scheduled study visits on Weeks 2, 4, 6, 8, 10, 12, 
16, 20, 24, 36, 44, 52, and 56; and will be asked to complete a PD diary on the 3 consecutive 
days directly preceding visits on Weeks 12, 24 and 52. Prior to each 3-day PD diary completion 


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period, patients will be telephoned to be reminded to comply with the PD diary instructions. 
Patients will be requested to bring their PD diary to the scheduled visits. Safety evaluations will 
be performed at each study visit. At specified visits, patients will be asked to return their IMP 
dispensed at the previous visit (including all unopened and opened IMP bottles) and to bring 
their other medications to the visit. Patients will be instructed to have already taken their 
normally scheduled dose of levodopa and their IMP prior to arriving at the study site in order to 
have their UPDRS Part III evaluated in the ON state (within approximately 1 to 3 hours after 
taking their levodopa dose). UPDRS in OFF will not be evaluated. Pharmacokinetic (PK) blood 
samples will be collected for tozadenant at Week 2 as outlined in Table 1, Schedule of 
Events/Evaluations. Patients will also be scheduled for a laboratory draw (hematology 
measurement only) at Weeks 4, 8, 10, 16, 20 and 44 as outlined in Table 1.1. All patients 
completing the study will be scheduled for a required postdose Safety Follow-Up Visit 
28 ± 3 days after completion of the 52-week open-label treatment period. In the event of Early 
Termination, patients will be asked to complete an Early Termination Visit as soon as possible 
and to return for a Safety Follow-Up Visit 28 ± 3 days after their last dose of IMP, unless the 
Early Termination Visit itself occurred 28 or more days after the last dose of IMP. 
Please refer to the Schedule of Events/Evaluations in Table 1 and Table 1.1 for specific timing of 
assessments and Section 6.2 for detailed study procedures. 
6.2 
Detailed Study Procedures 
6.2.1 
Recruitment and Informed Consent Process 
Interested patients will be scheduled to meet with a qualified investigative staff member and 
receive an explanation of the study purpose and requirements in lay language. If interested in 
participating, patients will be given an IRB/IEC-approved study-specific informed consent form 
(ICF) to read and ask questions and share with family members if requested. Prior to a patient’s 
participation in the study, written informed consent will be obtained in accordance with ICH 
GCP. The written IRB/IEC-approved ICF will be signed and dated by the patient and by the 
person who conducted the informed consent discussion. In addition, a statement to document the 
informed consenting process will be recorded in the patient’s source documents. 
Any patient who has difficulty understanding the ICF will discuss it with a research staff 
member. Research staff will work closely with patients in an effort to help them understand the 
requirements of their participation. Patients’ questions must be answered fully by trained and 
qualified staff. Any patient who is unable to demonstrate understanding of the information 
contained in the ICF will be excluded from study participation. 
The ICF and any other information provided to patients will be revised whenever important new 
information becomes available that is relevant to a patient’s consent and continued participation 
in the study. The revised ICF and information must receive IRB/IEC approval/favorable opinion 
prior to use, and a copy of the IRB/IEC’s approval/favorable opinion will be provided to the 
Sponsor/Sponsor’s designee. The investigator, or a person designated by the investigator, will 
fully inform all patients of all pertinent aspects of the study and any new information relevant to 
the patients’ willingness to continue participation in the study. This communication with the 
patient should be documented by the patient signing and dating the revised ICF and by written 


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documentation of this discussion with the patient in the subject´s source documents available to 
Sponsor/Sponsor’s designee or regulatory authorities for onsite review. 
Patients who consent to participate in the study will receive a copy of the signed ICF and any 
other information provided to patients prior to the participation in the study. The original signed 
forms will be maintained at the investigator’s site. 
After providing and documenting consent on the IRB/IEC-approved written ICF, patients will be 
assigned their patient screening number and proceed to the Screening Period. 
6.2.2 
Visit 1 (Week -6 to -1) Screening Period 
The following assessments will be obtained during the Screening Period and used to determine 
whether a patient meets eligibility criteria for the study. Patients meeting eligibility criteria at 
Screening must also meet eligibility criteria at the Baseline Visit. Patients meeting eligibility 
criteria at Screening must also meet eligibility criteria at the Baseline Visit including the 
completion of a valid 3 day Baseline PD diary. The PD diary training and evaluation instructions 
are described in Section 7.1 and Appendix 15.13. 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Screening Visit 
with the courier (see Central Laboratory Procedures Manual). 
6.2.2.1 
Screening Assessments 
1. Obtain written informed consent (see Section 6.2.1), and provide a copy to the patient. 
2. Obtain demographics and previous medical history, including any co-existing 
pretreatment AEs. 
3. Obtain neurological and PD history. 
4. Obtain complete medication history including anti-PD medications (current and prior 
history). Record the date and approximate time of the most recent dose of levodopa taken 
prior to the Screening assessment. 
5. Perform physical and neurological examination. 
6. Obtain weight, height and calculate BMI. 
7. Obtain and record serial BP and pulse measurements after at least 5 minutes supine rest 
and again after standing for approximately 1 and 3 minutes. Repeat these BP and pulse 
measurements 2 more times approximately 10 minutes apart. 
8. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. 
9. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 


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b. Modified Hoehn and Yahr stage in the ON state (estimate OFF state per history and 
document for entry criteria). 
c. Administer the following assessment: 
• MMSE-II. (If the MMSE-II is not validated in the requisite language, the MMSE 
[Original] may be used.) 
10. Administer the following assessments (may be done anytime during visit): 
a. C-SSRS. 
b. Assessment for episodes of sudden onset of sleep. 
c. mMIDI (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor).  
11. For all applicable patients: Document method of contraception. 
12. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. For females who are postmenopausal for less than 2 years and who are not surgically 
sterile: obtain a blood sample for FSH. 
b. For females of childbearing potential: urine pregnancy test. 
c. Hematology and chemistry (including liver function tests). 
d. TSH, free T3, free T4, and thyroperoxidase antibody. 
e. Urine sample for urinalysis. 
13. Instruct the patient (and any caregiver that will assist the patient to complete PD diaries 
during the study) on how to complete the PD diary, including the definitions of ON and 
OFF. 
a. Have patient (and caregiver, as applicable) review the PD diary training video.  
b. Perform patient (and caregiver, as applicable) PD diary training. 
c. Review the definitions of ON and OFF, including ON time according to categories 
“without dyskinesia”, “with non-troublesome dyskinesia” or “with troublesome 
dyskinesia”. Emphasize the need for the patient to be consistent in their use of the 
definitions when rating their status in the PD diary during the study.  
d. When instructions appear to have been understood by the patient (and caregiver, as 
applicable), initiate a diary concordance session during which the patient and the 
diary trainer/rater concurrently complete separate training diaries during at least 
5 consecutive half-hour intervals (minimum 2.5 hours). 
• During the diary concordance session, the patient must experience both ON 
and OFF. The 2.5 hour session may be extended, as needed, so that the patient 
experiences OFF. If the patient is OFF at the beginning of the session, they may 
be administered their next dose of levodopa-containing medication in order to 
experience ON. 
• During this time, other study-related assessments that do not interfere with the 
half-hourly ratings may take place. 


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14. When the diary concordance session is completed, the diary trainer/rater will review and 
assess diary concordance between the patient and the trainer/rater. 
• For the session, the patient is required to reach at least 80% overall diary 
concordance with the trainer/rater including at least 1 OFF interval. 
• If the concordance criteria are not achieved, the trainer/rater will schedule a 
second PD diary training and diary concordance session within the 6-week 
Screening Period, unless the patient declines further participation. 
15. If the patient does not otherwise meet inclusion and exclusion criteria, e.g., if a laboratory 
result disqualifies the patient from participating in the study, the patient is considered a 
screen failure. Record the primary reason for screen failure in the source documents, 
appropriate eCRF module and all applicable eCRFs for a screen failure. For patients who 
remain eligible, proceed with instructions in Section 6.2.2.2. 
16. If the investigator determines the patient meets the inclusion and exclusion criteria: 
a. Schedule the Baseline visit to occur within 6 weeks from the date of the Screening 
Visit and at a time approximately 1 to 3 hours after the patient has taken a scheduled 
dose of levodopa (preferably their morning dose of levodopa) to ensure the UPDRS 
can be collected in the ON state. 
b. Instruct the patient to bring their medications (including anti-PD medications) to the 
Baseline visit so that they are able to maintain their regular treatment schedule.  
6.2.2.2 
Screening / “Practice” PD Diary 
Following successful completion of the PD diary training and a diary concordance session, 
patients/caregivers will be required to complete practice diaries on 3 consecutive pre-specified 
days (24-hour periods starting at 6 AM each day). The trainer/rater will telephone the patient to 
remind them to start keeping the practice diary prior to the start date, to review the ON and OFF 
definitions, and to answer any questions the patient may have regarding completion instructions. 
Practice PD diaries will be returned to the diary trainer/rater and reviewed with 
patients/caregivers, over the telephone or in person, to assess the diaries for validity and 
completeness and to ensure PD diary completion instructions are fully understood
 
 
 
 
 
 
 
Patients with invalid practice diaries will be asked by the diary trainer/rater either to complete a 
second diary training and diary concordance session followed by a repeat 3-day practice diary, or 
else asked to repeat the 3-day practice diary, depending on the patient’s understanding of the 
diary completion instructions. Patients who do not satisfy concordance criteria during a second 
diary training and/or who return a second set of practice diaries that are invalid, will be 
considered screen failures.  
For patients who return a valid 3-day practice diary, proceed with instructions in Section 6.2.2.3. 


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6.2.2.3 
Patient Preliminary Review and Acceptance 
1. Once a patient returns a valid practice diary and is considered eligible for the study by the 
investigator: 
a. The patient will be instructed to complete the Baseline PD diary on 3 consecutive 
prespecified days prior to the Baseline Visit. The trainer/rater will telephone the 
patient prior to the start date to remind them to start keeping the PD diary, to review 
the ON and OFF definitions, and to answer any questions the patients or caregiver 
may have regarding completion instructions. 
b. The Baseline Visit will be scheduled approximately 1 to 3 hours after the patient has 
taken a scheduled dose of levodopa (preferably their morning dose of levodopa) to 
ensure the UPDRS can be collected in the ON state. 
c. Instruct the patient to bring their medications (including anti-PD medications) to the 
visit so that they are able to maintain their regular treatment schedule. 
d. Schedule the Baseline Visit, which must occur within 6 weeks from the date of the 
Screening Visit. 
2. If the patient is a screen failure, record the primary reason for screen failure in the source 
documents and appropriate eCRF module and all applicable eCRFs for a screen failure. 
6.2.3 
Visit 2 Baseline 
6.2.3.1 
Predosing Baseline Procedures 
Assignment of IMP to the patient using the IXRS will occur at Baseline (Visit 2), after the 
patient’s eligibility for study participation has been confirmed (see Section 6.2.3.3) and all 
predosing Baseline procedures have been performed (see Section 6.2.3.2). 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Baseline Visit 
with the courier (see Central Laboratory Procedures Manual). 
Note: Patients will continue to take their anti-PD medications and other medications according to 
their regular treatment schedule. 
6.2.3.2 
Perform Baseline Assessments 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Baseline Visit 
with the courier (see Central Laboratory Procedures Manual). 
1. For all applicable patients: Determine contraceptive method used by patient and 
document. 
2. Obtain samples for the following laboratory tests and record the date and time of 
collection:  
a. For females of childbearing potential: urine pregnancy test. 
b. Hematology and chemistry (including liver function tests). 
c. TSH, free T3, and free T4. 
d. Urine sample for urinalysis. 


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3. Obtain and record serial BP and pulse measurements after at least 5 minutes supine rest 
and again after standing for approximately 1 and 3 minutes. Repeat these BP and pulse 
measurements 2 more times approximately 10 minutes apart. 
4. Obtain three 12-lead ECGs (3 serial readings, performed several minutes apart). Ensure 
the ECGs are collected when the patient is not experiencing dyskinesia that would 
interfere with an adequate recording. 
5. Record the date and approximate time of the most recent dose of levodopa taken prior to 
UPDRS assessment. 
6. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• PDQ-39. 
• EQ-5D-5L. 
• Non-motor Symptom Assessment Scale. 
c. Have the patient complete the following self-assessment questionnaires:  
• ESS. 
7. Administer the following assessments (may be done anytime during visit): 
a. C-SSRS. 
b. Fall questionnaire. 
c. Assessment for episodes of sudden onset of sleep. 
8. If the patient does not meet the criteria for study participation, the patient is considered a 
screen failure. Record the primary reason for screen failure in the source documents and 
appropriate eCRF module. 
6.2.3.3 
Confirm Patient’s Eligibility for Study Participation 
1. Review the Baseline PD diary to assess for validity and confirm the patient’s eligibility 
by demonstrating 2.5 hours of OFF time on each of the 3 days. The Baseline PD Diary 
will also be sent to 
by the trainer/rater or designee for an additional 
review.  The Baseline Diary can be sent for 
review either by fax or e-mail:  
 
 
 
 
 
 
Note: Patients not meeting criteria for a valid PD diary at the Baseline Visit may be 
retrained and can return for another Baseline assessment within the 6-week Screening 
Period. 


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2. Review patient’s medical history and co-existing pretreatment AEs since the Screening 
Visit and confirm continued eligibility for the study. 
a. If appropriate, a physical or neurological examination will be performed in the event 
of an ongoing pretreatment AE. 
3. Record concomitant medication use and confirm that no changes have occurred in the 
patient’s concomitant medications (particularly anti-PD medications) since Screening that 
would make the patient ineligible for the study. 
4. If the patient does not meet the criteria for study participation, the patient is considered a 
screen failure. Record the primary reason for screen failure in the source documents and 
appropriate eCRF module. 
6.2.3.4 
Assignment and Dispensing of Investigational Medicinal Product 
Note: Sites participating in Expanded PK Sampling should refer to Appendix 15.9.1 for 
Assignment and Dispensing of IMP instructions. 
1. For patients meeting all entry criteria, complete the IMP assignment transaction using the 
IXRS by following the procedures provided. 
a. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this 
study visit. Each bottle consists of either 50 tablets of 120 mg tozadenant or 100 
tablets of 60 mg tozadenant. 
b. Record the date IMP was dispensed in IMP dispensing records including patient 
number, assigned IMP bottle number(s), and date and time IMP was dispensed. 
c. Review the dosing instructions for the IMP with the patient, answer any questions, 
and remind the patient to return the IMP (including all used, unused and partially 
used bottles) at the next visit. 
d. Patients will be instructed to take either two (2) 60 mg tablets or one (1) 120 mg 
tablet of the dispensed IMP by mouth BID, in the morning and in the evening 
preferably at the same time each day, for a total of either two (2) 120 mg tablets or 
four (4) 60 mg tablets per day. The evening dose should be approximately 12 hours 
after the morning dose. Patients will be instructed to take their morning and evening 
doses 1 hour before or 2 hours after a meal and to refrain from eating for 1 hour after 
dosing. Patients should take the first dose of IMP at home after the Baseline Visit.  
2. Instruct the patient to take the first dose of IMP at home on the evening of dispensation. 
3. Ensure that the patient understood the dosing instructions and the use of the extra doses 
included in the bottle if visit delayed and/or use of visit window. 
4. Schedule the Week 2 visit. If needed, use the visit window in relation to the date of the 
Baseline visit.  
6.2.4 
Visit 3 (Week 2) 
Note: Sites participating in Expanded PK Sampling should refer to Appendix 15.9.2 for Week 2 
assessments. 


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Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 2 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since Screening and document. 
2. Obtain sample for the following laboratory tests and record the date and time of 
collection: 
a. PK blood sample(s) for plasma tozadenant concentration.  
i. 
Sparse PK Sampling: Collect one (1) PK blood sample at the most convenient 
time during the visit. Record the patient-reported date and approximate time 
when the patient took the most recent dose of IMP. Record the date and time 
of PK sample collection. 
ii. 
Expanded PK Sampling (Select Sites Only): Sites participating in Expanded 
PK Sampling should refer to Appendix 15.9.2. 
Note: For processing, labeling and shipping of samples, follow the 
instructions provided in the Central Laboratory Procedures Manual. 
b. Hematology and chemistry (inclusive of liver function tests). 
c. TSH, free T3, and free T4. 
d. For females of childbearing potential: urine pregnancy test. 
e. Urinalysis. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Assess AEs by asking open-ended queries and record the assessments. 
4. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
5. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
6. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
7. Record the date and approximate time of the most recent dose of levodopa taken prior to 
the UPDRS assessment. 
8. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 


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c. Have the patient complete the following self-assessment questionnaire:  
• ESS. 
9. Administer the following assessments (may be done anytime during visit): 
a. C-SSRS. 
b. mMIDI. (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor.) 
c. Assessment for episodes of sudden onset of sleep. 
d. Healthcare Resource Utilization. 
10. Collect the IMP (including all used, unused and partially used bottles) dispensed at the 
Baseline Visit. 
a. Record the date and approximate time when the patient took the last dose of IMP. 
b. Assess and document IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
c. Review and reconcile any discrepancies with the patient. 
11. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this study 
visit. Each bottle consists of either 100 × 60 mg tablets or 50 × 120 mg tablets. 
a. Record the date IMP was dispensed in IMP dispensing records. 
12. Review the dosing instructions for the IMP with the patient, answer any questions, and 
remind the patient to return the IMP (including all used, unused and partially used 
bottles) at the next visit. 
13. Ensure that the patient understood the dosing instructions and the use of extra doses 
included in the bottle if visit delayed and/or use of visit window. 
14. Schedule the next study visit (Week 4). If needed, use the visit window in relation to the 
date of the Baseline visit. 
6.2.5 
Visit 3.5 (Week 4) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 4 
visit with the courier (see Central Laboratory Procedures Manual). 
1. Obtain hematology sample and record the date and time of collection. For 
processing, labeling and shipping of sample, follow the instructions provided in the 
Central Laboratory Procedures Manual. 
2. Schedule the next study visit (Week 6). If needed, use the visit window in relation to 
the date of the Baseline visit. 
6.2.6 
Visit 4 (Week 6) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 6 visit 
with the courier (see Central Laboratory Procedures Manual). 


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1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests and record the date and time of 
collection:  
a. Hematology and chemistry (inclusive of liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Assess AEs by asking open-ended queries and record the assessments. 
4. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
5. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
6. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
7. Record the date and approximate time of the most recent dose of levodopa taken prior to 
the UPDRS assessment. 
8. 8. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 
c. Have the patient complete the following self-assessment questionnaire:  
• ESS. 
9. Administer the following assessments (may be done anytime during visit): 
a. mMIDI. (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor.) 
b. C-SSRS. 
c. Assessment for episodes of sudden onset of sleep. 
d. Healthcare Resource Utilization. 
10. Collect the IMP (including all used, unused and partially used bottles) dispensed at the 
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a. Record the date and approximate time when the patient took the most recent dose of 
IMP. 
b. Assess and document IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
c. Review and reconcile any discrepancies with the patient. 
11. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this study 
visit. Each bottle consists of either 100 × 60 mg tablets or 50 × 120 mg tablets. 
a. Record the date IMP was dispensed in IMP dispensing records. 
12. Review the dosing instructions for the IMP with the patient, answer any questions, and 
remind the patient to return the IMP (including all used, unused and partially used 
bottles) at the next visit. 
13. Ensure that the patient understood the dosing instructions and the use of extra doses 
included in the bottle if visit delayed and/or use of visit window. 
14. Schedule the next study visit (Week 8). If needed, use the visit window in relation to the 
date of the Baseline visit. 
6.2.7 
Visit 4.3 (Week 8) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 8 
visit with the courier (see Central Laboratory Procedures Manual). 
1. Obtain hematology sample and record the date and time of collection. For 
processing, labeling and shipping of sample, follow the instructions provided in the 
Central Laboratory Procedures Manual. 
2. Schedule the next study visit (Week 10). If needed, use the visit window in relation 
to the date of the Baseline visit. 
6.2.8 
Visit 4.8 (Week 10) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 10 
visit with the courier (see Central Laboratory Procedures Manual). 
1. Obtain hematology sample and record the date and time of collection. For 
processing, labeling and shipping of sample, follow the instructions provided in the 
Central Laboratory Procedures Manual. 
2. Instruct the patient to complete the PD diary on the 3 consecutive days (i.e., 
3 consecutive 24-hour periods) directly preceding the Week 12 visit. Provide the 
patient with the PD diary. 
3. Schedule the next study visit (Week 12). If needed, use the visit window in relation 
to the date of the Baseline visit. 


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6.2.9 
Telephone Call on Week 12 (to Occur Prior to PD Diary Start Date) 
Patients will be telephoned prior to the start of the 3-day PD diary completion period preceding 
the Week 12 visit. 
Note: The telephone call should take into account the window for study visits to ensure the call is 
made, at the latest, on the day prior to the start of the PD diary completion period. 
1. Patients will be reminded of the following: 
a. To comply with instructions for taking the IMP. 
b. To complete the PD diary according to the instructions (see Section 7.1). The patients 
will be reminded by the trainer/rater to apply the ON and OFF definitions during PD 
diary completion on the 3 consecutive days (i.e., 3 consecutive, 24-hour periods) 
directly preceding the scheduled Week 12 visit. Any questions from the patient 
regarding PD diary completion will be addressed. 
c. To bring the PD diary with them to the visit. 
d. To bring the IMP with them to the visit. 
e. To take the IMP in the morning before the visit. 
f. To take all doses of their routine medications (including anti-PD medications) 
according to their normal schedule on the day of the scheduled visit and to bring their 
medications to the visit. 
6.2.10 
Visit 5 (Week 12) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 12 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests and record the date and time of 
collection:  
a. Hematology and chemistry (including liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Review the patient’s PD diary recordings for the 3 consecutive days (i.e., 3 consecutive 
24-hour periods) directly preceding this visit, and address any illegible or unclear entries. 
4. Assess AEs by asking open-ended queries and record the assessments. 
5. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
6. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 


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7. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
8. Obtain weight. 
9. Record the date and approximate time of the most recent dose of levodopa taken prior to 
the UPDRS assessment. 
10. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 
c. Have the patient complete the following self-assessment questionnaire:  
• ESS. 
11. Administer the following assessments (may be done anytime during visit): 
a. mMIDI. (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor.) 
b. C-SSRS. 
c. Assessment for episodes of sudden onset of sleep. 
d. Healthcare Resource Utilization. 
12. Perform physical and neurological examination, and assess any changes from Baseline 
for clinical significance. 
13. Collect the IMP (including all used, unused and partially used bottles) dispensed at the 
Week 6 visit. 
a. Record the date and approximate time when the patient took the last dose of IMP. 
b. Assess and document IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
c. Review and reconcile any discrepancies with the patient. 
14. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this study 
visit. Each bottle consists of either 100 × 60 mg tablets or 50 × 120 mg tablets. 
a. Record the date IMP was dispensed in IMP dispensing records. 
15. Review the dosing instructions for the IMP with the patient, answer any questions, and 
remind the patient to return the IMP (including all used, unused and partially used 
bottles) at the next visit. 
16. Ensure that the patient understood the dosing instructions and the use of extra doses 
included in the bottle if visit delayed and/or use of visit window. 


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17. Schedule the next study visit (Week 16). If needed, use the visit window in relation to the 
date of the Baseline visit. 
6.2.11 
Visit 5.3 (Week 16) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 16 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. Obtain hematology sample and record the date and time of collection. For processing, 
labeling and shipping of sample, follow the instructions provided in the Central 
Laboratory Procedures Manual. 
2. Schedule the next study visit (Week 20). If needed, use the visit window in relation to the 
date of the Baseline visit. 
6.2.12 
Visit 5.8 (Week 20) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 20 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. Obtain hematology sample and record the date and time of collection. For processing, 
labeling and shipping of sample, follow the instructions provided in the Central 
Laboratory Procedures Manual. 
2. Instruct the patient to complete the PD diary on the 3 consecutive days (i.e., 
3 consecutive 24-hour periods) directly preceding the Week 24 visit. Provide the patient 
with the PD diary. 
3. Schedule the next study visit (Week 24). If needed, use the visit window in relation to the 
date of the Baseline visit. 
6.2.13 
Telephone Call on Week 24 (to Occur Prior to PD Diary Start Date) 
Patients will be telephoned prior to the start of the 3-day PD diary completion period preceding 
the Week 24 visit.  
Note: The telephone call should take into account the window for study visits to ensure the call is 
made, at the latest, on the day prior to the start of the PD diary completion period. 
1. Patients will be reminded of the following: 
a. To comply with instructions for taking the IMP. 
b. To complete the PD diary according to the instructions (see Section 7.1). The patients 
will be reminded by the trainer/rater to apply the ON and OFF definitions during PD 
diary completion on the 3 consecutive days (i.e., 3 consecutive, 24-hour periods) 
directly preceding the scheduled Week 24 visit. Any questions from the patient 
regarding PD diary completion will be addressed. 
c. To bring the PD diary with them to the visit. 
d. To bring the IMP with them to the visit. 
e. To take the IMP in the morning before the visit. 


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f. To take all doses of their routine medications (including anti-PD medications) 
according to their normal schedule on the day of the scheduled visit and to bring their 
medications to the visit. 
6.2.14 
Visit 6 (Week 24) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 24 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Hematology and chemistry (including liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Review the patient’s PD diary recordings for the 3 consecutive days (i.e., 3 consecutive 
24-hour periods) directly preceding this visit, and address any illegible or unclear entries. 
4. Assess AEs by asking open-ended queries and record the assessments. 
5. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
6. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
7. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
8. Obtain weight. 
9. Record the date and approximate time of the most recent dose of levodopa taken prior to 
the UPDRS assessment. 
10. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 
• PDQ-39. 


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• EQ-5D-5L. 
• Non-motor Symptom Assessment Scale. 
c. Have the patient complete the following self-assessment questionnaire:  
• ESS. 
11. Administer the following assessments (may be done anytime during visit): 
a. mMIDI. (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor.) 
b. C-SSRS. 
c. Fall questionnaire. 
d. Assessment for episodes of sudden onset of sleep. 
e. Healthcare Resource Utilization. 
12. Perform physical and neurological examination, and assess any changes from Baseline 
for clinical significance. 
13. Collect the IMP (including all used, unused and partially used bottles) dispensed at the 
Week 12 visit. 
a. Record the date and approximate time when the patient took the last dose of IMP. 
b. Assess and document IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
c. Review and reconcile any discrepancies with the patient. 
14. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this study 
visit. Each bottle consists of either 100 × 60 mg tablets or 50 × 120 mg tablets. 
a. Record the date IMP was dispensed in IMP dispensing records. 
15. Review the dosing instructions for the IMP with the patient, answer any questions, and 
remind the patient to return the IMP (including all used, unused and partially used 
bottles) at the next visit. 
16. Ensure that the patient understood the dosing instructions and the use of extra doses 
included in the bottle if visit delayed and/or use of visit window. 
17. Schedule the Week 36 Visit. If needed, use the visit window in relation to the date of the 
Baseline visit. 
6.2.15 
Visit 7 (Week 36) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 36 Visit 
with the courier (see Central Laboratory Procedures Manual). 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests, and record the date and time of 
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a. Hematology and chemistry (including liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Assess AEs by asking open-ended queries and record the assessments. 
4. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
5. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
6. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
7. Record the date and approximate time of the most recent dose of levodopa taken prior to 
the UPDRS assessment. 
8. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 
c. Have the patient complete the following self-assessment questionnaire:  
• ESS. 
9. Administer the following assessments (may be done anytime during visit): 
a. mMIDI. (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor.) 
b. C-SSRS. 
c. Assessment for episodes of sudden onset of sleep. 
d. Healthcare Resource Utilization. 
10. Perform physical and neurological examination, and assess any changes from Baseline 
for clinical significance. 
11. Collect the unopened and opened IMP bottles dispensed at the Week 24 visit. 
12. Assess and document IMP accountability and compliance (document any missed dose(s), 
lost tablets and number of tablets taken). 
a. Review and reconcile any discrepancies with the patient. 


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13. Dispense open-label IMP (bottles) based on the dosage (60 mg BID or 120 mg BID) as 
determined by the investigator. 
a. Record the date IMP was dispensed in IMP dispensing records. 
14. Review the dosing instructions for open-label IMP with the patient, answer any 
questions, and remind the patient to return unopened and opened IMP bottles at the next 
visit. 
a. Ensure that the patient understood the dosing instructions and the use of extra doses 
included in the bottle if visit delayed and/or use of visit window. 
15. Schedule the Week 44 Visit. If needed, use the visit window in relation to the date of the 
Baseline visit. 
6.2.16 
Visit 7.5 (Week 44) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 48 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. Obtain hematology sample and record the date and time of collection. For processing, 
labeling and shipping of sample, follow the instructions provided in the Central 
Laboratory Procedures Manual. 
2. Instruct the patient to complete the PD diary on the 3 consecutive days (i.e., 
3 consecutive 24-hour periods) directly preceding the Week 52 visit. Provide the patient 
with the PD diary. 
3. Schedule the next study visit (Week 52). If needed, use the visit window in relation to the 
date of the Baseline visit. 
6.2.17 
Telephone Call on Week 52 (to Occur Prior to PD Diary Start Date) 
Patients will be telephoned prior to the start of the 3-day PD diary completion period preceding 
the Week 52 visit.  
Note: The telephone call should take into account the window for study visits to ensure the call is 
made, at the latest, on the day prior to the start of the PD diary completion period. 
1. Patients will be reminded of the following: 
a. To comply with instructions for taking the IMP. 
b. To complete the PD diary according to the instructions (see Section 7.1). The patients 
will be reminded by the trainer/rater to apply the ON and OFF definitions during PD 
diary completion on the 3 consecutive days (i.e., 3 consecutive, 24-hour periods) 
directly preceding the scheduled Week 52 visit. Any questions from the patient 
regarding PD diary completion will be addressed. 
c. To bring the PD diary with them to the visit. 
d. To bring the IMP with them to the visit. 
e. To take the IMP in the morning before the visit. 


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f. To take all doses of their routine medications (including anti-PD medications) 
according to their normal schedule on the day of the scheduled visit and to bring their 
medications to the visit. 
6.2.18 
Visit 8 (Week 52) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 52 Visit 
with the courier (see Central Laboratory Procedures Manual). 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests, and record the date and time of 
collection: 
a. Hematology and chemistry (including liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Review the patient’s PD diary recordings for the 3 consecutive days (i.e., 3 consecutive 
24-hour periods) directly preceding this visit, and address any illegible or unclear entries. 
4. Assess AEs by asking open-ended queries and record the assessments. 
5. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
6. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
7. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
8. Obtain weight. 
9. Record the date and approximate time of the most recent dose of levodopa taken prior to 
the UPDRS assessment. 
10. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 
• PDQ-39. 


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• EQ-5D-5L. 
• Non-motor Symptom Assessment Scale. 
c. Have the patient complete the following self-assessment questionnaire:  
• ESS. 
11. Administer the following assessments (may be done anytime during visit): 
a. mMIDI. (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor.) 
b. C-SSRS. 
c. Fall questionnaire. 
d. Assessment for episodes of sudden onset of sleep. 
e. Healthcare Resource Utilization. 
12. Perform physical and neurological examination, and assess any changes from Baseline 
for clinical significance. 
13. Collect the unopened and opened IMP bottles dispensed at the Week 36 Visit. 
14. Assess and document IMP accountability and compliance (document any missed dose(s), 
lost tablets and number of tablets taken). 
a. Review and reconcile any discrepancies with the patient. 
15. Schedule the Safety Follow-Up Visit (Week 56). If needed, use the visit window in 
relation to the date of the Baseline visit. 
6.2.19 
Safety Follow-Up Visit (Visit 9, Week 56) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Safety 
Follow-Up Visit (Week 56) with the courier (see Central Laboratory Procedures Manual). 
All patients who complete dosing and study evaluations through Week 52 will be scheduled for a 
required Safety Follow-Up Visit at Week 56. If a patient took the last dose of IMP less than 
28 days prior to the Early Termination Visit, a Safety Follow-Up Visit is required. 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests, and record the date and time of 
collection: 
a. Hematology and chemistry (including liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Assess AEs by asking open-ended queries and record the assessments. 


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4. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
5. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
6. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
7. Obtain weight. 
8. Perform physical and neurological examination and assess any changes from Baseline for 
clinical significance. 
9. Have the patient complete the following self-assessment questionnaire (to be collected 
during patient’s ON state): 
a. ESS. 
10. Administer the following assessments (may be done anytime during visit): 
a. mMIDI. 
b. C-SSRS. 
c. Assessment for episodes of sudden onset of sleep. 
6.2.20 
Early Termination Visit 
Note: Confirm the arrangement for laboratory sample pick-up on the day of patient’s Early 
Termination Visit with the courier (see Central Laboratory Procedures Manual). 
If the patient has discontinued IMP, perform this visit as soon as possible after the last dose of 
IMP.  
If the patient took the last dose of IMP 28 or more days prior to the Early Termination Visit, a 
Safety Follow-Up Visit (Section 6.2.19) is not required. If a patient took the last dose of IMP less 
than 28 days prior to the Early Termination Visit, a Safety Follow-Up Visit (Section 6.2.19) is 
required. 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Hematology and chemistry (inclusive of liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. If the Early Termination Visit coincides with previously planned scheduled visit for 
which a PD diary was completed, review the patient’s PD diary recordings for 


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the 3 consecutive days (i.e., 3 consecutive 24-hour periods) directly preceding this visit, 
and address any illegible or unclear entries. 
Note: Efficacy-related measures (e.g., PD Diary) will not be completed at an Early 
Termination Visit if the subject stopped taking study drug more than 24 hours prior to the 
assessment of the measure. 
4. Assess AEs by asking open-ended queries and record the assessments. 
5. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
6. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
7. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
8. Obtain weight. 
9. Perform physical and neurological examination, and assess any changes from Baseline 
for clinical significance. 
10. Record the date and approximate time of the most recent dose of levodopa taken prior to 
the UPDRS assessment. 
11. Perform the following assessments in the ON state: 
Note: UPDRS will not be completed at an Early Termination Visit if the subject stopped 
taking study drug more than 24 hours prior to the Early Termination Visit. 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be 
performed approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in the ON state will be 
measured at a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 
• PDQ-39. 
• EQ-5D-5L. 
• Non-motor Symptom Assessment Scale. 
c. Have the patient complete the following self-assessment questionnaire:  
• ESS. 
12. Administer the following assessments (may be done anytime during visit): 
a. mMIDI. 
b. C-SSRS. 
c. Fall questionnaire. 


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d. Assessment for episodes of sudden onset of sleep. 
e. Healthcare Resource Utilization. 
13. Collect the unopened and opened IMP bottles from the patient. 
14. Record the patient-reported date and approximate time when the patient took the last dose 
of IMP. 
15. Assess and document IMP accountability and compliance (document any missed dose[s], 
lost tablets, and number of tablets taken). In case of discrepancies, review and reconcile 
them with the patient. 
6.2.21 
Unscheduled Visit 
Note: Confirm the arrangement for laboratory sample pick-up on the day of an Unscheduled 
Visit with the courier (see Central Laboratory Procedures Manual). 
An Unscheduled Visit is defined as any additional visit performed at the investigator’s 
discretion, at any time between Baseline (Visit 2) and the Safety Follow-Up Visit (Week 56). 
6.2.21.1 
Required Assessments for Unscheduled Visit 
The following assessments must be performed: 
1. Assess AEs by asking open-ended queries and record the assessments. 
2. Record concomitant medication use; assess and record any changes to anti-PD 
medication dose or regimen. 
3. Collect the unopened and opened IMP bottles dispensed at the most recent study visit (if 
applicable). 
4. Obtain and record the date and approximate time when the patient took the most recent 
dose of IMP. 
5. Assess and document IMP accountability and compliance (document any missed dose[s], 
lost tablets, and number of tablets taken). In case of discrepancies, review and reconcile 
them with the patient. 
If the purpose of the unscheduled visit is to collect a hematology sample (to comply with the 
weekly hematology monitoring, see Section 4.3.2), then only the following assessments must 
be performed: 
1. Confirm the arrangement for laboratory sample pick-up with the courier. Obtain 
hematology sample and record the date and time of collection. For processing, 
labeling and shipping of sample, follow the instructions provided in the Central 
Laboratory Procedures Manual. 
2. Assess AEs by asking open-ended queries and record the assessments. 
3. Record concomitant medication use; assess and record any changes to anti PD 
medication dose or regimen. 


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6.2.21.2 
Additional Assessments at Investigator’s Discretion 
The following additional assessments may be performed at an Unscheduled Visit for assessment 
of an AE, at the investigator’s discretion depending on the type of AE (e.g., an out-of-range lab 
value, presence of suicidality, impulsivity, etc.): 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive 
method since previous visit and document. 
2. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Hematology and chemistry (inclusive of liver function tests). 
b. TSH, free T3, and free T4. 
c. Urine sample for urinalysis. 
d. For females of childbearing potential: urine pregnancy test. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
3. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and 
again after standing for approximately 1 and 3 minutes. 
4. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
5. Obtain weight. 
6. Perform physical and neurological examination, and assess any changes from Baseline 
for clinical significance. 
7. Administer C-SSRS if suicide risk concern. 
8. Administer mMIDI. (Note: After Baseline, if patient has one or more positive modules on 
the mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor.) 
9. n consultation with the Medical Monitor, discuss any other appropriate diagnostic tests 
required to evaluate patient’s AE. 
10. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this study 
visit. Each bottle consists of either 100 × 60 mg tablets or 50 × 120 mg tablets. 
7.0 
ASSESSMENT OF DISEASE ACTIVITY 
7.1 
Hauser Parkinson’s Disease Home Diary 
The Hauser Parkinson’s Disease Home Diary will be completed throughout the study on 
specified days directly preceding the scheduled study visits/assessments as outlined in the study 
procedures. Motor activity will be recorded as OFF, ON (mobility improved), or asleep time. 
Patients will be asked to record ON time according to dyskinesia categories “without 


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dyskinesia”, “with non-troublesome dyskinesia” or “with troublesome dyskinesia” (Hauser et al, 
2000). 
During Screening, patients (and/or caregivers) will be trained to complete a PD diary to record 
their status at half-hourly intervals as OFF, ON without dyskinesia, ON with non-troublesome 
dyskinesia, ON with troublesome dyskinesia, or asleep. The PD diary trainer/rater will 
emphasize the need for the patient to be consistent in their use of the definitions when rating 
their status in the PD diary during the study. 
When instructions appear to have been understood by the patient (and caregiver, as applicable), 
a PD diary concordance session will be initiated during which the patient and trainer/rater will 
concurrently complete separate training diaries for at least 5 consecutive half-hour intervals 
(minimum 2.5 hours). During the diary concordance session, the patient must experience both 
ON and OFF. The 2.5 hour session may be extended, as needed, so that the patient experiences 
OFF. If the patient is OFF at the beginning of the diary concordance session, they may be 
administered their next dose of levodopa-containing medication in order to experience ON. 
When the session is completed, the trainer/rater will review and assess diary concordance 
between the patient and the trainer/rater. For the session, the patient is required to reach at least 
80% overall diary concordance with the trainer/rater including at least 1 OFF interval. If the 
concordance criteria are not achieved, the trainer/rater will schedule a second PD diary training 
and diary concordance session within the 6-week Screening Period, unless the patient declines 
further participation. 
Following successful completion of the PD diary training and a diary concordance session, 
patients/caregivers will be required to complete practice PD diaries on 3 consecutive prespecified 
days (24-hour periods starting at 6 AM each day). The patient will be telephoned and reminded 
to start keeping the PD diary prior to the start date, to review the ON and OFF definitions, and to 
answer any questions the patient may have regarding completion instructions.  
Practice PD diaries will be returned to the diary trainer/rater and reviewed with patients/ 
caregivers over the telephone or in person to ensure PD diary completion instructions are fully 
understood. Patients with invalid practice diaries will be asked by the trainer/rater either to 
complete a second PD diary training and diary concordance session followed by a repeat 3-day 
practice diary, or else asked to repeat the 3-day practice diary, depending on the patient’s 
understanding of the diary instructions. Patients who do not satisfy diary concordance criteria 
during a second PD diary training and/or who return a second set of practice diaries that are 
invalid, will be considered screen failures. 
Patients who return valid practice PD diaries and who the investigator considers eligible for the 
study will have the Baseline Visit scheduled within 6 weeks from the Screening Visit. They will 
be instructed to complete the Baseline PD diary on the 3 consecutive days directly preceding the 
scheduled Baseline Visit. Patients will be telephoned prior to the start of the Baseline PD diary 
session. During the call the trainer/rater will: 
1. Remind about the date when patient should start to complete the Baseline PD diary.  
2. Remind to complete the Baseline PD diary starting at 6:00 AM on the required date and 
to continue recording until 6:00 AM of the day of the visit.  


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3. Review completion instructions including the ON and OFF definitions and address any 
questions from the patient.  
4. Patients will be requested to bring the Baseline PD diary to the Baseline Visit at which 
the PD diary will be assessed for validity and to confirm the patient’s eligibility. 
Those not meeting the criteria for valid Baseline PD diary completion may be retrained, as 
described above, and may return for another Baseline assessment within the 6-week Screening 
Period. 
After randomization, patients will be telephoned prior to the start of each subsequent PD diary 
session. The purpose of these calls is to: 
1. Remind about the date when patient should start to complete the PD diary.  
2. Remind to complete the PD diary starting at 6:00 AM on the required date and to 
continue recording until 6:00 AM of the day of the visit.  
3. Review completion instructions including the ON and OFF definitions and address any 
questions from the patient.  
4. Ask patient to bring their PD diaries when scheduled for a visit (Weeks 12, 24 and 52). 
The PD diary trainer/rater will evaluate PD diaries after receiving them and discuss with the 
patient if invalid entries are noted to remind them of correct procedures. 
Only Sponsor/Sponsor’s designee-approved trainers/raters may administer the PD diary training 
and concordance session in accordance with the requirements for training as documented on the 
Certificate of Rater Approval.  
An example of the diary and instructions are provided in Appendices 15.13 and 15.14. 
7.2 
Unified Parkinson’s Disease Rating Scale (UPDRS) 
The UPDRS is a scale that was developed as an effort to incorporate elements from existing 
scales to provide a comprehensive but efficient and flexible means to monitor PD-related 
disability and impairment (Fahn et al, 1987). 
The scale itself has four components, largely derived from preexisting scales that were reviewed 
and modified by a consortium of movement disorders specialists (Part I, Mentation, Behavior 
and Mood; Part II, Activities of Daily Living [ADL]; Part III, Motor Examination; Part IV, 
Complications of Therapy). One of the core advantages of the UPDRS is that it was developed as 
a compound scale to capture multiple aspects of PD. It assesses both motor disability 
(Part II: ADL) and motor impairment (Part III: Motor Examination). In addition, Part I addresses 
mental dysfunction and mood, and Part IV assesses treatment-related motor and non-motor 
complications. Of all available clinical scales for the assessment of Parkinsonian motor 
impairment and disability, the UPDRS is currently the most commonly used. 
Only Sponsor/Sponsor’s designee-accepted raters may administer the UPDRS subscales in 
accordance with the requirements for background, experience in a research setting and training 
as documented on the Certificate of Rater Approval. 


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Patients will be instructed to have already taken their normally scheduled dose of levodopa and 
their IMP prior to arriving at the study site in order to have their UPDRS Part III evaluated in the 
ON state (within approximately 1 to 3 hours after taking their levodopa dose). UPDRS in the ON 
state will be measured at a time representative of the ON state in that patient, not in “best” ON. 
UPDRS Part III in OFF will be not be evaluated. 
An example of the scale is provided in Appendix 15.1. 
7.3 
Fall Questionnaire 
A Fall Questionnaire will be utilized to solicit information about patient falls, defined as 
coming to rest on the ground inadvertently from a standing position, during this study. The 
assessment will ask if a patient has been experiencing falls over the past 3 months, and if so, 
approximately how many falls have occurred during that interval. 
An example of the Fall Questionnaire is provided in Appendix 15.8. 
7.4 
Clinical/Patient Global Impression Scales (CGI-I and PGI-I) 
Clinical Global Impression of Improvement (CGI-I): 
For the CGI-I, the investigator or designee is asked to rate the patient’s total improvement, 
whether or not in his or her judgment it is due entirely to drug treatment, based on a 1-7 point 
weighted scale ranging from “very much improved” (1) to “very much worse” (7). A zero score 
is assigned if the score is not assessed. 
Patient Global Impression of Improvement (PGI-I): 
For the PGI-I, the patient is asked to rate the total improvement of their PD, whether or not in the 
patient’s judgment it is due entirely to drug treatment, based on a 1-7 point weighted scale 
ranging from “very much improved” (1) to “very much worse” (7). A zero score is assigned if 
the score is not assessed. 
Examples of the CGI-I and PGI-I scales are provided in Appendix 15.10. 
7.5 
Parkinson’s Disease Quality of Life Questionnaire (PDQ-39) 
The PDQ-39 is a copyrighted instrument to assess symptoms of PD with 39 questions relating to 
mobility, activities of daily living, emotional well-being, social support, cognition, 
communication and bodily discomfort. The questionnaire asks a patient to rate each question 
regarding their PD symptoms over the past month.  
An example of the PDQ-39 is provided in Appendix 15.11. 
7.6 
Non-Motor Symptom Assessment Scale 
The Non-motor Symptoms Questionnaire is an established questionnaire with 30 qualitative 
questions covering all important non-motor symptoms of PD. 
An example of the Non-Motor Symptom Assessment Scale is provided in Appendix 15.12. 


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7.7 
EuroQol 5D-5L Health Questionnaire (EQ-5D-5L) 
The EQ-5D-5L™ is a standardized, patient-reported, generic instrument for measuring health 
outcome (EuroQol Group, 1990; Herdman et al, 2011). It provides a simple descriptive profile 
and a single index value for health status. The instrument consists of the EQ-5D-5L descriptive 
system and the EQ Visual Analogue Scale (EQ VAS). The descriptive system consists of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), 
with 5 levels of severity within each particular EQ-5D dimension. The EQ VAS records the 
respondent’s self-rated health on a 20-cm vertical VAS with endpoints labeled “the best health 
you can imagine” and “the worst health you can imagine”. This information can be used as a 
quantitative measure of health as judged by the individual respondents. 
7.8 
Healthcare Resource Utilization 
Information about hospitalizations (i.e., inpatient admissions) and emergency room visits will be 
collected using the Healthcare Resource Utilization Questionnaire (Section 15.15) and captured 
in the eCRF according to the schedule shown in Table 1. In addition to hospital admission and 
discharge dates, and emergency room visit dates, the reason for the hospital admission or 
emergency room visit and whether or not it was Parkinson’s disease-related will be recorded. 
An example of the Healthcare Resource Utilization Questionnaire is provided in 
Appendix 15.15. 
8.0 
ASSESSMENT OF PLASMA DRUG CONCENTRATION 
Pharmacokinetic blood samples for determination of plasma tozadenant concentration will be 
collected at the Week 2 study visit. 
 will be collected 
at the most convenient time during the visit (“Sparse PK Sampling”).  
 
be done (“Expanded PK Sampling”).  
For Sparse PK Sampling, the patient-reported date and approximate time of the most recent IMP 
dosing prior to the sampling will be recorded. 
Sites participating in Expanded PK Sampling should refer to Appendix 15.9 for additional 
details. 
Specific procedures for tozadenant PK blood sample collection and processing, storage, 
shipping, and analysis will be provided in the Central Laboratory Procedures Manual. 
All samples for tozadenant bioanalysis will be destroyed upon authorization by the Sponsor or 
Sponsor’s designee, after finalization of the clinical study report. 


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9.0 
ASSESSMENT OF SAFETY 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (i.e., after 
the signing of the ICF), including any pretreatment and post-treatment periods required by the 
protocol, must be recorded in source documents and the eCRF even if no investigational product 
was taken but specific study procedures were conducted. This includes all AEs not present prior 
to the initial Screening Visit and all AEs that recurred or worsened after the initial Screening 
Visit. Events that occur prior to dosing are captured as medical history and pretreatment AEs. 
Events that occur after Baseline and prior to dosing are captured as AEs. 
Signs or symptoms of the condition/disease for which the investigational product is being studied 
should be recorded as AEs only if their nature changes considerably or their frequency or 
intensity increases in a clinically significant manner as compared to the clinical profile known to 
the investigator from the patient’s history or during the baseline period. 
9.1.2 
Procedures for Reporting and Recording Adverse Events 
The patient will be given the opportunity to report AEs spontaneously. An open-ended, 
non-leading prompt will also be given at each study visit to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the investigator should review self-assessment procedures employed in the study. 
9.1.3 
Description of Adverse Events 
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, whenever possible, rather than recording individual symptoms or 
signs. The eCRF and source documents should be consistent. Any discrepancies between the 
patient’s own words on his/her own records and the corresponding medical terminology should 
be clarified in the source documentation. 
Details for completion of the AE eCRF (including judgment of relationship to IMP and 
assessment of intensity) are described in the eCRF Completion Guidelines. 
9.1.4 
Follow Up of Adverse Events 
An AE will be followed until it has resolved, has a stable sequelae, the investigator determines 
that it is no longer clinically significant, or the patient is lost to follow up. 


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If an AE is still ongoing at the end of the study for a patient, follow up will be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it is 
clinically significant, or until the patient is lost to follow up. If no follow up is provided, the 
investigator must provide a justification. Follow up will usually be continued for 30 days after 
the patient has discontinued his/her IMP. 
9.1.5 
Rule for Repetition of an Adverse Event 
An increase in the intensity of pretreatment AE / medical history should lead to the repetition of 
the event being reported with: 
• The outcome of “worsening” and the outcome or end date of the pretreatment AE / 
medical history event that is not related to the natural course of the disease being the 
same as the start date of the AE. 
• The AE verbatim term being the same for the pretreatment AE / medical history, so 
that the repeated AE can be easily identified as the worsening of the first one. 
9.1.6 
Pregnancy 
In the event a patient becomes pregnant after the first intake of any IMP, the Sponsor’s drug 
safety representative should be informed immediately. The patient should be withdrawn from the 
study as soon as pregnancy is known, and the following should be completed: 
1. The patient should immediately stop the intake of the IMP. 
2. The patient should return for an Early Termination Visit as soon as possible. 
3. A Safety Follow-Up Visit should be scheduled 28 ± 3 days after the patient has 
discontinued IMP. 
4. The investigator must inform the patient of information currently known about potential 
risks and about available treatment alternatives. 
In cases where the partner of a male patient enrolled in a clinical study becomes pregnant, 
Sponsor will ask the investigator or designee to contact the patient and his partner to request 
consent via the Pregnant Partner Information Release Form. If the partner agrees to provide 
additional information, the Pregnancy Report and Outcome Form will be forwarded to the 
patient’s partner for completion. 
The pregnancy will be documented on the Pregnancy Report and Outcome Form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed-up using the Pregnancy Report and Outcome Form in which the investigator has to 
report on the health of the mother and of the child. The health of the child must be followed for 
30 days after birth for any significant medical issues. 
In certain circumstances, Sponsor may request that follow up is continued for a period longer 
than 30 days after birth. 
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion, or 
anomaly/birth defect of the child. Those SAEs must be additionally reported using the Sponsor-
provided SAE Report Form. 


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9.1.7 
Overdose of Investigational Medicinal Product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in source documents and in the Drug Accountability module of the eCRF. Any SAE or 
nonserious AE associated with excessive dosing must be followed as any other SAE or 
nonserious AE. These events are only considered AEs or SAEs if there are associated clinical 
signs and symptoms or if the act of taking the excess medicine itself is an AE or SAE (e.g., 
suicide attempt). 
9.1.8 
Safety Signal Detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that the DSMB, investigators, clinical study patients, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Medical Monitor or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Sponsor’s drug 
safety representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at the Sponsor may identify additional safety measures 
(e.g., AEs, vital signs, laboratory or ECG results) for which data will be periodically reviewed 
during the study. The DSMB will be informed as defined in the DSMB charter. 
9.2 
Serious Adverse Events 
9.2.1 
Definition of Serious Adverse Event 
Once it is determined that a patient experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet one or more of the following criteria: 
1. Results in death. 
2. Life-threatening, i.e., places the patient, in the view of the investigator, at immediate risk 
of death at the time of the event. 
Note: Life-threatening does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Significant or persistent disability/incapacity, i.e., results in a substantial disruption of a 
person’s ability to conduct normal life functions. 
4. Congenital anomaly/birth defect, i.e., an AE that occurs in the child or fetus of a patient 
exposed to a study drug prior to conception or during pregnancy. 
5. Important medical event, i.e., an event that may not be immediately life-threatening or 
result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the other outcomes listed in the definition of serious. 
Note: Important medical events may include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias that do not result in 


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inpatient hospitalization, or the development of drug dependency or drug abuse. 
Interruption, discontinuation, or adjustment of dose level of study drug alone will not be 
considered an intervention that satisfies the definition of important medical event. 
6. Initial inpatient hospitalization or prolongation of hospitalization. 
Note: A patient admitted to a hospital, even if he/she is released on the same day, meets 
the criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization 
criteria. However, emergency room visits that do not result in admission to the hospital 
would not qualify for this criteria and, instead, should be evaluated for one of the other 
criteria in the definition of serious (e.g., life-threatening adverse experience, important 
medical event). 
Hospitalizations for reasons not associated with the occurrence of an AE (e.g., 
preplanned surgery or elective surgery for a preexisting condition that has not worsened 
or manifested in an unusual or uncharacteristic manner) do not qualify for reporting. For 
example, if a patient has a condition recorded on his/her medical history and later has a 
preplanned surgery for this condition, it is not appropriate to record the surgery or 
hospitalization as an SAE, since there is no AE upon which to assess the serious criteria. 
Please note that, if the preexisting condition has worsened or manifested in an unusual or 
uncharacteristic manner, this would then qualify as an AE and, if necessary, the 
seriousness of the event would need to be determined. 
Note: The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This is not the same as “serious,” which is 
based on patient/event outcome or action criteria usually associated with events that pose a threat 
to a patient’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
9.2.2 
Procedures for Reporting Serious Adverse Events 
If an SAE is reported, the Sponsor must be informed within 24 hours of receipt of this 
information by the site. The SAE Report Form must be sent to: 
 
 
 
 
 
 
 
 
 
 
 
 
The email address, fax and telephone number used for SAE reporting is also provided on the 
SAE/ Pregnancy Reporting Form Cover Page, along with Sponsor contact information. An SAE 
Report Form will be provided to the investigator. The SAE Report Form must be completed in 
English. 


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The investigator must forward to the Sponsor (or its representative) a duly completed SAE 
Report Form provided by the Sponsor, even if the data are incomplete, or if it is obvious that 
more data will be needed in order to draw any conclusions. Information recorded on this form 
will be entered into the global safety database. 
It is important for the investigator, when completing the SAE Report Form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the investigator is very important for the Sponsor to consider in assessing the safety of the 
IMP and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Additional information (e.g., autopsy or laboratory reports) received by the investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the SAE Report Form. 
The investigator is specifically requested to collect and report to the Sponsor (or its 
representative) any SAEs (even if the investigator is certain that they are in no way associated 
with the IMP) up to 4 weeks from the date of last IMP for each patient, and to also inform 
participating patients of the need to inform the investigator of any SAE within this period. 
Serious AEs that the investigator thinks may be associated with the IMP must be reported to the 
Sponsor regardless of the time between the event and the end of the study. 
Upon receipt of the SAE Report Form, the Sponsor will perform an assessment of expectedness 
of the reported SAE. The assessment of the expectedness of the SAE is based on the current IB. 
9.2.3 
Follow Up of Serious Adverse Events 
An SAE will be followed until it has resolved, has a stable sequelae, the investigator determines 
that it is no longer clinically significant, or the patient is lost to follow up. 
Information on SAEs obtained after clinical database lock will be captured through the global 
safety database without limitation of time. 
9.2.4 
Immediate Reporting of Adverse Events 
The following AEs must be reported immediately: 
• SAE: AE that the investigator classifies as serious by the above definitions regardless 
of causality. 
• Suspected transmission of an infectious agent via a medicinal product. 
9.3 
Laboratory Measurements 
The laboratory tests listed below (Table 3) are to be performed and analyzed as outlined in the 
Schedule of Events/Evaluations (Table 1). 
Sample collection kits and the laboratory procedures manual with detailed sample processing and 
shipping instruction will be provided by the accredited central laboratory. 


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All laboratory samples will be destroyed upon authorization by the Sponsor or Sponsor’s 
designee, at the finalization of the clinical study report. 
The following laboratory parameters will be measured: 
Table 3: 
Laboratory Measurements 
Hematology 
Chemistry 
Thyroid 
Urinalysis b 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
Monocytes 
Neutrophils 
Platelet count 
RBC count 
WBC count 
AST 
ALT 
ALP 
Albumin 
Bicarbonate 
Calcium 
Chloride 
Creatine phosphokinase with automatic 
Troponin-I and CK-MB if value 
> 2 x the ULN 
Creatinine 
Glucose 
GGT 
LDH 
Phosphate 
Potassium 
Sodium 
Total bilirubin a 
Total cholesterol 
Total protein 
Urea/BUN 
Uric acid 
Follicle stimulating hormone 
(females postmenopausal <2 years, 
only) 
TSH 
Free T3 
Free T4 
Thyroperoxidase 
antibody 
(screening only) 
Protein 
Glucose 
pH 
Blood 
Ketones 
Specific gravity 
Urine pregnancy 
test (females of 
childbearing 
potential, only) 
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; 
CK-MB, creatine phosphokinase-MB; GGT, gamma-glutamyl transpeptidase; LDH, lactate dehydrogenase; 
pH, reverse logarithmic representation of relative hydrogen proton (H+) concentration; RBC, red blood cell; 
T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; ULN, upper limit of normal; WBC, white 
blood cell. 
aConjugated and unconjugated. 
bIf urine dipstick is positive for leukocytes, protein, or erythrocytes, a microscopic evaluation and culture will be 
performed. 


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9.4 
Other Safety Measurements 
9.4.1 
Blood Pressure and Pulse Measurements 
Blood pressure and pulse rate should be obtained in a quiet room at a comfortable temperature, 
with the patient’s arm unconstrained by clothing or other material. A full set of measurements 
will include BP and pulse obtained after at least 5 minutes supine rest, followed by BP and pulse 
obtained after the patient has been standing for approximately 1 and 3 minutes. At Screening and 
Baseline (Visit 2), the full set of BP and pulse measurements will be collected on 3 occasions 
approximately 10 minutes apart. If repeats are performed for either supine or standing BP, the 
full set (BP and pulse) should be repeated after 5 minutes supine rest (i.e., supine followed by 
standing measurements). The measurements will be obtained throughout the study using an 
appropriate cuff size from the patient’s non-dominant arm. If possible, all measurements for a 
given patient will be obtained from the same arm using the same cuff. The cuff should be placed 
on the designated arm at least 5 minutes prior to collection. If available, an automatic BP cuff 
(sphygmomanometer) with a digital readout will be used. 
Supine and standing systolic and diastolic BP and pulse rate will be recorded at the nominal time 
points specified in the Schedule of Events/Evaluations (Table 1). If, for any reason, an accurate 
reading cannot be obtained (e.g., dyskinesia), collect the measurement as close to the nominal 
time point as feasible and record the date and time of collection. 
Patients noted to have an elevated BP post-baseline, with a supine systolic BP ≥ 160 mmHg 
and/or a diastolic BP ≥ 100 mmHg that is present at 2 consecutive post-baseline study visits, will 
be discontinued from study (see Section 4.3.2). 
9.4.2 
Twelve-lead Electrocardiogram (ECG) 
A resting supine 12-lead ECG will be collected at the time points specified in the Schedule of 
Events/Evaluations (Table 1) after the patient has been in a supine position for a minimum of 
5 minutes. 
The 12-lead ECG includes standard PR, QRS, QT and QTc (heart rate-corrected QT) intervals as 
read by the ECG machine provided by the cardiac core lab. Fridericia’s correction (QTcF) must 
be used for correction of the QT interval. 
A central ECG core lab will overread all ECGs and provide the final interpretation. At Screening 
the results will be available within 72 hours of the visit. At Baseline, the overread of the 3 serial 
ECGs will be available within 24 hours. The investigator should use the original ECG-provided 
printout showing QTcF interval to meet eligibility requirements at Baseline rather than the 
overread QTcF interval that will arrive after the Baseline visit. 
9.4.3 
Epworth Sleepiness Scale (ESS) 
The ESS is a copyrighted short self-administered assessment that measures daytime sleepiness. 
The instrument asks patients to rate the probability of dozing in eight different day-to-day 
scenarios. The ratings are as follows: 
0 = no chance of dozing 


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1 = slight chance of dozing 
2 = moderate chance of dozing 
3 = high chance of dozing 
The scores for the eight situations are then added to one total score. A score within the range 
0−9 is considered to be normal while a score within the range of 10−24 would indicate medical 
help should be solicited. 
An example of the ESS is provided in Appendix 15.2. 
9.4.4 
Assessment for Episodes of Sudden Onset of Sleep 
To assess the potential development of episodes of sudden onset of sleep, patients will be asked 
if they experienced any abrupt episodes of unplanned sleep during or while engaged in some 
activity where they are not expected to occur (e.g., eating/drinking, speaking, or driving), which 
may or may not have been preceded by somnolence or sedation. Any positive response should be 
further evaluated to determine whether the patient’s continued participation in the study puts 
them at risk and whether they should be discontinued from the study (see Appendix 15.3). 
9.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be assessed by trained study personnel using the C-SSRS (Posner et al, 2011). 
The C-SSRS is a copyrighted standardized suicidality rating system conducted by a certified 
rater. The interview measures presence of suicidality and consists of 4 categories: suicidal 
ideation, intensity of ideation, suicidal behavior, and actual/potential lethality. This scale will be 
used for screening as well as to assess for the occurrence of any suicidal ideation and/or behavior 
during the study. 
9.4.6 
Modified Minnesota Impulse Disorders Interview (mMIDI) 
The Minnesota Impulse Disorders Interview has been previously used in Parkinson’s subjects to 
monitor for development of impulse control disorders (ICDs). The mMIDI is applicable for both 
initial identification of a potential ICD and for monitoring ICDs during a clinical trial. The 
mMIDI focuses on the five most common ICDs which may be associated with dopamine agonist 
use: compulsive buying, compulsive gambling, compulsive eating, hypersexuality and punding. 
The mMIDI will be considered positive if a subject gives a positive answer to any question after 
the gateway question in a specific module. After Baseline, if a patient has one or more positive 
modules on the mMIDI, their continued participation in the study should be discussed with the 
Medical Monitor. 
An example of the mMIDI is provided in Appendix 15.4. 
10.0 STUDY MANAGEMENT AND ADMINISTRATION 
10.1 Adherence to Protocol 
The investigator should not deviate from the protocol. In medical emergencies, the investigator 
may use his/her medical judgment and may remove a study participant from immediate hazard 


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before notifying the Sponsor (or its representative) and the IRB/IEC in writing regarding the type 
of emergency and the course of action taken. 
10.2 Monitoring 
The Sponsor/Sponsor’s designee will monitor the study to meet ICH GCP guidelines and 
applicable regulatory requirements, and to ensure that study initiation, conduct, and closure are 
adequate. Monitoring of the study may be delegated by the Sponsor/Sponsor’s designee to a 
contract research organization (CRO) or a contract monitor. 
The investigator and his/her staff are expected to cooperate with the Sponsor/Sponsor’s designee 
and to be available during the monitoring visits to answer questions sufficiently and to provide 
any missing information. The investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The investigator will allow the Sponsor/Sponsor’s designee to periodically review all eCRFs and 
corresponding source documents (e.g., hospital and laboratory records for each study 
participant). Monitoring visits will provide the Sponsor/Sponsor’s designee with the opportunity 
to evaluate the progress of the study, verify the accuracy and completeness of eCRFs, ensure that 
all protocol requirements, applicable authorities’ regulations, and investigator’s obligations are 
being fulfilled, and resolve any inconsistencies in the study records. 
10.2.1 
Definition of Source Data 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies of eCRFs are not considered acceptable source 
documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, for example. Source documents should be kept in a secure, limited access area. 
None of the data will be recorded directly in the eCRF and therefore all source documentation 
will appear in a source document as defined above. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (e.g., ECG reports). Once printed, these copies should be signed and dated 
by the investigator and become a permanent part of the patient’s source documents. The 
investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as ECG tracings/reports or electroencephalogram records, must be 
saved and stored as instructed by the Sponsor/Sponsor’s designee. 


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10.2.2 
Source Data Verification 
Source data verification ensures accuracy and credibility of the data obtained. All data reported 
on the eCRF should be supported by source documents, unless otherwise specified in 
Section 10.2.1. 
The patient’s consent and enrollment in the study must be recorded in the patient’s medical 
record. These data should identify the study and document the dates of the patient’s participation. 
During monitoring visits, reported data are reviewed with regard to being accurate, complete, 
and verifiable based on source documents (including, but not limited to, consent forms, patient 
files, recordings from automated instruments, tracings [ECG], x-ray films, and laboratory notes). 
10.3 Data Handling 
10.3.1 
Case Report Form Completion 
The study will be performed using electronic data capture (EDC). The investigator is responsible 
for prompt reporting of accurate, complete, and legible data in the eCRFs and in all required 
reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the eCRF. 
In accordance with the applicable regulatory requirements, the confidentiality of records that 
could identify patients must be protected, respecting the privacy and confidentiality rules. 
The investigator will maintain a Site Delegation Personnel Log to document signatures and 
initials of all persons qualified and authorized by the investigator to make entries and/or 
corrections to the source documents. Any corrections to non-electronic source documents are 
made by striking through the incorrect entry with a single line and entering the correct 
information adjacent to the incorrect entry. The correction must be dated, initialed, and explained 
(if necessary) by the person making the correction and must not obscure the original entry. 
For source documents such as automated pharmacy records, the investigator or designee will 
review during Screening and prior to assignment of IMP using the IXRS any pharmacy records 
in the medical chart and other physician medical notes and review the information with the 
patient and clarify with a note in the chart any items that are inconsistent or medications that may 
have been prescribed but the patient is not currently taking and have been discontinued. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
10.3.2 
Database Entry and Reconciliation 
Electronic case report forms will be available for review by the Clinical Research Associate 
(CRA), Sponsor and Sponsor’s designee after completion by the site. The eCRFs will be 
monitored remotely and onsite by the CRO after documented training and in accordance with the 


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monitoring plan. The CRA will review the eCRF data on a regular basis and post any queries for 
the site to complete prior to the scheduled onsite monitoring visits. Only those individuals who 
are qualified and authorized by the investigator to complete eCRFs will be trained and receive 
passwords allowing eCRF completion. 
The completed eCRF must be electronically reviewed, signed, and dated by a qualified physician 
who is designated as Principal or Sub-investigator for the study. The investigator must retain the 
original source documents. A final portable document format (PDF) copy of the eCRFs will be 
provided to the study site by the CRO or designee at the end of the study for archival purposes. 
If a patient is a screen failure, the primary reason for screen failure will be recorded in the eCRF. 
An electronic audit trail system will be maintained within the eCRF to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
10.3.3 
Patient Identification Code List 
The investigator will keep a Patient Identification Code list. This list remains with the 
investigator and is used for unambiguous identification of each patient. 
10.3.4 
Planned Safety Data Monitoring 
Concurrent safety data monitoring is planned for this study, for which responsibility will be 
assigned to an independent DSMB. The DSMB will oversee the safety of the study by reviewing 
relevant data on a regular basis. The DSMB will consist of members who are independent from 
Biotie Therapies. Study enrollment will not be halted during planned DSMB reviews of safety 
data. The objectives and procedures for the DSMB are detailed in the DSMB charter. 
10.4 Termination of the Study 
Sponsor reserves the right to temporarily suspend or prematurely discontinue this study either at 
a single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, Sponsor (or its representative) will inform 
the investigators/institutions and the regulatory authorities of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirements. The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the Sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirements. In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with Sponsor procedures for the study. 
10.5 Archiving and Data Retention 
The investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, informed consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 


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All essential documents are to be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or by an agreement with Sponsor (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The 
investigator will contact Sponsor for authorization prior to the destruction of any study records or 
in the event of accidental loss or destruction of any study records. The investigator will also 
notify Sponsor should he/she relocate or move the study-related files to a location other than that 
specified in the Sponsor’s study master file. 
10.6 Audit and Inspection 
The investigator will permit study-related audits and inspections mandated by domestic or 
foreign regulatory authorities or study-related audits mandated by the Sponsor’s Clinical QA or 
designee, after reasonable notice. 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
patients enrolled have been protected, that enrolled patients (i.e., those signing consent and 
undergoing study procedures) are appropriate for the study, and that all data relevant for the 
evaluation of the IMP have been processed and reported in compliance with the planned 
arrangements, the protocol, investigational site, and IRB/IEC standard operating procedures 
(SOPs), ICH GCP, and applicable regulatory requirements. The investigator will work with the 
Sponsor to resolve any audit observations and implement corrective and preventative actions as 
appropriate. 
The investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the investigator will immediately 
inform the Sponsor/Sponsor’s designee. 
10.7 Good Clinical Practice 
Noncompliance with the protocol, ICH Guidelines and GCP regulations, or local regulatory 
requirements by the investigator, institution, institution staff, or designees of the Sponsor will 
lead to prompt action by the Sponsor/Sponsor’s designee to secure compliance. Continued 
noncompliance may result in the termination of the site’s involvement in the study. 
11.0 STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
11.1 Definition of Analysis Sets 
Safety Set (SS): The SS will consist of all enrolled patients who received at least one dose of 
IMP.  
Other analysis sets will be defined in statistical analysis plan as needed. 


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11.2 Study Variables 
11.2.1 
Safety Variables 
Safety variables include the following:  
1. TEAEs. 
2. Physical and neurological examination. 
3. Supine and standing pulse and BP. 
4. Standard 12-lead ECG: RR, PR, QRS, QT and QTcF. 
5. Laboratory parameters: hematology, chemistry, thyroid function (thyroid stimulating 
hormone [TSH], free triiodothyronine [T3], and free thyroxine [T4]), and urinalysis. 
6. Daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS), including 
assessment of episodes of sudden onset of sleep. 
7. Modified Minnesota Impulse Disorders Interview (mMIDI).  
8. Columbia-Suicide Severity Rating Scale (C-SSRS). 
11.2.2 
Pharmacokinetic Variables 
• Tozadenant PK concentrations and PK parameters at Week 2. 
11.2.3 
Other Variables 
• Unified Parkinson’s Disease Rating Scale (UPDRS) Part II (Activity of Daily Living 
[ADL] subscale) + Part III (motor subscale) total score. 
• UPDRS Part II (ADL subscale) score. 
• UPDRS Part III (motor subscale) score in the ON state. 
• UPDRS Part I total score. 
• UPDRS Part IV, including dyskinesia as measured by questions 32, 33 and 34 and motor 
fluctuations as measured by question 39. 
• Clinical Global Impression of Improvement  (CGI-I). 
• Patient’s Global Impression of Improvement  (PGI-I). 
• Parkinson’s Disease Quality of Life Questionnaire (PDQ-39; total score and individual 
domain scores). 
• Non-motor Symptom Questionnaire. 
• EuroQol 5D-5L Health Questionnaire (EQ-5D-5L). 
• Patient-completed diaries (Change from Baseline in the number of hours per day spent as 
follows: OFF, ON time without troublesome dyskinesia, total ON time, ON time with 
troublesome dyskinesia and asleep time) 


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• Healthcare Resource Utilization. 
• Fall Questionnaire. 
11.3 General Statistical Considerations 
Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical variables, the number and percentage of patients in each category will be presented. 
The denominator for percentages will be based on the number of patients available for the 
purpose of analysis. For continuous variables, descriptive statistics will include number of 
patients (n), mean, standard deviation (SD), median, minimum, and maximum. 
Baseline values for efficacy and safety variables will be determined from the last non-missing 
data collected prior to the first dose of study medication unless otherwise specified. 
11.4 Planned Efficacy Analyses 
Not applicable. 
11.5 Planned Safety Analyses 
The primary safety variables will be the occurrence of TEAEs including nonserious and serious 
TEAEs, and TEAEs leading to permanent withdrawal of study medication during the study. 
All AEs will be presented by Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class (SOC), high level term and preferred term (PT). The data will be displayed as the 
number of patients experiencing the AEs, percentage of patients, and number of AEs. Note that 
counting will be by patient, and event and patients are only counted once within each MedDRA 
SOC or PT. 
Laboratory test results, vital signs, ECGs, ESS, C-SSRS, mMIDI will be summarized 
descriptively. The descriptive statistics will be provided for the observed data and for the change 
from Baseline at each measured time point as appropriate. In addition, laboratory test results will 
be classified as below the lower limit of normal, within normal limits, and above the ULN. Shift 
tables will be used to summarize changes from Baseline to each visit. Clinically significant 
physical or neurological examination findings and any clinically significant out of range 
laboratory tests will be recorded as adverse events and will also be documented in the AE 
summaries. 
Dyskinesia as measured by questions 32, 33 and 34 of UPDRS Part IV, ESS, weight, physical 
and neurological examination results, and UPDRS will be summarized descriptively. Descriptive 
statistics will be presented for continuous variables utilizing the observed data and the change 
from baseline (at each measured time point) where appropriate. Frequencies and percentages will 
be presented for categorical variables.  
All safety analyses will be based on the SS population. 
 


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11.6 Other Analyses 
Patient Disposition 
The number of patients who were screened, enrolled, completed scheduled follow up, and 
prematurely withdrew study participation will be summarized. Reasons for non-participation and 
for withdrawal from study will also be presented. 
Exposure to IMP/Compliance 
Exposure to IMP/compliance will be summarized and details will be specified in the SAP. 
Prior and Concomitant Medication Use 
All prior and concomitant medications taken during the study period will be summarized and 
listed for each patient, including dosage and indication. Medications will be coded using the 
World Health Organization (WHO) Drug Dictionary Enhanced and classified as past medication 
(last dose taken prior to the first dose of IMP), concomitant medication ongoing at Baseline, or 
concomitant medication initiated after Baseline. The percentage of patients taking each 
medication (or class of medications) will be summarized. 
Plasma Drug Concentrations 
Results of the assays of tozadenant will be descriptively analyzed and reported.  
Exploratory Analyses 
Change from baseline to will be evaluated for the following: 
• Unified Parkinson’s Disease Rating Scale (UPDRS) Part II (Activity of Daily Living 
[ADL] subscale) + Part III (motor subscale) total score. 
• UPDRS Part II (ADL subscale) score. 
• UPDRS Part III (motor subscale) score in the ON state. 
• UPDRS Part I total score. 
• UPDRS Part IV, including dyskinesia as measured by questions 32, 33 and 34 and motor 
fluctuations as measured by question 39. 
• Clinical Global Impression of Improvement  (CGI-I). 
• Patient’s Global Impression of Improvement  (PGI-I). 
• Parkinson’s Disease Quality of Life Questionnaire (PDQ-39; total score and individual 
domain scores). 
• Non-motor Symptom Assessment Scale. 
• EuroQol 5D-5L Health Questionnaire (EQ-5D-5L). 
• Patient-completed diaries (Change from Baseline in the number of hours per day spent as 
follows: OFF, ON time without troublesome dyskinesia, total ON time, ON time with 
troublesome dyskinesia and asleep time) 
• Healthcare Resource Utilization. 


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• Fall questionnaire. 
These analyses will be documented by descriptive statistics. 
11.7 Handling of Protocol Deviations 
Important protocol deviations are deviations from the protocol which could potentially have a 
meaningful impact on either the primary efficacy or safety conclusion. The criteria for 
identifying important protocol deviations and the classification of important protocol deviations 
will be defined prior to data analysis. To the extent feasible, rules for identifying protocol 
deviations will be defined without review of the data and without consideration of the frequency 
of occurrence of such deviations. Whenever possible, criteria for identifying important protocol 
deviations will be implemented algorithmically to ensure consistency in the classification of 
important protocol deviations across all patients. 
11.8 Handling of Dropouts or Missing Data 
A valid diary will not have more than 2 hours (4 invalid entries) over a given 24-hour period. An 
invalid diary entry is defined as more than one entry recorded in a given half-hour interval, an 
unreadable entry, or the absence of an entry in a given half-hour interval. The average diary 
information from 3 valid diaries (if available) for each visit will be used to calculate diary-based 
efficacy endpoints. If there are only 2 valid diaries for a visit then the average information from 
the 2 valid diaries will be used. If only one diary is valid, information from the single valid diary 
will be used. If no valid diaries are available for a patient visit then the diary information is 
considered missing. 
The total time ‘OFF’ will be determined by using the mean of the 3-day diary data immediately 
before each visit. A diary day will be regarded to be valid if at least 22 hours of the 24 hour clock 
are filled in. The missing hours will be imputed according to the proportions of being “on 
without dyskinesia”, “on with troublesome dyskinesia”, “on with non-troublesome dyskinesia”, 
“off” and asleep. The visit data will be regarded to be valid if at least 2 days out of 3 are valid. 
11.9 Determination of Sample Size 
Approximately 645 patients will be screened, assuming a 30% screen failure rate, to enroll 
450 patients. 
12.0 ETHICS AND REGULATORY REQUIREMENTS 
12.1 Informed Consent 
Patient’s informed consent must be obtained and documented in accordance with local 
regulations, ICH GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the patient in both oral and written form by the investigator (or 


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designee). Each patient will have the opportunity to discuss the study and its alternatives with the 
investigator. 
Prior to participation in the study, the written ICF will be signed and personally dated by the 
patient, and by the person who conducted the informed consent discussion (investigator or 
designee). The patient must receive a copy of the signed and dated ICF. As part of the consent 
process, each patient must consent to direct access to his/her medical records for study-related 
monitoring, auditing, IRB/IEC review, and regulatory inspection. 
If the ICF is amended during the study, the investigator (or the Sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended ICF. 
All studies conducted at centers in the United States must abide by the Health Insurance 
Portability and Accountability Act (HIPAA). 
The patient may withdraw his/her consent to participate in the study at any time. A patient is 
considered to be in the study once they have signed the ICF. An eCRF must not be started, nor 
may any study-specific procedure be performed for a given patient, without having obtained the 
patient’s written consent to participate in the study. 
12.2 Institutional Review Boards and Independent Ethics Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The investigator and CRO will ensure that an appropriately constituted IRB/IEC that complies 
with the requirements of the current ICH GCP version or applicable country-specific regulations 
will be responsible for the initial and continuing review and approval of the clinical study. Prior 
to initiation of the study, the investigator or if a central IRB/IEC is used, the Sponsor/Sponsor’s 
designee will forward copies of the protocol, ICF, IB, investigator’s curriculum vitae (if 
applicable), advertisement (if applicable), and all other patient-related documents to be used for 
the study to the IRB/IEC for its review and approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human patients or others, and any protocol deviations, 
to eliminate immediate hazards to patients. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the patients. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of patient risk involved, but no less than 


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once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
Sponsor (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
12.3 Patient Privacy 
Sponsor staff (or designee) will affirm and uphold the patient’s confidentiality. Sponsor staff (or 
designee) will affirm that the patient’s date of birth and initials will not be collected in the 
European Union (EU) or other regions where it is not permitted. Throughout this study, all data 
forwarded to the Sponsor/Sponsor’s designee will be identified only by the patient number 
and/or site identifier (ID) and patient screening number.  
The investigator agrees that representatives of Sponsor, its designee, representatives of the 
relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that 
portion of the patient’s primary medical records that directly concerns this study (including, but 
not limited to, laboratory test result reports, ECG reports, admission/discharge summaries for 
hospital admissions occurring during a patient’s study participation, and autopsy reports for 
deaths occurring during the study). 
12.4 Protocol Amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by the Sponsor, the IRB/IEC, and the regulatory authorities (if required), prior to 
being implemented. 
13.0 FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the investigator and institution 
clinical trial agreements with the Sponsor/CRO, as applicable. 
 


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14.0 REFERENCES 
Bibbiani F, Oh JD, Petzer JP, Castagnoli N Jr, Chen JF, Schwarzschild MA, et al. (2003). A2A 
antagonist prevents dopamine agonist-induced motor complications in animal models of 
Parkinson’s disease. Exp Neurol. 184(1):285–94. 
Black KJ, Koller JM, Campbell MC, Gusnard DA, Bandak SI (2010). Quantification of indirect 
pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. 
J Neurosci. 30(48):16284–92. 
Fahn S, Elton RL, Members of the UPDRS Development Committee (1987). Unified Parkinson's 
Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, eds. Recent 
developments in Parkinson's disease. Florham Park, NJ: MacMillan Health Care 
Information, pp. 153-63, 293-304. 
CPMP/ICH/135/95. Note for guidance on Good Clinical Practice (EMEA) (Jul 2002). 
Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O’Brien CF, et al. (2000). 
A home diary to assess functional status in patients with Parkinson’s disease with motor 
fluctuations and dyskinesia. Clin Neuropharmacol. 23(2):75–81. 
Hauser RA, Olanow CW, Kieburtz KD, Pourcher E, Docu-Axelerad A, Lew M, et al. (2014). 
Tozadenant (SYN115) in patients with Parkinson’s disease who have motor fluctuations on 
levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol. 13(8):767-76. 
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, et al. (2011). Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
20(10):1727–36. 
Hoehn MM, Yahr MD (1967). Parkinsonism: onset, progression and mortality. 
Neurology. 17:427–42. 
Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB, Chen JF (2009). Adenosine, adenosine 
A 2A antagonists, and Parkinson’s disease. Parkinsonism Relat Disord. 15(6):406–13. 
Olanow CW, Stern MB, Sethi K (2009). Scientific and clinical basis for the treatment of 
Parkinson’s disease. Neurology. 72(21 Suppl 4):S1–136. 
Pinna A (2009). Novel investigational adenosine A2A receptor antagonists for Parkinson’s 
disease. Expert Opin Investig Drugs. 18(11):1619–31. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. (2011). The 
Columbia–Suicide Severity Rating Scale: initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 168:1266–77. 
Schwarzschild MA, Xu K, Oztas E, Petzer JP, Castagnoli K, Castagnoli N Jr, et al. (2003). 
Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of 
Parkinson’s disease. Neurology. 61(11 Suppl 6):S55–61. 
The EuroQol Group (1990). EuroQol – a new facility for the measurement of health-related 
quality of life. Health Policy. 16(3):199–208. 


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Von Campenhausen S, Bornschein B, Wick R, Bötzel K, Sampaio C, Poewe W, et al. (2005). 
Prevalence and incidence of Parkinson’s disease in Europe. Eur Neuropsycho-
pharmacol. 15(4):473–90. 
Yu L, Schwarzschild MA, Chen JF (2006). Cross-sensitization between caffeine- and L-dopa 
induced behaviors in hemiparkinsonian mice. Neurosci Lett. 393(1):31–5. 
 


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15.0 APPENDICES 
15.1 Unified Parkinson’s Disease Rating Scale (UPDRS) 
UNIFIED PARKINSON’S DISEASE RATING SCALE 
 
Part I MENTATION, BEHAVIOR AND MOOD (RATE ITEMS 1 TO 4 BY INTERVIEW) 
When completing this section, indicate the patient’s level of function during the past week. 
 
1. Intellectual Impairment 
0 = None. 
1 = Mild. Consistent forgetfulness with partial recollection of events and no other difficulties. 
2 = Moderate memory loss, with disorientation and moderate difficulty handling complex problems. Mild but 
definite impairment of function at home with need of occasional prompting. 
3 = Severe memory loss with disorientation for time and often to place. Severe impairment in handling problems. 
4 = Severe memory loss with orientation preserved to person only. Unable to make judgments or solve problems. 
Requires much help with personal care. Cannot be left alone at all. 
 
2. Thought Disorder (DUE TO DEMENTIA OR DRUG INTOXICATION)  
0 = None. 
1 = Vivid dreaming. 
2 = “Benign” hallucinations with insight retained. 
3 = Occasional to frequent hallucinations or delusions; without insight; could interfere with daily activities. 
4 = Persistent hallucinations, delusions, or florid psychosis. Not able to care for self. 
 
3. Depression 
0 = Not present. 
1 = Periods of sadness or guilt greater than normal, never sustained for days or weeks. 
2 = Sustained depression (1 week or more). 
3 = Sustained depression with vegetative symptoms (insomnia, anorexia, weight loss, loss of interest). 
4 = Sustained depression with vegetative symptoms and suicidal thoughts or intent. 
 
4. Motivation/Initiative 
0 = Normal. 
1 = Less assertive than usual; more passive. 
2 = Loss of initiative or disinterest in elective (nonroutine) activities. 
3 = Loss of initiative or disinterest in day to day (routine) activities. 
4 = Withdrawn, complete loss of motivation. 


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Part II. ACTIVITIES OF DAILY LIVING (RATE ITEMS 5 TO 17 BY INTERVIEW) 
When completing this section, indicate the patient’s level of function during the past week. 
 
5. Speech 
0 = Normal. 
1 = Mildly affected. No difficulty being understood. 
2 = Moderately affected. Sometimes asked to repeat statements. 
3 = Severely affected. Frequently asked to repeat statements. 
4 = Unintelligible most of the time. 
 
6. Salivation 
0 = Normal. 
1 = Slight but definite excess of saliva in mouth; may have nighttime drooling. 
2 = Moderately excessive saliva; may have minimal drooling. 
3 = Marked excess of saliva with some drooling. 
4 = Marked drooling, requires constant tissue or handkerchief. 
 
7. Swallowing 
0 = Normal. 
1 = Rare choking. 
2 = Occasional choking. 
3 = Requires soft food. 
4 = Requires NG tube or gastrostomy feeding. 
 
8. Handwriting 
0 = Normal. 
1 = Slightly slow or small. 
2 = Moderately slow or small; all words are legible. 
3 = Severely affected; not all words are legible. 
4 = The majority of words are not legible. 
 
9. Cutting food and handling utensils 
0 = Normal. 
1 = Somewhat slow and clumsy, but no help needed. 
2 = Can cut most foods, although clumsy and slow; some help needed. 
3 = Food must be cut by someone, but can still feed slowly. 
4 = Needs to be fed. 
 
10. Dressing 
0 = Normal. 
1 = Somewhat slow, but no help needed. 
2 = Occasional assistance with buttoning, getting arms in sleeves. 
3 = Considerable help required, but can do some things alone. 
4 = Helpless. 
 
11. Hygiene 
0 = Normal. 
1 = Somewhat slow, but no help needed. 
2 = Needs help to shower or bathe; or very slow in hygienic care. 
3 = Requires assistance for washing, brushing teeth, combing hair, going to bathroom. 
4 = Foley catheter or other mechanical aids. 
 


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12. Turning in bed and adjusting bed clothes 
0 = Normal. 
1 = Somewhat slow and clumsy, but no help needed. 
2 = Can turn alone or adjust sheets, but with great difficulty. 
3 = Can initiate, but not turn or adjust sheets alone. 
4 = Helpless. 
 
13. Falling (unrelated to freezing) 
0 = None. 
1 = Rare falling. 
2 = Occasionally falls, less than once per day. 
3 = Falls an average of once daily. 
4 = Falls more than once daily. 
 
14. Freezing when walking 
0 = None. 
1 = Rare freezing when walking; may have start-hesitation. 
2 = Occasional freezing when walking. 
3 = Frequent freezing. Occasionally falls from freezing. 
4 = Frequent falls from freezing. 
 
15. Walking 
0 = Normal. 
1 = Mild difficulty. May not swing arms or may tend to drag leg. 
2 = Moderate difficulty, but requires little or no assistance. 
3 = Severe disturbance of walking, requiring assistance. 
4 = Cannot walk at all, even with assistance. 
 
16. Tremor 
0 = Absent. 
1 = Slight and infrequently present. 
2 = Moderate; bothersome to patient. 
3 = Severe; interferes with many activities. 
4 = Marked; interferes with most activities. 
 
17. Sensory complaints related to parkinsonism 
0 = None. 
1 = Occasionally has numbness, tingling, or mild aching. 
2 = Frequently has numbness, tingling, or aching; not distressing. 
3 = Frequent painful sensations. 
4 = Excruciating pain. 


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Part III. MOTOR EXAMINATION (Acceptable responses are 0, 1, 2, 3, 4) 
Instructions: All efforts should be made to conduct the motor exam while the patient is in a stable state (e.g., “On” 
for the entire exam or “Off” for the entire exam). If unstable, re-examine the patient in a stable state, if possible. 
 
18. Speech 
0 = Normal. 
1 = Slight loss of expression, diction and/or volume. 
2 = Monotone, slurred but understandable; moderately impaired. 
3 = Marked impairment, difficult to understand. 
4 = Unintelligible. 
 
19. Facial Expression 
0 = Normal. 
1 = Minimal hypomimia, could be normal “Poker Face”. 
2 = Slight but definitely abnormal diminution of facial expression 
3 = Moderate hypomimia; lips parted some of the time. 
4 = Masked or fixed facies with severe or complete loss of facial expression; lips parted 1/4 inch or more. 
 
20. Tremor at rest 
0 = Absent. 
1 = Slight and infrequently present. 
2 = Mild in amplitude and persistent. Or moderate in amplitude, but only intermittently present. 
3 = Moderate in amplitude and present most of the time. 
4 = Marked in amplitude and present most of the time. 
 
20a. Face, lips + chin: ________ 
20b. Right Hand: _________ 
20c. Left Hand:________ 
20d: Right Foot:______ 
20e: Left Foot: _____ 
 
21. Action or Postural Tremor of hands 
0 = Absent. 
1 = Slight; present with action. 
2 = Moderate in amplitude, present with action. 
3 = Moderate in amplitude with posture holding as well as action. 
4 = Marked in amplitude; interferes with feeding. 
21a. Right Hand:_____ 
21b. Left Hand: ___ 
 
22. Rigidity (Judged on passive movement of major joints with patient relaxed in sitting position. Cogwheeling to 
be ignored.) 
0 = Absent. 
1 = Slight or detectable only when activated by mirror or other movements. 
2 = Mild to moderate. 
3 = Marked, but full range of motion easily achieved. 
4 = Severe, range of motion achieved with difficulty. 
22a. Neck 
 
22b. RUE 
 
22c. LUE 
 
 
22d. RLE 
 
 
22e. LLE 
 
 
 


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23. Finger Taps (Patient taps thumb with index finger in rapid succession with widest amplitude possible, each 
hand separately.) 
0 = Normal. 
1 = Mild slowing and/or reduction in amplitude. 
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 
4 = Can barely perform the task 
23a. Right Hand:_____ 
23b. Left Hand: ___ 
 
24. Hand Movements (Patient opens and closes hands in rapid succession with widest amplitude possible, each 
hand separately.) 
0 = Normal. 
1 = Mild slowing and/or reduction in amplitude. 
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 
4 = Can barely perform the task. 
24a. Right Hand:_____ 
24b. Left Hand: ___ 
 
25. Rapid Alternating Movements of Hands (Pronation-supination movements of hands, vertically or horizontally, 
with as large an amplitude as possible, both hands simultaneously.) 
0 = Normal. 
1 = Mild slowing and/or reduction in amplitude. 
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 
4 = Can barely perform the task. 
25a. Right Hand:_____ 
25b. Left Hand: ___ 
 
26. Leg Agility (Patient taps heel on the ground in rapid succession picking up entire leg. Amplitude should be 
about 3 inches.) 
0 = Normal. 
1 = Mild slowing and/or reduction in amplitude. 
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 
4 = Can barely perform the task. 
26a. Right Leg:_____ 
26b. Left Leg ___ 
 
27. Arising from Chair (Patient attempts to arise from a straight-back wood or metal chair with arms folded across 
chest.) 
0 = Normal. 
1 = Slow; or may need more than one attempt. 
2 = Pushes self up from arms of seat. 
3 = Tends to fall back and may have to try more than one time, but can get up without help. 
4 = Unable to arise without help. 
 
28. Posture 
0 = Normal erect. 
1 = Not quite erect, slightly stooped posture; could be normal for older person. 
2 = Moderately stooped posture, definitely abnormal; can be slightly leaning to one side. 
3 = Severely stooped posture with kyphosis; can be moderately leaning to one side. 
4 = Marked flexion with extreme abnormality of posture. 
 


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29. Gait 
0 = Normal. 
1 = Walks slowly, may shuffle with short steps, but no festination or propulsion. 
2 = Walks with difficulty, but requires little or no assistance; may have some festination, short steps, or propulsion. 
3 = Severe disturbance of gait, requiring assistance. 
4 = Cannot walk at all, even with assistance. 
 
30. Postural Stability (Response to sudden, strong posterior displacement produced by pull on shoulders while 
patient is erect, with eyes open and feet slightly apart. Patient is prepared.) 
0 = Normal. 
1 = Retropulsion, but recovers unaided. 
2 = Absence of postural response; would fall if not caught by examiner. 
3 = Very unstable, tends to lose balance spontaneously. 
4 = Unable to stand without assistance. 
 
31. Body Bradykinesia and Hypokinesia (Combining slowness, hesitancy, decreased armswing, small amplitude, 
and poverty of movement in general.) 
0 = None. 
1 = Minimal slowness, giving movement a deliberate character; could be normal for some persons. Possibly reduced 
amplitude. 
2 = Mild degree of slowness and poverty of movement which is definitely abnormal. Alternatively, some reduced 
amplitude. 
3 = Moderate slowness, poverty or small amplitude of movement. 
4 = Marked slowness, poverty or small amplitude of movement. 
 
Indicate the patient’s PD state during the examination: 
1. 
“On” during exam 
2. 
 Fluctuated during the exam 
3. 
 “Off” during exam 


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Part IV. COMPLICATIONS OF THERAPY (In the past week) 
 
A. DYSKINESIAS 
32. Duration: What proportion of the waking day are dyskinesias present? (Historical information.) 
0 = None 
1 = 1-25% of day. 
2 = 26-50% of day. 
3 = 51-75% of day. 
4 = 76-100% of day. 
 
33. Disability: How disabling are the dyskinesias? (Historical information; may be modified by office 
examination.) 
0 = Not disabling. 
1 = Mildly disabling. 
2 = Moderately disabling. 
3 = Severely disabling. 
4 = Completely disabled. 
 
34. Painful Dyskinesias: How painful are the dyskinesias? 
0 = No painful dyskinesias. 
1 = Slight. 
2 = Moderate. 
3 = Severe. 
4 = Marked. 
 
35. Presence of Early Morning Dystonia (Historical information.) 
0 = No 
1 = Yes 
 
B. CLINICAL FLUCTUATIONS 
36. Are any “off” periods predictable as to timing after a dose of medication? 
0 = No 
1 = Yes 
 
37. Are any “off” periods unpredictable as to timing after a dose of medication? 
0 = No 
1 = Yes 
 
38. Do any of the “off” periods come on suddenly, e.g., over a few seconds? 
0 = No 
1 = Yes 
 
39. What proportion of the waking day is the patient “off” on average? 
0 = None 
1 = 1-25% of day. 
2 = 26-50% of day. 
3 = 51-75% of day. 
4 = 76-100% of day. 


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C. OTHER COMPLICATIONS 
40. Does the patient have anorexia, nausea, or vomiting? 
0 = No 
1 = Yes 
 
41. Does the patient have any sleep disturbances, e.g., insomnia or hypersomnolence? 
0 = No 
1 = Yes 
 
42. Does the patient have symptomatic orthostasis?  
0 = No 
1 = Yes 
 
Fahn S, Elton RL, Members of the UPDRS Development Committee (1987). Unified Parkinson's Disease Rating 
Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, eds. Recent developments in Parkinson's disease. Florham 
Park, NJ: MacMillan Health Care Information, pp. 153-63, 293-304. 
 


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15.2 Epworth Sleepiness Scale 
Epworth Sleepiness Scale (ESS) 
 
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 have not 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 you can. 
Situation 
Chance Of Dozing 
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 1990-1997 


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15.3 Assessment for Episodes of Sudden Onset of Sleep 
Assessment for Episodes of Sudden Onset of Sleep 
Definition of sudden onset of sleep: Abrupt episodes of unplanned sleep during activities of daily 
living where they are not expected to occur. These events may or may not be preceded by 
somnolence or sedation. 
 
Instructions for the Screening Visit: 
Did the subject experience any sudden onset of sleep in the last 6 weeks? (Check only 1 box) 
Yes, but the subject felt sleepy before (This is an indication of a possible sudden onset of sleep). 
Yes, subject fell asleep completely unexpected without prior sleepiness (This is an indication of a possible 
sudden onset of sleep). 
Yes, sometimes with, sometimes without prior sleepiness (This is an indication of a possible sudden onset 
of sleep). 
No 
If the subject responds “Yes” to any of the above, the investigator should record the applicable response into the 
subject’s Medical History. (e.g., “possible sudden onset of sleep”) 
 
Instructions for Visits After Screening: 
Did the subject experience any sudden onset of sleep since the last visit? (Check only 1 box) 
Yes, but the subject felt sleepy before (This is an indication of a possible sudden onset of sleep). 
Yes, subject fell asleep completely unexpected without prior sleepiness (This is an indication of a possible 
sudden onset of sleep). 
Yes, sometimes with, sometimes without prior sleepiness (This is an indication of a possible sudden onset 
of sleep). 
No 
If the subject responds “Yes” to any of the above (indicating a possible sudden onset of sleep), the investigator 
should evaluate if this is a change from Screening and if so report as an Adverse Event and determine whether the 
subject’s continued participation in the study puts them at risk and whether they should be discontinued from the 
study. 
 


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15.4 Modified Minnesota Impulse Disorders Interview (mMIDI) 
Modified Minnesota Impulse Disorders Interview (mMIDI) 
 
Module 1: Buying Disorder Screen 
 
Gateway Question:  
Do you or others think that you have a problem with buying things too often or with 
spending too much money?  
0  
 
1 
No  
 
Yes 
If NO, go to the next module. If Yes, proceed with the following questions: 
1. Do you ever experience an irresistible urge or uncontrollable need to buy things or 
mounting tension that can only be relieved by buying? 
□0 
 □1 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
 
2. Has problem buying led to social, marital, family, financial or work problems or caused 
you to experience significant distress? 
□0 
 □1 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
 
Module 1 score: ______________ (add up all numbers, including gateway question) 
 


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Module 2: Compulsive Gambling Screen 
 
Gateway Question: 
Do you gamble?  
□0 
 
 □1 
No  
 
 
Yes 
 
If NO, go to the next module. If Yes, proceed with the following questions: 
 
1. Do you or others think that you have ever had a problem with gambling? 
□0 
 
 □1 
 
 
 □2 
 
 
 
 
 □3 
No  
 
 
Rarely  
 
 
Occasionally  
 
 
Frequently 
2. Have you ever felt guilty about the way you gamble or what happens when you gamble? 
□0 
 
 □1 
 
 
 □2 
 
 
 
 □3 
No  
 
 
Rarely  
 
 
Occasionally  
 
Frequently 
3. Have you been preoccupied with gambling or obtaining money to gamble? 
□0 
 
 □1 
 
 
 □2 
 
 
 
 
 □3 
No  
 
 
Rarely  
 
 
Occasionally  
 
 
Frequently 
4. Have you gambled larger amounts of money or over longer periods of time than you 
intended to? 
□0 
 
 □1 
 
 
 □2 
 
 
 
 □3 
No  
 
 
Rarely  
 
 
Occasionally  
 
Frequently 
 
Module 2 score: ______________ (add up all numbers, including gateway question) 
 


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Module 3: Compulsive Sexual Behavior Screen 
 
Gateway Question:  
Do you or others that you know think that you have a problem with being overly preoccupied 
with some aspect of your sexuality or being overly sexually active?  
□0 
 
 □1 
No  
 
 
Yes 
 
If NO, go to the next module. If Yes, proceed with the following questions: 
1. Do you have repetitive sexual fantasies which you feel are out of your control or cause 
you distress? 
□0 
 □1 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
 
2. Do you have repetitive sexual urges which you feel are out of your control or cause you 
distress? 
□0 
 □1 
 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
 
Occasionally  
 
Frequently 
 
3. Do you engage in repetitive sexual behavior which you feel is out of control or causes 
you distress? 
□0 
 
 □1 
 
 
 □2 
 
 
 
 □3 
No  
 
 
Rarely  
 
 
Occasionally  
 
Frequently 
 
Module 3 score: ______________ (add up all numbers, including gateway question) 
 
 
 


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Module 4: Compulsive Eating Module 
 
Gateway Question:  
Do you or others that you know think that you have a problem with being overly preoccupied 
with food or actively overeating?  
□0 
 
 □1 
No  
 
 
Yes 
 
If NO, go to the next module. If Yes, proceed with the following questions: 
 
1. Do you have repetitive fantasies about eating which are out of your control or cause you 
distress? 
□0 
 
 □1 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
 
2. Do you have repetitive urges to eat which you feel are out of your control or cause you 
distress? 
□0 
 
 □1 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
 
3. Do you engage in constant or overly frequent eating which you feel is out of control or 
causes you distress? 
□0 
 □1 
 
 □2 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
Frequently 
 
Module 4 score: ______________ (add up all numbers, including gateway question) 
 


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Module 5: Punding Behavior Screen 
 
Gateway Question: 
Do you find yourself fascinated with or performing repetitive and/or mechanical tasks such 
as taking apart and putting back together simple mechanical objects, or picking at oneself, or 
sorting and arranging common objects?  
□0 
 
 □1 
No  
 
 
Yes 
If NO, end the module. If Yes, proceed with the following questions: 
1. Do you collect things such as rocks, coins or books, and line them up together? 
□0 
 □1 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
2. Do you disassemble mechanical things such as doorknobs, watches, radios or other 
objects, and then re-assemble them? 
□0 
 □1 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
3. Do you find performing such repetitive tasks comforting? 
□0 
 □1 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
4. Do you get frustrated if you are unable to perform such repetitive tasks? 
□0 
 □1 
 
 □2 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
 
5. Have you ever taken amphetamines? 
□0 
 □1 
 
 □2 
 
 
 
 □3 
No  
 
Rarely  
 
Occasionally  
 
Frequently 
 
Module 5 score: ______________ (add up all numbers, including gateway question) 
 


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SCORING: 
The mMIDI consists of 5 modules: compulsive buying, compulsive gambling, compulsive 
eating, hypersexuality and punding. 
 
Positive Answer: 
Any answer other than “no” on any question is considered a “yes”/positive answer. 
 
Negative Module: 
A module is considered negative if the patient’s answer to a gateway (initial) question is “no” or 
if a patient answers “yes” to a gateway question and “no” to all of the remaining answers after 
the gateway question in that module. 
 
Positive Module: 
A module is considered positive if a patient gives a positive answer (rarely = 1, occasionally = 2, 
frequently = 3) to any question after the gateway (initial) question in one or more of the 
5 modules. 
 
During screening, if a subject has evidence of an impulse control disorder (ICD) (i.e., one 
or more positive modules on the mMIDI) the subject is ineligible for the study unless a 
structured clinical interview confirms that the subject does not have an ICD. 
After administration of study drug, if a subject has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the Medical 
Monitor. 
Total Score (add up all module scores):______________ 
 
Modules (Circle One Answer for Each Module: Positive or Negative): 
Module 1: Buying Disorder: 
 
 
 □Positive  □Negative 
Module 2: Compulsive Gambling:  
 □Positive  □Negative 
Module 3: Compulsive Sexual Behavior: □Positive  □Negative 
Module 4: Compulsive Eating:  
 
 □Positive  □Negative 
Module 5: Punding Behavior:  
 
 □Positive  □Negative 
 
 
 


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15.5 UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria 
Step 1: Diagnosis of Parkinsonian syndrome 
-Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed 
and amplitude of repetitive actions) 
-At least one of the following: 
-Muscular rigidity 
-4-6 Hz rest tremor 
-Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive 
dysfunction. 
 
Step 2: Exclusion criteria for Parkinson’s disease 
-History of repeated strokes with stepwise progression of Parkinsonian features 
-History of repeated head injury 
-History of definite encephalitis 
-Oculogyric crises 
-Neuroleptic treatment at onset of symptoms 
-More than one affected relative 
-Sustained remission 
-Strictly unilateral features after 3 years 
-Supranuclear gaze palsy 
-Cerebellar signs 
-Early severe autonomic involvement 
-Early severe dementia with disturbances of memory, language, and praxis 
-Babinski sign 
-Presence of cerebral tumor or communicating hydrocephalus on CT scan 
-Negative response to large doses of levodopa (if malabsorption excluded) 
-MPTP exposure 
 
Step 3: Supportive prospective positive criteria for Parkinson’s disease 
(Three or more required for diagnosis of definite Parkinson’s disease) 
 
-Unilateral onset 
-Rest tremor present 
-Progressive disorder 
-Persistent asymmetry affecting side of onset most 
-Excellent response (70-100%) to levodopa 
-Severe levodopa-induced chorea 
-Levodopa response for 5 years or more 
-Clinical course of 10 years or more 
 
 
 


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15.6 Modified Hoehn and Yahr 
Modified Hoehn and Yahr PD Staging 
The Modified Hoehn and Yahr PD Staging is a scale expressing the severity of the symptoms of 
PD. It provides a practical classification of 5 stages of ever increasing severity. The stages are 
defined as: 
Stage 0 
= 
No signs of disease. 
Stage 1 
= 
Unilateral disease. 
Stage 1.5 
= 
Unilateral plus axial involvement. 
Stage 2 
= 
Bilateral disease, without impairment of balance. 
Stage 2.5 
= 
Mild bilateral disease, with recovery on pull test. 
Stage 3 
= 
Mild to moderate bilateral disease; some postural instability; physically 
independent. 
Stage 4 
= 
Severe disability; still able to walk or stand unassisted 
Stage 5 
= 
Wheelchair bound or bedridden unless aided. 
 
Hoehn MM, Yahr MD (1967). Parkinsonism: onset, progression and mortality. Neurology. 17(5):427-42. 


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15.7 
 
 
  
 
 
 
 
 
 
 
  
 
 
• 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
  
 
 


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15.8 Fall Questionnaire 
Fall Questionnaire 
Baseline (Visit 2): 
Have you been experiencing falls over the past 3 months?  Yes/No 
If yes, approximately how many falls have occurred in the past 3 months?_____ 
 
At Week 24 (Visit 6) and Week 52 (Visit 8): 
Have you been experiencing falls over the past 3 months?  Yes/No 
If yes, approximately how many falls have occurred in the past 3 months?_____ 
 
In the event of an Early Termination Visit: 
Have you been experiencing falls over the past 3 months?  Yes/No 
If yes, approximately how many falls have occurred in the past 3 months?_____ 
 
 
 


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15.9 Expanded Pharmacokinetic Sampling Procedures – Applicable to Select 
Sites Only 
For those subjects who have consented to participate in the expanded tozadenant PK sampling, 
Sections 15.9.1 and 15.9.2 should be referred to instead of Sections 6.2.3.4 (Baseline Assignment 
and Dispensing and Investigational Medicinal Product) and 6.2.4 (Visit 3/Week 2), respectively. 
Pharmacokinetic blood samples for determination of plasma tozadenant concentration will be 
collected at the Week 2 study visit at select sites only. The Schedule of Events for subjects 
participating in Expanded PK Sampling is provided in Table 4. 
15.9.1 
Baseline (Visit 2) Assignment and Dispensing and Investigational Medicinal 
Product for Subjects Participating in Expanded PK Sampling (Replacement 
Section for Section 6.2.3.4) 
1. For patients meeting all entry criteria, complete the IMP assignment transaction using the 
IXRS by following the procedures provided. 
a. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this study 
visit. Each bottle consists of either 50 tablets of 120 mg tozadenant or 100 tablets of 
60 mg tozadenant. 
b. Record the date IMP was dispensed in IMP dispensing records including patient number, 
assigned IMP bottle number(s), and date and time IMP was dispensed. 
c. Review the dosing instructions for the IMP with the patient, answer any questions, and 
remind the patient to return the IMP (including all used, unused and partially used 
bottles) at the next visit. 
d. Patients will be instructed to take either two (2) 60 mg tablets or one (1) 120 mg tablet of 
the dispensed IMP by mouth twice daily (BID), in the morning and in the evening 
preferably at the same time each day, for a total of either two (2) 120 mg tablets or 
four (4) 60 mg tablets per day. The evening dose should be approximately 12 hours after 
the morning dose. Patients will be instructed to take their morning and evening doses 
1 hour before or 2 hours after a meal and to refrain from eating for 1 hour after dosing. 
Patients should take the first dose of IMP at home after the Baseline Visit.  
2. Instruct the patient to take the first dose of IMP at home on the evening of dispensation. 
3. Ensure that the patient understood the dosing instructions and the use of the extra doses 
included in the bottle if visit delayed and/or use of visit window. 
4.  Subjects participating in the expanded tozadenant PK sampling will be advised to 
refrain from taking their 120 mg IMP dose on the day of the Week 2 visit, prior to the 
visit. 
5. Schedule the Week 2 visit. If needed, use the visit window in relation to the date of the 
Baseline visit.  


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15.9.2 
Visit 3 (Week 2) for Subjects Participating in Expanded PK Sampling 
(Replacement Section for Section 6.2.5) 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 2 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. For all applicable patients: Verify continuation of (or any change to) contraceptive method 
since Screening and document. 
2. Obtain sample for the following laboratory tests and record the date and time of 
collection: 
a. Expanded PK blood sample(s) for plasma tozadenant concentration.  
i. 
Collect one (1) pre-dose/trough PK blood sample before the administration of 
IMP. Record the date and time of PK sample collection. Document the date 
and time of the previous IMP dosing. 
ii. 
Administer the 120mg dose during the visit from the IMP bottle previously 
dispensed at Baseline visit. Record the date and time when the patient took 
the 120mg dose of IMP.  
iii. 
 
 
Note: For processing, labeling and shipping of samples, follow the instructions provided in 
the Central Laboratory Procedures Manual. 
b. Hematology and chemistry (inclusive of liver function tests). 
c. TSH, free T3, and free T4. 
d. For females of childbearing potential: urine pregnancy test. 
e. Urinalysis. 
Note: For processing, labeling and shipping of samples, follow the instructions provided in 
the Central Laboratory Procedures Manual. 
3. Assess AEs by asking open-ended queries and record the assessments. 
4. Record concomitant medication use; assess and record any changes to anti-PD medication 
dose or regimen. 
5. Obtain and record BP and pulse measurements after at least 5 minutes supine rest and again 
after standing for approximately 1 and 3 minutes. 
6. Obtain 12-lead ECG. Ensure the ECG is collected when the patient is not experiencing 
dyskinesia that would interfere with an adequate recording. Assess any changes from 
Baseline for clinical significance. 
7. Record the date and approximate time of the most recent dose of levodopa taken prior to the 
UPDRS assessment. 


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8. Perform the following assessments in the ON state: 
a. Perform full UPDRS Parts I, II, III (motor) and IV. UPDRS Part III should be performed 
approximately 1 to 3 hours after the patient has taken a scheduled dose of levodopa 
(preferably their morning dose of levodopa). UPDRS in the ON state will be measured at 
a time representative of the ON state in that patient, not in “best” ON. 
b. Administer the following assessments: 
• CGI-I. 
• PGI-I. 
c. Have the patient complete the following self-assessment questionnaire:  
• 
ESS. 
9. Administer the following assessments (may be done anytime during visit): 
a. C-SSRS. 
b. mMIDI. (Note: After Baseline, if patient has one or more positive modules on the 
mMIDI, their continued participation in the study should be discussed with the Medical 
Monitor.) 
c. Assessment for episodes of sudden onset of sleep. 
d.. Healthcare Resource Utilization. 
10. Collect the IMP (including all used, unused and partially used bottles) dispensed at the 
Baseline Visit. 
a. Record the date and approximate time when the patient took the last dose of IMP. 
b. Assess and document IMP accountability and compliance (document any missed dose(s), 
lost tablets and number of tablets taken). 
c. Review and reconcile any discrepancies with the patient. 
11. Dispense the open-label IMP bottle(s) assigned by the IXRS to the patient for this study visit. 
Each bottle consists of either 100 × 60 mg tablets or 50 × 120 mg tablets. 
a. Record the date IMP was dispensed in IMP dispensing records. 
12. Review the dosing instructions for the IMP with the patient, answer any questions, and 
remind the patient to return the IMP (including all used, unused and partially used bottles) at 
the next visit. 
13. Ensure that the patient understood the dosing instructions and the use of extra doses included 
in the bottle if visit delayed and/or use of visit window. 
14. Schedule the next study visit (Week 4). If needed, use the visit window in relation to the date 
of the Baseline visit. 
 


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Table 4: 
Schedule of Events/Evaluations for Subjects Participating in Expanded PK Sampling 
 
Study Period Screening a Baseline 
Predose 
Open-Label Treatment 
(52 weeks) 
Safety 
Follow-Up 
Early 
Termination x 
Unschedule
d 
 
Study Week b 
−6 to −1 
BL 
2 
(± 3 d) 
6 
(± 3 d) 
12 
(± 3 d) 
24 
(± 7 d) 
36 
(± 7 d) 
52 
(± 14 d) 
[16 weeks] 
56 
(28 ± 3 d after 
last dose of IMP) 
 
 
Assessments 
Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
B98 
B97 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History, 
including neurological and PD history 
X 
 
 
 
 
 
 
 
 
 
 
Recording of concomitant and  
anti-PD medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP c, pulse c 
X d 
X d 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
12-lead ECG f 
X 
X g 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Weight (include height at Screening) 
X 
 
 
 
X 
X 
 
X 
X 
X 
X e 
Physical and neurological examination 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X e 
PD diary training and diary concordance 
session 
X 
 
 
 
 
 
 
 
 
 
 
Modified Hoehn and Yahr staging (observed 
ON; OFF estimated per history) h 
X 
 
 
 
 
 
 
 
 
 
 
UPDRS Parts I, II, III and IV i 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
MMSE-II (in ON state) 
X 
 
 
 
 
 
 
 
 
 
 
mMIDI j 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
ESS h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PD diary collection (phone call prior to start 
of 3 consecutive 24 hour diary completion 
periods) 
X k 
X k 
 
 
X l 
X l 
 
X l 
 
X m 
 
PD diary review 
X 
X 
 
 
X 
X 
 
X m 
 
X m 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
CGI-I h 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
PGI-I h 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
PDQ-39 h 
 
X 
 
 
 
X 
 
X 
 
X 
 
Sudden onset of sleep 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fall questionnaire 
 
X 
 
 
 
X 
 
X 
 
X 
 
Healthcare Resource Utillization 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Non-motor Symptom Questionnaireh 
 
X 
 
 
 
X 
 
X 
 
X 
 
EQ-5D-5L h 
 
X 
 
 
 
X 
 
X 
 
X 
 
Recording of AEs 
X n 
X n 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Period Screening a Baseline 
Predose 
Open-Label Treatment 
(52 weeks) 
Safety 
Follow-Up 
Early 
Termination x 
Unschedule
d 
 
Study Week b 
−6 to −1 
BL 
2 
(± 3 d) 
6 
(± 3 d) 
12 
(± 3 d) 
24 
(± 7 d) 
36 
(± 7 d) 
52 
(± 14 d) 
[16 weeks] 
56 
(28 ± 3 d after 
last dose of IMP) 
 
 
Assessments 
Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
B98 
B97 
Laboratory tests: hematology o, chemistry p 
(including thyroid function q) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
FSH test, females who are postmenopausal 
for < 2 years 
X 
 
 
 
 
 
 
 
 
 
 
Method of contraception r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Urine pregnancy test, females of 
childbearing potential s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Urinalysis t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Review of inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Final verification of eligibility 
 
X 
 
 
 
 
 
 
 
 
 
Tozadenant blood sampling 
 
 
  
 
 
 
 
 
 
 
 
IMP dispensing and/or return v 
X w 
X 
X 
X 
X 
X 
X 
 
X 
X e 
eCRF completion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE, adverse event; BP, blood pressure; CGI-I, Clinical Global Impression of Improvement; C-SSRS, Columbia-Suicide Severity Rating Scale; d, day; ECG, electrocardiogram; 
eCRF, electronic case report form; ESS, Epworth Sleepiness Scale; ET, Early Termination; FSH, follicle stimulating hormone; IMP, investigational medicinal product; mMIDI, 
Modified Minnesota Impulse Disorders Interview; MMSE-II, Mini-Mental State Exam – Second Edition (MMSE-II); PD, Parkinson’s disease; PDQ-39, Parkinson’s Disease 
Quality of Life Questionnaire; PGI-I, Patient’s Global Impression of Improvement; UPDRS, Unified Parkinson’s Disease Rating Scale; V, Visit. 
Footnotes 
a Screening period may not exceed 6 weeks.  
b Visit windows for scheduled visits after Baseline (V2) are in relation to the date of the Baseline Visit (V2). 
c Obtain and record BP and pulse measurements after at least 5 minutes supine rest and again after standing for approximately 1 minute and 3 minutes. 
d At Screening and Baseline (before dosing), obtain and record serial BP and pulse measurements after at least 5 minutes supine rest and again after standing for approximately 
1 and 3 minutes. Repeat these BP and pulse measurements 2 more times approximately 10 minutes apart. 
e Optional activities (e.g., additional assessments for evaluation of AEs) that may be performed at the investigator’s discretion. 
f A resting supine 12-lead ECG will be collected after the patient has been in a supine position for a minimum of 5 minutes. Ensure the ECG is collected when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
g At Baseline, obtain three 12-lead ECGs (i.e., 3 serial readings, performed several minutes apart). Ensure the ECGs are collected when the patient is not experiencing dyskinesia 
that would interfere with an adequate recording. 
h To be collected during patient’s ON state. 
i UPDRS to be measured in ON state. UPDRS Part III should be measured approximately 1 to 3 hours after patients have taken a scheduled dose of levodopa (preferably their 
morning dose of levodopa). Patients will be instructed to have already taken their normally scheduled dose of levodopa and their IMP before arriving at the study site in order to 
have their UPDRS Part III evaluated in the ON state. UPDRS in the ON state will be measured at a time representative of the ON state in that patient, not in the patient’s “best” 
ON. 


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Table 4: Schedule of Events/Evaluations for Subjects Participating in Expanded PK Sampling (continued) 
j At Screening, send patient for structured clinical interview if one or more positive mMIDI modules. If the structured clinical interview confirms that the subject does not have an 
ICD, he/she will not be considered ineligible on that basis. After Baseline, if patient has one or more positive modules on the mMIDI, their continued participation in the study 
should be discussed with the Medical Monitor. 
k The 3-day practice diary during the Screening Period and the 3-day Baseline diary must both be valid in order to enroll a patient. The trainer/rater will call the patient before the 
scheduled start of the diary completion periods to remind him or her to keep the PD diary and to review completion instructions. The patient will also be reminded to send the 
completed practice diary to the trainer/rater and to bring their Baseline diary to the Baseline Visit. If the practice or Baseline diary is invalid, the patient may be retrained and 
complete another practice or Baseline diary within the 6-week window of the Screening Period, if the patient is otherwise eligible for the study. 
l PD diary collected over the 3 consecutive 24-hour periods before the day of the scheduled study visits on Weeks 12, 24 and 52. The PD diary trainer/rater will call the patient 
before the scheduled start of the 3-day PD diary completion period (at the latest, on the last working day before the scheduled start of the PD diary completion) and review 
completion instructions. The patient will also be reminded to bring their PD diary to the visit. The trainer/rater will instruct the patient if the PD diary contains missing and/or 
invalid entries to reinforce instructions for appropriate completion. 
m Done only if the ET date coincides with the scheduled diary collection return date. 
n Pretreatment AEs. 
o Hematology tests: Hemoglobin concentration, hematocrit, red blood cell count, total and differential white blood cell, thrombocyte (platelet) count. 
p Blood chemistry (including liver function) tests: Aspartate amino transferase (AST), alanine amino transferase, (ALT), gamma-glutamyl transpeptidase (GGT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin (conjugated and unconjugated), albumin, creatinine, urea/BUN, bicarbonate, uric acid, total protein, sodium, 
chloride, potassium, calcium, phosphate, glucose, cholesterol, creatine phosphokinase (CK). 
q TSH, free T3, and free T4. 
r For applicable patients: At Screening, document method of contraception used by patient. At subsequent visits, verify continuation of (or any change to) contraceptive method. 
s For females of childbearing potential: urine pregnancy test. 
t Urinalysis: Specific gravity, pH, ketones, blood, protein, glucose. If urine dipstick is positive for leukocytes, protein, or erythrocytes, a microscopic evaluation and culture will 
be performed. 
 
 
 
v Patients will be instructed to take the assigned dose of open-label tozadenant by mouth BID, in the morning and in the evening preferably at the same time each day. The evening 
dose should be approximately 12 hours after the morning dose. Patients will be instructed to take their morning and evening doses at least 1 hour before or 2 hours after a meal 
and to refrain from eating for at least 1 hour after dosing. 
w Patients will be instructed to refrain from taking their 120 mg IMP dose on the day of the Week 2 visit, prior to the visit. 
x If patient has discontinued IMP, perform Early Termination Visit as soon as possible after the last dose of IMP. If patient took the last dose of IMP 28 or more days prior to the 
Early Termination Visit, a Safety Follow-Up Visit (Section 6.2.19) is not required. 
 
 
 


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Table 4.1: 
Schedule of Events/ Evaluations for Hematology Monitoring 
 
 
Study Period 
Open-Label Treatment 
(52 weeks) 
Weekly monitoringb 
(if required) 
 
Study Week 
4 
(±3 d) 
8 
(±3 d) 
10 
(±3 d) 
16 
(±3 d) 
20 
(±3 d) 
44 
(±14 d) 
 
Assessments 
Study Visit V3.5 V4.3 V4.8 V5.3 V5.8 V7.5 
 
Laboratory test: hematology a  
X 
X 
X 
X 
X 
X 
X 
Recording of AEs 
 
 
 
 
 
 
X 
Recording of concomitant and Anti-PD medications 
 
 
 
 
 
 
X 
eCRF completion  
X 
X 
X 
X 
X 
X 
X 
aHematology tests: Hemoglobin concentration, hematocrit, red blood cell count, neutrophils, total and differential white blood cell, thrombocyte (platelet) count. 
bOnly for patients that require weekly hematology monitoring per section 4.3.2. To be captured as an unscheduled visit in EDC/RAVE. 
 
 


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15.10 Clinical/Patient Global Impression Scales (CGI-I and PGI-I) 
Clinical Global Impression of Improvement (CGI-I) 
 
Rate total improvement whether or not in your judgment it is due entirely to drug treatment. 
Compared to his/her condition at admission to the study, 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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Patient Global Impression of Improvement (PGI-I) 
 
Rate total improvement of your Parkinson’s disease, whether or not in your judgment it is due 
entirely to drug treatment. Compared to your condition at admission to the study, how much 
have you changed? Place an X in one of the boxes below best describing your impression. 
 
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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15.11 Parkinson’s Disease Quality of Life Questionnaire (PDQ-39) 
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. 
 
 
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. 
 
 
Page 1 of 5 
 
 
 


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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. 
 
 
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. 
 
 
Page 2 of 5 
 
 
 


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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. 
 
 
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. 
 
 
Page 3 of 5 
 
 
 


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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. 
 
 
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. 
 
 
Page 4 of 5 
 
 
 


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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. 
 
 
 
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. 
 
 
Page 5 of 5 
 
 
 


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15.12 Non-Motor Symptom Assessment Scale for Parkinson’s Disease 
Patient ID No:____________________________  
Initials:_____________ 
Age:____________ 
 
Symptoms assessed over the last month. Each symptom scored with respect to:  
• Severity:  
– 0 – None,  
– 1 – Mild: symptoms present but causes little distress or disturbance to patient,  
– 2 -  Moderate: some distress or disturbance to patient;  
– 3 – Severe: major source of distress or disturbance to patient. 
• Frequency:  
– 1 – Rarely (< 1/week); 
– 2 – Often (1/week); 
– 3 – Frequent (several times per week); 
– 4 – Very Frequent (daily or all the time) 
Domains will be weighed differentially. Yes/No answers are no included in final frequency × 
severity calculation. (Bracketed text in questions within the scale is included as an explanatory 
aid). 
 
Domain 1: Cardiovascular including falls 
Severity 
Frequency 
Frequency × 
Severity 
1. 
Does the patient experience light-headedness, 
dizziness, weakness on standing from sitting or lying 
position? 
 
 
 
2. 
Does the patient fall because of fainting or blacking 
out? 
 
 
 
SCORE: 
 
 
 
 


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Domain 2: Sleep/fatigue 
Severity 
Frequency 
Frequency × 
Severity 
3. 
Does the patient doze off or fall asleep unintentionally 
during daytime activities? (For example, during 
conversation, during mealtimes, or while watching 
television or reading). 
 
 
 
4. 
Does fatigue (tiredness) or lack or energy (not 
slowness) limit the patient’s daytime activities? 
 
 
 
5. 
Does the patient have difficulties falling or staying 
asleep? 
 
 
 
6. 
Does the patient experience an urge to move the legs 
or restlessness in legs that improves with movement 
when he/she is sitting or lying down inactive? 
 
 
 
SCORE: 
 
 
 
Domain 3: Mood/cognition 
Severity 
Frequency 
Frequency × 
Severity 
7. 
Has the patient lost interest in his/her surroundings? 
 
 
 
8. 
Has the patient lost interest in doing things or lack 
motivation to start new activities? 
 
 
 
9. 
Does the patient feel nervous, worried or frightened 
for no apparent reason? 
 
 
 
10. 
Does the patient seem sad or depressed or has he/she 
reported such feelings? 
 
 
 
11. 
Does the patient have flat moods without the normal 
“highs” and “lows”? 
 
 
 
12. 
Does the patient have difficulty in experiencing 
pleasure from their usual activities or report that they 
lack pleasure? 
 
 
 
SCORE: 
 
 


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Domain 4: Perceptual problems/hallucinations 
Severity 
Frequency 
Frequency × 
Severity 
13. 
Does the patient indicate that he/she sees things that 
are not there? 
 
 
 
14. 
Does the patient have beliefs that you know are not 
true? (For example, about being harmed, being robbed 
or being unfaithful) 
 
 
 
15. 
Does the patient experience double vision? (2 separate 
real objects and not blurred vision) 
 
 
 
SCORE: 
 
 
 
Domain 5: Attention/memory 
Severity 
Frequency 
Frequency × 
Severity 
16. 
Does the patient have problems sustaining 
concentration during activities? (For example, reading 
or having a conversation) 
 
 
 
17. 
Does the patient forget things that he/she has been 
told a short time ago or events that happened in the 
last few days? 
 
 
 
18. 
Does the patient forget to do things? (For example, 
take tablets or turn off domestic appliances?) 
 
 
 
SCORE: 
 
 
 
 


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Domain 6: Gastrointestinal tract 
Severity 
Frequency 
Frequency × 
Severity 
19. 
Does the patient dribble saliva during the day? 
 
 
 
20. 
Does the patient have difficulty swallowing? 
 
 
 
21. 
Does the patient suffer from constipation? (Bowel 
action less than three times weekly) 
 
 
 
SCORE: 
 
 
 
Domain 7: Urinary 
Severity 
Frequency 
Frequency × 
Severity 
22. 
Does the patient have difficulty holding urine? 
(Urgency) 
 
 
 
23. 
Does the patient have to void within 2 hours of last 
voiding? (Frequency) 
 
 
 
24. 
Does the patient have to get up regularly at night to 
pass urine? (Nocturia) 
 
 
 
SCORE: 
 
 
 
Domain 8: Sexual function 
Severity 
Frequency 
Frequency × 
Severity 
25. 
Does the patient have altered interest in sex? (Very 
much increased or decreased, please underline) 
 
 
 
26. 
Does the patient have problems having sex? 
 
 
 
SCORE: 
 
 
 


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Domain 9: Miscellaneous 
Severity 
Frequency 
Frequency × 
Severity 
27. 
Does the patient suffer from pain not explained by 
other known conditions? (is it related to intake of 
drugs and is it relieved by anti-parkinson drugs?) 
 
 
 
28. 
Does the patient report a change in ability to taste or 
smell? 
 
 
 
29. 
Does the patient report a recent change in weight (not 
related to dieting)? 
 
 
 
30. 
Does the patient experience excessive sweating (not 
related to hot weather)? 
 
 
 
SCORE: 
 
 
 
TOTAL SCORE: 
 
 
Developed by the International Parkinson’s Disease Non-Motor Group. 
Contacts: ray.chaudhuri@uhl.nhs.uk or alison.forbes@uhl.nhs.uk 
 


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EXAMPLE 
15.13 Hauser Parkinson’s Disease Home Diary 
 
time 
 
asleep 
 
OFF 
 
ON 
without 
dyskinesia 
ON with 
non-trouble 
some 
dyskinesia 
 
ON with 
troublesome 
dyskinesia 
 
 
time 
 
asleep 
 
OFF 
 
ON 
without 
dyskinesia 
ON with 
non-trouble 
some 
dyskinesia 
 
ON with 
troublesome 
dyskinesia 
6:00-6:30 AM 
 
 
 
 
 
 
6:00-6:30 PM 
 
 
 
 
 
6:30-7:00 AM 
 
 
 
 
 
 
6:30-7:00 PM 
 
 
 
 
 
7:00-7:30 AM 
 
 
 
 
 
 
7:00-7:30 PM 
 
 
 
 
 
7:30-8:00 AM 
 
 
 
 
 
 
7:30-8:00 PM 
 
 
 
 
 
8:00-8:30 AM 
 
 
 
 
 
 
8:00-8:30 PM 
 
 
 
 
 
8:30-9:00 AM 
 
 
 
 
 
 
8:30-9:00 PM 
 
 
 
 
 
9:00-9:30 AM 
 
 
 
 
 
 
9:00-9:30 PM 
 
 
 
 
 
9:30-10:00 AM 
 
 
 
 
 
 
9:30-10:00 PM 
 
 
 
 
 
10:00-10:30 AM 
 
 
 
 
 
 
10:00-10:30 PM 
 
 
 
 
 
10:30-11:00 AM 
 
 
 
 
 
 
10:30-11:00 PM  
 
 
 
 
 
11:00-11:30 AM 
 
 
 
 
 
 
11:00-11:30 PM  
 
 
 
 
 
11:30-12:00 PM 
 
 
 
 
 
 
11:30-12:00 AM  
 
 
 
 
 
12:00-12:30 PM 
 
 
 
 
 
 
12:00-12:30 AM  
 
 
 
 
 
12:30-1:00 PM 
 
 
 
 
 
 
12:30-1:00 AM  
 
 
 
 
 
1:00-1:30 PM 
 
 
 
 
 
 
1:00-1:30 AM  
 
 
 
 
 
1:30-2:00 PM 
 
 
 
 
 
 
1:30-2:00 AM  
 
 
 
 
 
2:00-2:30 PM  
 
 
 
 
 
 
2:00-2:30 AM  
 
 
 
 
 
2:30-3:00 PM 
 
 
 
 
 
 
2:30-3:00 AM  
 
 
 
 
 
3:00-3:30 PM 
 
 
 
 
 
 
3:00 -3:30 AM 
 
 
 
 
 
3:30-4:00 PM 
 
 
 
 
 
 
3:30-4:00 AM 
 
 
 
 
 
4:00-4:30 PM 
 
 
 
 
 
 
4:00-4:30 AM 
 
 
 
 
 
4:30-5:00 PM 
 
 
 
 
 
 
4:30-5:00 AM 
 
 
 
 
 
5:00-5:30 PM 
 
 
 
 
 
 
5:00-5:30 AM  
 
 
 
 
 
5:30-6:00 PM  
 
 
 
 
 
 
5:30-6:00 AM  
 
 
 
 
 
© The University of South Florida, 2000. All rights reserved. Hauser et al. J Clin Neurophar 2000; 23:75-81. 
PARKINSON’S DISEASE DIARY 
 
Instructions: For each half-hour time period place one X mark to indicate your predominant status during most of that half-hour period. 
ON = Time when medication is providing benefit with regard to mobility, slowness, and stiffness. 
OFF = Time when medication has worn off and is no longer providing benefit with regard to mobility, slowness, and stiffness 
Dyskinesia = Involuntary twisting, turning movements. These movements are an effect of medication and occur during ON time. 
Non-troublesome dyskinesia does not interfere with function or cause meaningful discomfort. 
Troublesome dyskinesia interferes with function or causes meaningful discomfort. 
Tremor is shaking back and forth and is not considered dyskinesia. 


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15.14 PD Home Diary Training, Concordance, Validation 
Parkinson’s Diary Completion Basics: 
 Patient records motor state for half-hour intervals over a 24-hour period 
 What counts is the predominant state during a given 30-minute interval 
 Patients rate their ON and OFF status every 30 minutes while awake and immediately 
record their rating 
 On waking in the morning, patients will record the 30-minute intervals that they were 
asleep 
 Diary Completion is performed during the Screening Period and on the 3 consecutive 
days directly preceding scheduled visits 
 Screening/Practice Diary (Weeks −6 to −1) 
 before Baseline Visit (Week −1) 
 before Week 12 Visit 
 before Week 24 Visit 
 before Week 52 Visit 
 Recording time starts at 6 AM and ends 72 hours later at 6 AM. 
 
 
 
 
 
 
 
 
 
 
 
For each half-hour time period place one check mark  
to indicate your predominant status during most of that period. 
  
 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
Asleep 
 
 
 
OFF 
 
 
 
ON 
without 
dyskinesias 
 
ON with 
non-trouble
some 
dyskinesia 
ON with 
troublesome 
dyskinesias 
 
  
 
 
 
 
 
 
 
 
 
 
06:00 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
06:30 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
07:00 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
07:30 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
08:00 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
08:30 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
09:00 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record predominant 
status from 07:00-7:30 
Record predominant 
status from 08:30-9:00 


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Parkinson’s Diary Patient Training: 
During the Screening Period, patients and Sponsor accepted trainers will view the Hauser PD 
diary training video and instructions on completion of the diary will be clarified. The patient and 
trainer/rater will then concurrently complete separate training diaries during at least 5 half-hour 
intervals (minimum 2.5 hours). The patient should experience both ON and OFF during this 
time, and the diary concordance session may be extended to allow the patient to experience OFF. 
If the patient is OFF at the beginning of the diary concordance session, they may be administered 
their next dose of levodopa-containing medication in order to experience ON. 
Note: 
 Definitions of ON and OFF will be reviewed with the patient during the training session 
in accordance with the provided definitions.  
 Predominant state at the end of every 30-minute interval is reported as: 
 Off 
 On without dyskinesias 
 On with non-troublesome dyskinesias 
 On with troublesome dyskinesias (only the Patient can define what troublesome 
means to them) 
 Asleep (Note: This state will not occur during training. Instruction to record the 
asleep time when they awake in the morning must be provided verbally to the 
patient during this session) 
 Patient cannot change the definitions for ON and OFF. 
Trainer/Rater and Patient Diary Concordance Assessment: 
 The diary trainer/rater and the patient view the Hauser PD diary training video and 
discuss how the patient would define the triggers for their own ON and OFF state. 
 When the patient appears to understand instructions for diary completion, the minimum 
2.5 hour concordance session begins. 
 Trainer/rater completes a diary by observing the patient each 30-minute period 
and rates the patient as OFF or “ON with dyskinesia” or “ON without dyskinesia” 
using the definitions of ON and OFF. 
 Patient completes a diary each 30-minute period in the presence of the 
trainer/rater and at the same time the trainer/rater records their observation. The 
patient rates OFF or “ON without dyskinesia”, “ON with non-troublesome 
dyskinesia”, or “ON with troublesome dyskinesia” using the definitions of ON 
and OFF. 
 Distinction between non-troublesome or troublesome dyskinesias is the decision of the 
patient and not to be rated by the trainer/rater. 


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 Concordance (√) has to be at least 80%, e.g., at least 4 of 5 half-hour intervals rated in the 
same way by the diary trainer/rater and the patient during a minimum period of 2.5 hours 
including at least 1 OFF interval. For an ON rating to be considered concordant, there 
must be agreement between the patient and the trainer/rater on the presence (or absence) 
of dyskinesia. The trainer/rater will only rate the presence or absence of dyskinesia, 
whereas the patient will be asked to record dyskinesia using the categories “without 
dyskinesia”, “with non-troublesome dyskinesia”, or “with troublesome dyskinesia”. 
 Review valid and invalid entries with the patient. 
 If sufficient concordance is not reached during the first diary concordance session, the 
trainer/rater will schedule a second PD diary training and concordance session, unless the 
patient refuses further study participation. 
Trainer/Rater rates  
Patient rates  
Concordance reached 
OFF 
OFF 
Yes 
ON without dyskinesias 
ON without dyskinesias  
Yes 
On with dyskinesias 
On with non-troublesome 
dyskinesias 
 
OR 
 
On with troublesome dyskinesias 
Yes (only patient can determine if 
dyskinesias are troublesome) 
ON with dyskinesia 
OFF 
No (confusion with OFF vs. 
dyskinetic state) 
OFF 
On with dyskinesias  
No (confusion with OFF vs. 
dyskinetic state) 
OFF 
On with troublesome dyskinesias  
No (confusion with OFF vs. 
dyskinetic state) 
ON without dyskinesia 
On with troublesome dyskinesia 
OR 
On with non-troublesome 
dyskinesia  
No (patient may be rating 
dyskinesia not seen by trainer) 
 


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AFTER CONCORDANCE IS REACHED: 
 Provide the patient with a copy of their screening training diary (trainer/rater keeps both 
originals at site). 
 Provide the patient with a practice diary which they are required to complete on 
3 prespecified days (i.e., 3 consecutive 24-hour periods agreed to by the patient and the 
trainer) and return to the trainer/rater for review.  
 If the patient is not confirmed to be eligible, inform the patient they are not considered 
eligible and cancel Baseline Visit. 
 If preliminary eligibility of the patient is confirmed by the Investigator, send a Baseline 
diary to the patient and schedule the Baseline Visit. 
 Instruct the patient to complete the Baseline diary on the 3 prespecified days 
(i.e., 3 consecutive 24-hour periods) directly preceding the Baseline Visit. 
 Telephone the patient prior to the scheduled Baseline diary completion. The patient will 
be reminded by the trainer/rater to apply the ON and OFF definitions discussed during 
PD diary completion. Any questions from the patient regarding PD diary completion will 
be addressed. 
 


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OVERVIEW OF INVALID ENTRIES 
 Invalid entries are missing or double entries. 
 No more than 4 invalid entries for each 24 h period. 
 Patient with more than 4 invalid entries at Baseline may be retrained within the 6-week 
screening window. 
Correct  
Wrong  
 “X” marks the predominant state for each 
30-minute interval, therefore total time in a 
given state is X times 30 minutes. 
 “X” marks start or end time of a given state. 
Each “X” is entered immediately at the end of 
each given 30-minute interval while awake. 
When asleep, an “X” in the respective “asleep” 
box is entered immediately after waking up. If 
patient awakens at night they should record 
status for each 30-minute interval awake during 
the night. 
 “Awake” is interpreted as “daytime” and 
periods with “on” or “off” occurring during the 
night are not marked. If they awaken in the 
night, the patient forgets to mark their status. 
Recording time starts at 6 AM and ends at 
6 AM after the 3-day period, i.e., ends at 6 AM 
on the day of scheduled visits. 
Recording time during Days -3 and -2, thus 
ending on the day before scheduled visits. 
Any 30-minute interval is to be rated and counts 
for calculation, whether during the day or 
night. 
Early morning “off” time is not included in 
calculation of total daily “off” time. 
 
Please Refer to the Parkinson’s Diary Training Video for Examples and Further 
Instructions for Valid and Invalid Entries. 
 


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HAUSER PD HOME DIARY VALIDATION AND CALCULATIONS 
In the example below, the patient has indicated that he/she is OFF for most of the time in 5 of the 
30-minute intervals or 2.5 hours (5 x 0.5 hours = 2.5 hours, and not 2 hours from 7:00 to 9:00). 
Each X therefore represents the predominant status for that 30-minute time interval.  
Time 
Asleep 
OFF 
ON without 
dyskinesia 
ON with 
non-troublesome 
dyskinesia 
ON with 
troublesome 
dyskinesia 
7:00-7:30 AM 
 
X 
 
 
 
7:30-8:00 AM 
 
X 
 
 
 
8:00-8:30 AM 
 
X 
 
 
 
8:30-9:00 AM 
 
X 
 
 
 
9:00-9:30 AM 
 
X 
 
 
 
In the diary example on first 24-hour patient diary, the total OFF time is 5 hours and in the 
second 24-hour patient diary, the total OFF time is 7 hours. 
 


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First 24 hour period: (10 x 0.5 hours) = 5 hours OFF time 
 
Second 24 hour period: (14 x 0.5 hours) = 7 hours OFF time 
time 
asleep 
OFF 
ON 
without 
dyskinesia 
ON with 
non-troublesome 
dyskinesia 
ON with troublesome 
dyskinesia 
 
time 
asleep 
OFF 
ON 
without 
dyskinesia 
ON with 
non-troublesome 
dyskinesia 
ON with troublesome 
dyskinesia 
6:00-6:30 AM 
X 
 
 
 
 
 
6:00-6:30 AM 
X 
 
 
 
 
6:30-7:00 AM 
X 
 
 
 
 
 
6:30-7:00 AM 
X 
 
 
 
 
7:00-7:30 AM 
X 
 
 
 
 
 
7:00-7:30 AM 
X 
 
 
 
 
7:30-8:00 AM 
X 
 
 
 
 
 
7:30-8:00 AM 
X 
 
 
 
 
8:00-8:30 AM 
X 
 
 
 
 
 
8:00-8:30 AM 
X 
 
 
 
 
8:30-9:00 AM 
 
X 
 
 
 
 
8:30-9:00 AM 
 
X 
 
 
 
9:00-9:30 AM 
 
X 
 
 
 
 
9:00-9:30 AM 
 
X 
 
 
 
9:30-10:00 AM 
 
X 
 
 
 
 
9:30-10:00 AM 
 
X 
 
 
 
10:00-10:30 AM 
 
X 
 
 
 
 
10:00-10:30 AM 
 
X 
 
 
 
10:30-11:00 AM 
 
 
 
X 
 
 
10:30-11:00 AM 
 
 
 
X 
 
11:00-11:30 AM 
 
 
 
X 
 
 
11:00-11:30 AM 
 
X 
 
 
 
11:30-12:00 PM 
 
 
 
 
X 
 
11:30-12:00 PM 
 
 
 
 
X 
12:00-12:30 PM 
 
 
 
 
X 
 
12:00-12:30 PM 
 
 
 
 
X 
12:30-1:00 PM 
 
 
X 
 
 
 
12:30-1:00 PM 
 
X 
 
 
 
1:00-1:30 PM  
 
 
X 
 
 
 
1:00-1:30 PM  
 
 
X 
 
 
1:30-2:00 PM  
 
 
X 
 
 
 
1:30-2:00 PM  
 
 
X 
 
 
2:00-2:30 PM  
 
 
X 
 
 
 
2:00-2:30 PM  
 
 
X 
 
 
2:30-3:00 PM  
 
 
X 
 
 
 
2:30-3:00 PM  
 
 
X 
 
 
3:00 -3:30 PM 
 
 
X 
 
 
 
3:00 -3:30 PM 
 
 
X 
 
 
3:30-4:00 PM 
 
 
X 
 
 
 
3:30-4:00 PM 
 
 
X 
 
 
4:00-4:30 PM 
 
 
X 
 
 
 
4:00-4:30 PM 
 
X 
 
 
 
4:30-5:00 PM 
 
 
X 
 
 
 
4:30-5:00 PM 
 
 
X 
 
 
5:00-5:30 PM 
 
 
X 
 
 
 
5:00-5:30 PM 
 
 
X 
 
 
5:30-6:00 PM  
 
 
X 
 
 
 
5:30-6:00 PM  
 
 
X 
 
 
6:00-6:30 PM 
 
 
X 
 
 
 
6:00-6:30 PM 
 
 
X 
 
 
6:30-7:00 PM 
 
X 
 
 
 
 
6:30-7:00 PM 
 
X 
 
 
 
7:00-7:30 PM 
 
X 
 
 
 
 
7:00-7:30 PM 
 
X 
 
 
 
7:30-8:00 PM 
 
X 
 
 
 
 
7:30-8:00 PM 
 
X 
 
 
 
8:00-8:30 PM 
 
X 
 
 
 
 
8:00-8:30 PM 
 
X 
 
 
 
8:30-9:00 PM 
 
X 
 
 
 
 
8:30-9:00 PM 
 
X 
 
 
 
9:00-9:30 PM 
 
X 
 
 
 
 
9:00-9:30 PM 
 
X 
 
 
 
9:30-10:00 PM 
 
 
X 
 
 
 
9:30-10:00 PM 
 
X 
 
 
 
10:00-10:30 PM 
 
 
X 
 
 
 
10:00-10:30 PM 
 
 
X 
 
 
10:30-11:00 PM  
 
 
X 
 
 
 
10:30-11:00 PM  
 
 
X 
 
 
11:00-11:30 PM  
X 
 
 
 
 
 
11:00-11:30 PM  
X 
 
 
 
 
11:30-12:00 AM  
X 
 
 
 
 
 
11:30-12:00 AM  
X 
 
 
 
 
12:00-12:30 AM  
X 
 
 
 
 
 
12:00-12:30 AM  
X 
 
 
 
 
12:30-1:00 AM  
X 
 
 
 
 
 
12:30-1:00 AM  
X 
 
 
 
 
1:00-1:30 AM  
X 
 
 
 
 
 
1:00-1:30 AM 
X 
 
 
 
 
1:30-2:00 AM  
X 
 
 
 
 
 
1:30-2:00 AM 
X 
 
 
 
 
2:00-2:30 AM  
X 
 
 
 
 
 
2:00-2:30 AM 
X 
 
 
 
 
2:30-3:00 AM  
X 
 
 
 
 
 
2:30-3:00 AM 
X 
 
 
 
 
3:00-3:30 AM 
X 
 
 
 
 
 
3:00-3:30 AM 
X 
 
 
 
 
3:30-4:00 AM 
X 
 
 
 
 
 
3:30-4:00 AM 
X 
 
 
 
 
4:00-4:30 AM 
X 
 
 
 
 
 
4:00-4:30 AM 
X 
 
 
 
 
4:30-5:00 AM 
X 
 
 
 
 
 
4:30-5:00 AM 
X 
 
 
 
 
5:00-5:30 AM  
X 
 
 
 
 
 
5:00-5:30 AM 
X 
 
 
 
 
5:30-6:00 AM  
X 
 
 
 
 
 
5:30-6:00 AM 
X 
 
 
 
 


Biotie Therapies 
09 October 2017 
Clinical Study Protocol 
Tozadenant 
TOZ-CL06 
Confidential 
Version 3.0 
Page 143 of 143 
15.15 Healthcare Resource Utilization Questionnaire 
Healthcare Resource Utilization Questionnaire 
INPATIENT ADMISSIONS 
Instructions: Please record in the table below all inpatient admissions since the subject’s last scheduled clinic visit. 
Do not include inpatient admissions for the facilitation of assessments specific to this protocol not associated 
with any deterioration in condition. 
• 
If the subject had no inpatient admissions since the last scheduled clinic visit, please check the appropriate box 
below. 
• 
If the patient was hospitalized since the last scheduled clinic visit, please record the admission and discharge 
dates of each hospitalization. Also indicate if the type of each admission was Parkinson’s disease (PD)-related 
or Non-PD related along with the reason for each admission, e.g. pneumonia, which should be consistent with 
source documentation and eCRF entries. 
  □  No inpatient admissions since the subject’s last scheduled clinic visit 
 
Admission Date 
(dd / mmm / yyyy) 
Discharge Date 
(dd / mmm / yyyy) 
Type of Admission 
Reason for Admission 
1. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
□ PD-related 
□ Non-PD related 
 
2. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
□ PD-related 
□ Non-PD related 
 
3. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
□ PD-related 
□ Non-PD related 
 
 
EMERGENCY ROOM (ER) VISITS 
Instructions:  Please indicate how many times the subject visited an Emergency Room since the last scheduled 
clinic visit for PD-related and non-PD related reasons. 
• 
If the subject had no emergency room visits since the last scheduled clinic visit, please check the appropriate 
box below. 
• 
If the subject visited the emergency room since the last scheduled clinic visit, please record the date of each 
visit. Also indicate if the visit was PD-related or Non-PD related along with the reason for each visit, 
e.g. pneumonia, which should be consistent with source documentation and eCRF entries. 
• 
If an Emergency Room visit resulted in an inpatient admission, please record that event above as an inpatient 
admission only and do not record here.  
  □  No emergency room visits since the subject’s last scheduled clinic visit 
 
ER Visit Date 
(dd / mmm / yyyy) 
Type of ER Visit 
Reason for ER Visit 
1. 
_ _ / _ _ _ / _ _ _ _ 
□ PD-related 
□ Non-PD related 
 
2. 
_ _ / _ _ _ / _ _ _ _ 
□ PD-related 
□ Non-PD related 
 
3. 
_ _ / _ _ _ / _ _ _ _ 
□ PD-related 
□ Non-PD related 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
TOZ-CL06 
 
A Multicenter, Open-Label Study To Evaluate The Safety And Tolerability Of 
Tozadenant As Adjunctive Therapy In Levodopa-Treated Patients With 
Parkinson’s Disease Experiencing End Of Dose “Wearing-Off” 
 
 
 
 
 
 
 
 
Development Phase: 3 
 
Preparation Date: 13-FEB-2017 
Approval Date:  13-FEB-2018 
 Version number: 1.0 
Analysis Stage: Final Analysis 


 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
Version 1.0 
Page 3 of 30 
 
 
 
 
TABLE OF CONTENTS 
SIGNATURES .................................................................................................................................2 
1. 
INTRODUCTION ........................................................................................................6 
2. 
STUDY OBJECTIVES ................................................................................................6 
2.1. 
Primary Objectives .......................................................................................................6 
2.2. 
Secondary Objectives ...................................................................................................6 
3. 
STUDY DESIGN .........................................................................................................6 
3.1. 
Analysis sets ...............................................................................................................11 
3.1.1. 
Full Analysis Set (FAS) ..............................................................................................11 
3.1.2. 
Safety Set (SS) ............................................................................................................11 
3.1.3. 
modified Full Analysis Set (mFAS) ...........................................................................11 
3.1.4. 
Expanded PK Population (xPK) .................................................................................11 
3.2. 
Sample Size Considerations .......................................................................................11 
3.3. 
Randomization ............................................................................................................11 
4. 
STUDY VARIABLES AND COVARIATES ............................................................11 
4.1. 
Safety Variables ..........................................................................................................11 
4.2. 
Other variables ............................................................................................................12 
4.3. 
Pharmacokinetic Variables .........................................................................................12 
4.4. 
Predetermined Covariates and Prognostic Factors .....................................................12 
5. 
DEFINITIONS ...........................................................................................................12 
5.1. 
Treatment Group Labels .............................................................................................12 
5.2. 
Age ..............................................................................................................................13 
5.3. 
Valid Diary .................................................................................................................13 
5.4. 
Baseline for Diary Data ..............................................................................................13 
5.5. 
Baseline Complete UPDRS Assessment ....................................................................13 
5.6. 
Baseline for Blood Pressure and Pulse Rate and ECG ...............................................13 
5.7. 
Baseline for Variables excluding Diary Data, UPDRS, Blood Pressure, and 
Pulse Rate ...................................................................................................................13 
5.8. 
Change from Baseline.................................................................................................14 
5.9. 
Concomitant and Prior Medication other than Anti-PD Medications ........................14 
5.10. 
Concomitant Anti-PD Medications ............................................................................14 
5.10.1. 
Baseline Total Daily Levodopa ..................................................................................14 
5.10.2. 
Baseline Total Daily Levodopa Equivalents ..............................................................15 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
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5.11. 
Missing Adverse Event Relationship or Severity .......................................................15 
5.12. 
Treatment-Emergent Adverse Events (TEAEs) .........................................................15 
6. 
INTERIM ANALYSES ..............................................................................................15 
7. 
DATA REVIEW .........................................................................................................15 
7.1. 
Data Handling and Transfer ........................................................................................15 
8. 
UNBLINDING ...........................................................................................................16 
9. 
STATISTICAL METHODS .......................................................................................16 
9.1. 
Subject Disposition .....................................................................................................16 
9.2. 
Protocol Deviations and Violations ............................................................................17 
9.3. 
Treatments ..................................................................................................................17 
9.3.1. 
Extent of Study Drug Exposure ..................................................................................17 
9.3.2. 
Concomitant and Prior Medications other than Anti-PD Medications .......................18 
9.3.3. 
Concomitant and Prior Anti-PD Medications .............................................................18 
9.3.3.1. 
Total Levodopa Dose ..................................................................................................18 
9.3.3.2. 
Total Levodopa Equivalents .......................................................................................18 
9.4. 
Demographic and Baseline Characteristics ................................................................18 
9.5. 
Medical History Events ..............................................................................................19 
9.6. 
Exploratory Analyses ..................................................................................................19 
9.6.1. 
Exploratory Variables .................................................................................................19 
9.7. 
Pharmacokinetic Variables .........................................................................................20 
9.7.1. 
Tozadenant Plasma Concentrations at week 2 ............................................................20 
9.7.2. 
Tozadenant expanded PK ...........................................................................................20 
9.7.2.1. 
Tozadenant expanded PK Plasma concentration ........................................................20 
9.7.2.2. 
Tozadenant expanded PK Pharmacokinetic parameters .............................................20 
9.8. 
Safety Analyses...........................................................................................................21 
9.8.1. 
Adverse Events ...........................................................................................................21 
9.8.2. 
Deaths and Serious Adverse Events ...........................................................................22 
9.8.3. 
Laboratory Data ..........................................................................................................22 
9.8.4. 
Systolic and Diastolic Blood Pressure and Pulse Rate ...............................................22 
9.8.5. 
Body Weight ...............................................................................................................23 
9.8.6. 
Columbia-Suicide Severity Rating Scale ....................................................................24 
9.8.7. 
Modified Minnesota Impulsive Disorders Interview ..................................................24 
9.8.8. 
Epworth Sleepiness Scale and Assessment of Sudden Episodes of Sleep .................24 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
Version 1.0 
Page 5 of 30 
 
 
9.8.9. 
ECG ............................................................................................................................24 
9.8.10. 
Physical and Neurological Examinations ...................................................................25 
10. 
VALIDATION ...........................................................................................................25 
11. 
PROGRAMMING SPECIFICATIONS .....................................................................25 
11.1. 
Format of Appendix Tables/Figures/Listings .............................................................25 
12. 
REFERENCES ...........................................................................................................28 
APPENDIX 1 GLOSSARY OF ABBREVIATIONS .................................................................29 
APPENDIX 2 
LEVODOPA EQUIVALENT ALGORITHM ...................................................30 
 
 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Events/Evaluations....................................................................................8 


Confidential 
Version 1.0 
Page 6 of 30 
Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
 
 
 
1. 
INTRODUCTION 
TOZ-CL06 is a 52-week open-label study in levodopa-treated patients with PD experiencing 
end-of-dose “wearing-off”. This statistical analysis plan (SAP) describes the statistical methods 
to be used during the reporting and analyses of data collected in TOZ-CL06. 
This SAP should be read in conjunction with the study protocol. This plan is developed using the 
protocol version 2.0 dated 03-FEB-2017. 
 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
To evaluate the safety and tolerability of tozadenant in levodopa-treated PD patients 
experiencing motor fluctuations, based on assessment of treatment-emergent adverse events 
(TEAEs), vital signs, electrocardiograms (ECGs), and clinical laboratory tests. 
 
2.2. 
Secondary Objectives 
To evaluate the effects of tozadenant on the occurrence of daytime drowsiness, impulsive 
behavior, and suicidality. 
 
3. 
STUDY DESIGN 
This is a Phase 3, international, multicenter, open-label study in levodopa-treated patients with 
PD experiencing end-of-dose “wearing-off”. This study includes a Screening Period of up to 6 
weeks that starts with a Screening Visit, followed by a 52-week Open-Label Treatment Period 
and a Safety Follow-Up Visit 4 weeks after completion of investigational treatment. After 
providing written informed consent, patients will undergo screening evaluations. Patients must 
meet all inclusion criteria and none of the exclusion criteria and they must successfully complete 
the diary training and achieve 80% overall diary concordance with the PD diary trainer/rater 
including at least 1 OFF interval to be considered for enrollment. If preliminary eligibility is 
confirmed by the investigator, patients will then be scheduled for a Baseline Visit and will be 
required to return a valid set of Baseline diaries. Final eligibility will be determined at the 
Baseline Visit. 
Patients will return to the study site for evaluation at scheduled visits at Weeks 2, 6, 12, 24, 36, 
and 52. Patients will be contacted by telephone before the start of each 3-day PD diary 
completion period to be reminded to complete the diary. A final Safety Follow-Up Visit (Week 
56) will occur 28 ± 3 days after the patient’s last open-label dose of tozadenant. Upon starting 
study treatment, patients will receive open-label tozadenant at a dose of 120 mg BID. 
Adjustments to the open-label tozadenant dose are allowed to be made by the investigator 
starting at Week 2 and at any of the subsequent visits. Doses of 60 or 120 mg BID are permitted; 
the investigator may adjust a patient’s dose to either level as clinically indicated. The Interactive 
Response System (IXRS) will be used to assign, track and manage the tozadenant inventory at 
each study site. 


Confidential 
Version 1.0 
Page 7 of 30 
Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
 
 
The Schedule of Events/Evaluations for is shown below in Table 1. 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
Version 1.0 
Page 8 of 30 
 
 
Table 1: 
Schedule of Events/Evaluations 
 
Study Period Screening a 
Baseline 
Predose 
Open-Label Treatment 
(52 weeks) 
Safety 
Follow-Up 
Early 
Termination w Unscheduled 
Study Week b 
−6 to −1 
BL 
2 
(± 3 d) 
6 
(± 3 d) 
12 
(± 3 d) 
24 
(± 7 d) 
36 
(± 7 d) 
52 
(± 14 d) 
[16 weeks] 
56 
(28 ± 3 d after 
last dose of IMP) 
Assessments 
Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Written Informed Consent 
X 
Demographics and Medical History, including 
neurological and PD history 
X 
Recording of concomitant and 
anti-PD medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP c, pulse c 
X d 
X d 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
12-lead ECG f 
X 
X g 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Weight (include height at Screening) 
X 
X 
X 
X 
X 
X 
X e 
Physical and neurological examination 
X 
X 
X 
X 
X 
X 
X 
X e 
PD diary training and diary concordance session 
X 
Modified Hoehn and Yahr staging (observed ON; 
OFF estimated per history) h 
X 
UPDRS Parts I, II, III and IV i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MMSE-II (in ON state) 
X 
mMIDI j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
ESS h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD diary collection (phone call prior to start of 3 
consecutive 24 hour diary completion periods) 
X k 
X k 
X l 
X l 
X l 
X m 
PD diary review 
X 
X 
X 
X 
X m 
X m 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
CGI-C h 
X 
X 
X 
X 
X 
X 
X 
PGI-C h 
X 
X 
X 
X 
X 
X 
X 
PDQ-39 h 
X 
X 
X 
X 
Sudden onset of sleep 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fall questionnaire 
X 
X 
X 
X 
Healthcare Resource Utilization 
X 
X 
X 
X 
X 
X 
X 
Nonmotor Symptom Questionnaire 
X 
X 
X 
X 
EQ-5D-5L h 
X 
X 
X 
X 
Recording of AEs 
X n 
X n 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
Version 1.0 
Page 9 of 30 
 
 
 
Study Period Screening a 
Baseline 
Predose 
Open-Label Treatment 
(52 weeks) 
Safety 
Follow-Up 
Early 
Termination w Unscheduled 
Study Week b 
−6 to −1 
BL 
2 
(± 3 d) 
6 
(± 3 d) 
12 
(± 3 d) 
24 
(± 7 d) 
36 
(± 7 d) 
52 
(± 14 d) 
[16 weeks] 
56 
(28 ± 3 d after 
last dose of IMP) 
Assessments 
Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Laboratory tests: hematology o, chemistry p (including 
thyroid function q) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
FSH test, females who are postmenopausal for < 2 
years 
X 
Method of contraception r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Urine pregnancy test, females of 
childbearing potential s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Urinalysis t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Review of inclusion/exclusion criteria 
X 
Final verification of eligibility 
X 
Tozadenant blood sampling 
X u 
IMP dispensing and/or return v 
X 
X 
X 
X 
X 
X 
X 
X 
X e 
eCRF completion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE, adverse event; BP, blood pressure; CGI-C, Clinical Global Impression of Change; C-SSRS, Columbia-Suicide Severity Rating Scale; d, day; ECG, electrocardiogram; eCRF, 
electronic case report form; ESS, Epworth Sleepiness Scale; ET, Early Termination; FSH, follicle stimulating hormone; IMP, investigational medicinal product; mMIDI, 
Modified Minnesota Impulse Disorders Interview; MMSE-II, Mini-Mental State Exam – Second Edition (MMSE-II); PD, Parkinson’s disease; PDQ-39, Parkinson’s Disease 
Quality of Life Questionnaire; PGI-C, Patient’s Global Impression of Change; UPDRS, Unified Parkinson’s Disease Rating Scale; V, Visit. 
Footnotes 
a Screening period may not exceed 6 weeks. 
b Visit windows for scheduled visits after Baseline (V2) are in relation to the date of the Baseline Visit (V2). 
c Obtain and record BP and pulse measurements after at least 5 minutes supine rest and again after standing for approximately 1 minute and 3 minutes. 
d At Screening and Baseline (before dosing), obtain and record serial BP and pulse measurements after at least 5 minutes supine rest and again after standing for approximately 
1 and 3 minutes, on 3 occasions approximately 10 minutes apart. 
e Optional activities (e.g., additional assessments for evaluation of AEs) that may be performed at the investigator’s discretion. 
f A resting supine 12-lead ECG will be collected after the patient has been in a supine position for a minimum of 5 minutes. Ensure the ECG is collected when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
g At Baseline, obtain three 12-lead ECGs (i.e., 3 serial readings, performed several minutes apart). Ensure the ECGs are collected when the patient is not experiencing dyskinesia 
that would interfere with an adequate recording. 
h To be collected during patient’s ON state. 
i UPDRS to be measured in ON state. UPDRS Part III should be measured approximately 1 to 3 hours after patients have taken a scheduled dose of levodopa (preferably their 
morning dose of levodopa). Patients will be instructed to have already taken their normally scheduled dose of levodopa and their IMP before arriving at the study site in order to 
have their UPDRS Part III evaluated in the ON state. UPDRS in the ON state will be measured at a time representative of the ON state in that patient, not in the patient’s “best” 
ON. 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
Version 1.0 
Page 10 of 30 
 
 
Table 1: 
Schedule of Events/Evaluations (continued) 
j At Screening, send patient for structured clinical interview if one or more positive mMIDI modules. If the structured clinical interview confirms that the subject does not have an 
ICD, he/she will not be considered ineligible on that basis. After Baseline, if patient has one or more positive modules on the mMIDI, their continued participation in the study 
should be discussed with the Medical Monitor. 
k The 3-day practice diary during the Screening Period and the 3-day Baseline diary must both be valid in order to randomize a patient. The trainer/rater will call the patient before 
the scheduled start of the diary completion periods to remind him or her to keep the PD diary and to review completion instructions. The patient will also be reminded to send the 
completed practice diary to the trainer/rater and to bring their Baseline diary to the Baseline Visit. If the practice or Baseline diary is invalid, the patient may be retrained and 
complete another practice or Baseline diary within the 6-week window of the Screening Period, if the patient is otherwise eligible for the study. 
l PD diary collected over the 3 consecutive 24-hour periods before the day of the scheduled study visits on Week 2, 6, 12, 18, 24, 36, and 52. The PD diary trainer/rater will call 
the patient before the scheduled start of the 3-day PD diary completion period (at the latest, on the last working day before the scheduled start of the PD diary completion) and 
review completion instructions. The patient will also be reminded to bring their PD diary to the visit. The trainer/rater will instruct the patient if the PD diary contains missing 
and/or invalid entries to reinforce instructions for appropriate completion. 
m Done only if the ET date coincides with the scheduled diary collection return date. 
n Pretreatment AEs. 
o Hematology tests: Hemoglobin concentration, hematocrit, red blood cell count, total and differential white blood cell, thrombocyte (platelet) count. 
p Blood chemistry (including liver function) tests: Aspartate amino transferase (AST), alanine amino transferase, (ALT), gamma-glutamyl transpeptidase (GGT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin (conjugated and unconjugated), albumin, creatinine, urea/BUN, bicarbonate, uric acid, total protein, sodium, 
chloride, potassium, calcium, phosphate, glucose, cholesterol, creatine phosphokinase (CK). 
q TSH, free T3, and free T4. 
r For applicable patients: At Screening, document method of contraception used by patient. At subsequent visits, verify continuation of (or any change to) contraceptive method. 
s For females of childbearing potential: urine pregnancy test. 
t Urinalysis: Specific gravity, pH, ketones, blood, protein, glucose. If urine dipstick is positive for leukocytes, protein, or erythrocytes, a microscopic evaluation and culture will 
be performed. 
u A PK blood sample should be collected at the most convenient time during the Week 2 visit. Record the patient-reported date and approximate time when the patient took the 
most recent dose of IMP. Record the date and time of the PK sample collection. See Section 8.0 of the protocol. (Note: sites participating in Expanded PK Sampling should refer 
to Appendix 15.9). 
v Patients will be instructed to take the assigned dose of open-label tozadenant by mouth BID, in the morning and in the evening preferably at the same time each day. The evening 
dose should be approximately 12 hours after the morning dose. Patients will be instructed to take their morning and evening doses at least 1 hour before or 2 hours after a meal 
and to refrain from eating for at least 1 hour after dosing. 
w If patient has discontinued IMP, perform Early Termination Visit as soon as possible after the last dose of IMP. If patient took the last dose of IMP 28 or more days prior to the 
Early Termination Visit, a Safety Follow-Up Visit (Section 6.2.16) is not required. 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
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Page 11 of 30 
 
 
 
 
 
3.1. 
Analysis sets 
3.1.1. 
Full Analysis Set (FAS) 
The FAS will consist of all patients who are enrolled in the open-label phase 3 study. 
 
3.1.2. 
Safety Set (SS) 
The SS will consist of all enrolled patients who received at least one dose of IMP. 
 
3.1.3. 
modified Full Analysis Set (mFAS) 
The mFAS will consist of all enrolled patients who received at least one dose of IMP and who 
had at least one post-baseline visit. 
 
3.1.4. 
Expanded PK Population (xPK) 
The xPK Population will consist of all subjects with expanded PK and for whom there are 
adequate samples collected to provide analyzable PK data. 
 
3.2. 
Sample Size Considerations 
No formal sample size determination was performed for TOZ-CL06. With an anticipated 30% 
screen failure rate, approximately 645 patients will be screened to enroll 450 patients. 
 
3.3. 
Randomization 
Not applicable since this is an open-label study where all patients start with 120mg. 
 
4. 
STUDY VARIABLES AND COVARIATES 
4.1. 
Safety Variables 
Safety variables include the following: 
• Treatment-emergent adverse events (TEAE). 
• Physical and neurological examination. 
• Supine and standing pulse and blood pressure. 
• Standard 12-lead electrocardiogram (ECG): RR, PR, QRS, QT and QTcF. 
• Laboratory parameters: hematology, chemistry, thyroid function (thyroid stimulating 
hormone [TSH], free T3, and free T4), and urinalysis. 
• Columbia-Suicide Severity Rating Scale (C-SSRS). 
• Daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) 
• Assessment of sudden episodes of sleep. 
• Modified Minnesota Impulsive Disorders Interview (mMIDI). 


Statistical Analysis Plan for Final Analysis v1.0 
Acorda Therapeutics, Inc. 
Date: 13 Feb 2018 
Study TOZ-CL06 
Confidential 
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4.2. 
Other variables 
Other variables include the following: 
• Unified Parkinson’s Disease Rating Scale (UPDRS) Part II (Activity of Daily Living 
(ADL) subscale) + Part III (motor subscale) total score. 
• UPDRS Part II (ADL subscale) score. 
• UPDRS Part III (motor subscale) score in the ON state. 
• UPDRS Part I total score. 
• UPDRS Part IV total score. 
• Dyskinesia as measured by questions 32, 33 and 34 of UPDRS Part IV. 
• Motor fluctuations as measured by question 39 of UPDRS Part IV. 
• Clinical Global Impression of Improvement (CGI-I). 
• Patient’s Global Impression of Improvement (PGI-I). 
• Parkinson’s Disease Quality of Life Questionnaire (PDQ-39; total score and 
individual domain scores). 
• Non-motor Symptom Questionnaire. 
• EuroQol 5D-5L Health Questionnaire (EQ-5D-5L). 
• Patient-completed diaries (number of hours per day spent as follows: OFF, ON time 
without troublesome dyskinesia, total ON time, ON time with troublesome dyskinesia 
and asleep time). 
• Healthcare Resource Utilization 
• Fall Questionnaire 
4.3. 
Pharmacokinetic Variables 
• Tozadenant PK concentrations at Week 2 and PK concentration and PK parameters 
cmax, tmax, and AUC0-last for expanded PK. 
4.4. 
Predetermined Covariates and Prognostic Factors 
Not applicable as exploratory analyses will be documented by descriptive statistics. 
 
5. 
DEFINITIONS 
5.1. 
Treatment Group Labels 
The following treatment group label will be used in the TFLs: 
• Tozadenant 


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5.2. 
Age 
The following SAS® code is used to calculate subject age (years): 
Age = floor((intck(‘month’, birth date, IC date) - (day(IC date) < day(birth date))) / 12), 
Where intck is a SAS® function counting integer days between birth date and informed consent 
date. 
 
5.3. 
Valid Diary 
A valid diary record will not have more than 4 invalid entries (double or missed entries) over one 
24-hour period. An invalid diary entry is defined as more than 1 entry recorded in a given half- 
hour interval, an unreadable entry, or the absence of an entry in a given half-hour interval. 
 
5.4. 
Baseline for Diary Data 
Baseline is defined as the average of the 3-day Baseline diary preceding the first dose. 
 
5.5. 
Baseline Complete UPDRS Assessment 
A valid UPDRS assessment is one in which UPDRS Part III has been completed in the ON state. 
The UPDRS assessment utilized as the baseline will be the later of the Screening or 
Baseline visit assessment that is valid. 
The selected assessment will be used to determine the Baseline UPDRS Parts I – IV subscores 
and the UPDRS I-IV total score. If a valid UPDRS is not available at Screening or Baseline visit, 
then the subject will be excluded from “change from baseline” UPDRS summary statistics. 
 
5.6. 
Baseline for Blood Pressure and Pulse Rate and ECG 
Baseline is defined as the average of the 3 pre-dose measurements for the respective supine or 
standing measurements that are taken following 5 minutes supine rest and following 3 minutes 
standing, respectively and approximately 10 minutes apart prior to the first dose of IMP. Should 
one of the 3 measurements be missing, the baseline will be the average of the remaining two pre- 
dose measurements and if two or more of the 3 measurements are missing, the average of the 
three measurements from the screening visit will be used as baseline. Should one of the 3 
measurements be missing, the baseline will be the average of the remaining two screening 
measurements and if two or more of the 3 measurements are missing, baseline will be missing. 
Baseline for ECG will be calculated similarly. 
 
5.7. 
Baseline for Variables excluding Diary Data, UPDRS, Blood 
Pressure, and Pulse Rate 
Baseline is defined as the last measurement prior to the first dose of IMP. If for any parameter 
the study Day 1 pre-dose value is not done or missing, then the last value obtained at a Screening 
visit is used as Baseline. 


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5.8. 
Change from Baseline 
Change from baseline will be the calculated as the data value measured post-baseline visits 
minus baseline. 
 
5.9. 
Concomitant and Prior Medication other than Anti-PD Medications 
Concomitant medications other than anti-PD medications are defined as any medications 
ongoing at the start of treatment or with a start date and time on or after the date of first dose of 
IMP. Prior medications are defined as a medication with a stop date prior to first dose of IMP. 
For the classification of medications as prior or concomitant, medications with missing or partial 
stop dates will be considered as follows: 
• If the stop date is completely missing, the medication will be regarded as 
concomitant. 
• If the day and month are missing but the year is given and the year is prior to the year 
of first dose, the medication will be classified as prior medication. Otherwise such 
medications will be considered as concomitant. 
• If the day is missing but the month and year are given and the month and year are 
prior to the day of first dose, the medication will be classified as prior medication. 
Otherwise such medications will be considered as concomitant. 
 
5.10. 
Concomitant Anti-PD Medications 
During the study, patients’ concomitant anti-PD medications may be adjusted as needed under 
the investigator’s supervision. 
Concomitant anti-PD medications are defined as any medications ongoing at the start of 
treatment or with a start date and time on or after the date of first dose of IMP. Prior anti-PD 
medications are defined as a medication with a stop date prior to first dose of IMP. 
For the classification of anti-PD medications as prior or concomitant, medications with missing 
or partial stop dates will be considered as follows: 
• If the stop date is completely missing, the medication will be regarded as 
concomitant. 
• If the day and month are missing but the year is given and the year is prior to the year 
of first dose, the medication will be classified as prior medication. Otherwise such 
medications will be considered as concomitant. 
• If the day is missing but the month and year are given and the month and year are 
prior to the day of first dose, the medication will be classified as prior medication. 
Otherwise such medications will be considered as concomitant. 
 
5.10.1. 
Baseline Total Daily Levodopa 
The total daily levodopa dose at baseline will be calculated as dose x # of tablets x frequency per 
day for levodopa medications taken at baseline. 


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5.10.2. 
Baseline Total Daily Levodopa Equivalents 
The Levodopa Equivalents (LED) of each concomitant anti-PD drug being taken at baseline will 
be calculated as the total daily dose of the medication multiplied by a conversion factor to obtain 
the LED for the medication. The total daily LED will be the sum of each LED medication taken 
at baseline. Conversion factors for each medication will be based on Tomlinson et al, 2010 (see 
Section 12). Algorithm based on the Tomlinson paper is included in Appendix 2. 
5.11. 
Missing Adverse Event Relationship or Severity 
AEs with missing relationship will be considered as having a relationship of possibly related to 
study drug. AEs with missing or unknown severity will be considered severe. A subject with 
missing relationship or severity for an AE will be footnoted as having missing data in the 
corresponding tables and listings for the AE with missing data. 
 
5.12. 
Treatment-Emergent Adverse Events (TEAEs) 
TEAEs are AEs which first occur or increase in severity or relationship to study drug after the 
first dose of IMP through the Safety Follow-up. Should the day of the AE be “unknown” and the 
AE in question occurs in the same month or a following month as the date of first dose, the AE 
will be considered treatment emergent. Should the month of the AE be “unknown” and the AE in 
question occurs in the same year or a following year as the date of first dose, the AE will be 
considered treatment emergent. Should the start date be missing then the AE will be considered 
treatment emergent. 
 
6. 
INTERIM ANALYSES 
There is no planned interim analysis for this study. 
 
7. 
DATA REVIEW 
7.1. 
Data Handling and Transfer 
Data are entered electronically into a clinical database built by Prometrica and exported as SAS® 
datasets. Data analyses including summary tables, figures, and data listings are produced using 
SAS®. 
Medical conditions and AEs are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18.0 or higher, to assign a system organ class (SOC) and preferred term (PT) 
to each AE. Prior and concomitant medications are coded to preferred drug names using the 
World Health Organization Drug Dictionary (WHODRUG) version 2015:03 or higher. 
Clinical laboratory results and normal ranges will be provided as SAS datasets from the central 
clinical laboratory vendor. Protocol deviations and violations (PDVs) will be identified by the 
Sponsor prior to database lock and will be presented as data listings. 


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8. 
UNBLINDING 
Not applicable since this is an open-label study. 
 
9. 
STATISTICAL METHODS 
The software used for all summary statistics and statistical analyses will be SAS® (SAS Institute, 
Inc.)1 Version 9.2 or later. 
Most continuous data will be summarized with the following descriptive statistics: number of 
observations, mean, SD, median, minimum, and maximum; interquartile ranges will be provided 
as appropriate. Categorical data will be summarized with frequencies and percentages. 
Missing data will not be imputed. 
Formal statistical tests will be not be conducted and thus no p-values will be reported. 
For presentation of data, the mean and median will be presented to 1 decimal place greater than 
the original data, SD will be to 2 decimal places greater than the original data, and the minimum 
and maximum will have the same number of decimal places as the original data. The format for 
range will be “Min, Max”. Standard deviation will be abbreviated as “SD”. 
Data that is collected in an early termination visit may be included in the calculation of summary 
statistics for the week the early termination visit falls into, as long as the visit falls within the 
time-frame of a scheduled visit as displayed in Table 1. For example, if a subject has early 
termination visit 3 days prior to a previously scheduled week 12 visit, the data collected will be 
included in the calculation of summary statistics for week 12. If the diary data is collected from 
the site at this visit, the diary data would also be included in the calculation of summary statistics 
for week 12. If data is included for a study week as in this example above, it would not be 
included as part of the ‘early termination column’s’ summary statistics, i.e., data would only be 
used and included once in a summary statistic calculation, i.e., used only in calculation of 
summary statistics for week 12 in this example. 
For certain variables (i.e., ESS, UPDRS III), subjects should complete these at the site during an 
“ON” state, per the protocol. The site should have only collected this data if the subject was in 
fact in the “ON” state. However, in cases where the site collected the data anyway (i.e., in “OFF” 
or “fluctuating”), we will treat all data that shows up in the database as if they followed the 
protocol, i.e., we will not check for the subject being in the “ON” state before including in 
summary statistics. 
 
9.1. 
Subject Disposition 
Subject disposition data will be summarized for all patients who entered into TOZ-CL06. A table 
will include: 
• Number of patients screened 
• Number of patients enrolled 
• Number (%) of patients who completed the study 
• Number (%) of patients in the FAS 


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• Number (%) of patients in the SS 
• Number (%) of patients in the mFAS 
• Number (%) of patients in the xPK 
• Number (%) of patients out of those who enrolled who early discontinued along with 
reasons for withdrawal 
• Number (%) of patients out of those who enrolled who terminated early because of 
program termination 
The percentages (%) will be calculated using ‘Number of patients enrolled’ in the denominator. 
A listing of all patients who enrolled along with data on their disposition will be provided. 
A table will be presented to summarize the number and percent of patients enrolled at each site 
by region, country and all patients. 
A table will be presented to summarize the number and percent of patients who attended each 
study visit. 
 
9.2. 
Protocol Deviations and Violations 
Protocol deviations and violations (PDVs) will be identified and categorized as major or minor 
by the Sponsor prior to database lock. 
If there is a significant number of major protocol deviations and violations, they will be 
summarized by deviation/violation category. Otherwise, all PDVs will be documented in a data 
listing only. 
 
9.3. 
Treatments 
9.3.1. 
Extent of Study Drug Exposure 
The number of days of exposure to study drug and average daily dose (mg/day) will be 
summarized by study visit in the SS. Average daily dose will be calculated as (number of tablets 
dispensed minus the number of tablets returned minus the number of tablets lost) divided by 
number of days from visit i-1 to visit i and multiplied by the mg of the tablets. The proportion of 
subjects who took 60mg, 120mg will be summarized by study visit in the SS. Subjects who took 
only 60mg doses from visit i-1 to visit i will be included in the numerator for the 60mg category 
for visit i; subjects who took only 120mg doses from visit i-1 to visit i will be included in the 
numerator for the 120mg category for visit i. Descriptive statistics for the total number of tablets 
dispensed, number of tablets returned and number of tablets lost will be displayed by study visit 
and overall. Compliance with study drug will be calculated as (number of tablets dispensed 
minus the number of tablets returned minus the number of tablets lost) divided by the scheduled 
number of doses, expressed as a percentage. If this percentage is calculated greater than 100%, 
then compliance will be calculated 1 minus (the calculated percentage minus 1). Compliance will 
be summarized overall and by scheduled weeks for the safety analysis set. 
Study drug dispense and accountability with the reason for not returning tablets is captured on 
the CRF and will be presented in the data listings. 


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9.3.2. 
Concomitant and Prior Medications other than Anti-PD Medications 
Prior and concomitant medications other than anti-PD medications will be coded to a preferred 
name according to the WHODRUG coding dictionary version 2015:03 or higher. The number 
and percent of subjects will be summarized for prior and concomitant medications for each 
preferred term (PT) in the FAS and should be displayed by therapeutic class and preferred term. 
All prior and concomitant medications taken during the study will be listed for each subject 
including dosage and indication. 
 
9.3.3. 
Concomitant and Prior Anti-PD Medications 
During the study, patients’ concomitant anti-PD medications may be adjusted as needed under 
the investigator’s supervision. 
Prior and concomitant anti-PD medications will be coded to a preferred name according to the 
WHODRUG coding dictionary version 2015:03or higher. The number and percent of subjects 
will be summarized for prior and concomitant anti-PD medications for each preferred term (PT) 
and should be displayed by therapeutic class, chemical/therapeutic/pharmacological subgroup, 
and preferred term in the FAS. All prior and concomitant anti-PD medications will be listed 
separately for each subject. 
The last dose of anti-PD medication taken the evening before the day when UPDRS part III test 
are done in defined “ON“ state at Screening, Baseline (Pre-dose Day 1), Weeks 2, 6, 12, 24, 36 
and 52 will be documented in a subject data listing along with the date and time of UPDRS 
Part III performed before anti-PD medications. The subject data listing will include 
medication/treatment, dose, number of tablets or capsules taken, frequency, date of last dose and 
time of last dose. 
 
9.3.3.1. 
Total Levodopa Dose 
The total levodopa dose at baseline and during the study will be calculated for each subject at 
each visit and summarized descriptively for each visit in the FAS. A separate listing will also be 
created listing each subject’s calculated total levodopa dose by visit. 
 
9.3.3.2. 
Total Levodopa Equivalents 
The total levodopa equivalent at baseline and during the study will be calculated for each subject 
at each visit and summarized descriptively for each visit in the FAS. A separate listing will also 
be created listing each subject’s calculated total levodopa equivalent by visit. Appendix 2 
contains the rules to calculate levodopa equivalents. 
 
9.4. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively in the FAS. These 
variables include: 
• Gender 
• Race and ethnicity 
• Age (years) 


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• Body weight (kg) 
• Height (cm) 
• Body Mass Index (BMI) (kg/m2) 
• Duration of PD (years) 
• Hoehn and Yahr Staging of PD in ON state and OFF state (best estimate) 
Age will also be classified into 3 categories (≥ 30 to 54, ≥ 55 to 68 and ≥ 69 to 80 years). 
9.5. 
Medical History Events 
Medical conditions resolved by first dose of IMP and ongoing medical conditions will be 
summarized by MedDRA system organ class (SOC) and PT in the FAS. All medical conditions 
collected on the eCRF will be included in the listings. 
 
9.6. 
Exploratory Analyses 
All exploratory endpoints will be summarized descriptively in the mFAS. 
 
9.6.1. 
Exploratory Variables 
The exploratory variables including the change from Baseline (where applicable) will be 
summarized using descriptive statistics by visit: 
1. UPDRS Part II (ADL subscale) + Part III (motor subscale) total score 
2. UPDRS Part II (ADL subscale) score 
3. UPDRS Part III (motor subscale) score in the ON state 
4. UPDRS Part I total score 
5. UPDRS Part IV total score 
6. Dyskinesia as measured by questions 32, 33 and 34 of UPDRS Part IV 
7. Motor fluctuations as measured by question 39 of UPDRS Part IV 
8. Clinical Global Impression of Improvement (CGI-I) 
9. Patient’s Global Impression of Improvement (PGI-I) 
10. Parkinson’s Disease Quality of Life Questionnaire (PDQ-39; total score and individual 
domain scores) 
11. Non-motor Symptom Assessment Scale 
12. Patient-completed diaries (Change from Baseline in the number of hours per day spent as 
follows: OFF, ON time without troublesome dyskinesia, total ON time, ON time with 
troublesome dyskinesia and asleep time) 
13. Healthcare Resource Utilization 
14. EuroQol 5D-5L Health Questionnaire (EQ-5D-5L) 
15. Fall questionnaire 


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9.7. 
Pharmacokinetic Variables 
9.7.1. 
Tozadenant Plasma Concentrations at week 2 
Blood samples will be collected for determination of plasma tozadenant concentrations at Week 
2. 
Plasma concentration data will be presented for all subjects. In all calculations, zero (0 ng/mL) 
will be substituted for concentration below the quantification limit (BLQ; equivalent to <5 
ng/mL) of the assay. 
Elapsed time between dosing and plasma sampling will not be tightly controlled and is expected 
to vary considerably between patients. Summary statistics for tozadenant blood concentrations 
(number of sample analyzed, number of BLQ values, minimum, and maximum) will be 
presented on the safety set. 
All data collected on the tozadenant blood concentrations will be included in the data listings. 
 
9.7.2. 
Tozadenant expanded PK 
 
9.7.2.1. 
Tozadenant expanded PK Plasma concentration 
Plasma concentration for the expanded PK will be described using the PK population. 
For expanded PK blood samples for plasma concentration, one pre-dose/trough PK sample will 
be collected prior to the administration of tozadenant. After the administration of tozadenant, 
four additional samples will be collected at 3, 5, 6 and 8 hours. 
Trough concentration will be summarized in terms of n, arithmetic mean, SD, arithmetic CV%, 
median, minimum, maximum, geometric mean and geometric CV%. The plasma concentration 
at 3 hours, 5 hours, 6 hours, and 8 hours will be described similarly. Values that are BLQ will be 
set to zero when calculating the aforementioned descriptive statistics. If one or more of the 
concentration values in a data series is zero, the geometric mean and geometric CV% will not be 
calculated and will be denoted as NC. 
Concentrations will be listed to the same degree of accuracy as supplied by the bioanalytical 
laboratory. As well, units of concentration will be presented as they are received from the 
bioanalytical laboratory. 
Individual plasma concentration-time profiles and individual concentration listings will be 
presented using actual sampling times. Arithmetic mean plasma concentration-time profiles will 
be plotted on linear and semi-logarithmic scales. 
 
9.7.2.2. 
Tozadenant expanded PK Pharmacokinetic parameters 
Pharmacokinetic parameters for the expanded PK will be described using the PK population. 
The following pharmacokinetic parameters for tozadenant will be calculated using non- 
compartmental analysis using Phoenix WinNonlin Version 6.4 or higher: 
Parameter Definition 
AUC0-last 
Area under the concentration-time curve from time 0 to the last measurable 
concentration, as calculated by the trapezoidal method. 


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Cmax 
Maximum plasma concentration 
tmax 
Time of maximum measured plasma concentration (Cmax) 
Additional pharmacokinetic parameters may be determined where appropriate. 
Pharmacokinetic analysis will be carried out using actual postdose times recorded in the raw 
data. If actual times are missing, nominal times may be used. 
Cmax and tmax will be obtained directly from the plasma concentration-time profiles. If Cmax 
occurs at multiple timepoints, the earliest time will be used for tmax. 
Cmax and AUC0-last will be summarized in terms of n, arithmetic mean, SD, arithmetic CV%, 
median, minimum, maximum, geometric mean and geometric CV%. For the parameter tmax, the 
descriptive statistics will include n, arithmetic mean, SD, minimum, median, and maximum. 
 
9.7.2.2.1. Criteria for handling concentrations below the limit of quantification in 
Pharmacokinetic analysis 
Concentration values that are below the level of quantification (BLQ) will be set to zero, with 
defined exceptions as follows; 
• Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
• If an entire concentration-time profile is BLQ, the profile will be excluded from the 
PK analysis. 
• If a predose concentration is missing, these values will be set to zero. 
9.8. 
Safety Analyses 
All safety analyses will be performed on the SS. 
 
9.8.1. 
Adverse Events 
A summary of TEAEs that occur including the number of events reported, the number and 
percentage of subjects reporting at least 1 AE, the number and percentage of subjects 
discontinuing due to an AE, the number and percentage of subjects with at least 1 serious 
adverse event, and the number and percentage of deaths will be presented. 
A breakdown of the number and percentage of subjects reporting each TEAE will be presented, 
categorized by SOC and PT coded according to the MedDRA dictionary. Note that counting will 
be by subject, not event, and subjects are only counted once within each SOC or PT. 
A further tabulation of these data will be presented for TEAEs that are related to study drug, as 
defined by those AEs with relationship to study drug recorded on the eCRF as Possible or 
Probable. Events that are unrelated or remotely/Unlikely related will not be considered “related” 
for the Causality assessment. An AE with a missing relationship will be considered as having a 
relationship to study drug of possible. Subjects with multiple events within a particular SOC or 
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A summary of events reported, categorized by severity (mild, moderate, severe) will also be 
provided. AEs with missing or unknown severity will be considered severe. Subjects with 
multiple events within a particular SOC or PT will be counted under the category of their most 
severe event within that SOC or PT. 
A summary of adverse events leading to discontinuation will be provided, grouped by system 
organ class and preferred term. 
All AEs (including non-treatment-emergent events) recorded on the eCRF will be listed along 
with other information such as duration, severity, action taken, and perceived relationship to 
study drug. 
 
9.8.2. 
Deaths and Serious Adverse Events 
Serious TEAEs will be summarized by the number and percentage of subjects reporting each 
AE, categorized by SOC and PT coded according to the MedDRA dictionary. Note that counting 
will be by subject, not event, and subjects are only counted once within each SOC or PT. 
 
9.8.3. 
Laboratory Data 
Clinical laboratory values will be evaluated by subject for each laboratory parameter at Weeks 2, 
6, 12, 24, 36, 52, early termination and safety follow-up. Laboratory test results will be reported 
and they will be assigned a LNH classification by each laboratory according to whether the value 
was below (L), within (N), or above (H) the laboratory reference range. Reference (normal) 
ranges for laboratory parameters provided by the central lab will be included in the clinical study 
report for this study and will be used for shift tables. Summary tabulations of the continuous 
clinical laboratory (hematology, chemistry, thyroid function (TSH, free T3 and free T4), and 
urinalysis) data (n, mean, standard deviation, median, minimum, and maximum) for baseline, 
each scheduled visit (defined in Table 1), and change from baseline for laboratory data will be 
provided. Quantitative urinalysis data will only be listed. Shifts from baseline to each scheduled 
visit will be summarized for hematology, chemistry, thyroid, and urinalysis variables that are 
assigned a LNH classification. In addition, shifts from baseline to worst post-baseline for the 
same laboratory variables will be presented based on the LNH classification. 
Prespecified continuous laboratory hematology (WBC, Neutrophils, Lymphocytes) and 
chemistry (AST, ALT, GGT, Glucose, CK) parameters will have the worst post-baseline value 
plotted versus the baseline visit. The minimum lower limit of the normal range and the maximum 
upper limit of the normal range amongst laboratories will be drawn on the x and y axis as vertical 
lines. 
All laboratory data collected will be included in the data listings. 
 
9.8.4. 
Systolic and Diastolic Blood Pressure and Pulse Rate 
Systolic and diastolic blood pressure and pulse rate will be measured in both the supine and 
standing positions. The scheduled visits that will be summarized are Weeks 2, 6, 12, 24, 36, 52, 
early termination and safety follow-up. 
Summary tabulations of the systolic and diastolic blood pressure and pulse rate in both standing 
and supine positions as well as the orthostatic change (n, mean, standard deviation, median, 
minimum, and maximum) for each scheduled visit, and change from baseline will be provided. 


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At each scheduled visit and time point (Weeks 2, 6, 12, 24, 36, 52, early termination and safety 
follow-up), the number and percent of subjects meeting each abnormal criteria displayed below 
will be summarized. 
• Supine and standing systolic blood pressure 
− ≥160 mmHg 
− < 100 mmHg 
− 
≥20 mmHg increase from baseline 
− ≥20 mmHg decrease from baseline 
− ≥40 mmHg increase from baseline 
− ≥40 mmHg decrease from baseline 
• Supine and standing diastolic blood pressure 
− ≥100 mmHg 
− <50 mmHg 
− ≥10 mmHg increase from baseline 
− ≥10 mmHg decrease from baseline 
− ≥20 mmHg increase from baseline 
− ≥20 mmHg decrease from baseline 
• Supine and Standing Pulse rate 
− ≥120 bpm 
− <48 bpm 
− 
≥30 bpm increase from baseline 
− ≥30 bpm decrease from baseline 
• Orthostatic change ≥20 mmHg increase from baseline for systolic blood pressure and 
diastolic blood pressure 
• Orthostatic change ≥20 mmHg decrease from baseline for systolic blood pressure and 
diastolic blood pressure 
For Weeks 2, 6, 12, 24, 36, and 52 plots of the mean change from baseline at each timepoint will 
be displayed for blood pressure and pulse rate in supine and standing position and orthostatic 
change. 
All vital sign data collected will be included in the data listings. 
 
9.8.5. 
Body Weight 
Body weight will be summarized at Weeks 12, 24, 52, early termination and safety follow-up 
visits. 


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Summary tabulations of weight (n, mean, standard deviation, median, minimum, and maximum) 
at each scheduled visits, and change from baseline will be provided. 
All body weight data collected will be included in the data listings. 
 
9.8.6. 
Columbia-Suicide Severity Rating Scale 
The number and percent of subjects reporting "Yes" for each of the 5 questions to suicidal 
ideation and 6 questions about suicidal behavior will be summarized. In addition, for suicidal 
behavior, the total number of actual attempts, total number of interrupted attempts and total 
number of aborted attempts will be summarized (n, mean, standard deviation, median, minimum 
and maximum) by visit. 
All C-SSRS data collected will be included in the data listings. 
 
9.8.7. 
Modified Minnesota Impulsive Disorders Interview 
mMIDI is reported at Weeks 2, 6, 12, 24, 36, 52, early termination and safety follow-up. For the 
mMIDI module scores and total score, if a question is not answered with a module, then that 
given module score and the total score will not be determined for the subject at the visit. 
The mMIDI modules are Buying Disorder, Compulsive Gambling, Compulsive Sexual Behavior, 
Compulsive Eating, and Punding Behavior. The number and percent of subjects in each module 
with a positive/negative indication for the module will be reported. In addition, shift from 
baseline to each scheduled visit will be summarized. 
All mMIDI data collected will be included in the data listings. 
 
9.8.8. 
Epworth Sleepiness Scale and Assessment of Sudden Episodes of Sleep 
Epworth Sleepiness Scale (ESS) is reported at Weeks 2, 6, 12, 24, 36, 52, early termination and 
safety follow-up, collected during patient’s ON state. Daytime sleepiness as measured by the 
ESS, including assessment of episodes of sudden onset of sleep. ESS will summarized by visit. 
Assessment of sudden episodes of sleep will be analyzed similarly. 
All ESS data collected will be included in the data listings. 
 
9.8.9. 
ECG 
ECG data will be summarized for the following visits: Weeks 2, 6, 12, 24, 36, 52, early 
termination and safety follow-up. Descriptive statistics (n, mean, standard deviation, median, 
minimum and maximum) of each parameter (HR, PR, RR, QRS, QT, and QTcF) will be 
displayed for the observed value and change from baseline at each scheduled listed above. 
The number and percentage of subjects with maximum post-dose QT/QTcF interval within the 
following ranges will be summarized: 
• ≤450 msec 
• >450 msec and ≤480 msec 
• >480 msec and ≤ 500 msec 
• >500 msec. 


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In addition the number and percentage of subjects with maximum change from Baseline in 
QT/QTcF interval within the following ranges will be summarized: 
• ≤30 msec 
• >30 msec 
• ≤60 msec, and >60 msec. 
ECG findings will be classified as normal or abnormal, with abnormal values further classified 
according to clinical significance (yes/no).The percentage of subjects with clinically significant 
findings and clinically significant treatment-emergent findings will be summarized for each visit. 
All ECG data collected will be included in the data listings. 
 
9.8.10. 
Physical and Neurological Examinations 
Physical and neurological examinations are performed at Weeks 12, 32, 36, 52, early termination 
and safety follow-up visits. The number and percentage of subjects with normal/abnormal 
findings will be summarized by body system/neurological area and visit. 
All abnormalities reported will be included in the data listings. 
 
10. 
VALIDATION 
• 100% of unique tables will be independently programmed by a second programmer 
for numeric results. Statisticians will be involved in the process of programming and 
validating tables. 
• Figures will be checked for consistency against the corresponding tables and listings. 
• Listings will be checked for consistency against corresponding tables, figures, and 
derived datasets. 
The entire set of TFL will be checked for completeness and consistency. 
 
11. 
PROGRAMMING SPECIFICATIONS 
11.1. 
Format of Appendix Tables/Figures/Listings 
1. Unless otherwise specified, all computer-generated tables, figures and listings (TFL) 
should be produced (via SAS ODS) into RTF output, which can be imported in table 
format via Microsoft Word. The TFLs should be in landscape mode with required 
margins: at least 1.5 inches on top (the binding margin, or left for portrait output), at least 
1 inch on right, left, and bottom. All output should have the following headers on each 
page: 
• “CONFIDENTIAL” header in the upper center: 
• Two-line header at the upper left margin: 


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ACORDA THERAPEUTICS, INC. 
PROTOCOL No.: TOZ-CL06 
• Header with a date (time and date output was automatically generated via SAS) and 
page number at the upper right margin: 
DATE: &SYSTIME &SYSDATE 
PAGE: X of N 
TFLs should be internally paginated in relation to total length (i.e., page number should 
appear sequentially as page X of N, where N is the total number of pages within a table 
or listing). 
2. Each TFL should be identified by in a sequential numeric order, and the TFL designation 
(e.g., Table 1) should be centered above the title. A decimal system within the numeric 
numbering (i.e., x.y and x.y.z) should be used to identify TFLs with related contents. The 
title is centered in initial capital characters and should include the population type 
analyzed (e.g. Safety Population). The title and designation are single-spaced, but are 
separated from the TFL by at least a double space. 
 
Table No. 
 
First Line of Title 
Second Line of Title (if needed) 
Population Type Analyzed 
 
3. Column headings for tables and listings should be in initial upper-case characters. 
4. For variables with numeric values, include “unit” in column heading when appropriate. 
5. Footnotes should be single spaced, but separated by at least a double space from the 
bottom line of the TFL. The notes are left justified, with each note starting on a new line. 
Avoid numeric references, which can be confused with data; rather use asterisks and 
other non-numeric symbols to refer to footnotes. Patient-specific footnotes should be 
avoided. The source data set name (and for tables and figures the source listing number) 
as well as the source SAS program names and locations (with reduced font if necessary) 
should be displayed as the last footnotes in each TFL. For example the set of footnotes 
for a table: 
*: Footnote 1 
**: Footnote 2 
Note: Footnote 3 
Source Listing: Listing X (data set name) 
SOURCE PROGRAM: path\filename 
6. All data listings should be sorted by investigator site, patient within investigator site, and 
study visit date/time within patient where appropriate. 
7. For tables that summarize categorical (discrete) data, all categories between the 
maximum and minimum category should be presented in the table, even if there is zero 


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entry for a particular category. An Unknown or Missing category should be added to any 
variables to indicate missing information, if appropriate 
 
 
Severity 
Rating 
n 
Severe 
0 
Moderate 
8 
Mild 
3 
Missing 
2 
8. If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from 
the Study, etc.), then only those categories for which there is at least 1 patient represented 
in 1 or more groups should be included. 
9. Unless specified otherwise, tabular display of data for medical history, prior / 
concomitant medications, and all tabular displays of adverse event data should be 
presented by the body system, drug class, or SOC with the highest occurrence in 
decreasing order. Within the body system, drug class and SOC, medical history (by 
preferred term), drugs (by ATC1 code), and adverse events (by preferred term) should be 
displayed in decreasing order. If incidence for more than 1 term is identical, they should 
then be sorted alphabetically. Specifically, prior and concomitant medications other than 
Anti-Parkinson’s medications should be displayed by therapeutic class and preferred 
term. Prior and concomitant Anti-Parkinson’s medications should be displayed by 
therapeutic class, chemical/therapeutic/pharmacological subgroup, and preferred term. 
10. Unless otherwise specified, the estimated mean and median for a set of values should be 
printed out to one more decimal place than the original values and rounded appropriately. 
Standard errors (or standard deviations) should be printed out to two additional decimal 
places than the original values and rounded appropriately. The range should report the 
same as the original values. For example, for age (with original value in whole years): 
N 
xx 
Mean 
xx.x 
S.E. 
xx.xx 
Median 
xx.x 
Range 
xx-yy 
 
11. All fractional numeric values should be printed with a zero to the left of the decimal point 
(e.g., 0.12, 0.3). 
12. Unless otherwise specified, percentage values should be printed with one digit to the right 
of the decimal point (e.g., 12.8%, 5.4%). While count and percentage values are 
presented together, percentage values should be printed in parentheses 1 space after the 
count (e.g., 7 (12.8%), 13 (5.4%)). Any counts of 0 will be presented as 0 and not as 0 
(0%). Unless otherwise noted, for all percentages, the number of patients in the analysis 
set for the cohort who have an observation will be the denominator. 
13. Missing descriptive statistics due to non-estimability in tables, as well as missing data in 
patient listings should be represented as either a hyphen (“-“) with a corresponding 


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footnote (“ - = unknown or not evaluated”), or as “N/A” with the footnote “N/A = not 
applicable” whichever is appropriate. 
14. Dates printed as a result in the TFL should be printed in SAS DATE9. format 
(“DDMONYYYY”: 01 Jul 2002). Missing portions of dates should be represented on 
patient listings as dashes (e.g., -- Jul 99). Dates that are missing because they are not 
applicable for the patient should be listed as “N/A”, unless otherwise specified. 
15. All observed time values should be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45, or 11:26). 
16. Data in columns of a table should be formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned 
 
12. 
REFERENCES 
1) SAS Version 9.2, SAS Institute, Cary, NC 27513. 
2) Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE (2010).Systematic review 
of levodopa equivalency reporting in Parkinson’s disease. MovDisord. 25(15):2649-53. 


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APPENDIX 1 GLOSSARY OF ABBREVIATIONS 
 
 
 
ADaM 
ADL 
AE 
Analysis Dataset Model 
Activity of Daily Living 
Adverse Event 
BMI 
Body Mass Index 
BID 
CDISC 
CGI-S 
CGI-I 
Twice a Day 
Clinical Data Interchange Standards Consortium 
Clinical Global Impression-Severity 
Clinical Global Impression-Improvement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF 
ECG 
Electronic Case Report Form 
Electrocardiogram 
ESS 
FAS 
LLQ 
MedDRA 
Epworth Sleepiness Scale 
Full Analysis Set 
Lower Level of Quantitation 
Medical Dictionary for Regulatory Activities 
mMIDI 
mFAS 
Modified Minnesota Impulsive Disorders Interview 
Modified Full Analysis Set 
PD 
PDQ-39 
PGI-I 
PK 
PT 
Parkinson's Disease 
Parkinson's Disease Questionnaire 
Patient Global Impression-Improvement 
Pharmacokinetics 
Preferred Term 
SAP 
Statistical Analysis Plan 
SAE 
SD 
SDTM 
SOC 
SS 
TEAE 
TFL 
UPDRS 
WHODRUG 
Serious Adverse Event 
Standard Deviation 
Study Data Tabulation Model 
System Organ Class 
Safety Set 
Treatment Emergent Adverse Event 
Table, Figures and Listings 
Unified Parkinson’s Disease Rating Scale 
World Health Organization Drug Dictionary 


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APPENDIX 2 
LEVODOPA EQUIVALENT ALGORITHM 
Rules for Levodopa Equivalent 
a) Ignore carbidopa – carbidopa does not go into the calculation of LevoEq 
Steps: 
1. Calculate total immediate release daily Levodopa (note: there are combination drugs 
containing levodopa and you must separate these out and include in your calculation of 
daily Levodopa) by multiplying the mg per dose of levodopa by dosing frequency 
(BID=2, TID=3, QD=4, etc.) 
2. Calculate total control release daily Levodopa. Multiply this by 0.75 (to account for loss 
of bioavailability) 
3. Calculate total extended release Levodopa (i.e., Rytary). Multiply this by .60. 
4. Add 1) and 2) and 3) to get total daily Levodopa 
5. If Entacapone is taken (including combination drugs with Entacapone, i.e., Stalevo), 
multiply total daily Levodopa in 4) by 0.33. 
6. If Tolcapone is taken, multiply total daily Levodopa in 3) by 0.5 
7. If Duodopa is taken, multiply the daily mg by 1.11 
8. If Pramipexole (as salt) is taken, multiply the daily mg by 100 
9. If Ropinirole or RequipXL is taken, multiply the daily mg by 20 
10. If Rotigotine is taken, multiply the daily mg by 30 
11. If Selegiline – oral is taken, multiply the daily mg by 10 
12. If Selegiline – sublingual is taken, multiply the daily mg by 80 
13. If Rasagiline is taken, multiply the daily mg by 100 
14. If Amantadine is taken, multiply the daily mg by 1 
15. If Apomorphine is taken, multiply the daily mg by 10 
16. Calculate total LevoEq = 4) + 5) + 6) + 7) + 8) + 9) + 10) + 11) + 12) + 13) + 14) + 15)