Clinical trial NCT02258152
Conditions: Parkinson's Disease Dementia (PDD)
Keywords: PDD Parkinson's Disease Dementia patients taking a cholinesterase inhibitor.
Sponsor: Biotie Therapies Inc.
Start date: 2014-12-22; Completion date: 2017-10-03
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study placebo-controlled, randomized, double-blind study is to assess the safety and efficacy of SYN120 in patients with Parkinson's disease dementia (PDD) already treated with a stable dose of a cholinesterase inhibitor.

Detailed description:
This study includes a Screening Period of up to 6 weeks, a 16 week Treatment Period, and a 2 week Safety Follow Up Period.

Final eligibility will be determined at the Baseline Visit. Eligible patients will be randomized to receive placebo or SYN120 100 mg once a day (QD).

Arms: arm 1: None arm 2: None
Interventions: intervention 1: SYN120 intervention 2: Placebo
Intervention descriptions: intervention 1: SYN120 Doses to be Administered: 20 mg QD (1 week titration), 50 mg QD (1 week titration), 100 mg QD (14 weeks of maintenance). intervention 2: Placebo QD

Protocol documents:
Prot_000.pdf: 
Biotie Therapies, Inc. 
Amendment 2: 14 April 2016 
Clinical Study Protocol 
SYN120 
SYN120-CL03 
 
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 
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CLINICAL STUDY PROTOCOL 
Title 
SYN120 a Dual 5-HT6/5-HT2A Antagonist Proof of Concept 
Study to Evaluate its Safety, Tolerability and Efficacy in 
Parkinson’s Disease Dementia (SYNAPSE) 
Protocol Number 
SYN120-CL03 
Phase 
2a 
IND Number 
77,435 
Date of Amendment 2 
Date of Amendment 1 
Original Date of Issue 
14 April 2016 
16 April 2015 
02 October 2014 
Sponsor 
Biotie Therapies, Inc. 
701 Gateway Boulevard, Suite 350 
South San Francisco, CA 94080 USA 
 
Sponsor Study Director 
 
 
 
 
 
Sponsor Chief Medical 
Officer 
 
 
 


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Biotie Therapies, Inc. 
Amendment 2: 14 April 2016 
Clinical Study Protocol 
SYN120 
SYN120-CL03 
 
Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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STUDY CONTACT INFORMATION 
Biotie Therapies, Inc. – Sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 


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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. 
a) 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. 
a) 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: 
1) Hospitalizations for: 
a) 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). 
b) 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 course of the study or within 4 weeks 
after the last dose of study drug must be reported within 24 hours (1 working day) of site 
awareness by email and/or fax by completing the SAE form.  
 
 
 
 
 
 
 
Refer to additional SAE reporting instructions in Section 8.9. 
 
 


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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
The undersigned have reviewed the format and content of this protocol and have approved 
Clinical Study Protocol SYN120-CL03 entitled “SYN120 a Dual 5-HT6/5-HT2A Antagonist 
Proof of Concept Study to Evaluate its Safety, Tolerability and Efficacy in Parkinson’s Disease 
Dementia (SYNAPSE).” Any modification of the clinical study protocol must be agreed upon by 
the Sponsor and the Investigator and must be documented in writing. 
Sponsor: 
Biotie Therapies, Inc. 
Protocol Number: 
SYN120-CL03 
Amendment No.:  
2 
Date of Amendment: 
14 April 2016 
 
 


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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, Inc. 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, any consent form 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 SAEs to Biotie Therapies, Inc. 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, Inc. 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:  SYN120-CL03 
Date of  Amendment 2: 14 April 2016 
 
 
 
 
 
 
 
 
 
 
 
 
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 
AD 
Alzheimer’s disease 
ADAS-cog 
Alzheimer’s Disease Assessment Scale – cognitive subscale 
ADCS 
Alzheimer’s Disease Cooperative Study 
ADL 
activity of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase (alanine aminotransferase) 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
AST 
aspartate transaminase (aspartate aminotransferase) 
ARO 
academic research organization 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CIBIC+ 
Clinician's Interview Based Impression of Change Plus Caregiver Input 
CDR 
Cognitive Drug Research Computerized Cognition Battery 
CGIC 
Clinician’s Global Impression of Change 
CK 
creatine phosphokinase 
COMT 
catechol-O-methyltransferase 
CRA 
Clinical Research Associate 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eCRF  
electronic case report form 
ET 
early termination 
FDA 
US Food and Drug Administration 
FSH 
follicle stimulating hormone 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase (gamma-glutamyl transferase) 
GMP 
Good Manufacturing Practice 
hCG 
human chorionic gonadotropin 
hERG 
human ether-a-go-go-related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ID 
Identifier 
IEC 
Independent Ethics Committee 


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IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose 
MAO-B 
monoamine oxidase type B 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention-to-treat analysis set (mITT sample) 
MMRM 
mixed model repeated measurement 
MoCA 
Montreal Cognitive Assessment 
msec 
Millisecond 
NPI 
Neuropsychiatric Inventory 
PD 
Parkinson’s disease 
PDD 
Parkinson’s disease dementia 
PDAQ 
Brief Penn Daily Activity Questionnaire 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
PP 
per-protocol analysis set (PP set) 
PR 
interval from onset of P wave to start of QRS complex in 
electrocardiogram 
PRN 
as needed 
RO 
receptor occupying 
QA 
quality assurance 
QD 
once a day 
QRS 
interval from onset of Q wave to end of S wave in electrocardiogram 
QT 
interval between Q and T waves in electrocardiogram 
QTc 
heart rate-corrected QT 
QTcF 
heart rate-corrected QT calculated using Fridericia’s correction formula 
RR 
interval between successive peaks of R wave in electrocardiogram 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SS 
safety analysis set (safety sample) 
ST 
interval from end of QRS complex to beginning of T wave in 
electrocardiogram 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
UK 
United Kingdom 


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ULN 
upper limit of normal 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
US/USA 
United States of America 
UTI 
urinary tract infection 
V 
Visit 
W 
Week 
WHO 
World Health Organization 
 


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PROTOCOL SYNOPSIS 
Title 
SYN120 a Dual 5-HT6/5-HT2A Antagonist Proof of Concept Study to 
Evaluate its Safety, Tolerability and Efficacy in Parkinson’s Disease 
Dementia (SYNAPSE) 
Protocol Number 
SYN120-CL03 
Phase 
2a 
Number of Sites/ 
Location 
The study will take place in approximately 12 sites in the United 
States. 
Test Product,  
Dose and Mode of 
Administration  
Test Product: SYN120 tablets are manufactured in 10 mg and 50 mg 
dosage strengths. 
SYN120 Doses to be Administered: 
1. 20 mg QD (1 week titration) 
2. 50 mg QD (1 week titration) 
3. 100 mg QD (14 weeks of maintenance) 
Comparator: Placebo 
Mode of Administration: Oral; each daily dose is taken once in the 
morning, approximately 30–60 min after breakfast. 
Indication 
Parkinson’s disease dementia (PDD) 
Study Objectives 
Primary Efficacy Objective: 
The primary efficacy objective of this study is to assess the efficacy 
of a fixed dose of SYN120 on cognition as determined by the 
Cognitive Drug Research Computerized Cognition Battery (CDR) 
Continuity of Attention in patients with PDD treated with a stable 
dose of a cholinesterase inhibitor. 
Key Secondary Efficacy Objective: 
1. To assess the effects of SYN120 on CDR Quality of Episodic 
Memory. 
Other Secondary Efficacy Objectives: 
1. To assess the effects of SYN120 on the Alzheimer’s Disease 
Cooperative Study-Clinician’s Global Impression of Change 
(ADCS-CGIC). 
2. To assess the effects of SYN120 on the Alzheimer’s Disease 
Assessment Scale-Cognitive Subscale (ADAS-cog). 
3. To assess the effects of SYN120 on CDR Power of Attention. 
4. To assess the effects of SYN120 on CDR Speed of Memory 


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PROTOCOL SYNOPSIS 
Retrieval. 
5. To assess the effects of SYN120 on the Brief Penn Daily Activity 
Questionnaire (PDAQ). 
6. To assess the effects of SYN120 on the Scales for Outcomes in 
Parkinson’s Disease-Sleep Scale (SCOPA-SLEEP) (nighttime 
sleep and daytime sleepiness). 
7. To assess the effects of SYN120 on the Parkinson's Disease-
Adapted Scale for Assessment of Positive Symptoms 
(SAPS-PD). 
8. To assess the effects of SYN120 on the Neuropsychiatric 
Inventory (NPI). 
9. To assess the effects of SYN120 on the Montreal Cognitive 
Assessment (MoCA). 
Exploratory Objectives: 
To assess the effects of SYN120 on the individual component tasks 
of the CDR, i.e., Word Presentation, Immediate Word Recall, Picture 
Presentation, Simple Reaction Time, Digit Vigilance, Choice 
Reaction Time, Numeric Working Memory, Spatial Working 
Memory, Delayed Word Recall, Word Recognition, and Picture 
Recognition. 
Safety Objectives: 
The safety objectives are to assess the safety and tolerability of 
SYN120 by assessing adverse events (AEs), vital signs (including 
orthostatic blood pressure measurements), laboratory assessments, 
Unified Parkinson’s Disease Rating Scale (UPDRS) Parts I-IV, 
Columbia-Suicide Severity Rating Scale (C-SSRS), and ECGs. 
Study Population 
Men or women at least 50 years old who have received a diagnosis 
of probable PDD according to the Movement Disorder Society Task 
Force clinical diagnostic criteria for dementia associated with 
Parkinson's disease (Emre et al., 2007) and who are taking a 
cholinesterase inhibitor. 
Study Design 
This is a Phase 2a, multicenter, randomized, double-blind, placebo-
controlled, parallel-group, two-arm, 16-week study in PDD patients 
taking a cholinesterase inhibitor. This includes a Screening Period of 
up to 6 weeks that starts with a Screening Visit, a 16-week Treatment 
Period, and a 2-week Safety Follow Up Period. 
After providing written informed consent, patients will undergo a 
screening evaluation. Patients must meet all inclusion criteria and 
none of the exclusion criteria. Final eligibility will be determined at 


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PROTOCOL SYNOPSIS 
the Baseline Visit. 
Eligible patients will be randomized to receive placebo or 
SYN120 100 mg QD in a ratio of 1:1. Investigational Medicinal 
Product (IMP) will be dispensed to patients at each onsite visit and 
will be taken once daily for 16 consecutive weeks. SYN120 will be 
titrated as follows: 20 mg QD for the first 7 days, 50 mg QD for the 
next 7 days, and 100 mg QD for the remaining 14 weeks. Patients 
and caregivers will return to the study site for evaluations at 
Weeks 4, 8, and 16. Patients and caregivers will be telephoned at 
Weeks 2 and 12 to assess for AEs. Participants who discontinue IMP 
will remain on study following the normal schedule of assessments. 
Patients withdrawing consent will undergo an Early Termination 
Visit, ideally while still taking study medication, and return for a 
Safety Follow Up Visit approximately 2 weeks after their last dose 
administration. 
Number of Patients to 
be Randomized 
Approximately 80 patients will be randomized. 
Randomization 
At the Baseline Visit, patients will be randomly allocated in equal 
proportion to one of two treatment groups, SYN120 100 mg QD or 
placebo, according to a permuted-block randomization schedule, 
stratified by site. 
Dose Groups 
Group A: SYN120 100 mg QD. 
Group B: Placebo QD. 
Dose Regimen 
Randomized patients will be instructed to take 2 tablets of the 
dispensed blinded IMP in the morning, approximately 30-60 minutes 
after breakfast, preferably at the same time each day. 
After randomization, patients assigned to Group A will have their 
dose increased in a double-blind manner starting with 20 mg QD for 
the first 7 days, 50 mg QD for the next 7 days, and 100 mg QD for 
the remaining 14 weeks. Participants in Group B will take matching 
placebo tablets at each step of the titration. 
This is a fixed-dose study and study drug dosage may not be 
changed. Patients experiencing adverse effects considered study 
drug-related and not tolerated by the patient will discontinue IMP but 
remain on study. 


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PROTOCOL SYNOPSIS 
Concomitant 
Anti-Dementia and 
Anti-Parkinson 
Medications 
Patients must be on a stable regimen of a cholinesterase inhibitor for 
at least 12 weeks before randomization. Treatment with memantine 
(Ebixa® or generic equivalents) is permitted, provided the dose has 
been stable for a minimum of 8 weeks prior to randomization. 
After randomization, all efforts should be made to maintain patients 
on the same stable dose of every anti-dementia and anti-Parkinson 
medication throughout the study. The addition of a new 
anti-dementia or anti-Parkinson medication is not permitted during 
the study; however, a decrease in total daily anti-dementia or anti-
Parkinson medication dose because of medication-related AEs is 
permitted. Following a dose decrease of any anti-dementia or anti-
Parkinson medication, the dose may be increased again but cannot 
exceed the total daily dosage at randomization. 
Study Duration 
Each patient will participate in the study for approximately 
24 weeks: 
• Screening period: up to 6 weeks. 
• Treatment period: 16 weeks of dosing. 
• Safety Follow Up Visit: 2 weeks after the last dose of IMP. 
Enrollment Period 
Approximately 12 months. 
Efficacy Endpoints 
The primary efficacy endpoint is the change from Baseline to 
Week 16 on the CDR Computerized Cognition Battery Continuity of 
Attention captured in the ON state. 
The key secondary efficacy endpoint is the change from Baseline to 
Week 16 on the CDR Quality of Episodic Memory, captured in the 
ON state. 
The other secondary efficacy endpoints are the change from Baseline 
to Week 16 on the following measures: 
1. Alzheimer’s Disease Cooperative Study-Clinician’s Global 
Impression of Change (ADCS-CGIC) captured in the ON state. 
2. Alzheimer’s Disease Assessment Scale-cognitive subscale 
(ADAS-cog) total score captured in the ON state by an evaluator 
blinded to the results of all cognitive assessments. 
3. CDR Power of Attention in the ON state. 
4. CDR Speed of Memory Retrieval in the ON state. 
5. PDAQ  (reported by caregiver). 
6. SCOPA-SLEEP (nighttime sleep and daytime sleepiness). 
7. SAPS-PD. 


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PROTOCOL SYNOPSIS 
8. NPI (reported by caregiver). 
9. MoCA. 
Exploratory efficacy endpoints include the change from Baseline to 
Week 16 on the individual component tasks of the CDR, i.e., Word 
Presentation, Immediate Word Recall, Picture Presentation, Simple 
Reaction Time, Digit Vigilance, Choice Reaction Time, Numeric 
Working Memory, Spatial Working Memory, Delayed Word Recall, 
Word Recognition, and Picture Recognition. 
Inclusion and Exclusion 
Criteria 
Inclusion Criteria 
Patients must fulfill all the following inclusion criteria in order to be 
included in the study: 
1. Male or female and aged ≥ 50 years. 
2. Caregivers and patients (or legal representative) must understand 
and have signed an Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) approved informed consent form to 
participate in this study. 
3. Caregivers and patients (or legal representative) must be able to 
understand study requirements and be willing to follow 
instructions, attend all required study visits, and undergo all 
planned tests. 
4. Patients are required to have contact with a responsible caregiver 
at least 3 days per week. 
5. Patient has a documented history of idiopathic Parkinson’s 
disease (PD) consistent with the UK Parkinson’s Disease Society 
Brain Bank Diagnostic criteria. 
6. The patient and/or caregiver have noted a cognitive decline and 
the patient has a diagnosis of probable PD dementia (PDD) 
according to the Movement Disorder Society Task Force clinical 
diagnostic criteria for dementia associated with PD 
(Section 14.2), with the onset of PDD symptoms occurring at 
least one year after the diagnosis of PD. 
7. Patient has a Montreal Cognitive Assessment (MoCA) score of 
10 to 23, inclusive, at Screening. 
8. Patients must be on a stable regimen of cholinesterase inhibitor 
(Exelon®, Aricept®, or Reminyl® or their generic equivalent) 
for a minimum of 12 weeks prior to randomization. Treatment 
with memantine (Ebixa® or generic equivalents) is permitted, 
provided the dose has been stable for a minimum of 8 weeks 
prior to randomization. 
9. Patient is maintained on a regimen of permitted anti-Parkinson 
medications (containing levodopa, dopamine agonists, MAO-B 


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PROTOCOL SYNOPSIS 
inhibitors, or the COMT inhibitor entacapone), that has been 
stable for at least 4 weeks prior to Baseline. 
10. 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 one year absence of vaginal bleeding or spotting) as 
confirmed by FSH greater than or equal to 40 mIU/mL or 
40 IU/L 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. 
Note: For men and women, acceptable methods of contraception 
include use of a condom with spermicide or use of oral, 
implantable or injectable contraceptives, or IUD, or a diaphragm 
with spermicide or diaphragm with condom. 
11. Patients receiving treatment for depression may be enrolled if 
they have been on a stable daily dose of the antidepressant for 
≥8 weeks before Baseline. 
 
Exclusion Criteria 
Patients with any of the following characteristics will be excluded 
from the study: 
1. History of any significant neurologic or psychiatric disease other 
than PD not limited to, but including Alzheimer's disease (before 
onset of PD symptoms), multi-infarct or vascular dementia, 
Huntington's disease, normal pressure hydrocephalus, 
progressive supranuclear palsy, multiple sclerosis, intellectual 
disability/intellectual developmental disorder, Lewy body 
dementia, fronto-temporal dementia, major cortical stroke, major 
head trauma, primary or secondary cerebral neoplasia (except for 
benign stable extra-axial meningiomas), history of significant 
head trauma followed by persistent neurologic deficits, known 
structural brain abnormalities, delirium, schizophrenia or 
schizoaffective disorder. 
2. Treatment with any other investigational drug within 5 half-lives 
or 30 days prior to screening (whichever is longer) or any 
investigational device within 30 days. 
3. Any other condition or clinically significant abnormal findings 
on the physical or neurological examination, medical and 


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PROTOCOL SYNOPSIS 
psychiatric 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 study drug. 
4. Women who are pregnant or lactating. 
5. Orthostatic hypotension requiring medication. 
6. Hyperthyroidism or hypothyroidism, unless they meet all of the 
following conditions: 
a. They have received a stable dose of thyroid medication for at 
least 3 months prior to Baseline Visit. 
b. TSH concentrations are normal or within 10% of the upper or 
lower limit of the normal range. 
c. They are clinically euthyroid. 
7. Clinically significant abnormal Vitamin B12 levels at Screening. 
8. Any other out-of-range laboratory value at screening that have 
not been reviewed, approved, and documented as not clinically 
relevant by the Investigator. 
9. Have a known allergy or sensitivity to SYN120 or any of its 
components. 
10. Suicidal ideation on the C-SSRS of type 4 or type 5, or any 
suicidal behavior, in the past 6 months. Type 4 indicates active 
suicidal ideation with some intent to act, without a specific plan. 
Type 5 indicates active suicidal ideation with specific plan and 
intent. 
11. Use of centrally acting anticholinergic drugs 
 
 
 (Section 14.3). 
12. Treatment with any dopamine receptor blocking medication with 
the exception of low dose quetiapine (≤50 mg/day). 
13. History of neurosurgical intervention for PD. 
14. QTcF interval of ≥ 500 msec at Screening or an average QTcF 
interval ≥ 450 msec for males and ≥ 470 msec for females at 
Baseline (Section 7.16). 
15. Unpredictable motor fluctuations that would interfere with 
administering all cognitive assessments in the ON state. 
Overview of Study 
Procedures 
Consenting patients will be screened for eligibility. Eligible patients 
who meet all entry criteria after completion of all screening 
assessments will return within 6 weeks. Patients meeting all 
eligibility criteria at Baseline will be randomized to double-blind 
treatment which will consist of two tablets every morning. Patients 


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PROTOCOL SYNOPSIS 
randomized to SYN120 100 mg QD will receive two 10 mg tablets 
for the first 7 days, one placebo tablet and one 50 mg tablet for the 
next 7 days, and two 50 mg tablets every day for the remaining 
14 weeks. Participants randomized to placebo will receive the same 
number of placebo tablets on the same titration schedule. 
After randomization, patients will be evaluated at clinic visits at 
Week 4 (28 ± 3 days), Week 8 (56 ± 3 days), and Week 16 
(112 ± 3 days), and again 2 weeks (14 ± 3 days) following the 
Week 16 Visit (or at Early Termination, if applicable). Patients will 
also be contacted by the study site by telephone at Week 2 (14 ± 3 
days) and Week 12 (84 ± 3 days) for assessment of AEs. 
At the clinic visits, patients will be asked to bring their study drug to 
the study site. Blood pressure and pulse (supine and standing) will be 
measured at each outpatient visit. Patients will be assessed for safety 
and tolerability in a blinded fashion regularly throughout the study 
and 2 weeks after their last dose of study drug. 
Please refer to the Schedule of Events/Evaluations in Table 1 for 
specific timing of assessments. 
Criteria for 
Withdrawal from Study 
Investigational medicinal product may be discontinued for a given 
participant at any time if clinically significant out-of-range 
laboratory values or clinically significant abnormal findings on 
physical examination or intolerable AEs put the patient at additional 
risk, as judged by the Investigator. 
Patients will also discontinue IMP if their cognitive dysfunction or 
motor function worsens to the extent that in the judgment of the 
Investigator they require the addition of new medication to control 
their symptoms. 
Patients may withdraw consent and discontinue from the study for 
any reason. 
The Study Sponsor (Biotie Therapies) has the right to terminate the 
study at any time. 
All patients who withdraw consent prematurely will be requested to 
return for an onsite visit that includes all safety procedures as 
outlined for early termination in Table 1. For any early discontin-
uation, the patient should be requested to return for a Safety 
Follow Up Visit 2 weeks after the last dose of study drug, unless the 
Early Termination Visit itself occurs 2 or more weeks after the last 
dose of study drug. 


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PROTOCOL SYNOPSIS 
Safety Evaluations 
Please refer to Table 1 for Schedule of Events/Evaluations. 
Safety evaluations include: 
• AE reports 
• UPDRS 
• Supine and standing pulse and blood pressure 
• 12-lead ECGs 
• Safety labs: hematology, chemistry, urinalysis 
• C-SSRS 
• Concomitant medication assessment 
SYN120 Plasma 
Concentrations 
Blood samples will be collected for determination of SYN120 
plasma concentrations 
 
at Baseline (before the initiation of dosing), at Weeks 4, 
8 and 16, and at Early Termination (if applicable). In addition, 
samples may be collected during unscheduled visits performed for 
AEs (optional, at the discretion of the Investigator). 
Sample Size 
Justification 
The primary efficacy measure is the change from Baseline to 
Week 16 in the total score on the CDR Computerized Cognition 
Battery Continuity of Attention. Based on a two-tailed test at 
alpha = 0.05 and assuming up to 15% loss to follow up, a total 
sample size of 80 randomized participants provides at least 80% 
power for a true treatment-dependent difference in 16-week change 
in CDR Continuity of Attention equal to an effect size of 0.69. 
Additional power will be obtained from analysis using a shared-
baseline repeated measures analysis of variance (ANOVA). 
Analysis Populations 
Safety Analysis Set: The safety analysis set (SS) will consist of all 
randomized patients who received at least one dose of IMP. 
Modified Intention-to-Treat Analysis Set: The modified intention-to-
treat (mITT) analysis set will consist of all randomized patients who 
received at least one dose of IMP and who have at least one valid 
baseline and at least one valid post-baseline assessment of the 
primary efficacy endpoint. 
Per-Protocol Analysis Set: The per-protocol (PP) analysis set will 
consist of a subset of the mITT analysis set, excluding any 
participants or observations potentially affected by important 
protocol deviations that might influence the validity of the data for 
testing efficacy and as specified in the Statistical Analysis Plan prior 
to breaking the blind. 


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PROTOCOL SYNOPSIS 
Statistical Analysis 
Primary Outcome Variable 
The primary analysis will be performed on the mITT analysis set and 
will use a shared-baseline repeated measures ANOVA that includes 
fixed effects for visit and the interaction between treatment group 
and post-baseline visit, random center-specific intercepts, and 
unstructured within-person covariance. 
Secondary and Exploratory Outcome Variables 
Outcomes that are approximately normally distributed will be 
analyzed as described above for the primary outcome variable. 
Outcomes that are not normally distributed will be transformed or 
compared between the treatment groups using a van Elteren test that 
incorporates stratification by center. The key secondary outcome of 
CDR Quality of Episodic Memory will be tested for significance 
using the mITT analysis set at two-tailed alpha = 0.05. Other 
secondary outcomes will also be tested at two-tailed alpha = 0.05 
using the mITT analysis set, recognizing that the totality of results 
will be evaluated in judging the potential of SYN120 as a therapeutic 
agent for PDD. 
Safety Analysis 
The assessment of safety will focus on the frequencies of individual 
AEs, vital signs (particularly orthostatic hypotension), UPDRS, 
abnormal laboratory test results, and ECG abnormalities, particularly 
treatment-emergent events. The frequency and type of any observed 
suicidal ideation will be described. The analyses will use the SS, 
Fisher’s exact test for comparison of the proportion of participants in 
each treatment group experiencing a given AE or abnormal finding, 
and negative binomial regression for total counts of AEs. 
Tolerability 
Tolerance to SYN120 will be evaluated by recording the proportion 
of participants who discontinue IMP and by testing for a treatment-
dependent difference in the time to discontinuation. 
 


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Table 1: 
Schedule of Events/Evaluations 
Study Period
Screening a 
Baseline
Predose 
16-Week Treatment Period 
(Double-blinded Dosing) 
 (Days 1–112) 
Safety 
Follow Up 
(Post Dose 
Follow Up) 
Study Week
−6 to −1 
0 
 
2 
(±3 days)
4 
(±3 days)
8 
(±3 days) 
12 
(±3 days)
16 
(±3 days)
18 
(± 3 days) 
Early 
Term. 
Unscheduled 
Assessments 
Study Visit
V1 
V2 
V3 
(phone
call) 
V4 
V5 
V6 
(phone
call) 
V7 
V8 
V99 
V98 
Onsite clinic visit 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Obtain patient and caregiver informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics; medical history including 
neurological and PD/PDD history 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications including anti-dementia 
and anti-Parkinson meds 
X b 
X 
 
X 
X 
 
X 
X 
X 
X 
BP and pulse (supine and standing) c 
X x 3 
X 
 
X 
X 
 
X 
X 
X 
X d 
Weight (include height at Screening) 
X 
 
 
 
 
 
X 
 
X 
 
Physical and neurological examination 
X 
X d 
 
X 
X 
 
X 
 
X 
X d 
MoCA 
X 
 
 
 
 
 
X 
 
X 
 
Preliminary eligibility assessment by Investigator 
X 
 
 
 
 
 
 
 
 
 
CDR Computerized Cognition Battery e 
X x 2 
X 
 
 
X 
 
X 
 
X 
 
ADAS-cog e 
 
X 
 
 
 
 
X 
 
X 
 
ADCS-CGIC e 
 
 
 
 
 
 
X 
 
X 
 
PDAQ (reported by caregiver) 
 
X 
 
 
 
 
X 
 
X 
 
SCOPA-SLEEP 
 
X 
 
 
 
 
X 
 
X 
 
SAPS-PD  
 
X 
 
 
 
 
X 
 
X 
 
NPI (reported by caregiver) 
 
X 
 
 
 
 
X 
 
X 
 
UPDRS Parts I–IV f 
 
X 
 
X 
X 
 
X 
X 
X 
 
Study drug accountability 
 
X 
 
X 
X 
 
X 
 
X 
X 
Recording of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
 
X 
X 
 
X 
X 
X 
X d 
Dispense IMP to patient/caregiver and provide 
dosing instructions 
 
X 
 
X 
X 
 
 
 
 
X d 
FSH (♀ who are not surgically sterile and are 
postmenopausal, only) 
X 
 
 
 
 
 
 
 
 
 
Urine hCG (♀ of childbearing potential, only) g 
X 
X 
 
X 
X 
 
X 
 
X 
X d 
Hematology h, chemistry (including liver function) i 
X 
X 
 
X 
X 
 
X 
 
X 
X d 
TSH, freeT3 and free T4 
X 
 
 
 
 
 
 
 
 
 
Vitamin B12 
X 
 
 
 
 
 
 
 
 
 
Urinalysis j 
X 
X 
 
X 
X 
 
X 
 
X 
X d 
SYN120 blood sampling k 
 
X 
 
X l 
X l 
 
X 
 
X l 
X d, l 
12-lead electrocardiogram m 
X 
X n 
 
X 
X 
 
X 
 
X 
X d 
Pharmacogenetic sample collection (optional) 
 
X o 
 
X p 
X p 
 
X p 
 
 
 


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Table 1: 
Schedule of Events/Evaluations (cont.) 
 
♀ = female; AEs, adverse events; ADAS-cog, Alzheimer’s Disease Assessment Scale–cognitive subscale; ADCS-CGIC, Alzheimer’s Disease Cooperative Study-Clinician’s Global 
Impression of Change; BP, blood pressure; CDR, Cognitive Drug Research; C-SSRS, Columbia-Suicide Severity Risk Scale; ECG, electrocardiogram; FSH, follicle stimulating hormone; 
hCG, human chorionic gonadotropin; IMP, investigational medicinal product; MoCA, Montreal Cognitive Assessment; NPI, Neuropsychiatric Inventory; PD, Parkinson’s disease; 
PDAQ, Brief Penn Daily Activities Questionnaire; PDD, Parkinson’s disease dementia; SAPS-PD, PD-Adapted Scale for Assessment of Positive Symptoms; SCOPA-SLEEP, Scales for 
Outcomes in Parkinson’s Disease-Sleep Scale; TSH, thyroid stimulating hormone; UPDRS, Unified Parkinson’s Disease Rating Scale. 
Footnotes: 
a Screening period may not exceed 6 weeks. Note: For screen failures, document demographics and reason for ineligibility in source documents and eCRF. 
b At Screening, obtain complete medication history including anti-dementia and anti-Parkinson medications (current and those received within the past year). Record the date and time of the 
most recent dose of each anti-dementia and anti-Parkinson medication taken prior to the Screening assessment. 
c BP and pulse are to be measured after at least 5 minutes supine rest and again after standing for 1 and 3 minutes. At Screening Visit three sets of readings are performed approximately 10 
minutes apart. This is the only visit with 3 sets of BP readings. 
d Optional assessments that may be performed for evaluation of AEs, at the Investigator’s discretion. 
e Perform all cognitive and dementia-related assessments while patient is in ON state. Complete two training sessions during the screening period, as close to the Baseline visit as possible. 
f UPDRS is to be measured in ON 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 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. 
g For female patients of childbearing potential, perform a urine hCG pregnancy test and document method of contraception at Screening and verify continuation of contraceptive method at each 
visit. 
h Hematology: hemoglobin, hematocrit, red blood cell count, total and differential white blood cell, and platelet count. 
i Chemistry: aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), 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, and creatine phosphokinase (CK). 
j Urinalysis: specific gravity, pH, ketones, blood, protein, and glucose. If urine dipstick positive for leukocytes, protein or erythrocytes, microscopic evaluation will be performed. 
k Blood sample for determination of SYN120 plasma concentration 
 to be obtained at Baseline (Day 1) prior to initiation of dosing, Visit 4 
(Week 4), Visit 5 (Week 8), Visit 7 (Week 16), Early Termination (if applicable), and Unscheduled Visit (optional, as per footnote d). Record date and time of SYN120 sample collection.  
l For blood sample collections at Visit 4 (Week 4), Visit 5 (Week 8), Visit 7 (Week 16), and Early Termination or Unscheduled Visit (if applicable), record the date and time when the patient 
took the last dose of IMP. 
m Resting supine 12-lead ECGs will be collected after the patient has been in a supine, or if unable, semi-supine (no more than 45 degrees) position for a minimum of 5 minutes. ECGs should be 
collected at a time during study visit when the patient is not experiencing dyskinesia that would interfere with an adequate recording. 
n At Baseline, obtain triplicate 12-lead ECGs (3 serial readings performed several minutes apart). 
o At Baseline, for patients who give consent for optional pharmacogenetic substudy, collect single blood sample  (approximately 10 mL) for pharmacogenetic assessment. (If this 
sample is not collected at Baseline, it will be collected at the next possible in-clinic visit, i.e., Visit 4, 5 or 7.) See Section 7.13. 
p For patients who give consent for optional pharmacogenetic substudy but sample not collected at Baseline (or during previous visit), collect single blood sample  (approximately 10 
mL) for pharmacogenetic assessment. See Section 7.13. 
 
 


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TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ..........................................................................................2 
1.0 
BACKGROUND AND RATIONALE ...........................................................................28 
1.1 
Background ............................................................................................................28 
1.2 
Primary Target: 5-HT6R ........................................................................................28 
1.2.1 
Preclinical Cognitive Data Using 5-HT6R Antagonists (Other than 
SYN120) ...............................................................................................29 
1.2.2 
Clinical Data in AD Using 5-HT6R Antagonists (Other than 
SYN120) ...............................................................................................29 
1.2.3 
Preclinical Cognitive Data Using SYN120 ...........................................30 
1.3 
Secondary Target: 5-HT2AR .................................................................................32 
1.4 
Previous Clinical Trials with SYN120 ..................................................................33 
1.4.1 
Study SYN120-CL01 Part A (Single Ascending Dose) .......................33 
1.4.2 
Study SYN120-CL01 Part B (Multiple Ascending Dose) ....................34 
1.4.3 
SYN120 Positron Emission Tomography (PET) Study ........................34 
1.5 
Trial Design/Methods ............................................................................................35 
2.0 
OBJECTIVES AND ENDPOINTS ................................................................................36 
2.1 
Objectives ..............................................................................................................36 
2.1.1 
Primary Efficacy Objective ...................................................................36 
2.1.2 
Key Secondary Efficacy Objective .......................................................36 
2.1.3 
Other Secondary Efficacy Objectives ...................................................36 
2.1.4 
Safety Objectives ..................................................................................37 
2.2 
Efficacy Endpoints .................................................................................................37 
2.2.1 
Primary Efficacy Endpoint ....................................................................37 
2.2.2 
Key Secondary Efficacy Endpoint ........................................................37 
2.2.3 
Other Secondary Efficacy Endpoints ....................................................37 
2.2.4 
Exploratory Endpoints ..........................................................................38 
2.2.5 
Safety Endpoints ...................................................................................38 
2.2.6 
Tolerability ............................................................................................38 
3.0 
STUDY DESIGN ..............................................................................................................39 
3.1 
Study Description...................................................................................................39 
3.1.1 
Study Duration Per Patient ....................................................................39 
3.1.2 
Planned Number of Patients and Sites ..................................................39 
3.1.3 
Anticipated Regions and Countries .......................................................40 
3.2 
Schedule of Events/Evaluations .............................................................................40 
3.3 
Schematic Diagram ................................................................................................40 
3.4 
Rationale for Dose Selection and Placebo Control ................................................42 
4.0 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................42 


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4.1 
Inclusion Criteria ...................................................................................................42 
4.2 
Exclusion Criteria ..................................................................................................43 
4.3 
Criteria for Withdrawal from Study Drug or Study Participation .........................45 
4.3.1 
Study Drug Withdrawal ........................................................................45 
4.3.2 
Withdrawal from Study Participation ...................................................46 
5.0 
STUDY TREATMENT(S) ..............................................................................................47 
5.1 
Description of Investigational Medicinal Products ................................................47 
5.2 
Treatment(s) to be Administered ...........................................................................47 
5.3 
Packaging ...............................................................................................................47 
5.4 
Labeling .................................................................................................................48 
5.5 
Handling and Storage Requirements .....................................................................48 
5.6 
Dosing Instructions ................................................................................................48 
5.7 
Drug Accountability...............................................................................................49 
5.8 
Procedures for Monitoring Patient Compliance ....................................................49 
5.9 
Concomitant Medications/Treatments ...................................................................49 
5.9.1 
Allowed Anti-Dementia Medications/Treatments ................................49 
5.9.2 
Prohibited Concomitant Medications/Treatments ................................50 
5.9.3 
Other Concomitant Medications/Treatments ........................................50 
5.10 
Blinding..................................................................................................................50 
5.10.1 
Procedures for Breaking the Treatment Blind in an Emergency 
Situation ................................................................................................51 
5.11 
Randomization and Numbering of Patients ...........................................................51 
6.0 
STUDY PROCEDURES BY VISIT ...............................................................................52 
6.1 
Overview of Study Procedures ..............................................................................52 
6.2 
Detailed Study Procedures .....................................................................................53 
6.2.1 
Recruitment and Written Informed Consent .........................................53 
6.2.2 
Visit 1 (Week -6 to -1) Screening and Baseline Predose ......................54 
6.2.3 
Visit 2 (Week 0) Baseline .....................................................................56 
6.2.4 
Visit 3 (Week 2) Telephone Call ..........................................................59 
6.2.5 
Visit 4 (Week 4) Study Visit .................................................................59 
6.2.6 
Visit 5 (Week 8) Study Visit .................................................................61 
6.2.7 
Visit 6 (Week 12) Telephone Call ........................................................63 
6.2.8 
Visit 7 (Week 16) End of Dosing ..........................................................63 
6.2.9 
Safety Follow-Up Visit, Visit 8 (Week 18) ..........................................65 
6.2.10 
Early Termination Visit ........................................................................66 
6.2.11 
Unscheduled Visit .................................................................................67 
7.0 
ASSESSMENT METHODS ............................................................................................69 
7.1 
Cognitive Drug Research Computerized Cognition Battery .................................69 


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7.2 
Alzheimer’s Disease Cooperative Study - Clinician’s Global Impression of 
Change (ADCS-CGIC) ..........................................................................................72 
7.3 
Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-cog) 
(Revised 10OCT13) ...............................................................................................72 
7.4 
Brief Penn Daily Activity Questionnaire (PDAQ) ................................................72 
7.5 
Parkinson’s Disease-Adapted Scale for Assessment of Positive Symptoms 
(SAPS-PD) (2013 Shortened Version) ..................................................................73 
7.6 
Neuropsychiatric Inventory (NPI) (Version 12) ....................................................73 
7.7 
Scales for Outcomes in Parkinson’s Disease-Sleep Scale (SCOPA-SLEEP) .......74 
7.8 
Montreal Cognitive Assessment (MoCA) (Original v7.1,Alternates v7.2 and 
v.7.3) ......................................................................................................................74 
7.9 
Unified Parkinson’s Disease Rating Scale (UPDRS) ............................................75 
7.10 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Revised 14JAN09) .............75 
7.11 
Laboratory Tests ....................................................................................................76 
7.11.1 
Hormones (Serum FSH and Urine HCG) .............................................77 
7.11.2 
Hematology ...........................................................................................78 
7.11.3 
Chemistry ..............................................................................................78 
7.11.4 
Thyroid Function ...................................................................................78 
7.11.5 
Urinalysis ..............................................................................................78 
7.12 
Blood Sampling for Bioanalytical Analysis ..........................................................78 
7.13 
Pharmacogenetic Substudy (Optional) ..................................................................79 
7.14 
Blood Pressure and Pulse .......................................................................................79 
7.15 
Physical and Neurological Examination ................................................................80 
7.16 
Twelve-lead Electrocardiogram .............................................................................80 
7.17 
Adverse Events ......................................................................................................81 
7.18 
Concomitant Medications ......................................................................................81 
8.0 
ADVERSE EVENTS .......................................................................................................81 
8.1 
Definition of Adverse Event ..................................................................................81 
8.2 
Procedures for Reporting and Recording Adverse Events ....................................81 
8.3 
Description of Adverse Events ..............................................................................82 
8.4 
Follow Up of Adverse Events ................................................................................82 
8.5 
Rule for Repetition of an Adverse Event ...............................................................82 
8.6 
Pregnancy ...............................................................................................................82 
8.7 
Overdose of Investigational Medicinal Product ....................................................83 
8.8 
Safety Data Monitoring ..........................................................................................83 
8.9 
Serious Adverse Events .........................................................................................84 
8.9.1 
Definition of Serious Adverse Event ....................................................84 
8.9.2 
Procedures for Reporting Serious Adverse Events ...............................85 
8.9.3 
Follow Up of Serious Adverse Events ..................................................85 


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8.9.4 
Immediate Reporting of Adverse Events ..............................................86 
8.9.5 
Anticipated Serious Adverse Events .....................................................86 
9.0 
STUDY MANAGEMENT AND ADMINISTRATION ................................................86 
9.1 
Adherence to Protocol............................................................................................86 
9.2 
Monitoring .............................................................................................................86 
9.2.1 
Definition of Source Data .....................................................................87 
9.2.2 
Source Data Verification .......................................................................88 
9.3 
Data Handling ........................................................................................................88 
9.3.1 
Case Report Form Completion..............................................................88 
9.3.2 
Database Entry and Reconciliation .......................................................89 
9.3.3 
Patient Screening and Enrollment Log/Patient Identification Code 
List ........................................................................................................89 
9.4 
Termination of the Study .......................................................................................89 
9.5 
Archiving and Data Retention ...............................................................................90 
9.6 
Audit and Inspection ..............................................................................................90 
9.7 
Good Clinical Practice ...........................................................................................91 
10.0 
STATISTICS ....................................................................................................................91 
10.1 
Definition of Analysis Sets ....................................................................................91 
10.2 
Study Variables ......................................................................................................91 
10.2.1 
Efficacy Variables .................................................................................91 
10.2.2 
Exploratory Efficacy Variables .............................................................92 
10.2.3 
Pharmacokinetic Variables....................................................................92 
10.2.4 
Safety Variables ....................................................................................93 
10.3 
General Statistical Considerations .........................................................................93 
10.4 
Planned Efficacy Analyses ....................................................................................93 
10.4.1 
Analysis of the Primary Efficacy Variable ...........................................93 
10.4.2 
Key Secondary Efficacy Analyses ........................................................94 
10.4.3 
Multiplicity Adjustment for Primary and Key Secondary Endpoints ...94 
10.4.4 
Other Efficacy Analyses .......................................................................94 
10.5 
Planned Safety and Other Analyses .......................................................................95 
10.5.1 
Safety Analyses .....................................................................................95 
10.5.2 
Other Analyses ......................................................................................95 
10.6 
Handling of Protocol Deviations ...........................................................................96 
10.7 
Handling of Dropouts or Missing Data ..................................................................96 
10.8 
Determination of Sample Size ...............................................................................97 
11.0 
ETHICS AND REGULATORY REQUIREMENTS ...................................................97 
11.1 
Informed Consent...................................................................................................97 
11.2 
Patient Identification Cards ....................................................................................98 


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11.3 
Institutional Review Boards and Independent Ethics Committees ........................98 
11.4 
Patient Privacy .......................................................................................................99 
11.5 
Protocol Amendments ............................................................................................99 
12.0 
FINANCE, INSURANCE, AND PUBLICATION ........................................................99 
13.0 
REFERENCES ...............................................................................................................100 
14.0 
APPENDICES ................................................................................................................104 
14.1 
UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria .........104 
14.2 
Movement Disorder Society Task Force – Clinical Diagnostic Criteria for 
Dementia Associated with Parkinson’s Disease ..................................................105 
14.3 
Medications Prohibited Within 4 Weeks Before Randomization and During 
Study ....................................................................................................................108 
14.4 
Unified Parkinson’s Disease Rating Scale (UPDRS) ..........................................109 
14.5 
Scales for Outcomes in Parkinson’s Disease-Sleep Scale (SCOPA-SLEEP) .....117 
14.6 
Neuropsychiatric Inventory (NPI) .......................................................................120 
 
LIST OF TABLES 
Table 1: 
Schedule of Events/Evaluations .............................................................................21 
Table 2: 
Outcome of Modeling (5-HT6R Occupancy) .........................................................35 
Table 3: 
Outcome of Modeling (5-HT2AR Occupancy) .......................................................35 
Table 4: 
Description of Investigational Medicinal Products ................................................47 
Table 5: 
Laboratory Measurements .....................................................................................77 
 
LIST OF FIGURES 
 
 
 
 
 
 
 
 
 
 
 
Figure 6: 
Schematic Diagram of Study Design ........................................................................41 
 
 
 


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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. 
The epidemiology of cognitive impairment in PD suggests that impairments occur in a range of 
cognitive domains, including memory, executive, visuo-spatial, attentional/working memory, 
and language functions; dementia is a common outcome; and other non-motor symptoms 
(e.g., hallucinations and depression) are risk factors for dementia. Cognitive deficits are 
associated with neurotransmitter impairment, including acetylcholine, dopamine, and 
norepinephrine. 
1.2 
Primary Target: 5-HT6R 
Serotonin (5-HT) plays an important role in the regulation of many functions, including 
cognition, mood, sleep, and in pathological states such as Alzheimer’s disease (AD) and PD 
(Meneses et al., 2011). 5-HT6 receptors (5-HT6R) are coupled to G proteins, inducing cAMP 
production through stimulation of adenylate cyclase activity. Human 5-HT6 receptors are 
localized in brain regions involved in learning and memory processes including hippocampus, 
amygdala, striatum and neocortex (King et al., 2008). Using the radiolabelled 5-HT6R antagonist 
[125I] SB-258585, autoradiographic binding studies in rat brain show high receptor levels in 
striatum. Similarly, immunohistochemical staining shows high receptor levels in striatum, cortex, 
and hippocampus (Yun et al., 2007). The 5-HT6R primary location in the striatum is relevant as 
cognitive dysfunction in PD links to striatal changes, particularly fronto-striatal alterations. 
While the mechanism by which 5-HT6R antagonists improve cognition in preclinical models and 
AD clinical studies is unknown, possible explanations relevant to Parkinson’s disease dementia 
(PDD) involve multiple neurotransmitter systems. 5-HT6R modulates cholinergic, dopaminergic, 
and glutamatergic function (Dawson et al., 2001; Hirst et al., 2006; King et al., 2008; 
Riemer et al., 2003; Woolley et al., 2004). Immunohistochemical staining for 5-HT6R reveal 


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that it is localized on dendrites, cell bodies, and postsynaptic sites, and is expressed in 
cholinergic, glutamatergic and GABAergic neurons (Woolley et al., 2004; Yun et al., 2007). It 
has been consistently described that the influence of 5-HT6R on memory is mediated, at least 
partially, by increased cholinergic neurotransmission (Ramirez, 2013). 5-HT6R antagonists 
increase acetylcholine release in vitro (Marcos et al., 2006) and in vivo (Riemer et al., 2003). 
Woolley et al. reported on the co-localization of 5-HT6R with GABAergic neurons 
(Woolley et al., 2004); the co-localization together with microdialysis data suggest that 5-HT6R 
antagonists modulate cholinergic and glutamatergic systems via disinhibition of GABAergic 
neurons. The 5-HT6R agonist, WAY-181187, elicits robust increases in extracellular levels of 
GABA and attenuates long term potentiation. West et al. conclude that 5-HT6R plays a role in 
the modulation of synaptic plasticity in hippocampal area CA1 and that the regulation of 
GABAergic interneuron activity may underlie the cognition enhancing effects of 5-HT6R 
antagonists (West et al., 2009). 
1.2.1 
Preclinical Cognitive Data Using 5-HT6R Antagonists (Other than SYN120) 
A large body of preclinical data supports the use of 5-HT6R antagonists to improve cognition 
(Ramirez, 2013; Meneses et al., 2011; Fone, 2008). Blocking 5-HT6R produces anti-amnesic 
effects in the water maze, passive avoidance, autoshaping, fear conditioning, novel object 
recognition, and social memory (Meneses et al., 2001). 5-HT6R antagonists have been reported 
to be active in the novel object discrimination test in rats and to improve water maze retention in 
aged rat (Hirst et al., 2006). Consistently, 5-HT6R antagonists reverse scopolamine-induced 
cognitive deficits in the Morris water maze and novel object recognition test (de Bruin et al., 
2011). 5-HT6R blockade alleviates memory deficits more than improving memory in normal 
animals (Ramirez, 2013). 
Combining SB-271046 with a cholinesterase inhibitor produces an additive increase in passive 
avoidance and scopolamine-induced amnesia (Marcos et al., 2008). The combined 
administration of sub-threshold doses of two 5-HT6R antagonists, CMP X & CMP Y, with 
donepezil enhanced memory performance in rats with cognitive deficits induced by scopolamine 
(de Bruin et al., 2011). 
1.2.2 
Clinical Data in AD Using 5-HT6R Antagonists (Other than SYN120) 
SB-742457 (15 mg and 35 mg) was evaluated in a 3-arm, double-blind, placebo-controlled study 
in 684 mild to moderate AD patients taking donepezil. At 24 weeks, significant differences in 
favor of the 35 mg dose group were seen using ADAS-cog with a placebo-corrected change from 
baseline of 1.5 points, and a favorable trend on the Alzheimer’s Disease Cooperative Study – 
Activities of Daily Living (ADCS-ADL) (GlaxoSmithKline [GSK] Study AZ3110866). 
As monotherapy, SB-742457 was evaluated in three 6-month AD studies. In one, 371 patients 
received placebo or 5, 15, or 35 mg/day. A significant linear trend in response across increasing 
doses on the Clinician's Interview Based Impression of Change Plus Caregiver Input (CIBIC+) 


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was seen, and a near-significant linear trend in ADAS-cog compared to placebo was noted for 
the 35 mg/day group (Maher-Edwards et al., 2010). The second study was an exploratory study 
evaluating the efficacy of a dose of 35 mg/day that was titrated from 15 mg/day for the first 
4 weeks, with donepezil titrated from 5 mg/day to 10 mg/day during the first 4 weeks, and 
placebo. The differences from placebo at Week 24 for SB-742457 on CIBIC+ and ADAS-cog in 
this study were consistent with those observed in the previous Phase 2 study. There were also 
differences from placebo observed for donepezil. This study was not powered for formal 
hypothesis testing of superiority of either drug to placebo (Maher-Edwards et al., 2011). In the 
third study, 574 patients with mild to moderate AD received placebo, donepezil titrated from 
5 mg/day to 10 mg/day during the first 4 weeks, and SB-742457 at 15 or 35 mg/day. SB-742457 
at either dose did not show improvements in ADAS-cog and CIBIC+; donepezil showed a 
statistically significant improvement on CIBIC+, but not on ADAS-cog. In summary, this study 
was considered to partially flawed (GSK Study AZ3110865). 
A placebo-controlled study of AE58054 in 278 moderate AD patients on donepezil for 24 weeks 
demonstrated placebo-adjusted ADAS-cog changes from baseline of 2.2 (p=0.004). The 
ADCS-ADL, AD Cooperative Study-Clinician’s Global Impression of Change (ADCS-CGIC), 
and Neuropsychiatric Inventory (NPI) all showed favorable trends (Colding-Jǿrgensen et al., 
2014). 
1.2.3 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4 
 
 
 
 
 
 
 
 
 
 


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1.5 
Trial Design/Methods 
This placebo-controlled, randomized, double-blind study will assess the safety and efficacy of 
SYN120 in PDD patients as adjunctive therapy to a cholinesterase inhibitor. This 16-week study 
will randomize 80 patients to placebo or SYN120 100 mg daily in a 1:1 ratio. Patients will be 
required to be taking a cholinesterase inhibitor because this is largely considered to be the 
standard of care; furthermore, both preclinical and clinical data suggest that 5-HT6R antagonists 
exert a more robust efficacy signal as adjunct to cholinesterase inhibitors. 
The primary endpoint will be based on the CDR Computerized Cognition Battery Continuity of 
Attention. The key secondary endpoint is CDR Quality of Episodic Memory. Several secondary 
outcome variables will be used to further elucidate SYN120’s anti-dementia activity including 
the ADCS-CGIC, ADAS-cog, CDR Power of Attention, and CDR Speed of Memory Retrieval. 
ADCS-CGIC is a seven-point scale that provides a global rating of change from baseline. The 
ADAS-cog subscale consists of 11 tasks measuring alterations of memory, language, praxis, 
attention and other cognitive abilities. To assess function, the 15-item Brief Penn Daily 
Activities Questionnaire (PDAQ) will be used (Weintraub et al., 2013). The Scales for 
Outcomes in Parkinson’s Disease-Sleep Scale (SCOPA-SLEEP) will be used to assess if 
SYN120 improves nighttime sleep and daytime sleepiness. The Parkinson’s Disease-Adapted 
Scale for Assessment of Positive Symptoms (SAPS-PD) and NPI will be used to determine if 
SYN120 improves psychosis or neurobehavioral disturbances. 
 


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Overall, the safety and efficacy data collected to date support further evaluation of SYN120 as a 
treatment for patients with PDD. 
Please refer to the current SYN120 Investigator’s Brochure (IB) for further information. 
2.0 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective of this study is to assess the efficacy of a fixed dose of SYN120 
on cognition as determined by the Cognitive Drug Research Computerized Cognition Battery 
(CDR) Continuity of Attention in patients with PDD treated with a stable dose of a 
cholinesterase inhibitor. 
2.1.2 
Key Secondary Efficacy Objective 
The key secondary efficacy objective is to assess the effects of SYN120 on CDR Quality of 
Episodic Memory. 
2.1.3 
Other Secondary Efficacy Objectives 
The other secondary efficacy objectives are: 
1. To assess the effects of SYN120 on the Alzheimer’s Disease Cooperative Study-
Clinician’s Global Impression of Change (ADCS-CGIC). 
2. To assess the effects of SYN120 on the Alzheimer’s Disease Assessment Scale-Cognitive 
Subscale (ADAS-cog). 
3. To assess the effects of SYN120 on CDR Power of Attention. 
4. To assess the effects of SYN120 on CDR Speed of Memory Retrieval. 


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5. To assess the effects of SYN120 on the PDAQ. 
6. To assess the effects of SYN120 on the SCOPA-SLEEP (nighttime sleep and daytime 
sleepiness). 
7. To assess the effects of SYN120 on the SAPS-PD. 
8. To assess the effects of SYN120 on the NPI. 
9. To assess the effects of SYN120 on the Montreal Cognitive Assessment (MoCA). 
2.1.4 
Safety Objectives 
The safety objectives of this study are to assess the safety and tolerability of SYN120 by 
assessing AEs, vital signs (including orthostatic blood pressure measurements), laboratory 
assessments, Unified Parkinson’s Disease Rating Scale (UPDRS) Parts I-IV, Columbia-Suicide 
Severity Rating Scale (C-SSRS), and ECGs. 
2.2 
Efficacy Endpoints 
2.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline to Week 16 on the CDR 
Computerized Cognition Battery Continuity of Attention captured in the ON state. 
2.2.2 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the change from Baseline to Week 16 on the CDR 
Quality of Episodic Memory captured in the ON state. 
2.2.3 
Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are the change from Baseline to Week 16 on the 
following measures: 
1. Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change 
(ADCS-CGIC) captured in the ON state. 
2. Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) total score 
captured in the ON state by an evaluator blinded to the results of all cognitive 
assessments. 
3. CDR Power of Attention in the ON state. 
4. CDR Speed of Memory Retrieval in the ON state. 
5. PDAQ(reported by caregiver). 


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6. SCOPA-SLEEP (nighttime sleep and daytime sleepiness). 
7. SAPS-PD. 
8. NPI (reported by caregiver). 
9. MoCA. 
2.2.4 
Exploratory Endpoints 
Exploratory efficacy endpoints include the change from Baseline to Week 16 on the individual 
component tasks of the CDR, i.e., Word Presentation, Immediate Word Recall, Picture 
Presentation, Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Numeric Working 
Memory, Spatial Working Memory, Delayed Word Recall, Word Recognition, and Picture 
Recognition. 
2.2.5 
Safety Endpoints 
The safety of SYN120 will be evaluated using the following measures: 
1. AE reports. 
2. Supine and standing blood pressure (BP) and pulse. 
3. Safety labs: hematology, chemistry, and urinalysis. 
4. UPDRS Parts I-IV. 
5. C-SSRS. 
6. 12-lead ECGs. 
7. Concomitant medication assessment. 
2.2.6 
Tolerability 
Tolerability of SYN120 will be evaluated using the following measures: 
1. Proportion of participants discontinuing IMP. 
2. Proportion of participants discontinuing IMP due to an AE. 
3. Time to discontinuation of IMP. 


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3.0 
STUDY DESIGN 
3.1 
Study Description 
This is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
2-arm study in patients with PDD treated with a stable dose of a cholinesterase inhibitor. The 
study includes a Screening Period of up to 6 weeks that starts with a Screening Visit, followed by 
a 16-week Treatment Period and a 2-week post dose Safety Follow Up Period. After providing 
legally effective written informed consent, patients will undergo screening evaluations. Patients 
must meet all inclusion criteria and none of the exclusion criteria to be considered for 
randomization. Final eligibility will be determined at the Baseline Visit. 
Eligible patients will be randomized at the Baseline Visit (Week 0) to receive placebo or 
SYN120 (100 mg QD), in a ratio of 1:1. Double-blind investigational medicinal product (IMP) 
will be dispensed to patients upon randomization and at each clinic visit, with instructions to take 
2 tablets of IMP daily for 16 consecutive weeks. Patients will return to the study site for 
evaluation at Weeks 4, 8 and 16. They will be contacted by telephone at Weeks 2 and 12 for 
assessment of AEs. Patients will return to the study site for a Safety Follow Up Visit 
approximately 2 weeks after their last dose administration (i.e., 14 ± 3 days after the Week 16 
Visit). 
Unscheduled visits to the clinic because of AEs or lost or stolen IMP can be arranged as 
considered necessary by the Investigator. Patients terminating early will undergo an Early 
Termination Visit, ideally under study medication, and should return for a Safety Follow Up 
Visit approximately 2 weeks after their last dose administration. 
3.1.1 
Study Duration Per Patient 
Each patient will participate in the study for up to 24 weeks, which includes a Screening Period 
of up to 6 weeks, followed by a Baseline Visit, 16 weeks of double-blind treatment, and a 2-week 
post dosing Safety Follow-Up Visit: 
• Screening Period: 1–6 weeks. 
• Treatment Period: 16 weeks. 
• Safety Follow-Up Period: 2 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, 120 patients will be screened, assuming a 33% screen failure rate, to randomize 
80 patients. 
Approximately 12 sites will participate in the study. 


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3.1.3 
Anticipated Regions and Countries 
This study will be conducted in the US. 
3.2 
Schedule of Events/Evaluations 
The Schedule of Events/Evaluations is shown in Table 1. 
3.3 
Schematic Diagram 
A schematic diagram of the study design is provided in Figure 6, below. 
 


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Figure 6: 
Schematic Diagram of Study Design 
Screening Period 
(up to 6 weeks) 
16-Week Treatment Period 
(16 weeks of double-blind IMP) 
Safety Follow Up 
Period* 
 
Baseline/ 
Randomization 
Visit 
Telephone 
Call 
Onsite 
Visit 
Onsite 
Visit 
Telephone 
Call 
Onsite 
Visit 
Safety Follow Up 
Onsite Visit 
 
 
 
 
 
 
 
 
 
 
SYN120 
100 mg* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
W −6 to −1 
W0 
W2 
W4 
W8 
W12 
W16 
W18 
(14 ± 3 days after last 
dose of IMP) 
 
V=Visit; W=Week. 
* For each patient, dose escalation will proceed as follows: Total daily dose of 20 mg QD for the first 7 days, 50 mg QD for the next 7 days, and 100 mg QD for the 
remaining 14 weeks. 
 


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3.4 
Rationale for Dose Selection and Placebo Control 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo was chosen as a comparator to establish a clear effect of SYN120 in patients with PDD. 
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. Male or female and aged ≥ 50 years. 
2. Caregivers and patients (or legal representative) must understand and have signed an 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved informed 
consent form to participate in this study. 
3. Caregivers and patients (or legal representative) must be able to understand study 
requirements and be willing to follow instructions, attend all required study visits, and 
undergo all planned tests. 
4. Patients are required to have contact with a responsible caregiver at least 3 days per week. 
5. Patient has a documented history of idiopathic Parkinson’s disease (PD) consistent with the 
UK Parkinson’s Disease Society Brain Bank Diagnostic criteria. 
6. The patient and/or caregiver have noted a cognitive decline and the patient has a diagnosis of 
probable PD dementia (PDD) according to the Movement Disorder Society Task Force 
clinical diagnostic criteria for dementia associated with PD (Section 14.2), with the onset of 
PDD symptoms occurring at least one year after the diagnosis of PD. 


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7. Patient has a Montreal Cognitive Assessment (MoCA) score of 10 to 23, inclusive, at 
Screening. 
8. Patients must be on a stable regimen of cholinesterase inhibitor (Exelon®, Aricept®, or 
Reminyl® or their generic equivalent) for a minimum of 12 weeks prior to randomization. 
Treatment with memantine (Ebixa® or generic equivalents) is permitted, provided the dose 
has been stable for a minimum of 8 weeks prior to randomization. 
9. Patient is maintained on a regimen of permitted anti-Parkinson medications (containing 
levodopa, dopamine agonists, MAO-B inhibitors, the COMT inhibitor entacapone, or the 
NMDA receptor antagonist amantadine), that has been stable for at least 4 weeks prior to 
Baseline.  
10. 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 one year absence of 
vaginal bleeding or spotting) as confirmed by FSH greater than or equal to 40 mIU/mL or 
40 IU/L 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. 
Note: For men and women, acceptable methods of contraception include use of a condom 
with spermicide or use of oral, implantable or injectable contraceptives, or IUD, or a 
diaphragm with spermicide or diaphragm with condom. 
11. Patients receiving treatment for depression may be enrolled if they have been on a stable 
daily dose of the antidepressant for ≥8 weeks before Baseline. 
4.2 
Exclusion Criteria 
Patients with any of the following characteristics will be excluded from the study: 
1. History of any significant neurologic or psychiatric disease other than PD not limited to, 
but including Alzheimer's disease (before onset of PD symptoms), multi-infarct or vascular 
dementia, Huntington's disease, normal pressure hydrocephalus, progressive supranuclear 
palsy, multiple sclerosis, intellectual disability/intellectual developmental disorder, Lewy 
body dementia, fronto-temporal dementia, major cortical stroke, major head trauma, 
primary or secondary cerebral neoplasia (except for benign stable extra-axial 
meningiomas), history of significant head trauma followed by persistent neurologic 


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deficits, known structural brain abnormalities, delirium, schizophrenia or schizoaffective 
disorder. 
2. Treatment with any other investigational drug within 5 half-lives or 30 days prior to 
screening (whichever is longer) or any investigational device within 30 days. 
3. Any other condition or clinically significant abnormal findings on the physical or 
neurological examination, medical and psychiatric 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 study drug. 
4. Women who are pregnant or lactating. 
5. Orthostatic hypotension requiring medication. 
6. Hyperthyroidism or hypothyroidism, unless they meet all of the following conditions: 
a. They have received a stable dose of thyroid medication for at least 3 months prior to 
Baseline Visit. 
b. TSH concentrations are normal or within 10% of the upper or lower limit of the 
normal range. 
c. They are clinically euthyroid. 
7. Clinically significant abnormal Vitamin B12 levels at Screening. 
8. Any other out-of-range laboratory value at screening that have not been reviewed, 
approved, and documented as not clinically relevant by the Investigator. 
9. Have a known allergy or sensitivity to SYN120 or any of its components. 
10. Suicidal ideation on the C-SSRS of type 4 or type 5, or any suicidal behavior, in the past 
6 months. Type 4 indicates active suicidal ideation with some intent to act, without a 
specific plan. Type 5 indicates active suicidal ideation with specific plan and intent. 
11. Use of centrally acting anticholinergic drugs 
 
during the 4 weeks before randomization (Section 14.3). 
12. Treatment with any dopamine receptor blocking medication with the exception of low 
dose quetiapine (≤50 mg/day). 
13. History of neurosurgical intervention for PD. 


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14. QTcF interval of ≥ 500 msec at Screening or an average QTcF interval ≥ 450 msec for 
males and ≥ 470 msec for females at Baseline (Section 7.16). 
15. Unpredictable motor fluctuations that would interfere with administering all cognitive 
assessments in the ON state. 
4.3 
Criteria for Withdrawal from Study Drug or Study Participation 
4.3.1 
Study Drug Withdrawal 
Investigators must contact the Medical Monitor to discuss any of the following events which 
may lead to the patient discontinuing study drug: 
1. Patient is noncompliant with the study procedures or medications. 
2. Patient takes prohibited concomitant medications as defined in this protocol or receives 
prohibited neurosurgical intervention for PD. 
3. Patient has a clinically significant out-of-range laboratory value(s) or clinically significant 
abnormal finding(s) on physical examination or intolerable AEs (as determined by the 
patient) or that put the patient at additional risk as judged by the Investigator. 
4. Patient’s PDD symptoms worsen to the extent that, in the judgment of the Investigator, 
they require the addition of new anti-dementia medication or an increase in the dose of 
their concomitant cholinesterase inhibitor medication. 
Any withdrawal of a patient from the study or discontinuation of study drug should be discussed 
with the Medical Monitor. Patients must discontinue study drug if any of the following events 
occur: 
1. Patient develops an illness that would interfere with his or her continued participation. 
2. Patient or caregiver (or legal representative, if applicable) withdraws consent. 
3. There is confirmation of a 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. 


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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 (see 
Section 7.16). 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 alanine transaminase (ALT) or aspartate transaminase (AST) > 8x upper 
limit of normal (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%) must be immediately temporarily or 
permanently discontinued from investigational product. 
* Patients with significant elevation of ALP (ALP > 2x ULN) indicating biliary obstruction 
to be discussed with Study Physician. 
4.3.2 
Withdrawal from Study Participation 
Patients are free to withdraw from the study at any time, without prejudice to their continued 
care. 
All patients who discontinue prematurely from the study will be requested to return for a clinic 
visit that includes all safety procedures and efficacy measures as outlined for the Early 
Termination Visit in the Schedule of Events/Evaluations (Table 1). The Early Termination Visit 
should be done under IMP treatment, if possible. 
For any early discontinuation, the patient will be requested to return for a Safety Follow-Up Visit 
14 days after the last dose of IMP, unless the Early Termination Visit itself occurs 14 or more 
days after the last dose of IMP. All treatment-emergent, clinically significant AEs will be 
followed until resolution, return to Baseline level, or stabilization. 
Patients who prematurely withdraw from the study will not be replaced. 


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Investigators should attempt to obtain information on patients in the case of study withdrawal. 
Participants who discontinue study drug but do not withdraw consent should continue to be 
followed according to the normal schedule of assessments. 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. 
Investigators should contact the Medical Monitor, whenever possible, to discuss in advance the 
withdrawal of a patient from the study. 
5.0 
STUDY TREATMENT(S) 
5.1 
Description of Investigational Medicinal Products 
Table 4: 
Description of Investigational Medicinal Products 
 
SYN120 
Placebo for SYN120  
Dosage Form 
Tablets (yellow, film-coated) 
containing 10 or 50 mg 
SYN120 
Tablets (yellow, film-coated), 
matched to 10 or 50 mg 
SYN120 tablets (active) 
Route of Administration 
Oral 
Batch Number 
Will be assigned according to Good Manufacturing Practice 
(GMP) 
Re-test Date 
Will be assigned according to GMP 
 
5.2 
Treatment(s) to be Administered 
Investigational medicinal products are comprised of immediate-release, active and placebo 
tablets for oral administration, as described above. Placebo tablets are visually and physically 
indistinguishable from the active drug product and contain no active ingredient. 
5.3 
Packaging 
The IMP will be packaged in a double-blind fashion according to current GMP guidelines and 
applicable national laws and regulations. They will be packaged in such a way as to protect the 
products from deterioration during transport and storage. 


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IMP will be packaged in blister cards containing twenty-eight (28) days per card. Each blister 
card will be labeled with a unique number corresponding to the randomization assignment. In 
addition, for each dispensing event one (1) reserve wallet will be provided to accommodate visit 
windows. The first blister card to be dispensed has an orange label designated as Weeks 1-4 and 
contains the doses during titration. 
Sites will be supplied with an initial stock and resupply will be provided throughout the duration 
of the study in order to ensure sufficient supplies are available on site. 
5.4 
Labeling 
Investigational medicinal product will be labeled in accordance with current FDA requirements 
and GMP. 
5.5 
Handling and Storage Requirements 
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site in 
accordance with labeling and written storage instructions. Investigational medicinal product 
stored by the Investigator is to be kept in a secured area with limited access. 
SYN120 tablets and placebo tablets should be stored at temperatures between 15°C and 25°C 
(59°F to 77°F) or under conditions meeting the US Pharmacopeial Convention (USP) 
requirements for Controlled Room Temperature. Appropriate storage conditions must be ensured 
either by controlled room temperature or by completion of a temperature log in accordance with 
local requirements on a regular basis (e.g., once a week), 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 (or designee) before further use of the IMP. The Sponsor (or 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 (or 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 following the instructions 
on the label. 
5.6 
Dosing Instructions 
Randomized patients, after taking the first dose in the clinic, will be instructed to take 2 tablets 
of the dispensed blinded IMP in the morning, approximately 30-60 minutes after breakfast, 
preferably at the same time each day, using the blister cards dispensed by study site personnel for 
a given study week. 


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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 course of the study. Details of 
any IMP lost (due to breakage or wastage), not used, disposed of at the study site, or returned to 
the Sponsor or designee must also be recorded on the appropriate forms. All supplies and 
pharmacy documentation must be made available throughout the study for Sponsor (or designee) 
to review. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed. 
The Investigator must ensure that the IMP is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers) and unused IMP containers must be reconciled and either returned to Sponsor (or 
designee), preferably in their original package, or destroyed on-site according to the site’s 
SOP(s). Refer to the Pharmacy Manual for instructions. Investigational medicinal product 
intended for the study cannot be used for any other purpose than that described in this protocol. 
5.8 
Procedures for Monitoring Patient Compliance 
At each visit after IMP is dispensed, patients must return all unused IMP and empty IMP 
containers. 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 the patient’s Safety 
Follow Up Visit (or Early Termination Visit, if applicable), the authorized study staff will enter 
the date of the last dose of IMP into the eCRF registering 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 or designee, in conjunction with the Investigator, will make a decision as to whether the 
patient should remain on study drug. 
5.9 
Concomitant Medications/Treatments 
5.9.1 
Allowed Anti-Dementia Medications/Treatments 
Patients must be on a stable regimen of a cholinesterase inhibitor for at least 12 weeks before 
randomization. Treatment with memantine (Ebixa® or generic equivalents) is permitted, 
provided the dose has been stable for a minimum of 8 weeks prior to randomization. 
After randomization, all efforts should be made to maintain patients on the same stable dose of 
every anti-dementia and anti-Parkinson medication throughout the study. The addition of a new 
anti-dementia or anti-Parkinson medication is not permitted during the study; however, a 


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decrease in total daily anti-dementia or anti-Parkinson medication dose because of 
medication-related AEs is permitted. Following a dose decrease of any anti-dementia or anti-
Parkinson medication, the dose may be increased again but cannot exceed the total daily dosage 
at randomization. Patients will use their own supply of cholinesterase inhibitor and anti-
Parkinson medications. 
5.9.2 
Prohibited Concomitant Medications/Treatments 
The following concomitant medications and therapies are prohibited during the study: 
1. Neurosurgical intervention for PD, including but not limited to deep brain stimulation. 
2. Centrally acting anticholinergic drugs are prohibited for 4 weeks before randomization 
and throughout the study. See Section 14.3. 
3. 
 
 
5.9.3 
Other Concomitant Medications/Treatments 
Patients taking thyroid medication for hypothyroidism or hyperthyroidism must be on a stable 
dose for at least 3 months prior to the Screening Visit. 
Restrictions on pre-study use of medications are described in Section 4.2, Exclusion Criteria, and 
these restrictions will continue throughout the study. 
During the study, patients are asked to refrain from the use of any concomitant medication, 
including herbal and over-the-counter medicines, without the specific prior approval by the 
Investigator. Any medication taken by a patient during the course of the study and the reason for 
its use will be recorded in the source documents and eCRF. 
5.10 
Blinding 
The randomization schedule will be produced by an unblinded statistician who is otherwise not 
involved with the study team, Steering Committee, or Sponsor. The randomization schedule will 
use permuted blocks, stratified by site. The IMP vendor will generate unblinding scratch-off 
labels for patients’ randomization assignments based on the randomization schedule produced by 
the unblinded statistician. The randomization schedule and unblinding scratch-off labels will be 
kept strictly confidential until the time of unblinding and should not be scratched off without 
authorization. Blinding will not be compromised for individuals involved with operational 
aspects of the study or individuals involved with the planning and conduct of the final statistical 
analyses, including an independent statistician. Scratch-off labels should be removed from the 
kit and adhered in the patient’s source document. 


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The identity of the dosing group assignments will be concealed by identical appearance, 
packaging, labeling, and schedule of administration. 
5.10.1 
Procedures for Breaking the Treatment Blind in an Emergency Situation 
In the event of an emergency, during which knowledge of the IMP received would affect the 
medical management of the patient, or for a regulatory requirement, it will be possible for the 
Investigator to determine to which treatment arm and dose the patient has been allocated by 
accessing the unblinding scratch-off label for the given patient, which must be maintained in 
the source documentation. All sites will be provided with details of how to perform unblinding 
on an emergency basis at the start of the study. The Medical Monitor or equivalent should be 
consulted prior to unblinding, whenever possible. 
All events resulting in an unblinding event will be recorded and reported by the Investigator to 
the Medical Monitor and the Sponsor or designee. If the blind is broken for an individual patient 
due to a medical emergency, the date and time of unblinding together with the reason for the 
unblinding will be recorded in the patient’s source records, and all associated AE information 
will be included. The unblinding event and the date of unblinding will be noted in the eCRF to 
enable censoring of any data as appropriate. 
5.11 
Randomization and Numbering of Patients 
Assignment of the next available sequentially numbered kit at a given site will be used for 
assigning eligible patients to a treatment regimen based on a predetermined randomization 
schedule. The final randomization schedule will be created and sent to the clinical supply 
packaging vendor. The clinical supply packaging vendor is responsible for packaging blister 
cards of the blinded IMP into numbered kits according to the randomization and the visit 
schedule. 
To enroll a patient (Visit 1), the Investigator will assign a screening number to each patient, 
which serves as the patient identifier throughout the study. The patient number will be required 
in all communication between the Investigator (or designee) and the Sponsor or academic 
research organization (ARO) regarding a particular patient. Patient numbers and assigned IMP 
kit numbers will be tracked by the electronic data management system. 
To randomize a patient (Visit 2), the Investigator (or designee) will assign the next available 
sequentially numbered kit at the site to the patient. The assigned kit number will be recorded in 
the source and eCRF. The Investigator or a designated study coordinator or pharmacist will 
dispense the assigned IMP kit to the patient. 


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6.0 
STUDY PROCEDURES BY VISIT 
6.1 
Overview of Study Procedures 
An overview of the conduct of the study, including the timing of visits and assessments 
performed, may be found in Table 1. Details of assessment methods can be found in Section 7.0 
and Section 8.0, respectively, and in the applicable appendices. Pharmacokinetic sample 
collection is described in Section 7.12. Detailed procedures by study visit are provided in 
Section 6.2. 
Note: Laboratory supplies that are needed for protocol-specified tests will be provided by the 
central laboratory. 
Consenting patients will be screened for eligibility. Eligible patients who meet all the entry 
criteria at Baseline will be randomized to receive double-blind IMP for 24 weeks. The first dose 
of IMP will be administered at the study site during the Baseline Visit, approximately 30-60 
minutes after lunch or a substantial snack. It is recommended that patients remain at the 
clinic for 2-4 hours after initial dosing for observation. Patients will return to the study site 
for evaluation at Weeks 4, 8 and 16. They will be contacted by telephone at Weeks 2 and 12 for 
assessment of AEs. Patients and their caregivers will be requested to bring the IMP blister cards 
(used and unused) dispensed at the previous visit to the next clinic visit, to take their IMP in the 
morning, approximately 30 ‒ 60 min after breakfast, before the clinic visit (as applicable), and 
to bring their other medications with them to the clinic visit. 
Enrolled patients treated with levodopa who have end-of-dose motor fluctuations 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. UPDRS in 
OFF will not be evaluated. The Investigator or Sub-Investigator will perform the full UPDRS 
Parts I, II III (motor) and IV, approximately 1 to 3 hours after the patient has taken a scheduled 
dose of levodopa (preferably their morning dose of levodopa). UPDRS in ON will be measured 
at a time representative of the ON state in that patient, not in “best” ON. All cognitive and 
dementia-related assessments will be performed while the patient is in ON state. 
Blood pressure and pulse (supine and standing) will be taken at each outpatient visit. 
Patients will be assessed for safety and tolerability in a blinded fashion regularly throughout the 
study and approximately 2 weeks after their last dose of IMP. 
Please refer to the Schedule of Events/Evaluations in Table 1 for specific timing of assessments. 
At each visit, the investigator or Sub-Investigator will assess ON/OFF status only at the initiation 
of each assessment for each of the 3 cognitive scales (CDR, ADAS-cog and MoCA). 


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6.2 
Detailed Study Procedures 
6.2.1 
Recruitment and Written Informed Consent 
Interested patients and their caregivers (or legal representatives, if applicable) 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 still interested in participating after receiving an 
explanation of the study, patients and their caregivers (or legal representatives, if applicable) will 
be given an opportunity to review and inquire about the study-specific written informed consent 
form. Patients and their caregivers (or legal representatives, if applicable) should have ample 
time to think about the information in the written informed consent form and have a chance to 
discuss it with family members or other people. 
Any patient and caregiver (or legal representative, if applicable) who has difficulty 
understanding the information contained in the written informed consent form will be asked to 
reread the misunderstood portion(s) of the consent and discuss it with a research staff member 
until s/he shows complete understanding of the information discussed in the informed consent 
form, and may thus give full consent. Research staff will work closely with patients and their 
caregivers in an effort to help them understand the requirements of study participation. Patients’ 
and caregivers’ (or legal representatives’) questions must be answered fully by trained and 
qualified staff. Any patient or caregiver (or legal representative, if applicable) who is unable to 
demonstrate understanding of the information contained in the informed consent form will be 
excluded from study participation. 
Prior to a patient’s participation in the study, the written IRB/IEC-approved informed consent 
form will be signed and personally dated by the patient (or legal representative, if applicable) 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. 
The consent form and any other information provided to patients (or legal representative, if 
applicable) 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 consent form 
and information will receive IRB/IEC approval/favorable opinion prior to use, and a copy of said 
IRB approval/favorable opinion should be returned to the Sponsor. The Investigator, or a person 
designated by the Investigator, should 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 (or legal 
representative, if applicable) signing and personally dating the revised consent form and by 
written documentation of this discussion with the patient (or legal representative, if applicable) in 
the Investigator’s study files available to Sponsor for onsite review. 


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Each patient (or legal representative, if applicable) who consents to participate in the study will 
receive a copy of the signed and dated written informed consent form and any other information 
provided to patients prior to the participation in the study. The original signed forms will be 
maintained in the Investigator’s study file. 
After providing and documenting consent on the IRB/IEC-approved written informed consent 
form, patients will be assigned their patient screening number and proceed to the Screening 
Period. 
6.2.2 
Visit 1 (Week -6 to -1) Screening and Baseline Predose 
The following assessments will be obtained during the Screening Period and used to determine 
whether patients meet eligibility criteria for the study. Patients meeting eligibility criteria at 
Screening must also meet eligibility criteria at the Baseline Visit. 
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. Verify written informed consent has been signed and a copy provided to the patient and 
caregiver (or legal representative, if applicable). 
2. Obtain demographics and previous medical history including neurological and PD history. 
3. Assess and record any co-existing pretreatment AEs. 
4. Obtain complete medication history including anti-dementia and anti-Parkinson 
medications (current and those received within the past year). Record the date and time of 
the most recent dose of each anti-dementia and anti-Parkinson medication taken prior to 
the Screening assessment. 
5. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes, on 3 occasions approximately 10 minutes 
apart. 
6. Obtain weight and height. 
7. Perform physical and neurological exam. 
8. Administer the MoCA. 


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9. Administer the Cognitive Drug Research Computerized Cognition Battery (CDR) two 
times during the screening period, as close to the Baseline visit as possible. (Note: The 
CDR sample version administered at Screening will not be evaluated, but will be used to 
familiarize patients with the test procedures and reduce the risk of practice effects as a 
potential confounder.) 
10. Administer C-SSRS. 
11. Obtain 12-lead ECG and ensure the ECG is collected at a time when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
12. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Females who are not surgically sterile and are postmenopausal < 2 years: Obtain a 
blood sample for FSH. 
b. Females of childbearing potential: Obtain urine hCG pregnancy test; document method 
of contraception. 
c. Hematology and chemistry (including liver function tests). 
d. TSH, free T3, and free T4. 
e. Serum vitamin B12. 
f. Urine sample for urinalysis. 
13. If the patient does not meet the criteria for study participation, or if a laboratory result 
disqualifies the patient from participation in the study, the patient is considered a screen 
failure. Record the primary reason for screen failure in the appropriate eCRF module and 
on the Patient Screening/Enrollment Log. Schedule the patient’s next routine non-study 
visit as appropriate. 
14. For patients who appear to be eligible, proceed with scheduling the Baseline Visit, and 
instruct the patient and caregiver to bring the patient’s medications (including 
anti-dementia and anti-Parkinson medications) to the next study visit and to maintain their 
regular treatment schedule. 
15. If the patient is a screen failure, record the primary reason for screen failure in the 
appropriate eCRF module and on the Patient Screening/Enrollment Log. 
16. The following data must be collected for all consented individuals, even if they fail 
screening: demographics, and reason for ineligibility. 


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6.2.3 
Visit 2 (Week 0) Baseline 
6.2.3.1 
Pre-dosing Baseline Procedures 
Randomization will occur at the Baseline (Visit 2), after the patient’s eligibility for the study has 
been confirmed and all pre-dosing Baseline procedures have been performed. 
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-dementia and anti-Parkinson medications and other 
medications according to their regular treatment schedule. 
Note: Due to the time involved with the visit, the patient will need to eat lunch or a substantial 
snack during the visit approximately 30-60 minutes before dosing in the clinic.  
6.2.3.2 
Confirm Patient’s Eligibility for Study Participation 
1. Assess for any co-existing pretreatment AEs by asking open-ended queries and record the 
assessments. Evaluate pretreatment AEs (including any AEs noted during the Screening 
Visit plus any new onset AEs) to ensure patient’s continued eligibility for the study. 
a. If appropriate, a physical or neurological examination should be performed for an 
ongoing pretreatment AE. 
2. Record concomitant medication use and ensure there have been no changes in medication 
(particularly anti-dementia medication) since preliminary screening that would make the 
patient ineligible for the study. 
3. 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 appropriate eCRF 
module and on the Patient Screening/Enrollment Log. Schedule the patient’s next routine 
non-study visit as appropriate. 
6.2.3.3 
Perform Baseline Assessments 
1. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes. 


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2. Administer the following assessment instruments, in the order shown. The order may be 
adjusted to keep the physician assessments together; however, it is imperative that the 
CDR and ADAS-cog are performed first and second, in order to reduce the chance of 
patient fatigue. Perform all cognitive and dementia-related assessments while patient is in 
ON state. ON will be measured at a time representative of the ON state in that patient, not 
in “best” ON.   
a. CDR. 
b. ADAS-cog. 
c. Perform full UPDRS Parts I, II III (motor) and IV. 
For patients with motor fluctuations: Perform full UPDRS Parts I, II III (motor) and IV, 
approximately 1 to 3 hours after the patient has taken a scheduled dose of levodopa 
(preferably their morning dose of levodopa). UPDRS in ON will be measured at a time 
representative of the ON state in that patient, not in “best” ON. 
d. PDAQ (reported by caregiver). 
e. SCOPA-SLEEP. 
f. SAPS-PD. 
g. NPI (reported by caregiver).  
3. Administer C-SSRS. 
4. Obtain triplicate 12-lead ECGs (3 serial readings performed several minutes apart) and 
ensure the ECGs are collected at a time when the patient is not experiencing dyskinesia 
that would interfere with an adequate recording. 
5. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Females of childbearing potential: Obtain urine hCG pregnancy test; verify method of 
contraception has not changed since Screening. 
b. Hematology and chemistry (including liver function tests). 
c. Blood sample for SYN120 plasma concentration 
 
Record the date and time of SYN120 sample collection. 


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d. Blood sample for optional pharmacogenetic substudy (only if patient gave consent for 
the pharmacogenetic substudy): A single blood sample (approximately 10 mL) will be 
collected per patient. (If the sample is not collected at Baseline, it will be collected at 
the next possible visit.) See Section 7.13.  
e. Urine sample for urinalysis. 
6. 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 appropriate eCRF 
module and on the Patient Screening/Enrollment Log. Schedule the patient’s next routine 
non-study visit as appropriate. 
6.2.3.4 
Randomization and Dosing with Investigational Medicinal Product 
1. For patients meeting all entry criteria, obtain the randomization assignment by following 
the randomization procedures provided. 
2. Dispense the blister cards assigned according to the patient’s randomization assignment. 
a. Record the dates the patient should take IMP onto each blister card. 
3. Review the dosing instructions for the IMP with the patient and caregiver, answer any 
questions, and remind the patient and caregiver to return the blister cards at the next clinic 
visit. 
a. Patients and caregivers will be instructed that the patient is to take 2 tablets of the 
dispensed blinded IMP by mouth once daily, approximately 30-60 minutes after 
breakfast, preferably at the same time each day. 
b. Document patient and caregiver understood dosing instructions and the use of the extra 
days if visit delayed and/or use of visit window. 
4. Record the following information: patient randomization number, date and time blister 
card dispensed. 
a. Patient to take the first dose of IMP at study site, approximately 30 to 60 minutes after 
having consumed lunch or a substantial snack. All future doses will be taken 30-60 
minutes following breakfast. 
b. It is recommended that patients remain at the clinic for 2-4 hours for observation 
following dosing. If the patient develops symptoms consistent with hypotension, blood 
pressure and pulse readings should be performed. 
5. Schedule the Week 2 visit (telephone call). 


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6. Transcribe the randomization number on the paperwork for the laboratory samples that 
were drawn prior to receipt of IMP. 
7. Complete eCRF information in the designated modules. 
6.2.4 
Visit 3 (Week 2) Telephone Call 
1. Patients and caregivers will be reminded of the following: 
a. Instructions for taking the IMP. 
b. Need to bring the blister cards (used and unused) dispensed at the previous visit to the 
next clinic visit. 
c. Need to take the IMP in the morning, approximately 30 ‒ 60 min after breakfast, before 
the next clinic visit. 
d. Need to take all doses of their routine medications (including anti-dementia and 
anti-PD medications) according to their normal schedule on the day of the next clinic 
visit and to bring their medications with them to the visit. 
e. Date and time of the next clinic visit (Week 4). 
2. Assess AEs by asking open-ended queries and record the assessments. 
3. Complete eCRF information in the designated modules. 
6.2.5 
Visit 4 (Week 4) Study Visit 
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. Assess AEs by asking open-ended queries and record the assessments. 
2. Record concomitant medication use; assess and record any changes to anti-dementia or 
anti-Parkinson medication doses or regimens. 
3. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes. 
4. Perform physical and neurological exam. 


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5. Perform full UPDRS Parts I, II III (motor) and IV. 
For patients with motor fluctuations: Perform full UPDRS Parts I, II III (motor) and IV, 
approximately 1 to 3 hours after the patient has taken a scheduled dose of levodopa 
(preferably their morning dose of levodopa). UPDRS in ON will be measured at a time 
representative of the ON state in that patient, not in “best” ON. 
6. Administer C-SSRS. 
7. Obtain 12-lead ECG and ensure the ECG is collected at a time when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
8. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Females of childbearing potential: Obtain urine hCG pregnancy test; verify method of 
contraception has not changed since Screening. 
b. Hematology and chemistry (including liver function tests). 
c. Blood sample for SYN120 plasma concentration 
 
 Obtain and record the date and time when the patient took the 
last dose of IMP. Record the date and time of SYN120 sample collection. 
d. Blood sample for optional pharmacogenetic substudy (only if patient gave consent for 
the pharmacogenetic substudy and specimen was NOT collected during a previous 
visit): A single blood sample (approximately 10 mL) will be collected per patient. See 
Section 7.13. 
e. Urine sample for urinalysis. 
Note: For processing, labeling and shipping of samples, follow the instructions provided 
in the Central Laboratory Procedures Manual. 
9. Obtain the returned blister cards dispensed at the Baseline Visit: 
a. Assess and document the IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
b. Review and reconcile any discrepancies with the patient and caregiver. 


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10. Dispense blister card numbers per the patient’s randomization assignment (7 days per 
card) to the patient (includes 1 extra blister pack in case of delayed visit and/or use of visit 
window). 
a. Record the dates the patient should take IMP onto the blister cards. 
11. Review the dosing instructions for the IMP with the patient and caregiver, answer any 
questions, and remind the patient and caregiver to return blister cards at the next clinic 
visit. 
a. Document patient understood dosing instructions and the use of extra days if visit 
delayed and/or use of visit window. 
12. Schedule the next visit (Week 8). 
13. Complete eCRF information in the designated modules. 
6.2.6 
Visit 5 (Week 8) Study Visit 
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. Assess AEs by asking open-ended queries and record the assessments. 
2. Record concomitant medication use; assess and record any changes to anti-dementia or 
anti-Parkinson medication doses or regimens. 
3. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes. 
4. Perform physical and neurological exam. 
5. Administer the CDR while patient is in ON state. 
6. Perform full UPDRS Parts I, II III (motor) and IV. 
For patients with motor fluctuations: Perform full UPDRS Parts I, II III (motor) and IV, 
approximately 1 to 3 hours after the patient has taken a scheduled dose of levodopa 
(preferably their morning dose of levodopa). UPDRS in ON will be measured at a time 
representative of the ON state in that patient, not in “best” ON. 
7. Administer C-SSRS. 
8. Obtain 12-lead ECG and ensure the ECG is collected at a time when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 


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9. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Females of childbearing potential: Obtain urine hCG pregnancy test; verify method of 
contraception has not changed since Screening. 
b. Hematology and chemistry (including liver function tests). 
c. Blood sample for SYN120 plasma concentration 
 
 Obtain and record the date and time when the patient took the 
last dose of IMP. Record the date and time of SYN120 sample collection. 
d. Blood sample for optional pharmacogenetic substudy (only if patient gave consent for 
the pharmacogenetic substudy and specimen was NOT collected during a previous 
visit): A single blood sample (approximately 10 mL) will be collected per patient. See 
Section 7.13. 
e. Urine sample for urinalysis. 
Note: For processing, labeling and shipping of samples, follow the instructions provided in 
the Central Laboratory Procedures Manual. 
10. Obtain the returned blister cards dispensed at the Week 4 Visit: 
a. Assess and document the IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
b. Review and reconcile any discrepancies with the patient and caregiver. 
11. Dispense blister card numbers per the patient’s randomization assignment (7 days per 
card) to the patient (includes 1 extra blister pack in case of delayed visit and/or use of visit 
window). 
a. Record the dates the patient should take IMP onto the blister cards. 
12. Review the dosing instructions for the IMP with the patient and caregiver, answer any 
questions, and remind the patient and caregiver to return blister cards at the next clinic 
visit. 
a. Document patient and caregiver understood dosing instructions and the use of extra 
days if visit delayed and/or use of visit window. 
13. Schedule the Week 12 visit (telephone call). 
14. Complete eCRF information in the designated modules. 


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6.2.7 
Visit 6 (Week 12) Telephone Call 
1. Patients and caregivers will be reminded of the following: 
a. Instructions for taking the IMP. 
b. Need to bring the blister cards (used and unused) dispensed at the previous visit to the 
next clinic visit. 
c. Need to take the IMP in the morning, approximately 30 ‒ 60 min after breakfast, 
before the next clinic visit. 
d. Need to take all doses of their routine medications (including anti-dementia and 
anti-PD medications) according to their normal schedule on the day of the next clinic 
visit and to bring their medications with them to the visit. 
e. Date and time of the next clinic visit (Week 16). 
2. Assess AEs by asking open-ended queries and record the assessments. 
3. Complete eCRF information in the designated modules. 
6.2.8 
Visit 7 (Week 16) End of Dosing 
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. Assess AEs by asking open-ended queries and record the assessments. 
2. Record concomitant medication use; assess and record any changes to anti-dementia or 
anti-Parkinson medication doses or regimens. 
3. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes.. 
4. Obtain weight. 
5. Perform physical and neurological exam. 
6. Administer the following assessment instruments, in the order shown except for the 
ADCS-CGIC (see note, below). The order may be adjusted to keep the physician 
assessments together; however, it is imperative that the CDR and ADAS-cog are 
performed first and second, in order to limit patient fatigue. Perform all cognitive and 
dementia-related assessments while patient is in ON state.  ON will be measured at a time 
representative of the ON state in that patient, not in “best” ON. 


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a. CDR. 
b. ADAS-cog. 
c. ADCS-CGIC. (Note: The ADCS-CGIC evaluation may be performed at any point 
during the study visit based on clinical interview by an Investigator who is blinded to 
the cognitive evaluations.) 
d. Perform full UPDRS Parts I, II III (motor) and IV. 
For patients with motor fluctuations: Perform full UPDRS Parts I, II III (motor) and 
IV, approximately 1 to 3 hours after the patient has taken a scheduled dose of 
levodopa (preferably their morning dose of levodopa). UPDRS in ON will be 
measured at a time representative of the ON state in that patient, not in “best” ON.  
e. PDAQ (reported by caregiver). 
f. SCOPA-SLEEP. 
g. SAPS-PD. 
h. NPI (reported by caregiver). 
i. MoCA. 
7. Administer C-SSRS. 
8. Obtain 12-lead ECG and ensure the ECG is collected at a time when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
9. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Females of childbearing potential: Obtain urine hCG pregnancy test; verify method of 
contraception has not changed since Screening. 
b. Hematology and chemistry (including liver function tests). 
c. Blood sample for SYN120 plasma concentration 
 
 Obtain and record the date and time when the patient took the 
last dose of IMP. Record the date and time of SYN120 sample collection. 


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d. Blood sample for optional pharmacogenetic substudy (only if patient gave consent for 
the pharmacogenetic substudy and specimen was NOT collected during a previous 
visit): A single blood sample (approximately 10 mL) will be collected per patient. See 
Section 7.13. 
e. Urine sample for urinalysis. 
10. Obtain the returned blister cards dispensed at the Week 8 Visit: 
a. Assess and document the IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
b. Review and reconcile any discrepancies with the patient and caregiver. 
11. Schedule the Week 18 post dose Safety Follow-Up Visit. 
12. Complete eCRF information in the designated modules. 
6.2.9 
Safety Follow-Up Visit, Visit 8 (Week 18) 
The post dose Safety Follow-Up Visit should be scheduled 14 ± 3 days after the last dose of IMP. 
If the patient was terminated early from the study and the Early Termination Visit took place 
4 weeks or more after the last dose of IMP, this visit should not be conducted. 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the Week 18 visit 
with the courier (see Central Laboratory Procedures Manual). 
1. Assess AEs by asking open-ended queries and record the assessments. 
2. Record concomitant medication use; assess and record any changes to anti-dementia or 
anti-Parkinson medication doses or regimens. 
3. Perform full UPDRS Parts I, II III (motor) and IV. 
For patients with motor fluctuations: Perform full UPDRS Parts I, II III (motor) and IV, 
approximately 1 to 3 hours after the patient has taken a scheduled dose of levodopa 
(preferably their morning dose of levodopa). UPDRS in ON will be measured at a time 
representative of the ON state in that patient, not in “best” ON. 
4. Administer C-SSRS. 
5. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes. 
6. Complete eCRF information in the designated modules. 


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6.2.10 
Early Termination Visit 
Note: Confirm the arrangement for laboratory sample pick-up on the day of the patient’s 
termination visit with the courier (see Central Laboratory Procedures Manual). 
If the patient withdraws consent, perform this visit as soon as possible after the last dose of IMP. 
1. Assess AEs by asking open-ended queries and record the assessments. 
2. Record concomitant medication use; assess and record any changes to anti-dementia or 
anti-Parkinson medication doses or regimens. 
3. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes. 
4. Obtain weight. 
5. Perform physical and neurological exam. 
6. Administer the following assessment instruments, in the order shown except for the 
ADCS-CGIC (see note, below). The order may be adjusted to keep the physician 
assessments together; however, it is imperative that the CDR and ADAS-cog are 
performed first and second, in order to limit patient fatigue. Perform all cognitive and 
dementia-related assessments while patient is in ON state.  ON will be measured at a time 
representative of the ON state in that patient, not in “best” ON. 
a. CDR. 
b. ADAS-cog. 
c. ADCS-CGIC. (Note: The ADCS-CGIC evaluation may be performed at any point 
during the study visit based on clinical interview by an Investigator who is blinded to 
the cognitive evaluations.) 
d. Perform full UPDRS Parts I, II III (motor) and IV. 
For patients with motor fluctuations: Perform full UPDRS Parts I, II III (motor) and IV, 
approximately 1 to 3 hours after the patient has taken a scheduled dose of levodopa 
(preferably their morning dose of levodopa). UPDRS in ON will be measured at a time 
representative of the ON state in that patient, not in “best” ON. 
e. PDAQ (reported by caregiver). 
f. SCOPA-SLEEP. 


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g. SAPS-PD. 
h. NPI (reported by caregiver). 
i. MoCA. 
7. Administer C-SSRS. 
8. Obtain 12-lead ECG and ensure the ECG is collected at a time when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
9. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Females of childbearing potential: Obtain urine hCG pregnancy test; verify method of 
contraception has not changed since Screening. 
b. Hematology and chemistry (including liver function tests). 
c. Blood sample for SYN120 plasma concentration 
 
Obtain and record the date and time when the patient took the 
last dose of IMP. Record the date and time of SYN120 sample collection. 
d. Urine sample for urinalysis. 
10. Obtain the returned blister cards dispensed at the previous visit: 
a. Assess and document the IMP accountability and compliance (document any missed 
dose(s), lost tablets and number of tablets taken). 
b. Review and reconcile any discrepancies with the patient and caregiver. 
11. Complete eCRF information in the designated modules. 
6.2.11 
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 18). 
6.2.11.1 
Required Assessments for Unscheduled Visit 
The following assessments must be performed: 


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1. Assess AEs by asking open-ended queries and record the assessments. 
2. Record concomitant medication use; assess and record any changes to anti-dementia or 
anti-PD medication doses or regimens. 
3. Collect the dispensed IMP blister cards from the patient. 
4. Obtain and record the date and approximate time when the patient took the most recent 
dose of IMP. 
5. Assess and document the 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/caregiver. 
6. Complete the designated information in the designated eCRF modules. 
6.2.11.2 
Optional Assessments for Unscheduled Visit 
The following additional assessments may be performed at an Unscheduled Visit for assessment 
of an adverse event, at the Investigator’s discretion, depending on the type of AE 
(e.g., an out-of-range lab value): 
1. Obtain and record BP and pulse after at least 5 minutes supine rest and again after 
standing for approximately 1 and 3 minutes. 
2. Obtain the 12-lead ECG and ensure the ECG is collected at a time when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. Assess any 
changes from Baseline for clinical significance. 
3. Perform physical and neurological examination, and assess any changes from Baseline for 
clinical significance. 
4. Administer C-SSRS if suicide risk concern. 
5. Obtain samples for the following laboratory tests and record the date and time of 
collection: 
a. Females of childbearing potential: Obtain urine hCG pregnancy test; verify method of 
contraception has not changed since Screening. 
b. Hematology and chemistry (including liver function tests). 


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c. Blood sample for SYN120 plasma concentration 
 
 Obtain and record the date and time when the patient took the last dose of 
IMP. Record the date and time of SYN120 sample collection. 
d. Urine sample for urinalysis. 
Note: For processing, labeling and shipping of samples, follow the instructions provided in 
the Central Laboratory Procedures Manual. 
6. In consultation with the Medical Monitor, discuss any other appropriate diagnostic tests 
required to evaluate patient’s AE. 
7. Re-dispense remaining unused blister cards collected from the patient to continue IMP 
dosing to the next scheduled visit (if applicable). 
8. Complete eCRF information in the designated modules. 
7.0 
ASSESSMENT METHODS 
7.1 
Cognitive Drug Research Computerized Cognition Battery 
The Cognitive Drug Research Computerized Cognition Battery (CDR) (Wesnes et al., 1992; 
Wesnes et al., 2000) is a computerized neuropsychological test battery to assess cognitive tasks 
based on measures of choice reaction time, vigilance, and the sensitivity and speed of digit, word 
and picture recognition. The stimuli are presented on a computer screen and the subjects respond 
by pressing either a “Yes” or “No” on a response box. The CDR has been validated in demented 
patients and is provided through 
 
. The CDR will be administered at Screening to all patients 
(two training sessions required) and to randomized patients at Baseline (before the initiation of 
dosing) and at Weeks 8 and 16 (or at Early Termination, if applicable). The CDR sample version 
administered at Screening will not be evaluated, but will be used to familiarize patients with the 
test procedures and reduce the risk of practice effects as a potential confounder. 
The order of standard CDR System setup is: 
• Word Presentation: A list of words is presented on the screen one at a time for the subject 
to remember. 
• Immediate Word Recall: The subject is given 60 seconds to recall as many of the words 
as possible that were presented. 
• Picture Presentation: A series of pictures is presented on screen for the subject to 
remember. 


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• Simple Reaction Time: The subject is instructed to press the 'YES' response button as 
quickly as possible every time the word 'YES' is presented on the screen. Stimuli are 
presented with a varying inter-stimulus interval. 
• Digit Vigilance: A target digit is randomly selected and constantly displayed to the right 
of the screen. A series of digits is then presented in the center of the screen and the 
subject is required to press the 'YES' button as quickly as possible every time the digit in 
the series matches the target digit.  
• Choice Reaction Time: Either the word 'NO' or the word 'YES' is presented on the screen 
and the subject is instructed to press the corresponding button as quickly as possible. 
Each stimulus word is chosen randomly with equal probability and there is a varying 
inter-stimulus interval. 
• Numeric Working Memory: A series of digits is presented for the subject to hold in 
memory. This is followed by a series of probe digits in which the subject has to decide 
whether or not it was the original series and press the 'YES' or 'NO' response button (as 
appropriate), as quickly as possible. 
• Spatial Working Memory: A picture of a house is presented on the screen with windows 
lit. The subject has to memorize the position of the lit windows. For each of the 
subsequent presentations of the house, the subject is required to decide whether or not the 
one window that was lit was also lit in the original presentation. The subject responds by 
pressing the ‘YES’ or ’NO’ buttons (as appropriate), as quickly as possible. 
• Delayed Word Recall: The subject is given time to recall as many of the words as 
possible that were presented during word presentation. 
• Word Recognition: The original words plus distracter words are presented one at a time 
in a randomized order. For each word the subject is required to indicate whether or not 
the subject recognizes it as being from the original list of words by pressing the 'YES' or 
'NO' button (as appropriate), as quickly as possible. 
• Picture Recognition: The original pictures, plus distracter pictures, are presented one at a 
time in a randomized order. For each picture, the subject has to indicate whether or not 
the subject recognizes it as being from the original series by pressing the 'YES' or 'NO' 
button (as appropriate), as quickly as possible. 
The individual tasks measure the following cognitive domains: 
Attentional Tasks 
• Simple Reaction Time  


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• Digit Vigilance  
• Choice Reaction Time  
Working Memory Tasks  
• Numeric Working Memory  
• Spatial Working Memory  
Episodic Secondary Memory Tasks  
• Immediate Word Recall  
• Delayed Word Recall  
• Word Recognition  
• Picture Recognition  
These cognitive tasks are usually analyzed both separately and in different combinations to 
produce composite scores. The five composite scores were identified through a factor analysis 
and have been replicated in other studies (Wesnes et al., 2000). 
The five composite scores are: 
• Power of Attention: a measure of psychomotor ⁄ information processing speed. Indicates 
intensity of concentration at a particular moment. 
• Continuity of Attention: a measure of attention ⁄ concentration. The ability to sustain 
attention and avoid error. The ability to keep mind on a single task over time.  
• Quality of Working Memory: Assess ability to temporary store information.  
• Quality of Episodic Secondary Memory: Measures ability to store, hold and retrieve 
information of episodic nature. 
• Speed of Memory Retrieval: a measure of psychomotor ⁄ information processing speed. 
Time it takes to retrieve a memory. 
Only Sponsor-accepted raters may administer the CDR Computerized Cognition Battery in 
accordance with the requirements for background, experience in a research setting and training in 
accordance with the rater experience form. 


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7.2 
Alzheimer’s Disease Cooperative Study - Clinician’s Global Impression of Change 
(ADCS-CGIC) 
The ADCS-CGIC (Schneider et al., 1997) is a validated scale for assessing clinically relevant 
global change in patients with dementia, which was originally developed for patients with AD. 
The ADCS-CGIC consists of an organized but unstructured assessment of the patient’s function 
and mental status, a caregiver interview, and a standardized set of questions. Depending on a 
patient’s level of impairment, raters consider several domains (e.g., global cognition, attention 
and wakefulness, psychiatric symptoms) in formulating a CGIC rating. The assessments are 
integrated in a 7-point categorical scale that gives a global rating of change in symptoms from a 
baseline level. A score of 1 = marked improvement; 2 = moderate improvement; 3 = minimum 
improvement; 4 = no change; 5 = minimum worsening; 6 = moderate worsening; and 7 = marked 
worsening. The ADCS-CGIC will be collected at Week 16 (or at Early Termination prior to 
Week 16, if applicable), and may be performed at any point during the study visit based on 
clinical interview by an Investigator who is blinded to the cognitive evaluations. 
Only Sponsor-accepted raters may administer the ADCS-CGIC in accordance with the 
requirements for background, experience in a research setting and training in accordance with the 
rater experience form. 
7.3 
Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-cog) (Revised 
10OCT13) 
The ADAS-cog (Mohs et al., 1988; Mohs et al., 1997) is the cognitive subscale of the 
Alzheimer’s Disease Assessment Scale (ADAS), a validated instrument designed to measure the 
severity of the most prominent symptoms of dementia in patients with AD. The ADAS-cog 
subscale consists of 11 tasks measuring alterations of memory, language, praxis, attention and 
other cognitive abilities which comprise the core symptoms of AD and PDD. This study utilizes 
the original ADAS-cog and does not include the supplemental maze and number cancellation 
tasks. The ADAS-cog will be administered to randomized patients in this study at Baseline 
(before the initiation of dosing) and at Week 16 (or at Early Termination prior to Week 16, if 
applicable). 
Only Sponsor-accepted raters may administer the ADAS-cog in accordance with the 
requirements for background, experience in a research setting and training in accordance with the 
rater experience form. 
7.4 
Brief Penn Daily Activity Questionnaire (PDAQ) 
The PDAQ (Weintraub et al., 2013) is a 15-item questionnaire selected by an expert panel from 
a bank of 50 items. The PDAQ represents a new comprehensive instrument comprised of item-
response theory scaled items for rating daily cognitive function in patients with PD. The 
questionnaire correlates highly with global cognitive performance in PD patients and shows good 


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discriminant validity across stages of cognitive impairment. The informant version of the PDAQ 
will be administered to the caregiver of randomized patients in this study at Baseline (before the 
initiation of dosing) and at Week 16 (or at Early Termination prior to Week 16, if applicable). 
Only Sponsor-accepted raters may administer the Brief PDAQ in accordance with the 
requirements for background, experience in a research setting and training in accordance with the 
rater experience form. 
7.5 
Parkinson’s Disease-Adapted Scale for Assessment of Positive Symptoms (SAPS-
PD) (2013 Shortened Version) 
The SAPS-PD is the Parkinson’s disease-adapted version of the Scale for Assessment of Positive 
Symptoms (Andreasen, 1984) tailored to PDD. A shortened version of the SAPS-PD has 
recently been developed (Voss et al., 2013). The 2013 shortened version of the SAPS-PD will be 
administered to randomized patients in this study at Baseline (before the initiation of dosing) and 
at Week 16 (or at Early Termination prior to Week 16, if applicable). 
Only Sponsor-accepted raters may administer the SAPS-PD in accordance with the requirements 
for background, experience in a research setting and training in accordance with the rater 
experience form. 
7.6 
Neuropsychiatric Inventory (NPI) (Version 12) 
The NPI (Cummings et al., 1994) is a copyrighted validated instrument to assess dementia-
related behavioral symptoms. The NPI originally examined 10 sub-domains of behavioral 
functioning: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, 
disinhibition, irritability/lability, and aberrant motor activity. Sub-domains subsequently added 
include night-time behavioral disturbances and appetite/eating abnormalities (Cummings, 1997), 
as well as a caregiver distress scale (Kaufer et al., 1998). Due to its wide variety of domains 
compared to dementia measures, the NPI is used to screen for multiple types of dementia in 
addition to that caused by AD. The NPI will be reported bythe subject’s caregiver at Baseline 
(before the initiation of dosing) and at Week 16 (or at Early Termination prior to Week 16, if 
applicable). 
Only Sponsor-accepted raters may administer the NPI in accordance with the requirements for 
background, experience in a research setting and training in accordance with the rater experience 
form. 
A copy of the NPI is included in Appendix 14.6. 


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7.7 
Scales for Outcomes in Parkinson’s Disease-Sleep Scale (SCOPA-SLEEP) 
The SCOPA-SLEEP (Marinus et al., 2003) is a validated instrument to evaluate nighttime sleep 
and daytime sleepiness developed for research in patients with PD, a population that frequently 
experience sleep disturbances. The SCOPA-SLEEP consists of two scales, one that evaluates 
nighttime sleep and one that assesses daytime sleepiness. 
Only Sponsor accepted raters may administer the SCOPA-SLEEP in accordance with the 
requirements for background, experience in a research setting and training in accordance with the 
rater experience form. 
A copy of the SCOPA-SLEEP is included in Appendix 14.5. 
7.8 
Montreal Cognitive Assessment (MoCA) (Original v7.1,Alternates v7.2 and v.7.3) 
The MoCA (Nasreddine et al., 2005) is a validated brief screening instrument for cognitive 
dysfunction. The MoCA assesses the cognitive domains of attention and concentration, executive 
functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation. The MoCA takes approximately 10 minutes to administer by a trained clinician and 
must be administered in the local language and scored by a trained clinician. The maximum 
score is 30; a score of 26 or above is considered normal. The MoCA has validated translations in 
many languages [http://www.mocatest.org]. 
Only Sponsor accepted raters may administer the MoCA in accordance with the requirements for 
background, experience in a research setting and training in accordance with the rater experience 
form. 
Subjects may be given any version of the MoCA at the Screening Visit as long as they have NOT 
received the same MoCA version clinically within the last 3 months.  A different version of the 
MoCA should be used at the Week 16 or Early Termination visit (if applicable). The MoCA 
version used at a study visit should be accurately documented in Source Document and within 
the EDC for each visit. 
Re-screening:  In cases where the subject screen fails due to the MoCA score being out of the 
required inclusionary range at the Screening Visit, the subject may be re-screened if the subject’s 
score was > 23; a minimum of one month must have passed since their original MoCA 
assessment. If the subject’s MoCA score was < 10, they must have had a change in therapy or 
intervention that (in the opinion of the Site Investigator) may have improved the subject’s 
cognitive status.  Subjects who move forward with a re-screen must be evaluated using a 
different MoCA version (7.1, 7.2 or 7.3) than was used at the original Screening Visit, and 
subjects may be re-screened only once. 
 


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7.9 
Unified Parkinson’s Disease Rating Scale (UPDRS)  
The UPDRS (Fahn et al., 1987) 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. 
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; 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: Activities of Daily Living) 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. 
Patients with levodopa-related end-of-dose motor fluctuations will be instructed to have already 
taken their normally scheduled dose of levodopa and their study drug prior to arriving at the 
study site in order to have their UPDRS Part III evaluated in ON (within approximately 2 to 
3 hours after taking their levodopa dose). UPDRS in ON 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. 
Only Sponsor accepted raters may administer the UPDRS subscales in accordance with the 
requirements for background, experience in a research setting and training in accordance with the 
rater experience form. 
A copy of the UPDRS is included in Appendix 14.4. 
7.10 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Revised 14JAN09) 
Suicidality will be assessed by trained study personnel using the C-SSRS (Posner et al. 2011). 
The C-SSRS is a copyrighted standardized suicidal rating system conducted by a certified rater. 
The interview measures presence of suicidality and consists of four categories: suicide ideation, 
intensity of ideation, suicidal behavior and answer for actual attempts only. 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. 
Only Sponsor accepted trainers may administer the C-SSRS in accordance with the requirements 
for background, experience in a research setting and training in accordance with the rater 
experience form. 


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7.11 
Laboratory Tests 
The laboratory tests listed below (Table 5) 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. 
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: 


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Table 5: 
Laboratory Measurements 
Hematology 
Chemistry 
Thyroid b 
Urinalysis c 
basophils 
eosinophils 
lymphocytes 
neutrophils 
monocytes 
hemoglobin 
hematocrit 
platelet count 
RBC count 
WBC count 
calcium 
chloride 
sodium 
potassium 
albumin 
phosphate 
glucose 
urea/BUN 
bicarbonate 
uric acid 
total protein 
creatinine 
creatine phosphokinase with 
automatic troponin-I and CK-MB 
if value > 2x the ULN 
AST 
ALT 
ALP 
GGT 
total bilirubin a 
LDH 
total cholesterol 
serum FSH (at Screening, for female 
patients who are not surgically sterile and 
are postmenopausal) 
urine hCG (for female patients of 
childbearing potential) 
TSH 
free T3 
free T4 
protein 
glucose 
pH 
blood 
ketones 
specific gravity 
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; 
CK-MB, creatine phosphokinase-MB fraction; FSH, follicle stimulating hormone; GGT, gamma-glutamyl 
transpeptidase; hCG, human chorionic gonadotropin; 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. 
a 
Conjugated and unconjugated. 
b 
Assessed at Screening only. 
c 
If urine dipstick is positive for leukocytes, protein, or erythrocytes, a microscopic evaluation and culture will be 
performed. 
 
7.11.1 
Hormones (Serum FSH and Urine HCG) 
Follicle stimulating hormone (FSH) levels will be determined at Screening for all women who 
are not surgically sterile and are postmenopausal (at least one year absence of vaginal bleeding 


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or spotting). Postmenopausal status will be confirmed by an FSH level greater than or equal to 
40 mIU/mL or 40 IU/L. 
Urine human chorionic gonadotropin (hCG) pregnancy test will be performed for women of 
childbearing potential, at Screening and during the study as indicated in Table 1, Schedule of 
Events/Evaluations. 
7.11.2 
Hematology 
Hematology tests will consist of hemoglobin, hematocrit, red blood cell count, white blood cell 
count and differential, and platelet count, at Screening and during the study as indicated in 
Table 1, Schedule of Events/Evaluations. 
7.11.3 
Chemistry 
Serum chemistry tests will consist of aspartate aminotransferase (SGOT/AST), alanine 
aminotransferase, (SGPT/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, and creatine phosphokinase (CK), TSH, free T3 and T4, at 
Screening and during the study as indicated in Table 1, Schedule of Events/Evaluations. 
7.11.4 
Thyroid Function 
Thyroid function tests will consist of thyroid stimulating hormone (TSH), free T3 and free T4, 
at Screening. 
7.11.5 
Urinalysis 
Urinalysis will include specific gravity, pH, ketones, blood, protein, and glucose, at Screening 
and during the study as indicated in Table 1, Schedule of Events/Evaluations. If an urine dipstick 
is positive for leukocytes, protein or erythrocytes, a microscopic evaluation will be performed. 
7.12 
Blood Sampling for Bioanalytical Analysis 
Blood samples will be collected for determination of SYN120 plasma concentrations 
 
 Baseline (before the initiation of dosing), at 
Weeks 4, 8 and 16, at Early Termination (if applicable), and at unscheduled visits (optional). For 
each collection, the time of sampling and of the most recent IMP dosing prior to sampling will be 
recorded. 
Specific procedures for blood sample collection, plasma processing, storage, shipping, and 
analysis will be provided in the Central Laboratory Procedures Manual. 


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7.13 
Pharmacogenetic Substudy (Optional) 
Patients will be offered the option to participate in a pharmacogenetic substudy. Exploratory 
pharmacogenetic analyses are planned as a substudy with the objective of identifying inherited 
genetic factors which predict differential treatment response or intolerance to SYN120. Genetic 
polymorphisms related to the serotonin system (5HT6 and 5HT2a receptors) will be 
characterized. Other genetic features related to 
 Parkinson’s disease and 
cognition may also be tested. The intent is to develop a better understanding of Parkinson’s 
disease dementia and how patients respond to SYN120. 
Blood samples will be taken for pharmacogenetic assessment from each patient who agrees, in 
writing, to participate in these exploratory assessments. A separate section on the ICF regarding 
the pharmacogenetic substudy will be provided. Patients who indicate on the ICF that they agree 
to the pharmacogenetic assessment will be eligible for extra blood collection and inclusion in 
pharmacogenetic analyses. A single blood sample will be collected per patient (approximately 
10 ml) at Baseline or at the next possible visit. 
A separate lab instruction will be provided with detailed information on sample collection, 
handling, and shipment for all pharmacogenetic assessments. The sample collection data must be 
entered on the sample collection CRF (eCRF) page. 
Blood samples will be processed, DNA extracted, and samples stored 
 
 Samples may be shared with other investigators 
 
 Samples will be stored for up to 10 years. Participants may withdraw consent to use 
their samples at any time, in which case their samples and any derived biospecimens will be 
destroyed. Samples will be identified only by anonymous study ID number with linked 
phenotypic information gathered in the study. 
7.14 
Blood Pressure and Pulse 
A full set of BP and pulse measurements will be obtained at Screening (3 sets) and during the 
study (1 set) as indicated in Table 1, Schedule of Events/Evaluations. 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 consists of supine BP 
and pulse followed by standing BP and pulse. 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 with the 
appropriate cuff size from the non-dominant arm. All measurements will be obtained from the 
same arm and, if possible with the same cuff, using an automatic instrument with a digital 
readout, throughout the study. The automatic cuff should be placed on the designated arm at least 
5 minutes prior to collection. Measurements will be made after a minimum of 5 minutes rest in 
the supine position. Patients will then stand up for 1 and 3 minutes, and a standing measurement 


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will be obtained. The 3 sets of readings collected during the Screening Visit should be taken 
approximately 10 minutes apart. 
Supine and standing systolic and diastolic BP and pulse rate will be recorded at the nominal time 
points specified in Table 1, Schedule of Events/Evaluations. If for any reason (e.g., dyskinesia) 
an accurate reading cannot be obtained, collect the measurement as close to the nominal time 
point as feasible and record the date and time of collection. 
7.15 
Physical and Neurological Examination 
Physical examination including neurological examination will be collected at Screening and 
during the study as indicated in Table 1, Schedule of Events/Evaluations. Physical examination 
includes evaluation of the heart, lungs, abdomen, extremities, and skin. Neurological exam will 
consist of assessment of the cranial nerves (I-XII), sensory and motor system functions and 
reflexes. 
7.16 
Twelve-lead Electrocardiogram 
Resting supine 12-lead ECGs will be collected at the time points specified in Table 1, Schedule 
of Events/Evaluations, after the patient has been in a supine, or if unable, semi-supine (no more 
than 45 degrees) position for a minimum of 5 minutes. 
The 12-lead electrocardiogram includes standard PR, QRS, QT and QTc intervals as read by the 
ECG machine provided by the cardiac core lab. Fridericia’s correction (i.e., QTcF) must be used 
for the 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 ECG machine recorded 
QTcF value to determine patient eligibility.  
The ICH guideline E14 (section 2.1.1) suggests excluding from early phase studies subjects who 
have marked baseline prolongation of the QT interval, namely those in whom QTc interval has 
repeatedly been demonstrated to be > 450 milliseconds (msec). Therefore, to be eligible for this 
study patients must meet exclusion criteria #14 based on QTcF intervals as assessed at the 
Screening and Baseline Visits. 
At subsequent visits, if the QTcF interval is noted to be ≥ 450 msec (for male patients) or 
≥ 470 msec (for female patients), it is recommended that the ECG be repeated at 10 minute 
intervals, for a total of 3 ECGs, to determine if the QTcF prolongation is a consistent finding. If 
the patient is observed to have a QTcF interval consistently ≥ 500 msec and/or a QTcF interval 
consistently increased by ≥ 60 msec compared to the average baseline QTcF interval, study drug 


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should be discontinued (see Section 4.3.1, page 45). The average baseline QTcF interval is 
defined as the average of the three QTcF interval values obtained at Visit 2. 
The eligibility or continued participation in the trial of any patient with potentially significant 
ECG abnormalities should be discussed the Medical Monitor. 
7.17 
Adverse Events 
For details regarding AE assessments and reporting, please refer to Section 8.0. 
7.18 
Concomitant Medications 
For details regarding concomitant medications, please refer to Section 5.9 and Section 14.3. 
8.0 
ADVERSE EVENTS 
8.1 
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 informed consent form), including any pretreatment and post treatment periods 
required by the protocol, must be reported in 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 visit and all AEs that recurred or worsened after the initial visit. 
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 the Baseline Period. 
8.2 
Procedures for Reporting and Recording Adverse Events 
The patient will be given the opportunity to report AEs spontaneously. A general 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)?” 


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In addition, the Investigator should review any self-assessment procedures (e.g., diary cards) 
employed in the study. 
8.3 
Description of Adverse Events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, 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 (e.g., diary card) 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) are 
described in the eCRF Completion Guidelines. 
8.4 
Follow Up of Adverse Events 
An AE should 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. 
If an AE is still ongoing at the end of the study for a patient, follow up should 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. The follow up will usually be continued for 30 days 
after the patient has discontinued his/her IMP. 
8.5 
Rule for Repetition of an Adverse Event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening”. 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one. 
8.6 
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 discontinue study drug 
as soon as pregnancy is known, and the following should be completed: 
• The patient should immediately stop the intake of the IMP or be down-titrated as instructed. 


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• A Safety Follow Up Visit should be scheduled 4 weeks after the patient has discontinued 
IMP. 
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 Partner Pregnancy Consent 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. 
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. 
8.7 
Overdose of Investigational Medicinal Product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded 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). 
8.8 
Safety Data Monitoring 
Selected safety data from this study will be reviewed periodically to detect any clinical 
concern(s) potentially related to IMP so that Investigators, patients, and responsible oversight 
authorities including IRBs/IECs can be promptly informed of relevant safety-related findings. 
Responsibility for safety data monitoring will be assigned to a medically qualified, unblinded 
physician (Safety Data Monitor) who is independent from Biotie Therapies. The Safety Data 
Monitor will review reported SAEs and may identify additional safety data of interest 
(e.g., AEs, vital signs, laboratory or ECG results) to be requested from the unblinded 
biostatistician and reviewed periodically during the course of the study.  


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8.9 
Serious Adverse Events 
8.9.1 
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: 
• Death. 
• Life-threatening. 
Note: Life-threatening does not include a reaction that might have caused death had it 
occurred in a more severe form. 
• Significant or persistent disability/incapacity. 
• Congenital anomaly/birth defect (including that occurring in a fetus). 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or 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 inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
• 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 1 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 pre-existing 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 
pre-existing 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. 


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8.9.2 
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 (see contact information for SAE reporting listed in the Serious Adverse 
Event Reporting section at the front of the protocol). 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. 
An SAE Report Form will be provided to the Investigator. The SAE Report Form must be 
completed in English. 
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. 
8.9.3 
Follow Up of Serious Adverse Events 
An SAE should 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. 


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8.9.4 
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. 
8.9.5 
Anticipated Serious Adverse Events 
 
 
 
 
 
 
 
 
 
Investigators are obliged to report all SAEs as detailed in Section 8.9. 
9.0 
STUDY MANAGEMENT AND ADMINISTRATION 
9.1 
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 
before notifying the Sponsor (or its representative) and the IRB/IEC in writing regarding the type 
of emergency and the course of action taken. 
9.2 
Monitoring 
Sponsor (or designee) will monitor the study in accordance with the ICH GCP guideline and 
applicable regulatory requirements, and to ensure that study initiation, conduct, and closure are 


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adequate. Monitoring of the study may be delegated by the Sponsor or 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 (or 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 Sponsor (or 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 (or 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. 
9.2.1 
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 or electroencephalogram records, must be saved and stored 
as instructed by Sponsor (or designee). 


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9.2.2 
Source Data Verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (e.g., patient files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 9.2.1. 
9.3 
Data Handling 
9.3.1 
Case Report Form Completion 
The study will be performed using remote data capture. 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 will review during 
Screening and prior to randomization 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. 


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9.3.2 
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 
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 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 PDF 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 the patient is a screen failure, the primary reason for screen failure will be recorded in the 
eCRF and on the Patient Screening/Enrollment Log. No additional screening information will be 
entered into 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. 
9.3.3 
Patient Screening and Enrollment Log/Patient Identification Code List 
The patient’s screening and enrollment will be recorded into the eCRF and onto the paper Patient 
Screening and Enrollment Log. The Patient Screening/Enrollment Log will be sent to the 
Sponsor or the Sponsor’s designee on a weekly basis. 
The Investigator will keep a Patient Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each patient. 
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. 
9.4 
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 


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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. 
9.5 
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. 
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 (FDA, 1997 [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. 
9.6 
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 Sponsor (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 SOPs, ICH GCP, and applicable 
regulatory requirements. 
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 (or designee). 


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9.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action 
by the Sponsor (or designee) to secure compliance. Continued noncompliance may result in the 
termination of the site’s involvement in the study. 
10.0 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
10.1 
Definition of Analysis Sets 
Safety Sample (SS): The SS will consist of all randomized patients who received at least one 
dose of IMP. 
Modified Intention-to-Treat (mITT) Sample: The mITT sample will consist of all randomized 
patients who received at least one dose of IMP and who have at least one valid baseline and at 
least one valid post-baseline assessment of the primary efficacy endpoint. 
Per-Protocol Set (PP): The PP will consist of a subset of the mITT sample, excluding any 
participants or observations potentially affected by important protocol deviations that may 
influence the validity of the data for testing efficacy and as specified in the SAP prior to breaking 
the blind. 
All safety variables will be summarized using the SS. All efficacy variables will be summarized 
using the mITT sample. The PP will be utilized for sensitivity analyses to estimate efficacy 
among participants tolerant of study drug and with less reliance on model assumptions required 
to extrapolate after any loss to follow up. 
10.2 
Study Variables 
10.2.1 
Efficacy Variables 
10.2.1.1 
Primary Efficacy Variable 
The primary efficacy variable is the change from Baseline to Week 16 on the CDR 
Computerized Cognition Battery Continuity of Attention. 
10.2.1.2 
Key Secondary Efficacy Variable 
The key secondary efficacy endpoint is the change from Baseline to Week 16 on the CDR 
Quality of Episodic Memory. 


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10.2.1.3 
Other Efficacy Variables 
The other secondary efficacy endpoints are the change from Baseline to Week 16 on the 
following measures: 
1. 
ADCS-CGIC. 
2. 
ADAS-cog (total score). 
3. 
CDR Power of Attention. 
4. 
CDR Speed of Memory Retrieval. 
5. 
PDAQ. 
6. 
SCOPA-SLEEP. 
7. 
SAPS-PD. 
8. 
NPI. 
9. 
MoCA. 
10.2.2 
Exploratory Efficacy Variables 
Exploratory efficacy endpoints include the change from Baseline to Week 16 on the individual 
component tasks of the CDR: 
1. 
Word Presentation. 
2. 
 Immediate Word Recall. 
3. 
 Picture Presentation. 
4. 
 Simple Reaction Time. 
5. 
 Digit Vigilance. 
6. 
 Choice Reaction Time. 
7. 
 Numeric Working Memory. 
8. 
 Spatial Working Memory. 
9. 
 Delayed Word Recall. 
10. 
 Word Recognition. 
11. 
 Picture Recognition. 
10.2.3 
Pharmacokinetic Variables 
• SYN120 plasma concentrations 
 and time point of IMP intake 
and blood sampling. 


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10.2.4 
Safety Variables 
Safety variables include the following: 
• AEs. 
Change from Baseline in: 
• Vital sign parameters (pulse rate, systolic and diastolic BP). 
• Change in body weight. 
• Change from supine to standing BP (systolic and diastolic). 
• UPDRS. 
• C-SSRS. 
• Standard 12-lead ECG (RR, PR, QRS, QT, and QT intervals corrected for heart rate using 
Fridericia’s formula [QTcF]). 
• Laboratory parameters: hematology, chemistry, and urinalysis. 
10.3 
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 appropriate for the 
purpose of analysis. For continuous variables, descriptive statistics will include number of 
patients (n), mean, standard deviation (SD), median, minimum, and maximum. 
In general, 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. 
10.4 
Planned Efficacy Analyses 
10.4.1 
Analysis of the Primary Efficacy Variable 
The primary analysis will be performed on the mITT analysis set and will use a shared-baseline 
repeated measures analysis of variance (ANOVA) that includes fixed effects for visit (3 levels: 
baseline, Week 8, and Week 16) and the interaction between treatment group (2 levels: SYN120 
and placebo) and post-baseline visit (2 levels), random center-specific intercepts, and 
unstructured within-person covariance. The repeated measures model yields estimates that are 
unbiased as long as loss to follow up and missing assessments are predictable from observed 
scores. Use of a shared baseline (i.e., no treatment main effect) reflects the true state of the 
population sampled prior to randomization and has the advantage of adjusting for any chance 
differences at baseline in a manner similar to analysis of covariance (ANCOVA) (Liang and 
Zeger, 2000) with potentially greater efficiency with more than one follow up visit and drop-out. 


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Treatment-dependent differences in the change from Baseline to Week 16 on the CDR 
Computerized Cognition Battery Continuity of Attention will be estimated by linear contrasts 
and tested using a two-tailed Wald-test at alpha = 0.05. A significant mean improvement over 
16 weeks in CDR Continuity of Attention among participants randomized to SYN120 relative to 
mean changes among participants randomized to placebo would be considered evidence of 
therapeutic benefit from SYN120. As a sensitivity analysis if SYN120 is not found to be 
beneficial in the mITT sample, the same model will be applied to the PP sample and a 
nonparametric van Elteren test will be used to compare 16-week change scores in the PP sample, 
stratifying by center. 
10.4.2 
Key Secondary Efficacy Analyses 
The key secondary efficacy variable will be analyzed in the mITT sample using the model 
specified for the primary analysis of the primary efficacy variable. Treatment-dependent 
differences in the change from Baseline to Week 16 on the CDR Quality of Episodic Memory 
will be estimated by linear contrasts and tested using a two-tailed Wald-test at alpha = 0.05. 
Equivalent sensitivity analyses as are planned for the primary efficacy variable will be applied to 
the key secondary efficacy variable. 
10.4.3 
Multiplicity Adjustment for Primary and Key Secondary Endpoints 
If the effect of SYN120 on the primary outcome in the mITT sample is significant at 
alpha = 0.05, then testing the key secondary outcome at alpha = 0.05 maintains an overall type I 
error rate at 5% under a closed testing sequential analysis. When the primary analysis is not 
significant, we limit the overall type I error rate to 10% or less (depending on the magnitude of 
correlation between the primary and key secondary outcomes) when significance of the key 
secondary outcome alone is accepted as evidence of a therapeutic benefit from SYN120. 
10.4.4 
Other Efficacy Analyses 
All continuous other (non-key) secondary and exploratory efficacy variables that are 
approximately normally distributed or can be made so by simple transformation will be analyzed 
using the model defined in the primary efficacy analysis (Section 10.4.1) using the mITT sample 
in a first round of testing. Outcomes that are not normally distributed will be transformed or 
compared between the treatment groups using a van Elteren test that incorporates stratification 
by center. Comparisons will be tested at two-tailed alpha = 0.05, recognizing that the totality of 
results will be evaluated in judging the potential of SYN120 as a therapeutic agent for PDD. If 
not significant in the mITT sample, additional sensitivity analyses of the other (non-key) 
secondary efficacy variables will use the PP sample. 


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10.5 
Planned Safety and Other Analyses 
10.5.1 
Safety Analyses 
Safety data, including AEs, vital signs, UPDRS, ECGs, physical examination, and clinical 
laboratory test results will be summarized descriptively for each treatment group. The frequency 
and type of any observed suicidal ideation will be described. Descriptive statistics of continuous 
measures will be provided for the observed data and for the change from Baseline at each 
measured time point. Adverse events will be summaries by dose group as counts of events and as 
the proportion of patients experiencing any given type of AE as classified by MedDRA system 
organ class and preferred term. Overall rates of AEs will be compared between treatments by 
negative binomial regression. Proportions of participants experiencing a given type of event will 
be compared between treatments by Fisher’s exact test. 
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 are recorded as adverse events and will be 
documented in the AE summaries. 
Analyses will be performed for the SS as treated. 
10.5.2 
Other Analyses 
Patient Disposition 
The number of patients who were screened, randomized, completed scheduled follow up, and 
prematurely withdrew study participation will be summarized overall and by treatment group. 
Reasons for non-participation and for withdrawal from study will also be presented. 
Exposure to IMP/Compliance 
The number of days of exposure to IMP will be summarized by treatment group. Compliance 
with IMP will be calculated as the number of doses taken divided by the scheduled number of 
doses taken, expressed as a percentage. Compliance will be summarized overall and by week for 
each treatment group. Time to discontinuation of IMP will be estimated using Kaplan-Meier 
product-limit estimates. Treatment-dependent differences will be tested by log-rank test. 
Prior and Concomitant Medication Use 
All prior and concomitant medications taken during the study period will be listed for each 
patient, including dosage and indication. Each medication will be coded using the World Health 
Organization (WHO) Drug Dictionary Enhanced and classified as a past medication (last dose 
taken prior to the first dose of IMP), a concomitant medication ongoing at Baseline, or a 


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concomitant medication initiated after Baseline. The percentage of patients taking each 
medication (or class of medications) will be summarized overall and by treatment group. 
Pharmacokinetic Samples 
Results of the plasma assays of SYN120 will be descriptively analyzed and reported in the 
clinical study report. Separate population analysis on the data from this study alone or combined 
with data from other studies as deemed appropriate will be performed and reported separately. 
Optional Pharmacogenetic Substudy Data Analysis 
The exploratory pharmacogenetic analyses are designed to investigate the association 
between genetic factors (genotypes) and the prediction of treatment response or 
intolerance. The pharmacogenetic analyses are not intended to be used for regulatory 
judgments pertaining to the safety or efficacy of the investigational drug. However, these 
data may be considered for voluntary submission, consistent with applicable regulatory 
guidance on this topic, in order to develop the knowledge base necessary to establish the 
validity of genomic biomarkers. 
Pharmacogenetic data will be analyzed to describe frequencies of pre-specified 
polymorphisms related to 5HT6 and 5HT2a receptors, 
 Parkinson’s 
disease, and cognition. Exploratory analyses of association between specific genetic 
polymorphisms and treatment response will be performed by adding genotype, genotype × 
visit, and genotype × treatment × visit terms to models for primary and secondary efficacy 
outcomes. Exploratory analyses of association between specific genetic polymorphisms and 
treatment intolerance will be performed in logistic regression models with drug 
discontinuation or occurrence of specific adverse events as outcomes and genotype, 
treatment, and genotype × treatment interaction as predictors.  
10.6 
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. The criteria for identifying important 
protocol deviations and the classification of important protocol deviations will be defined prior 
to unblinding. 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. 
10.7 
Handling of Dropouts or Missing Data 
Participants who discontinue study drug or withdraw consent will be included in mITT analyses 
if they received at least one dose of study drug. In the absence of a substantial difference in the 


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rate of withdrawal, the planned repeated measures analysis should prevent bias in estimating 
treatment differences. If rates of withdrawal are notably higher among participants randomized 
to SYN120, a nonparametric analysis that assigns the worst observed outcome to participants 
who withdraw prior to Week 16 will be used a conservative estimate of treatment benefit. 
Additional sensitivity analyses may be pursued to impute missing values or otherwise construct 
models for unobserved outcomes. 
10.8 
Determination of Sample Size 
A total sample size of 80 or 40 in each group will provide at least 80% power to detect a true 
treatment difference equal to an effect size of 0.69 assuming up to 15% loss to follow up and 
using a two-tailed test at alpha = 0.05 based on a simple two-sample t-test. Additional power will 
be obtained from the proposed analysis using a shared-baseline repeated measures ANOVA. 
Approximately 120 patients will be screened, assuming a 33% screen failure rate, to randomize 
80 patients. 
11.0 
ETHICS AND REGULATORY REQUIREMENTS 
11.1 
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 
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 informed consent form should 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 
informed consent form. 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 informed consent form 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 informed consent form by the IRB/IEC and use of the amended form. 


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All studies conducted at centers in the United States that are considered “covered entities” 
according to the Health Insurance Portability and Accountability Act (HIPAA) must include the 
use of a HIPAA Authorization form. 
The patient may withdraw his/her consent to participate in the study at any time. A patient is 
considered as enrolled in the study when he/she has signed the informed consent form. An eCRF 
must not be started, nor may any study-specific procedure be performed for a given patient, 
without having obtained his/her written consent to participate in the study. 
11.2 
Patient Identification Cards 
Upon signing the informed consent the patient will be provided with a patient identification card 
in the language of the patient. The Investigator will fill in the patient identifying information and 
medical emergency contact information. The Investigator will instruct the patient to keep the 
card with him/her at all times. 
11.3 
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, Sponsor (or designee) 
will forward copies of the protocol, informed consent form, 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. 


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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 
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. 
11.4 
Patient Privacy 
Sponsor staff (or designee) will affirm and uphold the patient’s confidentiality. Throughout this 
study, all data forwarded to Sponsor (or designee) will be identified only by the patient 
randomization number and/or site identifier (ID) and 3-digit alpha-numeric patient screening 
number (S##). 
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). 
11.5 
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. 
12.0 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable. 
 


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13.0 
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14.0 
APPENDICES 
14.1 
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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14.2 
Movement Disorder Society Task Force – Clinical Diagnostic Criteria for Dementia 
Associated with Parkinson’s Disease 
Table 1. Features of Dementia Associated with Parkinson’s Disease 
I. Core Features 
1. Diagnosis of Parkinson’s disease according to Queen Square Brain Bank criteria 
2. A dementia syndrome with insidious onset and slow progression, developing within the 
context of established Parkinson’s disease and diagnosed by history, clinical, and mental 
examination, deﬁned as: 
• 
Impairment in more than one cognitive domain 
• 
Representing a decline from premorbid level 
• 
Deﬁcits severe enough to impair daily life (social, occupational, or personal care), 
independent of the impairment ascribable to motor or autonomic symptoms 
II. Associated Clinical Features 
1. Cognitive features: 
• 
Attention: Impaired. Impairment in spontaneous and focused attention, poor performance 
in attentional tasks; performance may ﬂuctuate during the day and from day to day 
• 
Executive functions: Impaired. Impairment in tasks requiring initiation, planning, concept 
formation, rule ﬁnding, set shifting or set maintenance; impaired mental speed 
(bradyphrenia) 
• 
Visuo-spatial functions: Impaired. Impairment in tasks requiring visual-spatial 
orientation, perception, or construction 
• 
Memory: Impaired. Impairment in free recall of recent events or in tasks requiring 
learning new material, memory usually improves with cueing, recognition is usually 
better than free recall 
• 
Language: Core functions largely preserved. Word ﬁnding difﬁculties and impaired 
comprehension of complex sentences may be present 
2. Behavioral features: 
• 
Apathy: decreased spontaneity; loss of motivation, interest, and effortful behavior 
• 
Changes in personality and mood including depressive features and anxiety 
• 
Hallucinations: mostly visual, usually complex, formed visions of people, animals or 
objects 
• 
Delusions: usually paranoid, such as inﬁdelity, or phantom boarder (unwelcome guests 
living in the home) delusions 
• 
Excessive daytime sleepiness 
III. Features Which Do Not Exclude PDD, but Make the Diagnosis Uncertain 
• 
Co-existence of any other abnormality which may by itself cause cognitive impairment, 
but judged not to be the cause of dementia, e.g. presence of relevant vascular disease in 
imaging 
• 
Time interval between the development of motor and cognitive symptoms not known 


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IV. Features Suggesting Other Conditions or Diseases as Cause of Mental Impairment, 
Which, When Present Make It Impossible to Reliably Diagnose PDD 
• 
Cognitive and behavioral symptoms appearing solely in the context of other conditions 
such as: 
- Acute confusion due to 
a. Systemic diseases or abnormalities 
b. Drug intoxication 
- Major Depression according to DSM IV 
• 
Features compatible with “Probable Vascular dementia” criteria according to NINDS-
AIREN (dementia in the context of cerebrovascular disease as indicated by focal signs in 
neurological exam such as hemiparesis, sensory deﬁcits, and evidence of relevant 
cerebrovascular disease by brain imaging AND a relationship between the two as 
indicated by the presence of one or more of the following: onset of dementia within 
3 months after a recognized stroke, abrupt deterioration in cognitive functions, and 
ﬂuctuating, stepwise progression of cognitive deﬁcits) 


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Table 2. Criteria for the Diagnosis of Probable and Possible PDD 
Probable PDD: 
A. Core features: Both must be present 
B. Associated clinical features: 
• 
Typical proﬁle of cognitive deﬁcits including impairment in at least two of the four core 
cognitive domains (impaired attention which may ﬂuctuate, impaired executive functions, 
impairment in visuo-spatial functions, and impaired free recall memory which usually 
improves with cueing) 
• 
The presence of at least one behavioral symptom (apathy, depressed or anxious mood, 
hallucinations, delusions, excessive daytime sleepiness) supports the diagnosis of 
Probable PDD, lack of behavioral symptoms, however, does not exclude the diagnosis 
C. None of the group III features present 
D. None of the group IV features present 
Possible PDD: 
A. Core features: Both must be present 
B. Associated clinical features: 
• 
Atypical proﬁle of cognitive impairment in one or more domains, such as prominent or 
receptive-type (ﬂuent) aphasia, or pure storage-failure type amnesia (memory does not 
improve with cueing or in recognition tasks) with preserved attention 
• 
Behavioral symptoms may or may not be present 
OR 
C. One or more of the group III features present 
D. None of the group IV features present 
Source: Emre et al., 2007. 


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14.3 
Medications Prohibited Within 4 Weeks Before Randomization and During Study 
Centrally Acting Anticholinergic Drugs 
Anti-muscarinic agents, including but not limited to: 
1. 
atropine 
2. 
benztropine (Cogentin) 
3. 
biperiden (Akineton) 
4. 
brompheniramine (Dimetapp) 
5. 
chlorpheniramine (Chlor-Trimeton) 
6. 
dicyclomine (Dicycloverine) 
7. 
dimenhydrinate (Dramamine) 
8. 
diphenhydramine (Benadryl, Sominex, Advil PM, etc.) 
9. 
doxylamine (Unisom) 
10. 
orphenadrine (Norflex, Disipal, etc.) 
11. 
oxybutynin (Ditropan, Driptane, Lyrinel XL) 
12. 
tolterodine (Detrol, Detrusitol) 
13. 
trihexyphenidyl (Artane, Tremin) 
14. 
scopolamine (Pamine, Transderm Scop) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.4 
Unified Parkinson’s Disease Rating Scale (UPDRS) 
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. 
 
A. The patient’s PD symptoms during the past week were: 
1 = Non Fluctuator 
2 = Fluctuator 
 
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. 
 
A. The patient’s PD symptoms during the past week were: 
 
1 = Non Fluctuator 
2 = Fluctuator 
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. 


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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. 
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 


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22e. LLE 
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. 


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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. 
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. 
 
A. Indicate the patient’s PD state during the examination: 
1 = Fluctuator - “On” during exam 
2 = Fluctuator - Fluctuated during the exam 
3 = Fluctuator - “Off” during exam 
4 = Non-fluctuator 


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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 “off” periods predictable as to timing after a dose of medication? 
0 = No 
1 = Yes 
37. Are “off” periods unpredictable as to timing after a dose of medication? 
0 = No 
1 = Yes 
38. Do “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 
 
Source: Fahn et al., 1987. 
 
 
 


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14.5 
Scales for Outcomes in Parkinson’s Disease-Sleep Scale (SCOPA-SLEEP) 
 
 
 
 
SCOPA-SLEEP 
 
By means of this questionnaire, we would like to find out to what extent in the past 
month you have had problems with sleeping. Some of the questions are about problems 
with sleeping at night, such as, for example, not being able to fall asleep or not managing 
to sleep on. Another set of questions is about problems with sleeping during the day, such
as dozing off (too) easily and having trouble staying awake. 
 
A. Use of sleeping tablets 
 
A1. 
How often did you use sleeping tablets in the last 
months? (prescribed by a physician or not) 

 
 
not at all 
less than 
once a 
week 
once or twice 
a week 
more than 3 
times a 
week 

 
 
A2. 
Which sleeping tablets did you use in the last month? 

 
name:   
amount per month:   
dose per tablet:   
 
name:   
amount per month:   
dose per tablet:   
 

 
name:   
amount per month:   
dose per tablet:   
 


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© This questionnaire is made available free of charge, with the permission of the authors, to all those undertaking non- profit 
and profit making research. Future users may be requested to share data for psychometric purposes. Use of this questionnaire 
in studies should be communicated to the developers. No changes may be made to the questionnaire without written 
permission. Please use the following reference in publications: Marinus J, Visser M, van Hilten JJ, Lammers GJ, Stiggelbout 
AM. Assessment of sleep and sleepiness in Parkinson disease. SLEEP 2003;26:1049-1054. For further information, please 
contact Dr. J. Marinus, Leiden University Medical Center, Department of Neurology (K5Q), P.O. Box 9600, NL-2300 RC 
Leiden (email: j.marinus@lumc.nl). 
 
Source: Marinus et al., 2003. 
 
D. Sleeping during the day and the evening 
 
D1.  
How often in the past month have you fallen asleep unexpectedly either during the 
day or in the evening? 


 
 
never 
sometimes  
regularly  
often 
 
D2.  
How often in the past month have you fallen asleep while sitting peacefully? 

 
never 
sometimes  
regularly  
often 

 
D3.  
How often in the past month have you fallen asleep while watching TV or reading?

 
never 
sometimes  
regularly  
often 

 
D4.  
How often in the past month have you fallen asleep while talking to someone? 

 
never 
sometimes  
regularly  
often 

 
D5.  
In the past month, have you had trouble staying awake during the day or in the 
evening? 

 
never 
sometimes  
regularly  
often 

 
D6. 
In the past month, have you experienced falling asleep during the day as a 
problem? 


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14.6 
Neuropsychiatric Inventory (NPI) 


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SAP_001.pdf: 
SYN120-CL03 Statistical Analysis Plan  
 
 
 
 
 
 
 
Version 1.0, 15 Nov 2017 
Page 1 of 24 
 
STATISTICAL ANALYSIS PLAN 
Title 
SYN120 a Dual 5-HT6/5-HT2A Antagonist Proof of Concept 
Study to Evaluate its Safety, Tolerability and Efficacy in 
Parkinson’s Disease Dementia (SYNAPSE) 
Protocol Number 
SYN120-CL03 
Phase 
2a 
IND Number 
77,435 
Statistical Analysis Plan 
Version 
1.0 
Date of Statistical 
Analysis Plan 
15 Nov 2017 
Date of Current Protocol 
Version 
Draft 15 April 2016 
Sponsor 
Acorda Therapeutics Inc. 
Sponsor Study Director 
 
 
 
 
 
Sponsor Chief Medical 
Officer 
 
 
 
 
 
 


SYN120-CL03 Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES 
Page 2 of24 


SYN120-CL03 Statistical Analysis Plan  
 
 
 
 
 
 
 
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 TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................5 
2. 
STUDY DESIGN .........................................................................................................5 
2.1. 
Overview .......................................................................................................................5 
2.2. 
Study Objectives ...........................................................................................................5 
2.3. 
Study Population ...........................................................................................................6 
2.4. 
Participant Flow ............................................................................................................6 
2.5. 
Treatment Allocation ....................................................................................................6 
2.6. 
Allocation Concealment ...............................................................................................6 
2.7. 
Schedule of Assessments ..............................................................................................7 
3. 
STATISTICAL METHODOLOGY .............................................................................8 
3.1. 
General Considerations .................................................................................................8 
3.1.1. 
Statistical Software .......................................................................................................8 
3.1.2. 
Summary Statistics .......................................................................................................8 
3.1.3. 
Precision .......................................................................................................................9 
3.2. 
Study Endpoints ............................................................................................................9 
3.2.1. 
Efficacy Endpoints ........................................................................................................9 
3.2.2. 
Safety Endpoints .........................................................................................................10 
3.2.3. 
Tolerability Endpoint ..................................................................................................11 
3.3. 
Measurement Definitions ............................................................................................11 
3.3.1. 
CDR Measures ............................................................................................................11 
3.3.2. 
CDR Datasets ..............................................................................................................13 
3.3.3. 
ADCS-CGIC ...............................................................................................................13 
3.3.4. 
ADAS-cog ..................................................................................................................13 
3.3.5. 
PDAQ-15 ....................................................................................................................13 
3.3.6. 
SAPS-PD ....................................................................................................................13 
3.3.7. 
SCOPA-SLEEP ..........................................................................................................14 
3.3.8. 
NPI ..............................................................................................................................14 
3.3.9. 
MoCA .........................................................................................................................14 
3.3.10. 
UPDRS .......................................................................................................................15 
3.3.11. 
Orthostasis ..................................................................................................................15 
3.3.12. 
Levodopa Equivalent Daily Dosage ...........................................................................15 


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3.4. 
Determination of Sample Size ....................................................................................16 
3.5. 
Analysis Samples ........................................................................................................17 
3.6. 
Baseline Characterization ...........................................................................................17 
3.7. 
Interim Analysis ..........................................................................................................17 
3.8. 
Efficacy Analysis ........................................................................................................18 
3.8.1. 
Primary Analysis of the Primary Efficacy Endpoint ..................................................18 
3.8.2. 
Secondary Analyses of the Primary Efficacy Endpoint .............................................18 
3.8.3. 
Secondary Efficacy Endpoints ....................................................................................19 
3.8.4. 
Subgroup Analyses .....................................................................................................19 
3.8.5. 
Multiplicity Adjustments ............................................................................................20 
3.8.6. 
Missing Data ...............................................................................................................20 
3.8.7. 
Clinical Interpretation .................................................................................................20 
3.9. 
Safety Analysis ...........................................................................................................20 
3.9.1. 
Treatment-emergent Adverse Events .........................................................................20 
3.9.2. 
Suicidality ...................................................................................................................21 
3.9.3. 
Safety Labs .................................................................................................................21 
3.9.4. 
Vital Signs ..................................................................................................................21 
3.9.5. 
Blood Pressure ............................................................................................................21 
3.9.6. 
Additional Continuous Safety Outcomes ...................................................................21 
3.10. 
Other Analyses ............................................................................................................22 
3.10.1. 
Participant Disposition ................................................................................................22 
3.10.2. 
Study Drug Compliance and Tolerance ......................................................................22 
3.10.3. 
Prior and Concomitant Medication Use .....................................................................22 
3.10.4. 
Pharmacokinetic Samples ...........................................................................................22 
3.11. 
Handling of Protocol Deviations ................................................................................22 
4. 
REFERENCES ...........................................................................................................23 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) defines the analysis samples, specifies the analysis, and 
guides the interpretation of results from the SYN120-CL03 or SYNAPSE clinical trial. The SAP 
supplements the clinical protocol. Readers are encouraged to refer to the clinical protocol for 
details on the rationale for the intervention, eligibility criteria, conduct of the trial, clinical 
assessments and the timing of their use in the trial, definitions and reporting of adverse events, 
data management conventions, and regulatory oversight and compliance procedures. The reader 
is referred to the Investigator's Brochure for additional details on physiochemistry and pre-
clinical and clinical pharmacokinetics and safety of the investigational product, SYN120. 
In case of discrepancies between the SAP and the clinical protocol concerning matters of 
analysis, the SAP is authoritative. On all other matters, the clinical protocol is authoritative. 
2. 
STUDY DESIGN 
2.1. 
Overview 
This is a multicenter, double-blind, placebo-controlled, two-arm, parallel-group, phase 2a 
randomized controlled trial to evaluate the safety, tolerability, and preliminary efficacy of a 16-
week course of 100 mg QD SYN120 in men or women with a diagnosis of Parkinson's disease 
dementia (PDD) who are taking a cholinesterase inhibitor. Trial participation includes a 
screening visit, randomization to SYN120 or placebo, 16 weeks of follow-up on study drug, and 
a final safety visit 2 weeks after last dose of study drug. The trial is registered at 
Clinicaltrials.gov as study NCT02258152 (see https://clinicaltrials.gov/ct2/show/NCT02258152). 
Participants may also separately consent to DNA testing for a pharmacogenetics substudy. The 
aims and planned analyses of the pharmacogenetics substudy are not described here. 
2.2. 
Study Objectives 
The primary efficacy objective of the SYN120-CL03 trial is to assess the effect of a fixed dosage 
of SYN120 on cognition as determined by the Cognitive Drug Research Computerized Cognition 
Battery (CDR) Continuity of Attention measure in patients with PDD treated with a stable dose 
of a cholinesterase inhibitor. The key secondary efficacy objective is to assess the effects of 
SYN120 in this population on CDR Quality of Episodic Memory. Other secondary and 
exploratory efficacy objectives include the effects of SYN120 on: (a) global impressions of 
change, (b) other measures of cognition, (c) activities of daily living, (d) nighttime sleep and 
daytime sleepiness, (e) positive symptoms, and (f) behavioral functioning.  
The safety objectives of the SYN120-CL03 trial are to assess the safety and tolerability of a fixed 
dosage of SYN120 by assessing adverse events (AEs), vital signs (including orthostatic blood 
pressure measurements), laboratory assessments, electrocardiography (ECG), Unified 
Parkinson’s Disease Rating Scale (UPDRS) Parts I through IV, changes in intensity of 
symptomatic therapy, and Columbia Suicide Severity Rating Scale (C-SSRS). 


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The pharmacokinetic objectives of the SYN120-CL03 trial are to estimate population-level 
pharmacokinetic parameters for plasma levels of SYN120. 
2.3. 
Study Population 
Individuals eligible for trial participation are men or women at least 50 years old who have 
received a diagnosis of probable PDD according to the Movement Disorder Society Task Force 
clinical diagnostic criteria for dementia associated with Parkinson's disease (Emre et al. 2007) 
and who are taking a cholinesterase inhibitor. Detailed inclusion and exclusion criteria are 
specified in the clinical protocol. 
Participants will be recruited from a total of 20 clinical sites located through the US.  
2.4. 
Participant Flow 
After providing informed consent and determining eligibility, approximately 80 participants will 
be randomized to receive SYN120 100 mg QD or placebo in a 1:1 ratio, stratified by clinical site. 
In the active arm, SYN120 is titrated as follows: 20 mg QD for the first 7 days, 50 mg QD for 
the next 7 days, and 100 mg QD for the remaining 14 weeks. Participants in the placebo arm 
receive a matching pseudo-titration of placebo. Participants who consent to participate in the 
pharmacogenetics substudy have a blood sample collected for DNA testing. Participants and 
caregivers return to the study site for evaluations at weeks 4, 8, and 16 and will be telephoned at 
weeks 2 and 12 to assess for AEs. Participants who discontinue study drug should remain on 
study following the normal schedule of assessments. Patients withdrawing consent will undergo 
an Early Termination Visit, ideally while still taking study drug. All participants are asked to 
return for a Safety Follow-up Visit approximately 2 weeks after their last dose administration. 
Detailed descriptions of study procedures and timing are specified in the clinical protocol. 
2.5. 
Treatment Allocation 
At the baseline visit, eligible participants are randomly allocated in equal proportion to one of 
two treatment groups, SYN120 100 mg QD or placebo, according to a permuted-block 
randomization schedule with a block size of 4, stratified by site. The randomization schedule was 
prepared by computer program by the unblinded study statistician. Stratification by site is 
achieved by distributing to sites allotments of study drug kits that consist of a full block from the 
permuted-block schedule.  
2.6. 
Allocation Concealment 
The randomization schedule is known only by the unblinded study statistician who generated the 
schedule and by the study drug distributor and the sponsor's quality control and bioanalytical 
staff and subcontractors as specified in the SYN120-CL03 Study Randomization Specification. 
Concealment of the true treatment allocation of specific participants is achieved by use of 
anonymous subject identifiers to link participants with specific study drug kits and by use of 
matching active and placebo tablets and titration schedules. Members of the SYNAPSE Steering 
Committee, site investigators and other site staff, clinical coordination and data management 
staff, the blinded study statistician, the medical monitor, and all participants are blinded to 
participant treatment allocations. The Safety Data Monitor (SDM) and members of the SDM 
Advisory Group are provided treatment-specific information in order to monitor the trial but 


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such information is masked by use of coded values to identify the treatment groups. The SDM 
may request the true treatment identities. 
2.7. 
Schedule of Assessments 
Study Period 
Screen 
inga 
Base-
line 
16-Week Treatment Period 
(Double-blinded Dosing) 
(Days 1–112) 
Safety 
Follow 
Up 
Study Week −6 to −1 
0 
2 
4 
8 
12 
16 
18 
Early 
Term. 
Unsche
duled 
Visit Window 
 
±3 days ±3 days ±3 days ±3 days ±3 days ±3 days ±3 days 
 
 
Assessments 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V99 
V98 
Onsite clinic visit 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Obtain patient and caregiver 
informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics; medical 
history including 
neurological and PD/PDD 
history 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
including anti-dementia and 
anti-Parkinson meds 
Xb 
X 
 
X 
X 
 
X 
X 
X 
X 
BP and pulse (supine and 
standing) c 
XXX 
X 
 
X 
X 
 
X 
X 
X 
X d 
Weight (include height at 
Screening) 
X 
 
 
 
 
 
X 
 
X 
 
Physical and neurological 
examination 
X 
X d 
 
X 
X 
 
X 
 
X 
X d 
MoCA 
X 
 
 
 
 
 
X 
 
X 
 
Preliminary eligibility 
assessment by Investigator 
X 
 
 
 
 
 
 
 
 
 
CDR Computerized 
Cognition Battery e 
XX 
X 
 
 
X 
 
X 
 
X 
 
ADAS-cog e 
 
X 
 
 
 
 
X 
 
X 
 
ADCS-CGIC e 
 
 
 
 
 
 
X 
 
X 
 
PDAQ (reported by 
caregiver) 
 
X 
 
 
 
 
X 
 
X 
 
SCOPA-SLEEP 
 
X 
 
 
 
 
X 
 
X 
 
SAPS-PD  
 
X 
 
 
 
 
X 
 
X 
 
NPI (reported by caregiver) 
 
X 
 
 
 
 
X 
 
X 
 
UPDRS Parts I–IV f 
 
X 
 
X 
X 
 
X 
X 
X 
 
Study drug accountability 
 
X 
 
X 
X 
 
X 
 
X 
X 
Recording of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
 
X 
X 
 
X 
X 
X 
X d 
Dispense IMP to 
patient/caregiver and provide 
dosing instructions 
 
X 
 
X 
X 
 
 
 
 
X d 
FSH (♀ who are not 
surgically sterile and are 
postmenopausal, only) 
X 
 
 
 
 
 
 
 
 
 
Urine hCG (♀ of 
childbearing potential, only) g 
X 
X 
 
X 
X 
 
X 
 
X 
X d 
Hematology h, chemistry 
(including liver function) i 
X 
X 
 
X 
X 
 
X 
 
X 
X d 
TSH, freeT3 and free T4 
X 
 
 
 
 
 
 
 
 
 
Vitamin B12 
X 
 
 
 
 
 
 
 
 
 
Urinalysis j 
X 
X 
 
X 
X 
 
X 
 
X 
X d 
SYN120 blood sampling k 
 
X 
 
X l 
X l 
 
X 
 
X l 
X d, l 
12-lead electrocardiogram m 
X 
X n 
 
X 
X 
 
X 
 
X 
X d 
Pharmacogenetic sample 
collection (optional) 
 
X o 
 
X p 
X p 
 
X p 
 
 
 


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♀ = female; AEs, adverse events; ADAS-cog, Alzheimer’s Disease Assessment Scale–cognitive subscale; ADCS-CGIC, Alzheimer’s 
Disease Cooperative Study-Clinician’s Global Impression of Change; BP, blood pressure; CDR, Cognitive Drug Research; C-SSRS, 
Columbia-Suicide Severity Risk Scale; ECG, electrocardiogram; FSH, follicle stimulating hormone; hCG, human chorionic 
gonadotropin; IMP, investigational medicinal product; MoCA, Montreal Cognitive Assessment; NPI, Neuropsychiatric Inventory; PD, 
Parkinson’s disease; PDAQ-15, Penn Parkinson's Daily Activities Questionnaire-15; PDD, Parkinson’s disease dementia; SAPS-PD, 
PD-adapted Scale for Assessment of Positive Symptoms; SCOPA-SLEEP, Scales for Outcomes in Parkinson’s Disease-Sleep Scale; 
TSH, thyroid stimulating hormone; UPDRS, Unified Parkinson’s Disease Rating Scale. 
Footnotes: 
a Screening period may not exceed 6 weeks. Note: For screen failures, document demographics and reason for ineligibility in source 
documents and eCRF. 
b At Screening, obtain complete medication history including anti-dementia and anti-Parkinson medications (current and those received 
within the past year). Record the date and time of the most recent dose of each anti-dementia and anti-Parkinson medication taken prior 
to the Screening assessment. 
c BP and pulse are to be measured after at least 5 minutes supine rest and again after standing for 1 and 3 minutes. 
d Optional assessments that may be performed for evaluation of AEs, at the Investigator’s discretion. 
e Perform all cognitive and dementia-related assessments while patient is in ON state. Complete two training sessions during the 
screening period, as close to the Baseline visit as possible. 
f UPDRS is to be measured in ON 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 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. 
g For female patients of childbearing potential, perform a urine hCG pregnancy test and document method of contraception at Screening 
and verify continuation of contraceptive method at each visit. 
h Hematology: hemoglobin, hematocrit, red blood cell count, total and differential white blood cell, and platelet count. 
i Chemistry: aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), 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, and creatine 
phosphokinase (CK). 
j Urinalysis: specific gravity, pH, ketones, blood, protein, and glucose. If urine dipstick positive for leukocytes, protein or erythrocytes, 
microscopic evaluation will be performed. 
k Blood sample for determination of SYN120 plasma concentration (and screening for presence of SYN120 metabolites ) to be obtained 
at Baseline (Day 1) prior to initiation of dosing, Visit 4 (Week 4), Visit 5 (Week 8), Visit 7 (Week 16), Early Termination (if 
applicable), and Unscheduled Visit (optional, as per footnote d). Record date and time of SYN120 sample collection.  
l For blood sample collections at Visit 4 (Week 4), Visit 5 (Week 8), Visit 7 (Week 16), and Early Termination or Unscheduled Visit (if 
applicable), record the date and time when the patient took the last dose of IMP. 
m Resting supine 12-lead ECGs will be collected after the patient has been in a supine, or if unable, semi-supine (no more than 45 
degrees) position for a minimum of 5 minutes. ECGs should be collected at a time during study visit when the patient is not 
experiencing dyskinesia that would interfere with an adequate recording. 
n At Baseline, obtain triplicate 12-lead ECGs (3 serial readings performed several minutes apart). 
o At Baseline, for patients who give consent for optional pharmacogenetic substudy, collect single blood sample  (approximately 10 mL) 
for pharmacogenetic assessment. (If this sample is not collected at Baseline, it will be collected at the next possible in-clinic visit, i.e., 
Visit 4, 5 or 7.) See Section 7.13 of the clinical protocol. 
p For patients who give consent for optional pharmacogenetic substudy but sample not collected at Baseline (or during previous visit), 
collect single blood sample  (approximately 10 mL) for pharmacogenetic assessment. See Section 7.13 of the clinical protocol. 
3. 
STATISTICAL METHODOLOGY 
3.1. 
General Considerations 
3.1.1. 
Statistical Software 
All statistical analyses will be performed using SAS (SAS Institute, NC, USA) or R (R 
Foundation for Statistical Computing, Vienna, Austria).  
3.1.2. 
Summary Statistics 
Data will be summarized with respect to disposition, demographics, pre-treatment 
characteristics, safety outcomes, tolerability, and efficacy outcomes. Summary statistics for 


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continuous variables will include the number of subjects, the mean, median, standard deviation, 
and range. For categorical data, summaries will include counts and percentages. 
3.1.3. 
Precision 
Results will generally be reported to 3 significant figures. Percentages will generally be reported 
to 0.1 percentage points. P-values will be reported to two digits when greater than or equal to 
0.10, to three digits when greater than or equal to 0.00095 and less than 0.10, and as <0.001 for 
all smaller values. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
The primary efficacy endpoint is the change from baseline to the week 16 visit in the CDR 
Continuity of Attention composite score captured in the ON state. 
The key secondary efficacy endpoint is the change from baseline to the week 16 visit in the CDR 
Quality of Episodic Memory composite score captured in the ON state. 
The other secondary efficacy endpoints are the change from baseline to the week 16 visit in the 
following measures: 
• Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change (ADCS-
CGIC),  
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) total score captured 
in the ON state by an evaluator blinded to the results of all cognitive assessments,  
• CDR Power of Attention composite score captured in the ON state,  
• CDR Speed of Memory Retrieval composite score captured in the ON state,  
• PDAQ-15 total score (reported by caregiver),  
• SCOPA-SLEEP nighttime sleep and daytime sleepiness scores,  
• SAPS-PD total score,  
• NPI total score, caregiver distress total score, and subscale total scores for delusions, 
hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, 
irritability/lability, aberrant motor activity, night-time behavioral disturbances, and appetite 
and eating abnormalities (reported by caregiver), and  
• MoCA total score. 
Exploratory efficacy endpoints include the change from baseline to the week 8 visit in the CDR 
Continuity of Attention and Quality of Episodic Memory composite scores captured in the ON 
state and the change from baseline to week 8 and 16 visits in the CDR Quality of Working 
Memory, Cognitive Reaction Time, and Reaction Time Variability composite scores captured in 
the ON state, individual component tasks of the CDR, i.e., Immediate Word Recall (Words 
recalled, Errors), Simple Reaction Time (Median Reaction Time), Digit Vigilance (Mean 
Reaction Time, Accuracy, False Alarms), Choice Reaction Time (Median Reaction Time, 
Accuracy), Numeric Working Memory (Median Reaction Time), Spatial Working Memory 


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(Median Reaction Time, Sensitivity Index), Delayed Word Recall (Words recalled, Errors), 
Word Recognition (Median Reaction Time, Original Stimuli Accuracy, Novel Stimuli 
Accuracy), and Picture Recognition (Median Reaction Time, Original Stimuli Accuracy, Novel 
Stimuli Accuracy), and scores for individual tasks of the ADAS-cog. 
3.2.2. 
Safety Endpoints 
The following safety endpoints will be evaluated: 
• Proportion of participants experiencing the following and event rates relative to time at risk 
of: (a) any treatment-emergent AE (TEAE), (b) any severe TEAE, (c) any serious TEAE, (d) 
any TEAE at least possibly related to study drug, (e) any TEAE leading to permanent study 
drug discontinuation or early termination from the trial, and (f) any TEAE resulting in death, 
summarized across all MedDRA terms 
• Proportion of participants experiencing and number of unique events of all TEAEs classified 
by seriousness, severity, relatedness to study drug, action taken with study drug, and 
outcome, summarized across all MedDRA terms 
• Proportion of participants experiencing and number of unique events of each type of TEAE 
and serious TEAE classified by MedDRA system organ class, high level term, and preferred 
term 
• Proportion of participants experiencing treatment-emergent orthostatic hypotension 
• Mean 16-week change from baseline in supine and standing SBP, supine and standing DBP, 
and differences from supine to standing SBP and DBP 
• Mean 16-week change from baseline in weight 
• Proportion of participants experiencing treatment-emergent clinically significant laboratory 
abnormalities classified by assay, whether the abnormality is below or above the normal 
range, and visit, with cross-classification of frequencies of abnormalities from baseline to 
each scheduled post-baseline visit at which safety labs are performed 
• Mean 16-week change from baseline in laboratory assays 
• Proportion of participants experiencing treatment-emergent clinically significant ECG 
abnormalities 
• Mean 16-week change from baseline in ECG parameters 
• Mean 16-week change from baseline in UPDRS Part I score, II score, III score, I through III 
total score, Part IV dyskinesia score, Part IV clinical fluctuations score, Part IV other 
complications score, and Part IV total score 
• Mean 16-week change from baseline in levodopa daily dosage (LDD) and levodopa 
equivalent daily dosage (LEDD) 
• Proportion of participants reporting any treatment-emergent suicidal ideation 
• Maximum post-baseline suicidal ideation planning, frequency, duration, controllability, 
deterrents, and reasons 


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• Proportion of participants reporting any post-baseline suicidal behavior, actual attempts, non-
suicidal self-injurious behavior, interrupted attempts, aborted attempts, preparatory acts or 
behaviors, or completed suicide 
• Maximum post-baseline suicidal behavior lethality and potential lethality 
Reported proportions will use as their denominator all participants in the Safety and Tolerability 
sample (see Section 3.5 below). 
3.2.3. 
Tolerability Endpoint 
Participants will be judged tolerant of study drug if they complete their week 16 visit without 
prior permanent discontinuation of study drug and without prior study drug suspension lasting 
longer than 14 days. Tolerability will be summarized as the proportion of participants in a 
treatment group who are tolerant of study drug. 
3.3. 
Measurement Definitions 
3.3.1. 
CDR Measures 
The CDR (Wesnes et al. 1992) is a computerized neuropsychological test battery to assess 
cognitive tasks based on measures of choice reaction time, vigilance, and the sensitivity and 
speed of digit, word and picture recognition. The stimuli are presented on a computer screen and 
the subjects respond by pressing either a “Yes” or “No” on a response box. Detailed of the 
assessments are described in the clinical protocol. 
Continuity of Attention (COA) measures the ability to sustain attention and avoid error. COA is 
calculated as (VIGACC*0.45) + (CRTACC*0.5) - VIGFA, where VIGACC is digit vigilance 
accuracy, CRTACC is choice reaction time accuracy, and VIGFA is digit vigilance false alarms. 
Higher COA scores represent greater sustained attention and avoidance of errors. 
Quality of Episodic Memory (QEM) measures the ability to store, hold, and retrieve information 
of an episodic nature. QEM is calculated as (DRECOACC + DRECNACC – 100) + 
(DPICOACC + DPICNACC – 100) +((IRCL – IRCLERR)*100 / 12) + ((DRCL – 
DRCLERR)*100 / 12), where DRECOACC is word recognition original stimuli accuracy, 
DRECNACC is word recognition new stimuli accuracy, DPICOACC is picture recognition 
original stimuli accuracy, DPICNACC is picture recognition new stimuli accuracy, IRCL is 
immediate word recall words recalled, IRCLERR is immediate word recall errors, DRCL is 
delayed word recall words recalled, and DRCLERR is delayed word recall errors. Higher QEM 
scores represent greater ability to store, hold, and retrieve information of an episodic nature. 
Quality of Working Memory (QWM) measures the ability to store and retrieve information in 
working memory. QWM is calculated as SPMSI + NWMSI, where SPMSI is the sensitivity 
index for spatial working memory and NWMSI is the sensitivity index for numeric working 
memory. Sensitivity index (Frey and Colliver 1973) measures the ability to identify previously 
presented stimuli and reject stimuli which were not previously presented. A score of 1 represents 
perfect discrimination; all of the previously presented stimuli are correctly identified and all 
distractor stimuli are correctly rejected as being novel. A score of -1 represents perfect reverse 
discrimination; none of the previously presented stimuli are correctly identified, and all distractor 
stimuli are selected as being novel. A score of 0 represents chance performance with no 


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discrimination between previously presented stimuli and distractor stimuli. Sensitivity index is 
calculated as (HIT - FA) / (2 (HIT + FA) - (HIT + FA)2), where HIT is the proportion of 
previously presented items that were correctly identified and FA is the proportion of novel items 
that were incorrectly identified. If both HIT and FA are 0 or both HIT and FA are 1, leading to 
an indeterminant ratio as calculated above, then the sensitivity index is assigned a value of zero. 
Higher QWM scores represent greater ability to store and retrieve information in working 
memory. 
Power of Attention (POA) measures the intensity of concentration at a particular moment. POA 
is calculated as SRTM + VIGRT + CRTM, where SRTM is median simple reaction time, 
VIGRT is mean digit vigilance reaction time, and CRTM is median choice reaction time. Higher 
POA scores represent less intensity of concentration at a particular moment. 
Speed of Memory Retrieval (SMR) measures the time it takes to retrieve a memory. SMR is 
calculated as SPMRTM + NWMRTM + DRECRTM + DPICRTM, where SPMRTM is median 
spatial working memory reaction time, NWMRTM is median numeric working memory reaction 
time, DRECRTM is median word recognition reaction time, and DPICRTM is median picture 
recognition reaction time. Higher SMR scores represent slower speed in retrieving memories. 
Immediate Word Recall is measured by the CDR variables IRCL (number of words correctly 
recalled) and IRCLERR (number of words recalled that were not presented during current testing 
session). 
Simple Reaction Time is measured by the CDR variable SRTM (median speed of individual 
correct responses). 
Digit Vigilance is measured by the CDR variables VIGRT (mean speed of individual responses 
to targets within 1.5 sec window), VIGACC (percentage of targets responded to within 1.5 sec 
window), and VIGFA (number of responses falling outside of 1.5 sec window). 
Choice Reaction Time is measured by the CDR variables CRTM (median speed of individual 
correct responses) and CRTACC (percentage of stimuli correctly identified). 
Numeric Working Memory is measured by the CDR variables NWMRTM (median speed of 
individual correct responses to all stimuli) and NWMSI (Frey and Colliver sensitivity index). 
Spatial Working Memory is measured by the CDR variables SPMRTM (median speed of 
individual correct responses to all stimuli) and SPMSI (Frey and Colliver sensitivity index). 
Delayed Word Recall is measured by the CDR variables DRCL (number of words correctly 
recalled) and DRCLERR (number of words recalled that were not presented during current 
testing session). 
Word Recognition is measured by the CDR variables DRECRTM (median speed of individual 
correct responses to all stimuli), DRECOACC (percentage of original stimuli correctly 
identified), and DRECNACC (percentage of novel stimuli correctly identified). 
Picture Recognition is measured by the CDR variables DPICRTM (median speed of individual 
correct responses to all stimuli), DPICOACC (percentage of original stimuli correctly identified), 
and DPICNACC (percentage of novel stimuli correctly identified). 


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3.3.2. 
CDR Datasets 
Two datasets will be obtained from Bracket: (1) raw data, and (2) adjudicated data. The 
adjudicated dataset, with modifications suggested by Dr. Wesnes that in his expert opinion 
would best reflect the cognitive status of participants at the time of testing, will be used for 
primary analysis. All changes from the raw data resulting from algorithmic flipping of data and 
from Dr. Wesnes' adjudication will be documented together with their justification. 
3.3.3. 
ADCS-CGIC 
The ADCS-CGIC (Schneider et al. 1997) is a single-question clinician-completed scale for 
assessing clinically relevant global change in patients with dementia based on an organized but 
unstructured assessment of the participants’s function and mental status, a caregiver interview, 
and a standardized set of questions. The ADCS CGIC evaluation will be performed by an 
Investigator who is blinded to other cognitive evaluations. The ADCS-CGIC score takes values 
from 1 to 7, with higher scores representing greater worsening, centered on a score of 4 for no 
change from baseline. 
3.3.4. 
ADAS-cog 
The ADAS-cog is the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale 
(ADAS; Rosen et al. Am J Psychiatry 1984) designed to measure the severity of the most 
prominent symptoms of dementia in patients with Alzheimer's disease (AD). The ADAS-cog 
subscale measures alterations of memory, language, praxis, attention and other cognitive abilities 
which comprise the core symptoms of AD and PDD through a series of clinician-administered 
tests. This study utilizes an early revision of the ADAS-cog (unpublished manual Mohs, 1994; 
see: http://adni.loni.usc.edu/data-samples/data-faq/) and does not include the supplemental 
delayed word recall or number cancellation tasks (cf. Petersen et al. 2005) nor the maze task (cf. 
Mohs et al. 1997). Item-level scores from the 11 tasks are summed for a total score (range 0 to 
70) with higher scores representing worse cognitive function. 
3.3.5. 
PDAQ-15 
The PDAQ-15 (Brennan et al. 2016) is a 15-item scale completed by a knowledgeable informant 
and designed to measure cognitive instrumental activities of daily living. Each item is rated from 
0 (Cannot Do) to 4 (None [=no difficulty doing]). All items are summed for a total score (range 0 
to 60) with higher scores indicating greater ability to perform instrumental activities of daily 
living. 
3.3.6. 
SAPS-PD 
The SAPS-PD (Voss et al. 2013) is a 9-item clinician-rated scale consisting of a subset of items 
(H1 Auditory Hallucinations, H3 Voices Conversing, H4 Somatic or Tactile Hallucinations, H6 
Visual Hallucinations, H7 Global Rating of Severity of Hallucinations, D1 Persecutory 
Delusions, D2 Delusions of Jealousy, D7 Ideas and Delusions of Reference, D13 Global Rating 
of Severity of Delusions) selected on the basis of their relevance to PDD from the full 20-item 
SAPS (Andreasen, 1984) and designed to measure positive symptoms in patients with 
schizophrenia. Each item is rated from 0 (absent) to 5 (severe). All items are summed for a total 
score (range 0 to 45) with higher scores indicating more severe positive symptoms. 


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3.3.7. 
SCOPA-SLEEP 
The SCOPA-SLEEP (Marinus et al. 2003) is a 13-item self-reported scale designed to evaluate 
nighttime sleep and daytime sleepiness among patients with PD. The SCOPA-SLEEP consists of 
four sections: (a) a single question (range 0 to 3) addressing the frequency of using sleeping 
tablets; (b) 5 questions addressing specific elements of nighttime sleep quality; (c) one question 
evaluating overall nighttime sleep quality over the previous month, and (d) 6 questions 
addressing daytime sleepiness. The 5 nighttime sleep questions rate the perceived extent of 
problems with sleep fragmentation, sleep efficiency, sleep duration, and early wakening, each 
rated from 0 (not at all) to 3 (a lot). They are summed for a total score (range 0 to 15) with higher 
scores indicating greater problems with nighttime sleep. The overall sleep quality question is 
rated on a 7-point scale (range 0 to 6) with higher scores indicating worse sleep quality. The 6 
daytime sleepiness questions rate the frequency of experiences indicative of sleepiness, each 
rates from 0 (never) to 3 (often). They are summed for a total score (range 0 to 18) with higher 
scores indicating greater daytime sleepiness. 
3.3.8. 
NPI 
The NPI (Cummings et al. 1994, Cummings 1997, Kaufer et al. 1998) is a caregiver-completed 
scale designed to evaluate 12 subdomains of behavioral functioning: delusions, hallucinations, 
agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor 
behavior, night-time behavior disturbances, and appetite and eating abnormalities. Each domain 
has a screening question that assesses the presence of the specific disturbance. If present, a series 
of 7 to 9 more detailed Yes/No subquestions are asked, the frequency is rated on a scale from 1 
(occasionally, less than once per week) to 4 (very frequently, once or more per day or 
continuously), the severity is rated on a scale from 1 (mild) to 3 (marked), and caregiver 
emotional distress is rated on a scale from 0 (not at all [distressed]) to 5 (very severely or 
extremely [distressed]). The total score for each domain (range 0 to 12) is calculated by 
multiplying the frequency by the severity or given a value of zero if presence of the disturbance 
for that domain was not endorsed. A total NPI score is calculated by adding all domain-specific 
total scores together (range 0 to 144) with higher scores indicating worse neuropsychiatric 
disturbance. A total caregiver distress score (NPI-D, range 0 to 60) is calculated by adding all 
domain-specific caregiver distress scores. 
3.3.9. 
MoCA 
The MoCA (Nasreddine et al. 2005) consists of 8 clinician-administered cognitive tasks designed 
to screen for mild cognitive impairment. The MoCA assesses attention and concentration, 
executive functions, memory, language, visuoconstructional skills, conceptual thinking, 
calculations, and orientation. One point is awarded for correct completion of each item of the 
visuospatial/executive function task (5 items), naming task (3 items), digit vigilance and tapping 
items of the attention task (3 items), the sentence repetition items of the language task (2 items), 
abstraction task (2 items), delayed recall task (5 items), and orientation task (6 items). One point 
is awarded for naming 11 or more words during the fluency item of the language task. Zero 
(none correct) to 3 (4 or more correct) points are awarded based on the number of correct 
subtractions by 7 starting at 100 in the attention task. One point is awarded if the participant has 
12 years or less of education unless the score is already 30. Scores for each task are summed for 
a total score (range 0 to 30) with higher scores indicating greater cognitive capacity. 


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3.3.10. 
UPDRS 
The UPDRS (Fahn et al. 1987) is a 4-part, clinician-completed scale: Part I, Mentation, Behavior 
and Mood; Part II, Activities of Daily Living; Part III, Motor Examination; Part IV, 
Complications of Therapy. Each item in Parts I (4 items), II (13 items), and III (27 items) is rated 
on a scale from 0 (normal, none, or condition absent; text varies by item) to 4 (the most severe 
state of a given condition; text varies by item). The items are summed separately by Part and 
across all three parts for four total scores (range Part I, 0 to 16; Part II, 0 to 52; Part III, 0 to 108; 
Parts I-III, 0 to 176) with higher scores indicating more severe impairments. Part IV contains 11 
items divided across three subsections: A, Dyskinesias (4 items); B, Clinical Fluctuations (4 
items); and C, Other Complications (3 items). Part IV A consists of 3 items rated on a scale from 
0 (no experience of a given condition; text varies by item) to 4 (the most severe state of a given 
condition; text varies by item) and 1 item rated on a scale from 0 (no; condition not present) to 1 
(yes; condition present). Part IV B consists of 1 item rated on a scale from 0 (none) to 4 (76 to 
100% of the day) and 3 items rated on a scale from 0 (no; condition not present) to 1 (yes; 
condition present). Part IV C consists of 3 items rated on a scale from 0 (no; condition not 
present) to 1 (yes; condition present). The items are summed separately by subsection and across 
all Part IV items for four total scores (range Part IV A, 0 to 13; Part IV B, 0 to 7; Part IV C, 0 to 
3; Part IV, 0 to 23) with higher scores indicating more severe complications. 
3.3.11. 
Orthostasis 
Orthostatic hypotension will be defined as a maximum decrease of 20 mm Hg or greater in 
systolic blood pressure (SBP) or a maximum decrease of 10 mm Hg or greater in diastolic blood 
pressure (DBP) when moving from a supine to a standing position, with measurements 
completed 1 min and 3 min after standing. 
3.3.12. 
Levodopa Equivalent Daily Dosage 
The levodopa equivalent daily dosage (LEDD) will be calculated using data from the 
concomitant medications log. The conversion from dopamergic drugs other than carbidopa-
levodopa will follow the recommendations by Tomlinson et al. (2010) with the following 
additions for more recently approved drugs. 
• Extended release formations of carbidopa-levodopa (Rytary™) will be converted at 60% of 
their actual levodopa content (which is 5 mg greater than their labeled content) based on 
mean post-baseline daily dosages reported in Hauser et al. (2013); 
• Extended release formations of ropinorole (RequipXL™) will be converted at 20 mg 
levodopa equivalent per mg ropinirole based on equivalent maximum recommended daily 
dosage. 
The full calculation is as follows: 
1. At each time any oral levodopa is taken per day, calculate the immediate release 
levodopa (e.g., Sinemet, Parcopa) dosage (mg) based on the number of tablets taken per 
dose and the dosage of levodopa in each tablet 
2. At each time any oral levodopa is taken per day, calculate the controlled release levodopa 
(e.g., Sinemet CR) dosage (mg) and multiply by 0.75 to account for loss of bioavailability 


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3. At each time any oral levodopa is taken per day, calculate the extended release levodopa 
(e.g., Rytary) dosage (mg), noting that the listed dosage per tablet is 5 mg less than the 
actual dosage, and multiply by 0.60 to account for loss of bioavailability 
4. At each time any oral levodopa is taken per day, calculate the total daily oral levodopa 
dosage by summing together the oral levodopa dosage from immediate release, controlled 
release, and extended release formulations (quantities 1 through 3) 
5. At each time any oral levodopa is taken per day, if entacapone but not tolcapone is taken 
at the same time, either separately or as a combination drug (e.g., Stalevo), then multiply 
the total levodopa dosage at that time (quantity 4) by 0.33 
6. At each time any oral levodopa is taken per day, if tolcapone (e.g., Tasmar) is taken at the 
same time, then multiply the total levodopa dosage at that time (quantity 4) by 0.50 
7. Calculated the COMT-adjusted total daily levodopa equivalent dosage associated with 
oral levodopa as the sum over all time points of quantities 4 through 6 
8. If enteral levodopa is taken without any COMT inhibitor, then multiply the total enteral 
levodopa (e.g., Duopa) daily dosage (mg) by 1.11 
9. If enteral levodopa is taken with entacapone but not tolcapone, then multiply the total 
daily enteral levodopa dosage (mg) by 1.48 
10. If enteral levodopa is taken with tolcapone, then multiply the total daily enteral levodopa 
dosage (mg) by 1.67 
11. If immediate release or modified release pramipexole (e.g., Mirapex) is taken, multiply 
the daily dosage (mg/day of the dihydrochloride monohydrate salt) by 100 
12. If immediate release or extended release ropinirole (e.g., Requip, Requip XL) is taken, 
multiply the dosage (mg/day) by 20 
13. If a rotigotine patch (e.g., Neupro) is used, multiply the dosage (mg/day) by 30 
14. If oral selegiline (e.g., Eldepryl) is taken, multiply the dosage (mg/day) by 10 
15. If sublingual selegiline (e.g., Zelapar) is taken, multiply the dosage (mg/day) by 80 
16. If oral rasagiline (e.g., Azilect) is taken, multiply the dosage (mg/day) by 100 
17. If oral amantadine (e.g., Symmetrel) is taken, multiply the dosage (mg/day) by 1 
18. If an injection or infusion of apomorphine (e.g., Apokyn) is taken, multiply the dosage 
(mg/day) by 10 
19. Calculate total LEDD as the sum of quantities 7 through 18. 
3.4. 
Determination of Sample Size 
The primary efficacy measure is the change from baseline to the week 16 visit in the CDR COA. 
Based on a two-tailed test at alpha = 0.05 and assuming up to 15% loss to follow up, a total 
sample size of 80 randomized participants provides at least 80% power for a true treatment-
dependent difference in 16-week change in CDR COA equal to an effect size of 0.69. Additional 
power will be obtained from analysis using a shared-baseline repeated-measures analysis of 


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variance. Effect sizes of similar magnitude were observed for several CDR measures in a 24-
week trial of memantine in patients with PDD and dementia with Lewy bodies (Wesnes et al. 
2014). 
3.5. 
Analysis Samples 
The following analysis samples will be used for testing safety, tolerability, efficacy, and 
pharmacokinetic endpoints: 
• Safety and Tolerability (ST) Sample: Participants who are eligible, randomized, and take at 
least one dose of study drug, classified according to the actual treatment received. 
• Efficacy Modified Intent-to-treat (mITT) Sample: Participants who are eligible, randomized, 
have at least one valid pre-treatment and at least one valid post-treatment CDR COA 
measurement, and take at least one dose of study drug, classified according to their 
randomized treatment assignment. This sample will include observations made after 
discontinuation of study drug should any such participants remain on study. 
• Efficacy Per-protocol (PP) Sample: Participants who are eligible, randomized, have at least 
one valid pre-treatment and one valid post-treatment CDR COA measurement, take at least 
one dose of study drug, and meet all other major protocol compliance criteria specified prior 
to unblinding, classified according to the actual treatment received. Observations made after 
permanent discontinuation of study drug (whether due to intolerance, early termination, loss 
to follow-up, or death) will be omitted, but completion of follow-up on study drug will not be 
required. Any other individual observations affected by important protocol deviations may 
also be excluded, as specified prior to unblinding. 
• Pharmacokinetic (PK) Sample: Participants in the ST sample who have at least one valid 
determination of their plasma SYN120 concentration. 
3.6. 
Baseline Characterization 
Each analysis sample will be summarized overall and by treatment group for the following 
characteristics: randomization site; age, gender, race, and ethnicity; education level, years of 
education; years since PD diagnosis, years since PDD diagnosis, UPDRS Part I, II, III, I-III, IV 
A, IV B, and IV C total scores, and Hoehn and Yahr Stage; CDR COA, QEM, QWM, POA, and 
SWM composite scores; ADAS-cog total score; MoCA total score; PDAQ-15 total score; SAPS-
PD total score; SCOPA-SLEEP nighttime sleep, overall sleep quality, and daytime sleepiness; 
NPI domain-specific and overall score and overall caregiver distress score; weight and body 
mass index; orthostasis and orthostatic changes in systolic and diastolic blood pressure; QTc 
interval by Fridericia's equation; baseline specific cholinesterase inhibitor; baseline memantine 
use, and baseline LDD and LEDD. The magnitude of differences between treatment groups will 
be summarized using Fisher's exact tests for nominal variables, exact Cochran-Armitage trend 
tests for ordinal variables, and two-sample t-tests for approximately continuous variables. 
3.7. 
Interim Analysis 
No interim analysis for futility, efficacy, or sample size re-estimation is planned. The 
independent Safety Data Monitor and the Safety Data Monitor Advisory Group review safety 
data quarterly and may request specific analyses at any time. 


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3.8. 
Efficacy Analysis 
3.8.1. 
Primary Analysis of the Primary Efficacy Endpoint 
The primary efficacy analysis will be performed on the mITT sample using the adjudicated CDR 
data and will use a shared-baseline, repeated-measures analysis of variance that includes fixed 
effects for visit (3 levels: Baseline, Week 8, and Week 16) and the interaction between treatment 
group (2 levels: SYN120 and placebo) and post-baseline visit (2 levels: Weeks 8 and 16), 
random center-specific intercepts, and unstructured within-person covariance. The interaction 
between treatment group and visit will be restricted to post-baseline visits by including a numeric 
indicator variable (0 pre-treatment, 1 post-treatment) in the interaction. Use of a shared baseline 
reflects the true state of the population sampled prior to randomization and has the advantage of 
adjusting for any chance differences at baseline in a manner similar to analysis of covariance 
(Liang and Zeger, 2000) with potentially greater efficiency with more than one follow-up visit 
and drop-out. Data from Early Termination visits will be assigned to the next scheduled post-
baseline visit. The following SAS code specifies the model: 
proc mixed data=xxx method=reml; 
  class site id trtrnd visit; 
  model Value = visit post*trtrnd*visit; 
  random intercept / subject=site type=vc; 
  repeated visit / subject=id(site) type=un; 
Treatment-dependent differences in the change from baseline to the week 16 visit on the CDR 
COA will be estimated by a linear contrast and tested using a two-tailed Wald-test at alpha = 
0.05. The following SAS code specifies the linear contrasts used to estimate treatment- and visit-
specific means, treatment- and visit-specific changes from baseline, and treatment-dependent 
visit-specific changes from baseline (with the sort order for treatment group being SYN120 first 
and placebo second): 
  estimate "0|Active |Wk  00" intercept 1 visit  1 0 0 post*trtrnd*visit 0 0 0  0 0 0 / cl; 
  estimate "0|Active |Wk  08" intercept 1 visit  0 1 0 post*trtrnd*visit 0 1 0  0 0 0 / cl; 
  estimate "0|Active |Wk  16" intercept 1 visit  0 0 1 post*trtrnd*visit 0 0 1  0 0 0 / cl; 
  estimate "1|Active |dWk 08" intercept 0 visit -1 1 0 post*trtrnd*visit 0 1 0  0 0 0 / cl; 
  estimate "1|Active |dWk 16" intercept 0 visit -1 0 1 post*trtrnd*visit 0 0 1  0 0 0 / cl; 
  estimate "0|Placebo|Wk  00" intercept 1 visit  1 0 0 post*trtrnd*visit 0 0 0  0 0 0 / cl; 
  estimate "0|Placebo|Wk  08" intercept 1 visit  0 1 0 post*trtrnd*visit 0 0 0  0 1 0 / cl; 
  estimate "0|Placebo|Wk  16" intercept 1 visit  0 0 1 post*trtrnd*visit 0 0 0  0 0 1 / cl; 
  estimate "1|Placebo|dWk 08" intercept 0 visit -1 1 0 post*trtrnd*visit 0 0 0  0 1 0 / cl; 
  estimate "1|Placebo|dWk 16" intercept 0 visit -1 0 1 post*trtrnd*visit 0 0 0  0 0 1 / cl; 
  estimate "2|ActvPlb|dWk 08" intercept 0 visit  0 0 0 post*trtrnd*visit 0 1 0  0 -1 0 / cl; 
  estimate "2|ActvPlb|dWk 16" intercept 0 visit  0 0 0 post*trtrnd*visit 0 0 1  0 0 -1 / cl; 
The estimate labeled "2|ActvPlb|dWk 16" specifies the primary hypothesis. A significant mean 
improvement over 16 weeks in CDR COA among participants randomized to SYN120 relative to 
mean changes among participants randomized to placebo would be considered evidence of 
therapeutic benefit from SYN120. 
3.8.2. 
Secondary Analyses of the Primary Efficacy Endpoint 
Several secondary analyses will be investigated to assess sensitivity of our estimates of treatment 
effect to alternative modeling assumptions and alternative handling of the CDR data. 
• Random-slopes model: The repeated-measures covariance will be replaced with random 
participant-level intercepts and slopes with unstructured covariance. Data from Early 
Termination visits will be placed at their observed follow-up time. The following SAS code 


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specifies the model and the linear contrasts used to estimate treatment-specific and treatment-
dependent changes over 16 weeks: 
proc mixed data=xxx method=reml; 
  class site id trtrnd; 
  model Value = week trtrnd*week; 
  random intercept / subject=site type=vc; 
  random intercept week / subject=id(site) type=un; 
  estimate "1|Active |Chg 16" intercept 0 week 16 trtrnd*week 16   0 / cl; 
  estimate "1|Placebo|Chg 16" intercept 0 week 16 trtrnd*week  0  16 / cl; 
  estimate "2|ActvPbl|Chg 16" intercept 0 week  0 trtrnd*week 16 -16 / cl; 
• Shared-baseline, repeated-measures ANOVA model with pMI for missing data: The shared-
baseline repeated-measures ANOVA model described above for the primary analysis will be 
applied to datasets generated by placebo multiple imputation (Ayele et al. 2014). Fifty 
imputed datasets will be generated for a given endpoint. 
• Cochran-Mantel-Haenszel row mean score LOCF: 16-week change scores will be compared 
by mean score test using modified ridit scores stratified by clinical site. The last observed 
CDR COA value will be carried forward when CDR COA values are not available from the 
Week 16 visit.  The following SAS code specifies the model: 
proc freq data=xxx; 
  table site * trtrnd* Value / cmh scores=modridit; 
• Cochran-Mantel-Haenszel row mean score WO: 16-week change scores will be compared by 
mean score test using modified ridit scores stratified by clinical site. The worst observed 
CDR COA 16-week change from baseline will be imputed when CDR COA values are not 
available from the Week 16 visit. 
• PP sample: The primary efficacy model and the secondary random-slopes model will be 
applied to the PP sample. 
• Alternative CDR data: The primary efficacy model and the secondary random-slopes model 
will be applied to mITT and PP samples using the raw CDR data. 
3.8.3. 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoint will all be analyzed using the same analysis samples and 
models as specified for the primary efficacy endpoint in Sections 3.8.1 and 3.8.2. Non-key 
secondary efficacy endpoints and exploratory efficacy endpoints will all be analyzed using the 
mITT sample and the primary efficacy analysis described in Section 3.8.1. Variables that are 
strictly positive and strongly right-skewed (e.g., CDR POA, CDR SWM, and other CDR 
measures of reaction time) will be analyzed on their original scale and after log-transformation. 
Estimates from analysis of log-transformed data will be back-transformed for reporting. 
3.8.4. 
Subgroup Analyses 
Differences in treatment efficacy will be explored in several pre-defined subgroups: site, age 
(median split), screening MoCA total score (median split), baseline LEDD (median split), and 
baseline cholinesterase inhibitor (donepezil vs. rivastigmine). Subgroup specific estimates will 
be obtained by including subgroup, subgroup × visit, and subgroup × treatment × post-baseline 
visit terms to models for primary and key secondary efficacy outcomes based on the mITT 
sample. 


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3.8.5. 
Multiplicity Adjustments 
A single primary efficacy outcome is specified with a single treatment comparison and a pre-
specified primary analysis with no interim analysis. Therefore, no multiplicity exists for the 
primary analysis, and interference will be based on two-tailed testing at alpha = 0.05. If the 
primary analysis is significant, then testing the key secondary outcome at alpha = 0.05 maintains 
an overall type I error rate at 5% under a closed testing sequential analysis. When the primary 
analysis is not significant, we limit the overall type I error rate to 10% or less (depending on the 
magnitude of correlation between the primary and key secondary outcomes) when significance 
of the key secondary outcome alone is accepted as evidence of a therapeutic benefit from 
SYN120. Results from analysis of non-key secondary efficacy endpoints, exploratory efficacy 
endpoints, and subgroup analyses will report nominal, comparison-wise p-values, recognizing 
that the totality of results will be evaluated in judging the potential of SYN120 as a therapeutic 
agent for PDD. 
3.8.6. 
Missing Data 
Baseline values for efficacy endpoints will be determined from the last non-missing data 
collected prior to the first dose of study medication. The planned repeated-measures model yields 
estimates that are unbiased conditional on the observed scores under a missing at random 
assumption. In addition, a secondary analysis of the primary endpoint will use placebo-based 
multiple imputation of missing data. The Cochran-Mantel-Haenszel row mean score LOCF and 
WO analyses provide estimates of treatment effect when normality assumptions are violated. 
Additional sensitivity analyses may be pursued to impute missing values or otherwise construct 
models for unobserved outcomes if more than 20% of participants are missing follow-up data for 
any reason. 
3.8.7. 
Clinical Interpretation 
Unadjusted summary statistics by treatment group and visit and estimates from the shared-
baseline, mixed model analyses for all CDR measures will be provided to Dr. Keith Wesnes by 
the study statistician. Dr Wesnes will provide a clinical interpretation of the effects of SYN120 
based on treatment-dependent effects on the CDR measures. This clinical interpretation will 
supplement the numerical and statistical results. 
3.9. 
Safety Analysis 
3.9.1. 
Treatment-emergent Adverse Events 
The incidence of TEAEs will be summarized by the number of events of a given classification 
experienced by participants in each treatment group and by the number and proportion of 
participants experiencing such an event in each treatment group in the ST sample. TEAEs will be 
summarized in aggregate across all MedDRA terms and separately by MedDRA term. 
Aggregate summaries of TEAE incidence will include: (a) any TEAE, (b) any severe TEAE, (c) 
any serious TEAE, (d) any TEAE at least possibly related to study drug, (e) any TEAE leading to 
permanent study drug discontinuation or early termination from the trial, and (f) any TEAE 
resulting in death. Aggregate summaries will be presented by treatments for event rates and 
proportion of participants.  


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Aggregate summaries of TEAE grade will include characteristics of: (a) seriousness, (b) severity, 
(c) relatedness to study drug, (d) action taken with study drug, and (e) outcome. For each level of 
a given TEAE characteristic, summaries will include the number of events of a given 
classification and by the number and proportion of participants for which that level of a 
characteristic was the worst they experienced (treating any unknown characteristic as not worst).  
TEAEs will also be summarized separately by MedDRA term at three levels: (a) System Organ 
Class, (b) High Level Term, and (c) Preferred Term. At each level, the number of events of a 
given classification and the number and proportion of participants experiencing such an event 
will be summarized for each treatment group.  
3.9.2. 
Suicidality 
The proportion of participants who report any post-baseline suicidal ideation or any post-baseline 
suicidal behavior will be summarized by treatment group. Suicidal behaviors will include: actual 
attempts, non-suicidal self-injurious behavior, interrupted attempts, aborted attempts, preparatory 
acts or behaviors, and completed suicide. The most severe ideation, maximal frequency, maximal 
duration, minimal controllability, minimal deterrents, maximal reasons for ideation, maximal 
actual lethality or medical damage, and maximal potential lethality will be summarized as 
means, standard deviations, medians, and ranges by treatment group. 
3.9.3. 
Safety Labs 
The absolute level and the absolute change from baseline for each safety laboratory assay will be 
summarized as means, standard deviations, medians, and ranges at each visit by treatment group. 
The proportion of participants with safety lab levels below the lower limit of normal or above the 
upper limit of normal will be summarized by treatment group by visit and at any post-baseline 
visit. Shift tables will be used to summarize changes in laboratory assays from baseline to the 
week 4, 8, and 16 visits when classified as below the lower limit of normal, within normal limits, 
and above the upper limit of normal separately by treatment group. 
3.9.4. 
Vital Signs 
The absolute level and the absolute change from baseline for vital signs will be summarized as 
means, standard deviations, medians, and ranges at each visit by treatment group. 
3.9.5. 
Blood Pressure 
The absolute level and the absolute change from baseline of supine and standing SBP, supine and 
standing DBP, and differences from supine to standing SBP and DBP will be summarized as 
means, standard deviations, medians, and ranges at each visit by treatment group. The proportion 
of participants who experience orthostatic hypotension (as defined in Section 3.3.11) at the week 
4, 8, and 16 visits and at any post-baseline visit will be summarized by treatment group. 
3.9.6. 
Additional Continuous Safety Outcomes 
The additional continuous safety outcomes of weight, ECG parameters, UPDRS scores (Part I 
score, Part II score, Part III score, Parts I through III total score, Part IV dyskinesia score, Part IV 
clinical fluctuations score, Part IV other complications score, and Part IV total score), LDD, and 
LEDD and their absolute change from baseline will be summarized as means, standard 


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deviations, medians, and ranges at each visit by treatment group. Treatment-dependent 
differences in 16-week change scores will be estimated in the ST sample for UPDRS scores 
using the shared-baseline, repeated-measures analysis of variance described for the primary 
efficacy analysis in Section 3.8.1. 
3.10. 
Other Analyses 
3.10.1. 
Participant Disposition 
The number of patients who were screened, randomized, completed scheduled follow up, and 
prematurely withdrew study participation will be summarized overall and by treatment group. 
Reasons for screen failure and for withdrawal from study will be presented. 
3.10.2. 
Study Drug Compliance and Tolerance 
The number of days of exposure to study drug will be summarized by treatment group. 
Compliance with study drug will be calculated as the number of doses taken divided by the 
scheduled number of doses taken prior to permanent discontinuation, expressed as a percentage. 
Compliance will be summarized overall and by 4-week interval for each treatment group. Time 
to discontinuation of study drug will be estimated using Kaplan-Meier product-limit estimates. 
Treatment-dependent differences will be tested by log-rank test. 
3.10.3. 
Prior and Concomitant Medication Use 
All prior and concomitant medications taken during the study period will be listed for each 
patient, including dosage and indication. Each medication will be coded using the World Health 
Organization Drug Dictionary Enhanced and classified as a past medication (last dose taken prior 
to the first dose of study drug), a concomitant medication ongoing at baseline, or a concomitant 
medication initiated after baseline. The percentage of patients taking each medication (or class of 
medications) will be summarized overall and by treatment group. 
3.10.4. 
Pharmacokinetic Samples 
Results of the plasma assays of SYN120 will be descriptively analyzed by treatment group and 
visit. Population estimates of Cmax, tmax, and half-life will be estimated based on self-reported 
time since last dose of study drug. Separate population analysis on the data from this study alone 
or combined with data from other studies as deemed appropriate will be performed and reported 
separately. 
3.11. 
Handling of Protocol Deviations 
Important protocol deviations are deviations from the protocol which could have a meaningful 
impact on either the primary efficacy or safety endpoints. The criteria for identifying important 
protocol deviations and the classification of important protocol deviations will be defined prior 
to unblinding. 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. 


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4. 
REFERENCES 
Andreasen N. (1984) Scale for the assessment of positive symptoms (SAPS). Iowa City, IA: 
University of Iowa. 
Ayele BT, Lipkovich I, Molenberghs G, Mallinckrodt CH. A multiple-imputation-based 
approach to sensitivity analyses and effectiveness assessments in longitudinal clinical trials. J 
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