Phase 2A, Double-blind, Placebo-controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of BTRX-246040 in Parkinson's Disease Subjects With Motor Fluctuations
Phase: PHASE2
Conditions: Parkinson Disease, Motor Disorder
Sponsor: BlackThorn Therapeutics, Inc.

CONFIDENTIAL 
 
PROTOCOL NEP-PD-201 
 
PHASE 2A, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF BTRX-246040 IN 
PARKINSON’S DISEASE SUBJECTS WITH MOTOR FLUCTUATIONS  
 
Sponsor: 
 
BlackThorn Therapeutics, Inc. 
780 Brannan Street 
San Francisco, CA 94103 
 
Date: 05 March 2019 
 
 
The information contained in this protocol is confidential and is intended for the use of clinical 
Investigators. It is the property of BlackThorn Therapeutics, Inc. and should not be copied by or 
distributed to persons not involved in the clinical investigation of BTRX-246040, unless such 
persons are bound by a confidentiality agreement with BlackThorn Therapeutics, Inc. This 
document and its associated attachments are subject to United States Freedom of Information 
Act (FOIA) Exemption 4. 
 
 
 
 

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Inclusion Criteria 
 
1. Diagnosed with Parkinson`s disease (consistent with the UK PD Society Brain Bank 
Criteria for the Diagnosis of PD)  
2. Men or women ≥ 30 years old and ≤ 76 years old 
3. Female subjects must be either surgically sterilized or 2 years post menopausal at 
screening 
4. Modified Hoehn and Yahr scale ≤ 3 in the ON state  
5. Montreal Cognitive Assessment (MoCA) Score ≥ 26  
6. Currently has a clear and decisive response to levodopa, and receiving a stable dose of 
levodopa (at least 4 doses per day of levodopa or ≥ 3 doses per day of RytaryTM 
(Carbidopa and levodopa Extended-Release Capsules) for at least four weeks prior to 
screening) 
7. Experiencing motor fluctuations during waking hours with at least 2 hours of OFF 
periods each day, including predictable early morning OFF periods, based on subject 
assessment   
8. Able to participate in the study in the practically defined OFF state 
9. All anti-parkinsonian medications maintained at a stable dose for at least 4 weeks prior 
to the initial Screening Visit with the exception of MAO-B inhibitors, which must be 
maintained at a stable level for at least 8 weeks prior to the screening visit 
10. Approved by a central Enrollment Authorization Committee as meeting entry criteria 
and being a suitable candidate for the study 
11. Male subjects agree to use a reliable method of birth control during the study and for at 
least 90 days following the last dose of BTRX-246040 or placebo.  
12. Informed and given ample time and opportunity to think about his/her participation in 
this study and has given his/her written informed consent on an Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) approved consent form  
13. Judged to be reliable and able to keep all appointments for clinic visits, tests, and 
procedures, including venipuncture, and examinations required by the protocol. 
 
Exclusion Criteria 
1. Diagnosis of secondary or an atypical Parkinsonian syndrome 
2. Severe disabling dyskinesia 
3. Clinically significant psychosis or hallucinations or history of psychosis in past 6 
months 
4. History of previous neurosurgery for PD 
5. Currently or previously on Duopa/Duodopa 
6. Currently taking apomorphine 
7. Has a diagnosis or history of a substance related disorder per DSM-V criteria 
(including alcohol but excluding nicotine and caffeine), during the 12 months prior to 
the Screening Visit 
8. Medical or recreational use of marijuana in the 6 months prior to the Screening Visit 
9. Has tested positive at the Screening Visit for drugs of abuse (opiates, cannabinoids, 
methadone, cocaine, and amphetamines [including ecstasy]) 

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10. Active suicidal ideation within one year prior to the Screening Visit as evidenced by 
answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-
Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 1 year 
11. Current major depressive episode or a Beck Depression Inventory-II (BDI-II) score of 
> 19. Subjects receiving treatment for depression with antidepressants may be enrolled 
if they have been on a stable daily dose for at least 8 weeks before the Screening Visit 
and are clinically stable in the opinion of the PI  
12. Currently or within 8 weeks of screening receiving bupropion 
13. Exposure to neuroleptics (antipsychotic drugs) for more than 1 month within the past 2 
years, or any exposure within the past year  
14. Any malignancy in the 5 years prior to randomization (excluding successfully treated 
basal cell carcinoma of the skin or cervical carcinoma in situ)  
15. Current or previous diagnosis of malignant melanoma or the presence of any 
suspicious skin lesion based on physical exam findings.  
16. Any other clinically significant medical condition or circumstance prior to 
randomization that, in the opinion of the Investigator, could affect subject safety, 
preclude evaluation of response, interfere with the ability to comply with study 
procedures, or prohibit completion of the study (e.g., uncontrolled diabetes mellitus, 
renal or hepatic impairment, coronary artery disease, evidence of significant active 
cardiac, respiratory, or hematologic disease, cancer with < 5 year remission (excluding 
successfully treated basal cell carcinoma of the skin or cervical carcinoma in situ), 
chronic pain, fibromyalgia or gastric bypass). 
17. Prior seizures (other than childhood febrile seizure) or other condition that would place 
the subject at increased risk of seizures or is taking anticonvulsants for seizure control. 
18. History of serious head injury (e.g., skull fracture, cerebral contusion, or trauma 
resulting in prolonged unconsciousness), intracranial neoplasm or hemorrhage.  
19. Orthostatic hypotension that is symptomatic or requires medication 
20. Participation in another study of an IMP or medical device currently or in the last 30 
days or within 5 half-lives of the IMP (whichever is longer) prior to Screening 
21. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 2x upper 
limit of normal (ULN) or glomerular filtration rate ≤ 60 mL/min at Visit 1 (screening) 
22. Nephritic syndrome, end-stage renal disease (and using renal replacement therapy such 
as hemodialysis or peritoneal dialysis), or a serum creatinine ≥ 2 mg/dL (≥ 172 
µmol/L) at the Screening Visit  
23. Any other clinically significant abnormalities (i.e., laboratory deviations requiring 
acute medical intervention or further medical evaluation) in laboratory results at 
screening including clinical chemistries, hematology, and urinalysis, that, in the 
judgment of the Investigator, should preclude a subject’s participation at study entry. 
24. ECG abnormalities at Visit 1 (screening) or Visit 2 that, in the judgment of the 
Investigator, are clinically significant related to the subject’s participation  
25. Using the following concomitant medications (contact the Sponsor-designated medical 
monitor to determine eligibility when in doubt):  
a) proton pump inhibitors within 5 half-lives of Screening 
b) fluoxetine and irreversible monoamine oxidase inhibitors within 4 weeks of 
Screening 

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26. Currently taking or have taken, within 5 half-lives of Screening, any medications or
supplements that are strong inhibitors or inducers of CYP3A4.
27. A known hypersensitivity to gelatin capsules.
28. Investigator site personnel directly affiliated with this study, and/or their immediate
families.  Immediate family is defined as a spouse, parent, child, or sibling, whether
biological or legally adopted.
29. Employees of the Sponsor or of any third-party organizations (TPOs) involved in study
who require exclusion of their employees.
30. Have participated in a clinical trial or any other type of medical research judged by the
Investigator to be scientifically or medically incompatible with this study within 30
days prior to Visit 1 (screening).  Contact the Sponsor-designated medical monitor to
determine eligibility when in doubt.
31. Previous completion or withdrawal from this study or any other study investigating
BTRX-246040 (previously called LY2940094).
Investigational Study Product, Dose and Mode of Administration: 
BTRX-246040 will be administered orally as follows: 
•
40 mg (
 in Cohort 1
•
80 mg (
 in Cohort 2
•
120 mg (
 in Cohort 3
Reference Therapy, Dose and Mode of Administration: 
Placebo will be administered orally at the same number of capsules as active drug at each 
Cohort.  Placebo capsules will consist of inactive ingredients and look identical to 
BTRX-246040. 
Planned Duration of Treatment: 
Study drug will be administered once on Day 1 
Criteria for Evaluation: 
Safety: Will be assessed descriptively by adverse events reporting which will include AEs, 
SAEs, vital signs, laboratory values, physical and neurological exams, C-SSRS, and ECGs. 
Tolerability: Will be assessed by percent who complete protocol 
Pharmacokinetics: Descriptive review of Pharmacokinetic (PK) 
 
 
Efficacy: Will be assessed descriptively for the following endpoints. 
Primary Endpoint:   
•
Maximal change in UPDRS Part III from pre-dose to post-dose on Day 1
Secondary Endpoints:
•
Duration of ON time on Day 1
•
Percentage of subjects that turn ON on Day 1
•
Time to ON on Day 1

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• Area under the curve for UPDRS Part III during the 8 hours of assessment on Day 1  
• Change from pre-dose dyskinesia rating (from the UPDRS Part III motor response and 
dyskinesia assessment) 
Statistical Methods:  
All data will be assessed descriptively as presented in the SAP, and no formal statistical 
comparisons will be performed.  
Sample Size Calculation: 
Formal sample size calculation will not occur. A sample size of 8 subjects per group is deemed 
sufficient to evaluate the preliminary safety, tolerability, and efficacy of the different dose 
levels. 
 
 

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TABLE OF CONTENTS 
 
1 
Synopsis ................................................................................................................................... 2 
Table of Contents .......................................................................................................................... 8 
2 
Protocol Signature Page....................................................................................................... 14 
3 
Abbreviations ........................................................................................................................ 15 
4 
Introduction .......................................................................................................................... 18 
5 
Objectives .............................................................................................................................. 21 
5.1 
Primary Objective ...................................................................................................................... 21 
6 
Investigational Plan .............................................................................................................. 22 
6.1 
Summary of Study Design ......................................................................................................... 22 
6.2 
Study Design and Control .......................................................................................................... 23 
7 
Study Population .................................................................................................................. 24 
7.1 
Inclusion Criteria........................................................................................................................ 24 
7.2 
Exclusion Criteria ....................................................................................................................... 25 
7.2.1 
Rationale for Exclusion of Certain Subjects ......................................................................... 27 
7.3 
Discontinuations ......................................................................................................................... 27 
7.3.1 
Early Discontinuation ............................................................................................................ 27 
7.3.2 
Discontinuation of the Study ................................................................................................. 28 
8 
Study Procedures.................................................................................................................. 29 
8.1 
Visit 1: Screening ........................................................................................................................ 29 
8.2 
Visit 2: Treatment Period (Day 1) ............................................................................................. 30 
8.3 
Visit 3: Safety Follow-up (Day 8 ±1) ......................................................................................... 31 
8.4 
Early Termination Visit ............................................................................................................. 32 
9 
Treatment .............................................................................................................................. 33 
9.1 
Treatments Administered .......................................................................................................... 33 

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9.2 
Materials and Supplies ............................................................................................................... 33 
9.3 
Method of Assignment to Treatment ........................................................................................ 33 
9.4 
Rationale for Selection of Doses in the Study ........................................................................... 33 
9.5 
Selection and Timing of Doses ................................................................................................... 34 
9.6 
Blinding ....................................................................................................................................... 35 
9.7 
Dosing Review Committee ......................................................................................................... 35 
9.8 
Concomitant Therapies .............................................................................................................. 35 
9.8.1 
Anti-PD Medications ............................................................................................................ 36 
9.8.2 
Prohibited Medications/Treatments ...................................................................................... 36 
10 Safety, Efficacy Evaluations, Blood Sample Collection and Testing, and Safety 
Measurements ............................................................................................................................. 37 
10.1 Efficacy Measures ....................................................................................................................... 37 
10.1.1 
Unified Parkinson’s Disease Rating Scale ............................................................................ 37 
10.2 Safety Measures .......................................................................................................................... 37 
10.2.1 
Adverse Events ...................................................................................................................... 38 
10.2.2 
Classification of an Adverse Event ....................................................................................... 38 
10.2.3 
Overdose ............................................................................................................................... 39 
10.2.4 
Pregnancy .............................................................................................................................. 40 
10.2.5 
Serious Adverse Events ......................................................................................................... 40 
10.2.6 
Suspected Unexpected Serious Adverse Reactions ............................................................... 41 
10.3 Measures to be performed only on at Screening ..................................................................... 41 
10.3.1 
Modified Hoehn and Yahr Scale ........................................................................................... 41 
10.3.2 
Montreal Cognitive Assessment (MoCA) ............................................................................. 41 
10.3.3 
Beck Depression Inventory-II ............................................................................................... 42 
10.4 Laboratory Procedures/Evaluations ......................................................................................... 42 
10.4.1 
Safety Laboratory Evaluations .............................................................................................. 42 
10.4.2 
Urine drug screen .................................................................................................................. 43 

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10.4.4 
Specimen Preparation, Handling and Storage ....................................................................... 44 
10.5 Other Safety Measures ............................................................................................................... 44 
10.5.1 
Vital Sign Measurements ...................................................................................................... 44 
10.5.2 
Height and Weight ................................................................................................................ 45 
10.5.3 
Physical Examination ............................................................................................................ 45 
10.5.4 
Neurological Examination..................................................................................................... 45 
10.5.5 
Collection of Electrocardiograms .......................................................................................... 45 
10.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS).............................................................. 46 
10.5.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease Rating Scale 
(QUIP-RS) ........................................................................................................................................... 46 
10.5.8 
Safety Monitoring ................................................................................................................. 47 
 
10.7 Appropriateness of Measurements ........................................................................................... 47 
11 Data Quality Assurance ....................................................................................................... 48 
11.1 Data Capture System ................................................................................................................. 48 
12 Sample Size and Statistical Methods .................................................................................. 49 
12.1 Determination of Sample Size ................................................................................................... 49 
12.2 Statistical and Analytical Plans ................................................................................................. 49 
12.2.1 
General Considerations ......................................................................................................... 49 
12.2.2 
Analysis Populations ............................................................................................................. 49 
12.2.3 
Subject Disposition ............................................................................................................... 49 
12.2.4 
Baseline Subject Characteristics ........................................................................................... 49 
12.2.5 
Concomitant Therapies ......................................................................................................... 50 
12.2.6 
Multiplicity Issue .................................................................................................................. 50 
12.2.7 
Efficacy Analysis .................................................................................................................. 50 
12.2.8 
Safety Analyses ..................................................................................................................... 50 

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13 Informed Consent, Ethical Review, and Regulatory Considerations .............................. 53 
13.1 Informed Consent ....................................................................................................................... 53 
13.2 Ethical Review ............................................................................................................................ 53 
13.3 Regulatory Considerations ........................................................................................................ 53 
13.3.1 
Investigator Information ........................................................................................................ 54 
13.3.2 
Protocol Signatures ............................................................................................................... 54 
14 References ............................................................................................................................. 55 
15 Appendices ............................................................................................................................ 57 
 
 
 

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List of Tables 
Table 1 Treatment Regimens ........................................................................................................ 33 
Table 2 Clinical Laboratory Tests ................................................................................................. 42 
Table 3: Schedule and volume of Blood Sampling ...................................................................... 44 
 
 

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List of Appendices 
 
Appendix 1 Schedule of Assessments .......................................................................................... 57 
Appendix 2 Examples of Inhibitors and Inducers of CYP3A4..................................................... 59 
 
 
 

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3 ABBREVIATIONS 
 
Ab 
Antibody 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
AUC 
Area Under the Curve 
AUD 
Alcohol Use Disorder 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Change 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum Plasma Drug Concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRP 
C-reactive protein 
C-SSRS 
Columbia Suicidality Severity Rating Scale 
DRC 
Dosing Review Committee 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
EAC 
Enrollment Authorization Committee 
EAF 
Enrollment Authorization Form 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FOIA 
Freedom of Information Act 
GCP 
Good Clinical Practice 
HAV 
Hepatitis A Virus 
HAV-Ab [IgM]  
Hepatitis A Virus Antibody 

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HBc Ab 
HBs Ag 
Hepatitis B Core Antibody 
Hepatitis B Surface Antigen  
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IFNγ 
interferon gamma  
IL-1ß, IL-2, IL-6, IL-10 
interleukin 1 beta, 2, 6 and 10  
IgM 
IND 
INR 
IRB 
Immunoglobulin M 
US Investigational New Drug Application 
International Normalized Ratio 
Investigational Review Board 
LC-MS/MS 
Liquid Chromatography-tandem Mass Spectrometry  
LS Means 
Least-square means 
MDD 
Major Depressive Disorder 
Noc/OFQ 
MoCA 
Nociceptin/Orphanin FQ 
Montreal Cognitive Assessment 
MOS 
Margin of Safety 
NOAEL 
No-Observed- Adverse-Effect-Level 
NONREM 
Nonlinear Mixed Effect Modeling 
NOPR 
Nociceptin Receptor 
PK 
Pharmacokinetic 
POC 
Proof-of-concept 
QD 
Once Daily 
QTcF 
QUIP-RS 
Fridericia’s correction method for QT Interval 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
Rating Scale 
RO 
Receptor Occupancy 

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SAE 
SAP 
Serious Adverse Event 
Statistical Analysis Plan 
SNRI 
Serotonin Norepinephrine Reuptake Inhibitor 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TEAE 
Treatment-emergent Adverse Event 
TNFα 
Tumor necrosis factor alpha  
TPO 
Third-party Organization 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
WHODD 
United States 
World Health Organization Drug Dictionary 

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4 INTRODUCTION 
Parkinson’s Disease (PD) is a progressive neurodegenerative motor disorder caused by the loss 
of dopamine-producing cells in the brain. The primary motor symptoms of PD are tremor, 
rigidity, bradykinesia and postural instability. Disabling non-motor symptoms of PD include 
depression, cognitive dysfunction, sleep disturbances, hallucinations, impulse control disorder 
and constipation. The pathogenesis of idiopathic PD is marked by the abnormal presence of 
Lewy bodies in the brain and the loss of dopamine neurons in the substantia nigra pars compacta 
(SNpc). Additional dysfunction in glutamate, GABA and acetylcholinergic signaling in 
corticothalamic motor circuits contribute to motor and non-motor symptoms in PD (DeLau & 
Breteler, 2006), (Galvan & Wichmann, 2008), (Moustafa & Poletti, 2013), (Tysnes & Storstein, 
2017). 
The standard of care for PD patients invariably centers on dopamine replacement 
pharmacotherapy, including L-DOPA, dopamine receptor agonists and modulators of dopamine 
synthesis and metabolism. Drugs that attenuate acetylcholinergic neurotransmission or that block 
the glutamate NMDA receptor are also approved for the treatment of PD motor symptoms. 
Medications for PD motor symptoms are frequently used in strategic combinations to exploit 
additive or synergistic therapeutic effects and to better manage motor symptom complications, 
e.g., L-DOPA-induced dyskinesias. Patients with poorly managed motor complications may be 
candidates for deep brain stimulation therapy (Delong & Wichmann, 2015). 
Nociceptin/orphanin-FQ (N/OFQ) is an endogenous neuropeptide that selectively activates the 
nociceptin receptor (NOPR). N/OFQ levels in cerebrospinal fluid are elevated in PD patients 
and, in post-mortem brains from PD patients, increased in the SN and decreased in dopamine-
depleted striatum samples. In rodents, N/OFQ increases glutamate release from SN pars 
reticulata neurons but inhibits activity and dopamine release from SNpc neurons and behavioral 
motor activity. In contrast, pharmacological blockade of NOPR, which are expressed in brain 
regions underlying locomotor behavior and reward processing, attenuates Parkinsonian-like 
disability in rodent and non-human primate models of PD (Viaro, et al., 2008), (Visanji, et al., 
2008), (Marti, et al., 2013). Moreover, NOPR antagonists reduce neurodegeneration of dopamine 
neurons and stimulate dopamine release in the substantia nigra, suggesting potential disease-
modifying mechanisms of action for anti-Parkinsonian therapeutic efficacy (Marti, et al., 2004), 
(Marti, et al., 2005).  
BTRX-246040 is a novel, potent and selective antagonist of human NOPR. 
 
  
 
 

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Study NEP-MDD-201 evaluated the efficacy and safety of BTRX-246040 in subjects with major 
depressive disorder (MDD). This randomized, double-blind, placebo-controlled, parallel-group 
study compared single-daily dosing of BTRX-246040 vs. placebo administered over 8 weeks. 
After screening, eligible subjects were randomized to either 40 mg of BTRX-246040 or placebo. 
After one week the BTRX-246040 dose was increased to 80 mg and allowed to be down-titrated 
to 40 mg at the next visit for tolerability. At the end of the treatment period investigational 
product is abruptly discontinued. One subject assigned to the placebo group had an SAE 
(Preferred Term: rhabdomyolysis). No deaths were reported. 
More information about the known and expected benefits, risks and reasonably anticipated AEs 
may be found in the Investigator’s Brochure (IB).  
 

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6 INVESTIGATIONAL PLAN 
6.1 SUMMARY OF STUDY DESIGN 
The study will consist of 3 sequential, ascending dose cohorts of 8 subjects each with a 6:2 
randomization to BTRX-246040 or placebo. The planned dosing for each cohort will be 40, 80, 
and 120 mg. After enrollment of the first cohort has been completed, doses for subsequent 
cohorts may be modified based on review of the available data (safety, tolerability, efficacy, and 
PK) by an unblinded Dosing Review Committee (DRC). A similar review and determination of 
dosing for the subsequent cohort will be performed after completion of cohorts 1 and 2 and based 
on all data available from previous cohorts.  
Following screening and acceptance by an Enrollment Authorization Committee, subjects in 
each cohort who meet entry criteria and sign an IRB approved informed consent, will present to 
the clinic on the morning of Day 1 in the practically defined OFF state (having withheld anti-
parkinsonian medications after 10:00 PM the evening prior). Prior to dosing on Day 1, subjects 
will be randomized to either placebo or BTRX-246040. Subjects will then be dosed with study 
drug and UPDRS Part III motor response, dyskinesia and ON/OFF status will be assessed pre-
dose and every 30 minutes for 4 hours and then hourly for 4 additional hours (i.e., 8 hours total 
post-dose).  Subjects who turn ON following study drug administration and remain ON after 8 
hours, should be called the next morning to record the time they turned OFF and the time they 
took their first regularly scheduled anti-parkinsonian medications after study drug, to a 
maximum of 24 hours. Subjects who turn ON following study drug administration and 
subsequently turn OFF may be administered their regularly scheduled levodopa dose and other 
anti-parkinsonian medications.  
 Subjects who 
reach and remain in the ON state for 8 hours may resume their regularly scheduled anti-
parkinsonian medications 8 hours post-dosing. Subjects should remain on study drug until they 
experience an OFF episode after a full ON for 8 hours. However, if after 4 hours post study drug 
dosing, a subject’s motor symptoms are severe and not responsive to study drug, the subject’s 
regularly scheduled levodopa dose and other anti-parkinsonian medications may be 
administered, if deemed necessary based on the judgment of the investigator. All subjects, 
whether they are administered their regularly scheduled anti-parkinson medication or not will 
continue with study procedures until the end of the observation period of 8 hours.  
Subjects will come to clinic in a fasted state and will be administered a standard low protein 
breakfast. 
Orthostatic vital signs will be assessed pre-dose and 2, 4, 6, and 8 hours after dosing.   
Subjects will return to the clinic 7 days later (Day 8) for a follow-up safety visit. 

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Following completion of cohorts 1 and 2, a Dosing Review Committee (DRC) meeting will take 
place to review available unblinded safety, tolerability, efficacy and, if available, PK data and 
determine if it is safe to go up to the next higher dosage for the next cohort. At any point the 
DRC can request that a dosage be repeated.   
6.2 STUDY DESIGN AND CONTROL 
The initial screening period is designed to ensure subjects meet the required inclusion and 
exclusion criteria, including diagnosis and stability of depressive symptoms and absence of 
psychiatric and medical conditions that would preclude study participation.  
The randomization, investigational product blinding, and placebo controls will serve to minimize 
the chance of bias in the implementation and execution of the study. Randomization to treatment 
assignment reduces the likelihood that results will reflect selection bias. Having both 
Investigators and subjects blinded to treatment assignment (double-blind) controls for 
expectation bias relative to any particular treatment condition. A placebo arm is included to 
control the subject and Investigator expectations of improvement during the study that could 
confound interpretation of pharmacological effects of treatment.  
 
 

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7 STUDY POPULATION 
Subjects who meet all Inclusion Criteria and are subsequently not excluded by the Exclusion 
Criteria will be eligible for participation in the study.  
7.1 INCLUSION CRITERIA 
Subjects are eligible to be included in the study only if they meet all the following criteria:  
1. Diagnosed with Parkinson`s disease (consistent with the UK PD Society Brain Bank 
Criteria for the Diagnosis of PD)  
2. Men or women ≥ 30 years old and ≤ 76 years old 
3. Female subjects must be either surgically sterilized or 2 years post menopausal at 
screening 
4. Modified Hoehn and Yahr scale ≤ 3 in the ON state  
5. Montreal Cognitive Assessment (MoCA) Score ≥ 26  
6. Currently has a clear and decisive response to levodopa, and receiving a stable dose of 
levodopa (at least 4 doses per day of levodopa or ≥ 3 doses per day of RytaryTM 
(Carbidopa and levodopa Extended-Release Capsules) for at least four weeks prior to 
screening) 
7. Experiencing motor fluctuations during waking hours with at least 2 hours of OFF 
periods each day, including predictable early morning OFF periods, based on subject 
assessment   
8. Able to participate in the study in the practically defined OFF state 
9. All anti-parkinsonian medications maintained at a stable dose for at least 4 weeks prior to 
the initial Screening Visit with the exception of MAO-B inhibitors, which must be 
maintained at a stable level for at least 8 weeks prior to the screening visit 
10. Approved by a central Enrollment Authorization Committee as meeting entry criteria and 
being a suitable candidate for the study 
11. Male subjects agree to use a reliable method of birth control during the study and for at 
least 90 days following the last dose of BTRX-246040 or placebo.  
12. Informed and given ample time and opportunity to think about his/her participation in 
this study and has given his/her written informed consent on an Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) approved consent form  
13. Judged to be reliable and able to keep all appointments for clinic visits, tests, and 
procedures, including venipuncture, and examinations required by the protocol. 

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7.2 EXCLUSION CRITERIA 
Subjects will be excluded from participation in the study if they meet any of the following 
criteria:  
1. Diagnosis of secondary or an atypical Parkinsonian syndrome 
2. Severe disabling dyskinesia 
3. Clinically significant psychosis or hallucinations or history of psychosis in past 6 months 
4. History of previous neurosurgery for PD 
5. Currently or previously on Duopa/Duodopa 
6. Currently taking apomorphine 
7. Has a diagnosis or history of a substance related disorder per DSM-V criteria (including 
alcohol but excluding nicotine and caffeine), during the 12 months prior to the Screening 
Visit 
8. Medical or recreational use of marijuana in the 6 months prior to the Screening Visit 
9. Has tested positive at the Screening Visit for drugs of abuse (opiates, cannabinoids, 
methadone, cocaine, and amphetamines [including ecstasy]) 
10. Active suicidal ideation within one year prior to the Screening Visit as evidenced by 
answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-
Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 1 year 
11. Current major depressive episode or a Beck Depression Inventory-II (BDI-II) score of 
> 19. Subjects receiving treatment for depression with antidepressants may be enrolled if 
they have been on a stable daily dose for at least 8 weeks before the Screening Visit and 
are clinically stable in the opinion of the PI  
12. Currently or within 8 weeks of screening receiving bupropion 
13. Exposure to neuroleptics (antipsychotic drugs) for more than 1 month within the past 2 
years, or any exposure within the past year  
14. Any malignancy in the 5 years prior to randomization (excluding successfully treated 
basal cell carcinoma of the skin or cervical carcinoma in situ)  
15. Current or previous diagnosis of malignant melanoma or the presence of any suspicious 
skin lesion based on physical exam findings.  
16. Any other clinically significant medical condition or circumstance prior to randomization 
that, in the opinion of the Investigator, could affect subject safety, preclude evaluation of 
response, interfere with the ability to comply with study procedures, or prohibit 
completion of the study (e.g., uncontrolled diabetes mellitus, renal or hepatic impairment, 
coronary artery disease, evidence of significant active cardiac, respiratory, or 
hematologic disease, cancer with < 5 year remission (excluding successfully treated basal 
cell carcinoma of the skin or cervical carcinoma in situ), chronic pain, fibromyalgia or 
gastric bypass). 

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17. Prior seizures (other than childhood febrile seizure) or other condition that would place 
the subject at increased risk of seizures or is taking anticonvulsants for seizure control. 
18. History of serious head injury (e.g., skull fracture, cerebral contusion, or trauma resulting 
in prolonged unconsciousness), intracranial neoplasm or hemorrhage.  
19. Orthostatic hypotension that is symptomatic or requires medication 
20. Participation in another study of an IMP or medical device currently or in the last 30 days 
or within 5 half-lives of the IMP (whichever is longer) prior to Screening 
21. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 2x upper 
limit of normal (ULN) or glomerular filtration rate ≤ 60 mL/min at Visit 1 (screening) 
22. Nephritic syndrome, end-stage renal disease (and using renal replacement therapy such as 
hemodialysis or peritoneal dialysis), or a serum creatinine ≥ 2 mg/dL (≥ 172 µmol/L) at 
the Screening Visit  
23. Any other clinically significant abnormalities (i.e., laboratory deviations requiring acute 
medical intervention or further medical evaluation) in laboratory results at screening 
including clinical chemistries, hematology, and urinalysis, that, in the judgment of the 
Investigator, should preclude a subject’s participation at study entry. 
24. ECG abnormalities at Visit 1 (screening) or Visit 2 that, in the judgment of the 
Investigator, are clinically significant related to the subject’s participation  
25. Using the following concomitant medications (contact the Sponsor-designated medical 
monitor to determine eligibility when in doubt):  
a) proton pump inhibitors within 5 half-lives of Screening 
b) fluoxetine and irreversible monoamine oxidase inhibitors within 4 weeks of 
Screening 
26. Currently taking or have taken, within 5 half-lives of Screening, any medications or 
supplements that are strong inhibitors or inducers of CYP3A4. 
27. A known hypersensitivity to gelatin capsules. 
28. Investigator site personnel directly affiliated with this study, and/or their immediate 
families.  Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted. 
29. Employees of the Sponsor or of any third-party organizations (TPOs) involved in study 
who require exclusion of their employees. 
30. Have participated in a clinical trial or any other type of medical research judged by the 
Investigator to be scientifically or medically incompatible with this study within 30 days 
prior to Visit 1 (screening).  Contact the Sponsor-designated medical monitor to 
determine eligibility when in doubt.  
31. Previous completion or withdrawal from this study or any other study investigating 
BTRX-246040 (previously called LY2940094). 

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7.2.1 RATIONALE FOR EXCLUSION OF CERTAIN SUBJECTS 
The exclusion criteria in section 7.2 are intended to ensure that subjects with conditions that 
could be exacerbated by participation in the study are excluded, and that subjects with conditions 
that could confound the interpretation of efficacy or safety results are excluded. No subject is to 
be excluded on the basis of race, ethnicity, or gender.  
Every effort should be made to encourage subjects who discontinue from the study early to 
complete all of the Day 8 visit procedures.  
7.3 DISCONTINUATIONS 
7.3.1 EARLY DISCONTINUATION  
Every effort should be made to encourage subjects who discontinue from the study early to 
complete all of the Day 8 visit procedures.  
If early discontinuation occurs, all appropriate reasons will be reported on the study completion 
CRF. Reasons for early disconuation are listed below. 
1. Physician Decision 
a. The Investigator/physician decides that the subject should be withdrawn from the 
study for any reason. 
2. Withdrawal by Subject 
a. The subject requests to be withdrawn from the study for any reason. If the reason 
to request withdrawal is an adverse event, this should be documented as the 
primary reason for discontinuation. 
3. Study Terminated by Sponsor 
a. The Sponsor stops the study for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations and good clinical practice (GCP). 
4. Adverse Event 
a. Discontinuation should be considered by the Investigator after consultation with 
the Sponsor or its Medical Monitor designee when a subject has the following 
abnormal liver tests: 
i. ALT or AST > 8 x ULN 
ii. ALT or AST > 3 x ULN and total bilirubin level > 2 x ULN 
iii. ALT or AST > 3 x ULN and prothrombin time > 1.5 x ULN 
iv. ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%).  

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b. If the subject is thought to be at risk of harm to him/herself or others at any time 
during the study, a further psychiatric assessment by the Investigator must be 
conducted. Subjects must be discontinued from study participation if they:  
i. are assessed as homicidal 
ii. are actively suicidal (any suicidal ideation with intent or specific plan or 
any suicide attempt) 
iii. are at serious suicidal risk as assessed by the C-SSRS (score of “YES” on 
item 4 or 5) 
The Investigator must assure that these subjects receive the appropriate psychiatric 
care and follow-up. 
c. Any subject who is discontinued from investigational product due to AEs or 
clinically significant laboratory abnormalities will be followed until resolution or 
clinical stabilization. 
d. The Investigator remains responsible for following, through an appropriate 
healthcare option, AEs that caused the subject to discontinue study drug. 
5. Lost to Follow-Up 
a. For subjects who are lost to follow-up, all steps performed to contact them (dates of 
telephone calls, registered letters, etc.) will be reported in the source documents. The 
Investigators are required to make at least two attempts to contact the subject for a 
follow-up safety visit.  
6. Other 
a. Any reason other than Physician Decision, Withdrawal by Subject, Study 
Terminated by Sponsor, Adverse Event, or Lost to Follow-up. 
 
7.3.2 DISCONTINUATION OF THE STUDY 
The study will be discontinued if the Sponsor judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and GCP.  
 

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8 STUDY PROCEDURES  
8.1 VISIT 1: SCREENING  
The total time for the screening period will be 28 days. Screening procedures may require more 
than one visit to complete. 
Before any screening procedure is performed, subject informed consent must be obtained. After 
obtaining the subject’s informed consent, the following procedures will be conducted - see 
schedule of Assessments (Appendix 1). The following order of procedures is recommended to 
prioritize eligibility and safety assessments: 
The Investigator (or his or her designee) will conduct/administer the following assessments:  
1. Collection of demographic data 
2. Collection of medical history, including PD history 
3. Physical and neurological examination 
4. Collection of concomitant medications 
5. Vital signs (BP and pulse both supine and standing, respiratory rate, temperature), height 
and weight 
6. Columbia-Suicide Severity Rating Scale (C-SSRS) – Baseline/Screening version 
7. Montreal Cognitive Assessment (MoCA) 
8. Beck Depression Inventory-II (BDI-II) 
9. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease -Rating Scale 
(QUIP-RS) Screening version 
10. UPDRS Part III and dyskinesia rating in the ON state, including Modified Hoehn and 
Yahr scale in the ON state 
11. UPDRS Part III and dyskinesia rating in the OFF state 
12. 12 lead ECG 
13. Urine Drug Screen 
14. Review of Inclusion/Exclusion criteria 
15. Safety laboratory collection (including clinical chemistry panel, hematology, coagulation 
[including PT, aPTT, INR] parameters and urinalysis) 
16. Enter subject information in interactive web-response system (IWRS)  

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17. Complete the Enrollment Authorization Form (EAF) if the PI determines that the subject 
is eligible for randomization. There is no need to complete the EAF if the subject is a 
known screen failure. 
The investigator will review results from all screening procedures to consider whether a subject 
has met all of the inclusion criteria and none of the exclusion criteria. The investigator will 
complete the Enrollment Authorization Form (EAF) for submission to the EAC for subjects who 
the investigator deems potentially eligible.  Upon receipt of the EAF, the EAC will review the 
provided information and the investigator will be notified of the EAC’s eligibility decision.  If 
the EAC rejects the inclusion of a subject, the reason for exclusion will be provided to the 
investigator.  Only after receiving confirmation from the EAC that the subject meets eligibility 
criteria may the investigator plan to enroll the subject.   
8.2 VISIT 2: TREATMENT PERIOD (DAY 1) 
For each cohort, subjects approved by the EAC for further participation in the study will return 
to the clinic within 28 days of the screening visit on the morning of Day 1, in the practically 
defined OFF state (having not taken any anti-PD medications since 10 PM the evening before). 
Subjects will come to clinic in a fasted state and will be administered a standard low protein 
breakfast.  Subjects will be randomized to either BTRX-246040 or placebo.   
In the clinic, subjects determined to be in the OFF state by the Investigator will be dosed with 
study drug and UPDRS Part III motor response and dyskinesia rating, and ON/OFF status will be 
assessed pre-dose and every 30 minutes post-dose for 4 hours, and then hourly for an additional 
4 hours (i.e., 8 hours total post-dose).  Time to ON and duration of ON, if applicable, will also be 
recorded.  
 
  
Subjects who reach and remain in the ON state for 8 hours may resume their regularly scheduled 
anti-parkinsonian medications 8 hours post-dosing. Subjects should remain on study drug until 
they experience an OFF episode after a full ON for 8 hours. However, if after 4 hours post study 
drug dosing, a subject’s motor symptoms are severe and not responsive to study drug, the 
subject’s regularly scheduled levodopa dose and other anti-parkinsonian medications may be 
administered, if deemed necessary based on the judgment of the investigator. All subjects 
whether they are administered their regularly scheduled anti-parkinsonian medications or not, 
will continue with study procedures unil the end of the observation period of 8 hours.  
The following assessments will be completed on Day 1 - see the Schedule of Assessments 
(Appendix 1) for details: 
1. Collection of concomitant medications 

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8. Collection of AEs. 
8.4 EARLY TERMINATION VISIT 
If the participant is willing, all of the procedures scheduled to be performed on the Day 8 visit 
should be conducted at the early termination visit (see Schedule of Assessments [Appendix 1]). 

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9 TREATMENT 
9.1 TREATMENTS ADMINISTERED 
This study involves a comparison of BTRX-246040 versus placebo taken orally as a single dose 
in 3 sequential ascending dose cohorts of 8 subjects each with a 6:2 randomization to 
BTRX-246040 or placebo.  The planned dosing for each cohort will be as noted in Table 1. 
Following completion of the first cohort, unblinded safety, tolerability, efficacy and, if available, 
PK data will be reviewed by an unblinded Dosing Review Committee (DRC) to determine if it is 
safe to proceed to the next higher dose level (see section 9.7). Similar dosing review and 
determination of dosing for each subsequent cohort will be performed based on all data available 
from previous cohorts. At any point, the DRC may request that a dosage be repeated rather than 
increased.  
Table 1 Treatment Regimens  
Treatment Group 
Regimen* 
BTRX-246040 
• Cohort 1 - 40 mg (
) 
• Cohort 2 - 80 mg (
) 
• Cohort 3 - 120 mg (
) 
Placebo 
• Cohort 1 - (
) 
• Cohort 2 - (
) 
• Cohort 3 - (
) 
9.2 MATERIALS AND SUPPLIES 
BTRX-246040 and placebo capsules and packaging will be identical to maintain Investigator and 
subject blinding. Subjects should be instructed to swallow capsules whole and not crush or chew 
and store the capsules in their original packaging at the temperature listed on the package label. 
Clinical trial materials will be labeled according to the regulatory requirements.  
9.3 METHOD OF ASSIGNMENT TO TREATMENT 
Subjects who meet all inclusion criteria and are subsequently not excluded by the exclusion 
criteria will be randomized to double-blind treatment at Visit 2 using an IWRS. Subjects will be 
randomized in a 6:2 ratio to one of two treatment arms (BTRX-246040 or placebo).   
9.4 RATIONALE FOR SELECTION OF DOSES IN THE STUDY 
The starting dose for cohort 1 will be 40 mg.  A
 
 

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Another Phase 2 study, NEP-MDD-201, compared single-daily dosing of BTRX-246040 vs. 
placebo administered over 8 weeks in a double-blind, placebo-controlled, parallel-group study. 
After screening, eligible subjects were randomized to either 40 mg of BTRX-246040 or placebo 
and after one week the dose was increased to 80 mg and allowed to be down-titrated to 40 mg at 
the next visit for tolerability. BTRX-246040 and placebo had a similar rate of dose reduction 
(3/53 [5.7%] vs. 2/51 [3.9%]). The most common TEAEs that occurred more frequently with 
BTRX-246040 than placebo were nausea (5/53 [9.4%] vs. 3/51 [5.9%]), upper respiratory tract 
infection (3/53 [5.7%] vs. 2/51 [3.9%]), gastroenteritis, urinary tract infection, anxiety, and 
irritability (all 3/53 [5.7%] vs. 1/51 [2.0%]). One subject assigned to the placebo group had an 
SAE (Preferred Term: rhabdomyolysis). No deaths were reported. 
In all three Phase 2 studies, most TEAEs were mild or moderate in severity. There were no 
notable treatment-related clinical laboratory findings or abnormal ECGs. Vital signs were 
generally within normal ranges, with no notable treatment-related changes reported following 40 
mg and following 80 mg QD BTRX-246040. In all studies, no increase in suicidal ideation or 
behavior relative to placebo was detected following BTRX-246040 administration, as assessed 
by the C-SSRS.  
 
 
 
 
 
  
As BTRX-246040 has not previously been tested in PD, three dosing cohorts (40, 80, and 120 
mg) of 8 subjects with a 6:2 randomization to BTRX-246040 or placebo are planned in order to 
explore the effective dose range.  
9.5 SELECTION AND TIMING OF DOSES 
BTRX-246040 has only been dosed with a light breakfast in clinical pharmacology studies to 
date; there are currently no PK data available for BTRX-246040 when dosed in the fasted state. 

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Therefore, in the current study, subjects will take the investigational study drug orally in the 
morning with a light breakfast.   
9.6 BLINDING 
This is a double-blind study. Subjects, site personnel, and the Sponsor will be blinded to 
treatment.  
The Investigator should make every effort to contact the medical monitor prior to unblinding a 
subject’s treatment assignment. If an Investigator, site personnel performing the assessments, or 
subject is unblinded, the subject must be discontinued from the study. In cases where there are 
ethical reasons to have the subject remain in the study, the Investigator must obtain specific 
approval from the Sponsor-designated Medical Monitor for the subject to continue in the study.  
9.7 DOSING REVIEW COMMITTEE 
Safety will be evaluated by the DRC, which will be comprised of the Principal Investigator, 
Medical Monitor and Pharmacovigilance to assess safety, tolerability, and efficacy of BTRX-
246040. The DRC may make the following decisions based on its review of the available data: 
• escalation to the next higher dose level 
• escalation of the dose level is not warranted because of dose-related toxicity 
• escalation is warranted to a lower dose than originally planned  
• escalation should be postponed pending collection of additional data from currently-
enrolled subjects 
• additional subjects should be added to a cohort to better understand safety at that level. 
After enrollment of the first cohort has been completed, doses for subsequent cohorts may be 
modified as above based on review of the available data (safety, tolerability, efficacy, and PK) 
by an unblinded Dosing Review Committee (DRC). A similar review and determination of 
dosing for the subsequent cohort will be performed after completion of cohorts 1 and 2 and based 
on all data available from previous cohorts. 
9.8 CONCOMITANT THERAPIES 
In general, stable doses of concomitant medications will be allowed during the study if stable 
dosing occurred during the 1 month prior to the screening visit. Subjects may receive 
antidepressant medications if the doses have been stable for at least 8 Weeks prior to the 
screening visit. The Investigator should instruct subjects to notify the study site about any new 
medications he/she takes and about any significant non-pharmacological therapies administered 
after the start of the study drug (e.g. acupuncture, hypnosis etc.). All medications, including over 
the counter medications and supplements, and also significant non-pharmacological therapies, 
administered after the subjects start treatment with study drug must be listed on the 
corresponding CRFs.  

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9.8.1 ANTI-PD MEDICATIONS 
Subjects are required to be on a stable regimen of permitted anti-PD medications for at least 4 
weeks (with the exception of MAO-B inhibitors, which must be stable for 8 weeks) prior to 
Screening (see inclusion and exclusion criteria Section 7.1 and 7.2). All efforts should be made 
to maintain subjects on the same stable dose and frequency of their anti PD medications 
throughout their participation. The addition of any new anti-PD medications or an increase in the 
dose of any anti-PD medications is not permitted.  Likewise, changes to the frequency (number 
of doses taken per day) or to the intervals between doses (duration of time between doses on a 
given day) of a subject’s anti-PD medication(s) are not permitted.  An as needed dose of 
levodopa or other anti-PD medication would be considered a change in frequency as it is not a 
regular part of the daily regimen. 
9.8.2 PROHIBITED MEDICATIONS/TREATMENTS 
The following concomitant medications are prohibited: 
• Current or previous use of Duopa/Dupdopa 
• Current use of Apomorphine 
• All anti-psychotic medications for more than 1 month within the past 2 years, or any 
exposure within the past year 
• Use of proton pump inhibitors within 5 half-lives of Visit 2 
• Fluoxetine and irreversible monoamine oxidase inhibitors within 4 weeks of Visit 2  
• Bupropion within 8 weeks of the screening visit 
• Current use or use within 5 half-lives of Screening of any medications or supplements 
that are strong inhibitors or inducers of CYP3A4.  Examples are provided below.  A 
further listing of strong CYP3A4 inhibitors and inducers can be found in Appendix 2. 
o  Strong CYP3A4 inhibitors include: 
 Antifungal azoles  
 Macrolide antibiotics  
 Human immunodeficiency virus protease inhibitors  
 Boceprevir 
 Nefazodone 
 Conivaptan 
o Strong CYP3A4 inducers include: 
 Rifampin 
 Phenytoin 
 Carbamazepine 
 Enzalutamide 
o St. John’s wort 
 
 

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10 SAFETY, EFFICACY EVALUATIONS, BLOOD SAMPLE COLLECTION 
AND TESTING, AND SAFETY MEASUREMENTS  
Study procedures and their timing are summarized in the Schedule of Assessments (Appendix 1)  
All scales and tasks will be completed and/or administered by qualified and trained site raters 
who meet the training requirements and qualifications of the scale or task standards set by the 
Sponsor and training vendors. 
10.1 EFFICACY MEASURES 
10.1.1 UNIFIED PARKINSON’S DISEASE RATING SCALE 
The UPDRS is well-established and the most widely used assessment to quantify the signs and 
symptoms of PD (Fahn, Elton, & Committee, 1987).  The total UPDRS consists of 4 parts which 
assess the following: 
1. 
Mentation, behavior and mood 
2. 
Activities of Daily Living (ADL) 
3. 
Motor function  
4. 
Complications of therapy 
Only Part III will be utilized in this trial. The UPDRS Part III is a 14-item rating scale, which 
consists of the motor examination. Each item is scored from 0 (Normal) to 4 (Most severe). The 
UPDRS Part III scale should only be administered by a rater who has adequate experience with 
subjects with PD and should be a trained neurologist or other trained research staff with 
experience in conducting the UPDRS. All attempts should be made to ensure that the same 
trained research staff member performs the UPDRS part III for a given subject. 
An additional single item to rate dyskinesia is added to the scale and is rated from 0 (No 
dyskinesia) to 4 (Severe dyskinesia: maximal amplitude and present during most of the exam). 
The UPDRS and dyskinesia rating will be conducted as indicated in the Schedule of Assessments 
(Appendix 1). 
10.2 SAFETY MEASURES 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subject.  
The Investigator is responsible for the appropriate medical care of subjects during the study.  
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that caused the subject to discontinue before completing the study. The 
subject should be followed until the event is resolved or explained. Frequency of follow-up 
evaluation is left to the discretion of the Investigator.  

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10.2.1 ADVERSE EVENTS 
An AE is any sign, symptom, illness, clinically significant abnormal laboratory value or ECG 
finding, or other untoward medical occurrence associated with the use of an investigational 
product that appears or worsens in a subject during a clinical study.  This definition does not 
imply a causal relationship between the AE and the investigational product.   
Adverse events beginning with the initial dose of investigational product or during the 
subsequent duration of their enrollment in the study will be considered treatment-emergent AEs 
(TEAE).  TEAEs will be recorded on the AE CRF to include the event, date of onset, severity, 
frequency, seriousness, date of resolution, action taken with respect to the AE (e.g., concomitant 
medication, non-pharmacological treatment, etc.), outcome, and relationship to the 
investigational product.  All TEAEs related to study drug will be followed through resolution or 
30 days after the subject terminates from the study, whichever occurs first.   
Medical conditions present or AEs occurring prior to the first dose of investigational product will 
be captured as medical history in the CRF.  Any AE occurring during the study that is related to 
a pre-existing condition or event that worsens in intensity or frequency after the first dose of 
investigational product will be recorded as a TEAE.  
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish drug effect.  
10.2.2 CLASSIFICATION OF AN ADVERSE EVENT 
10.2.2.1 SEVERITY OF EVENT 
Each AE will be assessed by the Investigator with regard to the categories discussed in the 
sections below.  The Investigator will assess all AEs for severity in accordance with the 
following standard ratings. 
MILD = of little concern to the subject and/or of no clinical significance; is not expected to have 
any effect on the subject’s health or well-being; 
MODERATE = discomfort enough to cause interference with or change in usual activities; is 
likely to require medical intervention and/or close follow-up; 
SEVERE = incapacitating or unable to work or participate in many or all usual activities, is of 
concern to the subject and/or poses substantial risk to the subject’s health or well-being; is likely 
to require medical intervention and/or close follow-up. 
For an AE that begins and ends on the same day and severity worsens over that day, one AE will 
be recorded and will be assessed with the highest level of severity for that day.  For an AE that 
continues over multiple days (past the initial day of onset), if an increase in severity level occurs, 
only the maximum level of severity will be documented.  For a non-TEAE in which the duration 
continues beyond administration of the first dose of study drug, if the AE increases in severity or 
frequency after study drug administration, then the initial AE will be closed and a new TEAE 

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will be opened documenting the new higher level of severity (at the maximum severity level for 
the remaining duration of the AE).  An AE characterized as intermittent requires documentation 
of onset and duration of each episode. 
10.2.2.2 RELATIONSHIP TO STUDY DRUG 
The Investigator will assess the causality/relationship between study drug and the AE.  One of 
the following categories should be selected based on medical judgment, considering the 
definitions below and all contributing factors: 
 
Related 
A clinical event, including laboratory test abnormality, occurs in a 
plausible time relationship to study drug administration and which 
concurrent disease or other drugs or chemicals cannot explain.  The 
response to withdrawal of the study drug should be clinically plausible.   
Probably 
Related 
A clinical event, including laboratory test abnormality, is a known effect 
of drug with a reasonable time sequence to administration of the drug, 
and which cannot be reasonably explained by the known characteristics 
of the participant’s clinical state. 
Possibly Related 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the study drug, but which could also 
be explained by concurrent disease or other drugs or chemicals.  
Information on treatment withdrawal may be lacking or unclear. 
Unlikely Related A clinical event, including laboratory test abnormality, with a temporal 
relationship to study drug administration which makes a causal 
relationship improbable and in which other drugs, chemicals, or 
underlying disease provide plausible explanations. 
Not Related 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with study drug administration.  Typically 
explained by extraneous factors (e.g., concomitant disease, environmental 
factors, or other drugs or chemicals) 
 
10.2.3 OVERDOSE 
In the event of an overdose of study drug, the Investigator should use clinical judgment in 
treating the overdose and contact the Sponsor-designated Medical Monitor, or designee.  The 
Investigator should refer to the relevant document(s) for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to the study 
drug.  Such documentation may include, but not be limited to the Investigator’s Brochure.  As 
the study drug will only be administered by study staff while the subject is in the clinic, the 
likelihood of an overdose occurring in this study is considered unlikely. 

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10.2.4 PREGNANCY 
Any pregnancy that occurs from baseline after study drug exposure until study completion must 
be reported to the Sponsor-designated Medical Monitor on a Pregnancy Notification Form within 
24 hours of learning of its occurrence. 
Each pregnancy must be reported as well to the Sponsor-designated Medical Monitor within 24 
hours of learning of its occurrence. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and child. 
10.2.5 SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that results in one of the following outcomes, 
regardless of the Investigator’s opinion of causation: 
1. death 
2. initial or prolonged in-subject hospitalization 
a. Surgeries planned prior to signing the ICF will not be considered SAEs. However, 
worsening of the underlying medical condition during the study will be 
considered an AE and must be captured as serious if any SAE-defining outcomes 
occur as a result. 
3. a life-threatening experience (that is, immediate risk of dying) 
4. persistent or significant disability/incapacity 
5. congenital anomaly/birth defect 
6. other medically important serious event as determined by the Investigator (for example, 
an AE that jeopardizes the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition). If a subject experiences an SAE 
after signing informed consent, but prior to receiving investigational product, the event 
will be captured as medical history in the CRF and not submitted as reportable-event 
unless the Investigator feels the event may have been caused by a protocol procedure. 
SAEs reported after a subject has taken a dose of investigational product will be collected in the 
pharmacovigilance system for 30 days after the last dose of investigational product. Thereafter, 
only SAEs that the Investigator feels were related to the investigational product or a protocol 
procedure must be reported. 
All SAEs must be captured on a study-specific SAE form in addition to the AE CRF.  Study site 
personnel must alert the Sponsor-designated Medical Monitor of the SAE and must submit the 
completed study-specific SAE form to the Sponsor-designated Medical Monitor within 24 hours 
of the site’s awareness of the SAE. 
The Investigator and supporting personnel responsible for subject care should discuss with the 
Sponsor-designated Medical Monitor or designee any need for supplemental investigations of 

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SAEs. The results of these additional assessments conducted must be reported to the Sponsor-
designated Medical Monitor. If a subject death occurs during participation in the study and a 
post-mortem examination is performed and a copy of the autopsy report is available, it should be 
submitted to the Sponsor-designated Medical Monitor. 
The Investigator is responsible for safety reporting in compliance with their Institutional Review 
Board (IRB). 
10.2.6 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the Investigator identifies as related to investigational product or procedure.  
The Sponsor is responsible for IND safety reporting as per 21 CFR 312.32.  
10.3  
MEASURES TO BE PERFORMED ONLY AT SCREENING 
10.3.1 MODIFIED HOEHN AND YAHR SCALE 
The Modified Hoehn and Yahr PD Staging is a scale expressing the severity of the symptoms of 
PD (Hoehn & Yahr, 1967).  It provides a practical classification of 5 stages of ever increasing 
severity.  The stages are defined as: 
• 
Stage 0 = No signs of disease. 
• 
Stage 1 = Unilateral disease. 
• 
Stage 1.5 = Unilateral plus axial involvement. 
• 
Stage 2 = Bilateral disease, without impairment of balance. 
• 
Stage 2.5 = Mild bilateral disease, with recovery on pull test. 
• 
Stage 3 = Mild to moderate bilateral disease; some postural instability; physically 
independent. 
• 
Stage 4 = Severe disability; still able to walk or stand unassisted 
• 
Stage 5 = Wheelchair bound or bedridden unless aided. 
Modified Hoehn and Yahr scale will be assessed in the ON state at Screening. 
10.3.2 MONTREAL COGNITIVE ASSESSMENT (MOCA) 
The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for 
detecting cognitive impairment (Nasreddine, et al., 2005).  It was designed as a rapid screening 
instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and 
concentration, executive functions, memory, language, visuoconstructional skills, conceptual 
thinking, calculations, and orientation. The total possible score is 30 points; a score of 26 or 
above is considered normal.  

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10.3.3 BECK DEPRESSION INVENTORY-II 
The BDI-II is a 21 question, multiple choice self-report inventory used to measure the severity of 
depression (Beck, Steer, & Brown, 1996).  In its current version, the BDI-II is designed for 
individuals aged 13 and over and is composed of items relating to symptoms of depression, such 
as hopelessness and irritability; cognitions, such as guilt or feelings of being punished; and 
physical symptoms, such as fatigue, weight loss, and lack of interest in sex.  Each question is 
scored on a scale value of 0 to 3, with higher total scores indicating more severe depressive 
symptoms. 
10.4 LABORATORY PROCEDURES/EVALUATIONS 
10.4.1 SAFETY LABORATORY EVALUATIONS 
Clinical laboratory evaluations (including clinical chemistry panel, hematology, coagulation 
[including PT, aPTT, INR] parameters and urinalysis) will be collected as indicated in the 
Schedule of Assessments (Appendix 1). 
A urine drug screen for selected drugs of abuse will be performed at Screening. 
Investigators must document their review of each safety laboratory report. 
Clinical laboratory assessments will be performed by a central laboratory.  Detailed processing, 
storage, and shipping instructions for the clinical samples will be provided in a separate 
Laboratory Manual.  
Additional clinical laboratory evaluations may be performed at other times if judged to be 
clinically appropriate or if the ongoing review of the data suggest a more detailed assessment of 
clinical laboratory safety evaluations is required.  Any changes to the scheduled times of clinical 
laboratory determination will be agreed to with the Sponsor and documented in the study master 
file. 
Table 2 Clinical Laboratory Tests 
The following laboratory variables will be determined: 
Hematology:  
Hemoglobin 
coagulation [including PT, aPTT, INR] parameters   
Hematocrit  
Erythrocyte count (red blood cell [RBC])  
Mean cell volume (MCV)  
Mean cell hemoglobin concentration (MCHC)  
Leukocytes (white blood cell [WBC])  
Neutrophils, segmented 
Clinical Chemistry: Serum 
concentrations of: 
Sodium 
Potassium  
Sodium bicarbonate  
Chloride 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 

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Absolute Neutrophil Count (ANC) 
Lymphocytes  
Monocytes 
Eosinophils 
Basophils 
Platelets 
Urinalysis: 
Specific gravity  
pH  
Protein  
Glucose  
Ketones  
Blood  
Urine leukocyte esterase 
Alanine aminotransferase/serum 
glutamic pyruvic transaminase 
(ALT/SGPT) 
Aspartate aminotransferase/serum 
glutamic oxaloacetic transaminase 
(AST/SGOT) 
Gamma-glutamyl transferase (GGT) 
Blood urea nitrogen (BUN) 
Creatinine 
Uric acid 
Phosphorous 
Calcium 
Glucose (random) 
Albumin 
Total cholesterol 
Creatine kinase (CK)a 
Urine Drug Screenb 
Amphetamines 
Barbiturates 
Benzodiazepine 
Cannabinoids 
Cocaine 
Ethyl alcohol 
Opiates 
Phencyclidine 
Propoxyphene 
Methadone 
Viral Serology: 
Hepatitis B Surface Antigen (HBs Ag) 
Hepatitis B Core Antibody (HBc Ab) 
Hepatitis C Antibody (HC Ab) 
Hepatitis A Antibody (HAV-Ab [IgM]) 
HIV 
a Creatine kinase muscle-brain isoenzyme (CK-MB) is to be assayed if CK results >1000 IU/L. 
b Performed at screening and at the Investigator's discretion throughout the study. 
10.4.2 URINE DRUG SCREEN 
A urine drug screen for drug abuse will include: amphetamines, barbiturates, benzodiazepine, 
cannabinoids, cocaine, ethyl alcohol, opiates, phencyclidine, propoxyphene, and methadone.  No 
retest is allowed for a positive result with a drug of abuse (e.g., cocaine, cannabinoids, 
phencyclidine, and methadone).   
The site must contact the Sponsor-designated Medical Monitor or designee for pre-approval 
before a retest of other drugs that presented as positive as long as the subject has a valid 
prescription and there is no evidence of a Substance Use Disorder. In the case of Alcohol (Ethyl 
Alcohol) as long as there is clear justification for the finding and no history nor lab pattern 

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10.5.2 HEIGHT AND WEIGHT 
Height and weight will be measured during the study as indicated in the Schedule of 
Assessments (Appendix 1). Height should be measured only once at screening with no shoes for 
correct measurement. The BMI will be calculated based on height and weight measured at 
screening. 
10.5.3 PHYSICAL EXAMINATION 
A routine physical examination of general appearance, skin (sufficient to detect any suspicious 
lesions, particularly any lesions potentially suggestive of melanoma), head, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, lymph nodes, and extremities will be 
performed at the time points specified in the Schedule of Assessments (Appendix 1).   
10.5.4 NEUROLOGICAL EXAMINATION 
Neurological examination of cranial nerves, motor system, sensory, and reflexes will be 
conducted at screening and all subsequent study visits. Complete neurological examination 
including mental status, cranial nerves, motor systems, deep tendon reflexes, cerebellar function 
(balance and coordination), gait, and sensory systems will be performed by a qualified physician 
in the ON state whenever possible, at the time points specified in the Schedule of Assessments 
(Appendix 1). 
10.5.5 COLLECTION OF ELECTROCARDIOGRAMS 
For each subject, single 12-lead digital ECGs will be collected as indicated in the Schedule of 
Assessments after resting for 5 min.  
The ECGs will initially be interpreted by a qualified physician (the Investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
After enrollment, if a clinically significant increase in the Fridericia’s correction method for the 
QT (QTcF) interval from baseline (e.g. QTcF ≥ 500 msec and/or QTcF increased ≥ 60 msec) or 
other clinically significant quantitative or qualitative change from baseline is identified, the 
subject will be assessed by the Investigator for symptoms (e.g., palpitations, near syncope, 
syncope) and to determine whether the subject can continue investigational product. The 
Investigator or qualified designee is responsible for determining if any change in subject 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation for each time point.  
All digital ECGs will be electronically transmitted to a designated central ECG laboratory. A 
cardiologist at the central ECG laboratory will then conduct a full over-read. A report based on 
data from this over-read will be issued to the investigative site. All data from the over-reads will 

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be placed in the Sponsor database for analytical and study report purposes. Any clinically 
significant finding that was present on the fully over-read ECG will be reported to the 
Investigator and to the Sponsor. 
When there are differences in ECG interpretation between the Investigator (or qualified 
designee) and the cardiologist at the central ECG laboratory, the Investigator’s (or qualified 
designee’s) interpretation will be used for study entry and immediate subject management. 
Interpretations from the cardiologist at the central ECG laboratory will be used for data analysis 
and report writing purposes.  
The Investigator (or qualified designee) must document his/her review of ECGs printed at the 
time of collection, the final over-read ECG report issued by the central ECG laboratory, and any 
alert reports.  
10.5.6 COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS will be used to assess suicidal tendency ("C-SSRS for Research", 2016).  The 
Baseline/Screening version of the C-SSRS will be used at the Screening visit.  This version 
assesses suicidality in a subject’s lifetime and during the past specified months.  The Since Last 
Visit version of the C-SSRS will be used at all other visits.  This version assesses suicidality 
since the subject’s last visit.  Efforts must be made to ensure that the same trained team member 
completes this questionnaire for each subject.   
If a suicide-related event is identified at any time during the study, a thorough evaluation should 
be performed by a study physician and appropriate medical care should be provided. In some 
subjects taking antidepressants, worsening of depression, suicidal events (suicidal thinking 
and/or behavior), or unusual changes in behavior have been reported, especially at the beginning 
of the drug therapy. It is important that subjects are instructed to notify their doctor immediately 
if they have any distressing thoughts or feelings at any time related to harm to either self or 
others.  Subjects who answered YES to questions 4 or 5 in the C-SSRS questionnaire at 
Screening are excluded and should be referred to a mental health professional. 
10.5.7 QUESTIONNAIRE FOR IMPULSIVE-COMPULSIVE DISORDERS IN PARKINSON’S DISEASE 
RATING SCALE (QUIP-RS) 
The QUIP-RS is an instrument used to measure the extent of impulsive and compulsive 
behaviors in PD patients (Weintraub, et al., 2012).  The Screening version of the QUIP-RS will 
be used at the Screening visit. This version assesses compulsive behaviors in PD patients over 
the last four weeks. THE QUIP-RS Since Last visit version will be used at all other visits. The 
QUIP-RS is The QUIP-RS consists of 4 questions which have to be answered for each disorder 
(gambling, sex, buying, eating, hobbyism, punding, and PD medication use) on a 5-point Likert 
scale.  The scoring range for each scale (ie, disorder) is 0–16.   The QUIP-RS will be completed 
as indicated in the Schedule of Assessments (Appendix 1). 
 
 

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10.5.8 SAFETY MONITORING 
The Sponsor-designated Medical Monitor and the study team will monitor blinded safety data 
throughout the course of the study. This will include review of AEs, SAEs, any AEs of special 
interest, ECG findings, neurological exams, laboratory results, vital signs, and other safety data. 
The unblinded Dosing Review Committee (DRC) will convene to review unblinded safety and 
tolerability data at the completion of cohorts 1 and 2 to determine if it is safe to proceed with the 
next higher dose, repeat the same dose or stop the study.  
10.5.8.1 COMPLAINT HANDLING 
The Sponsor collects product complaints on investigational products and drug delivery systems 
used in clinical studies in order to ensure the safety of study participants, to monitor quality, and 
to facilitate process and product improvements. 
Subjects will be instructed to contact the Investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.  
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by the Sponsor or its delegate will be reported. 
The Investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study: 
1. recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose 
2. submitting the completed product complaint form within 24 hours to the Sponsor or its 
designee.   
 
 
   
10.7 APPROPRIATENESS OF MEASUREMENTS 
Efficacy and safety assessments used in the study are generally regarded as reliable, accurate, 
and relevant in this subject population.  
 

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11 DATA QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
1. provide instructional material to the study sites, as appropriate 
2. provide start-up training to instruct the Investigators and study site personnel. 
This training will give instruction on the protocol, the completion of the eCRFs, study 
procedures, and on handling and administering the study drug 
3. make periodic visits to the study site 
4. be available for consultation and stay in contact with the study site personnel by email 
and telephone 
5. review and evaluate eCRF data and standard computer edits to detect errors in data 
collection 
6. conduct a quality review of the database. 
In addition, the Sponsor or its representatives may periodically check a sample of the subject 
data recorded against source documents at the study site. The study may be audited by the 
Sponsor, its representatives, and/or applicable regulatory agencies at any time. Investigators will 
be given notice before an audit occurs. 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable IRBs with 
direct access to original source documents.  
11.1 DATA CAPTURE SYSTEM 
The Sponsor will select a 21-CFR compliant electronic data capture system (EDC) and provide 
appropriately trained site personnel user permissions to enter information on the electronic CRFs 
(Case Report Forms). The site will maintain a separate source for the data entered onto CRFs. 
The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appears inconsistent, incomplete, or inaccurate. 
Electronic data collected on other devices will be transferred to the Sponsor’s selected EDC, as 
applicable. 
An identification code assigned via the use of the randomization envelopes to each subject will 
be used in lieu of the subject’s name to protect the subject’s identity when reporting study-
related data.  
 
 

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12 SAMPLE SIZE AND STATISTICAL METHODS 
12.1 DETERMINATION OF SAMPLE SIZE 
No formal sample size calculation is being calculated. A sample size of 8 subjects per cohort is 
deemed sufficient to evaluate the preliminary safety, tolerability, and efficacy of the different 
dose levels. 
12.2 STATISTICAL AND ANALYTICAL PLANS 
12.2.1 GENERAL CONSIDERATIONS 
Data collected from eCRFs, ECG, or clinical laboratory evaluations will be listed by treatment 
group and subject identification. 
Generally, if not specified, continuous data will be summarized by descriptive statistics, 
including number of subjects with data, mean, standard deviation, median, and range. 
Categorical data will be summarized by the number and percentage of subjects for each category 
or classification.  
A detailed statistical analysis plan (SAP) will be developed by the Sponsor or its designee and 
will be finalized before locking the study database. 
12.2.2 ANALYSIS POPULATIONS 
12.2.2.1 MODIFIED INTENTION TO TREAT POPULATION 
The modified Intention-to-Treat (mITT) Population will include all randomized subjects who 
received at least one dose of study drug and have at least 1 post-baseline scoring of motor 
activity.  In accordance with the intent-to-treat principle, all subjects will be kept in their 
randomized treatment group.  The mITT Population will serve as the primary population for 
efficacy evaluation. 
12.2.2.2 SAFETY POPULATION 
The Safety Population will include all subjects who received study drug.  All subjects will be 
evaluated according to actual treatment type received. 
12.2.3 SUBJECT DISPOSITION 
Subject disposition will be presented for the mITT and Safety Populations 
12.2.4 BASELINE SUBJECT CHARACTERISTICS 
Summary tables of demographics and other baseline characteristics will be presented for the 
mITT and Safety Populations to assess the comparability of the treatment groups at study start.  
For continuous variables, descriptive statistics (n, mean, SD, standard error, median, minimum, 
and maximum) will be provided.  For categorical variables, subject counts and percentages will 
be provided.  Categories for missing data will be presented if necessary. 
 
 

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12.2.5 CONCOMITANT THERAPIES 
Previous and concomitant drug therapy will be coded to Anatomical, Therapeutic, or Chemical 
(ATC) level and preferred drug name according to the World Health Organization Drug 
Dictionary (WHODD). These medications will be summarized by treatment group, ATC 
classification, and preferred drug name. This analysis will be conducted on the Safety 
Population. 
12.2.6 MULTIPLICITY ISSUE 
Not applicable. 
12.2.7 EFFICACY ANALYSIS 
All efficacy endpoints will be summarized by visit, including change from baseline information. 
12.2.7.1 PRIMARY EFFICACY ANALYSIS 
The maximal change from predose in UPDRS Part III scores will be summarized by data listings, 
descriptive statistics, and graphical displays.  This analysis will use the mITT Population. 
12.2.7.2 SENSITIVITY ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT  
No sensitivity analyses will be performed on the primary efficacy endpoint. 
12.2.7.3 SECONDARY EFFICACY ANALYSES 
The secondary endpoints consist of the following:   
• Duration of ON time on Day 1  
• Percentage of subjects that turn ON on Day 1 
• Time to ON on Day 1  
• Area under the curve for UPDRS Part III during the 8 hours of assessment on Day 1  
• Change from pre-dose dyskinesia rating (from the UPDRS Part III motor response and 
dyskinesia assessment) 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point.  For categorical 
variables, subject counts and percentages will be provided.  Summaries will be presented by 
treatment group.  Graphical displays will be created as appropriate, including for the UPDRS by 
time point. 
12.2.8  SAFETY ANALYSES 
Safety analysis will use the Safety Population.  The overall safety and tolerability of BTRX-
246040 treatment will be assessed by evaluating the safety and tolerability measures listed 
below. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point.  For categorical 

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variables, subject counts and percentages will be provided.  Summaries will be presented by 
treatment group. 
12.2.8.1 ADVERSE EVENTS 
Adverse events will be recorded from the time when a subject has signed the ICF through the 
Follow-Up period.  The MedDRA dictionary will be used to standardize the terms used by the 
Investigator to describe the AEs.  Adverse event analyses will include TEAEs, defined as AEs 
which start after the first dose of the study medication.  The TEAEs will be summarized as 
subject and event counts, complemented by percentages calculated for the subject count, unless 
specified otherwise.  At least the following analyses of TEAEs will be provided.   
• Breakdown of TEAEs by System Organ Class (SOC) and preferred term, according to 
MedDRA dictionary. 
• Breakdown of TEAEs by SOC, preferred term, and severity (event count only, 
percentages calculated out of the total number of TEAEs) 
• Breakdown of TEAEs by SOC, preferred term, and relationship to the study medication 
(event count only, percentages calculated out of the total number of TEAEs) 
• Breakdown of TEAEs leading to death by SOC and preferred term 
• Breakdown of Serious TEAEs other than deaths by SOC and preferred term 
• Breakdown of AEs leading to premature discontinuation by SOC and preferred term 
• Listings of non-TEAEs will also be provided. 
In case the number of TEAEs in the tabulations above is low, the tabulations will be replaced by 
data listings. 
12.2.8.2 SAFETY LABORATORY TESTS 
Summary statistics of laboratory data will be presented for each visit by treatment group.  Actual 
values and changes from baseline will be summarized using descriptive statistics.  Shifts (below, 
within, and above the normal range) from Baseline will be summarized as well. 
12.2.8.3 VITAL SIGNS 
Summary statistics for vital signs will be presented for each visit by treatment group.  Actual 
values and changes from baseline will be summarized using descriptive statistics. 
12.2.8.4 ELECTROCARDIOGRAMS 
Summary statistics for ECGs will be presented for each visit by treatment group.  Actual values 
and changes from baseline will be summarized using descriptive statistics. 
12.2.8.5 PHYSICAL EXAMINATION 
Summary data of physical examination results will be provided by study visit by treatment. 
 
 

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13 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS  
13.1 INFORMED CONSENT 
The Investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the subject’s willingness to continue his or her participation in the trial.  
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study, and to document that the 
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.  
The Investigator is responsible for ensuring that informed consent is given by each subject. This 
includes obtaining the appropriate signatures and dates on the ICF prior to the performance of 
any protocol procedures and prior to the administration of investigational product. 
13.2 ETHICAL REVIEW 
The Sponsor or its representatives must approve all ICFs before they are submitted to the IRB 
and are used at investigative sites(s). All ICFs must be compliant with the ICH guideline on 
GCP.  
Documentation of IRB approval of the protocol and the ICF must be provided to the Sponsor 
before the study may begin at the investigative site(s). The IRB(s) will review the protocol as 
required.  
Any member of the IRB who is directly affiliated with this study as an Investigator or as site 
personnel must abstain from the IRB’s vote on the approval of the protocol.  
13.3 REGULATORY CONSIDERATIONS 
This study will be conducted in accordance with: 
1. consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
2. the ICH GCP Guideline [E6] 
3. applicable laws and regulations. 
The Sponsor certifies that this study is being conducted under an active US Investigational New 
Drug (IND) application.  
Some of the obligations of the Sponsor will be assigned to a CRO.  

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13.3.1 INVESTIGATOR INFORMATION 
Physicians with a specialty in neurology or physicians with experience or with medical site staff 
with experience in treating PD will participate as Investigators in this clinical trial. 
13.3.2 PROTOCOL SIGNATURES 
The Sponsor’s responsible medical officer will approve the protocol, confirming that to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal Investigator will sign the protocol signature page and 
provide a copy of the signed page to a Sponsor representative. 
 
 

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Tysnes, O., & Storstein, A. (2017). Epidemiology of Parkinson's disease. Journal of Neural 
Transmission, 124(8), 901-905. 
Viaro, R., Sanchez-Pernaute, R., Marti, M., Trapella, C., Isacson, O., & Morari, M. (2008). 
Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induces parkinsonism. 
Neurobiology of Disease, 30(3), 430-438. 
Visanji, N., de Bie, R., Johnston, T., McCreary, A., Brotchie, J., & Fox, S. (2008). The 
nociceptin/orphanin FQ (NOP) receptor antagonist J-113397 enhances the effectes of 
levodopa in the MPTP-lesioned nonhuman primate model of Parkinson's disease. 
Movement Disorders, 23(13), 1922-1925. 
Weintraub, D., Mamikonyan, E., Papay, K., Shea, J. A., Xie, S. X., & Siderowf, A. (2012). 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale. 
Mov Disord, 27(2):22-7. 
Witkin, J. M., Statnick, M. A., Rorick-Kehn, L. M., Pintar, J. E., Ansonoff, M., Chen, Y., & … 
Ciccocioppo, R. (2014). The biology of Nociceptin/Orphanin FQ (N/OFQ) related to 
obesity, stress, anxiety, mood, and drug dependence. Pharmacology and Therapeutics, 
141(3), 283-299. 
Zaveri, N. T. (2016). Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in 
Translation from Preclinical Research to Clinical Utility. J Med Chem, 59 (15), 7011–
7028. 
 
 
 
 

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15                            APPENDICES 
Appendix 1 Schedule of Assessments 
                                                 
1 Unscheduled visits may be conducted at any time for safety reasons and/or for any other reason. 
2 Vital signs include supine (at least 5 min) and standing (after approximately 2 min) BP and pulse rate, body 
temperature and body weight.   
At Day 1, 3 sets each of supine and standing BP and pulse rate will be measured at least 15-20 minutes apart at 
pre-dose and will be measured once at 2, 4, 6, and 8 hours after dosing. 
3 Height will be measured only once, at Screening. Body weight will be measured once per visit. 
4 At screening, UPDRS Part III and dyskinesia rating should be done in the OFF and the ON state. This can be done 
in either the practically defined OFF state or after a subject wears OFF following a levodopa dose. 
5 At Day 1, UPDRS Part III and dyskinesia rating will be conducted in the OFF state Pre-dose and every 30 minutes 
for 4 hours and then hourly for another 4 hours (or until subject turns OFF) following study drug administration. If 
the subject remains ON after 8 hours, they should be called the next morning to record the time they turned OFF, 
and the time they took their first regularly scheduled anti-parkinsonian medications after study drug, to a maximum 
of 24 hours. 
Study Periods 
SCRN 
Treatment 
Period 
Follow-up or 
Early 
Termination 
Unscheduled 
visits1 
Visit no. 
1 
2 
3 
 
Study Day 
-28 to 0 
1 
8 (±1) 
 
Informed consent Form 
X 
 
 
 
Demographic Data 
X 
 
 
 
Medical History, including PD history 
X 
 
 
 
Vital signs2  
X 
X 
X 
X 
Height and weight3 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
X 
Neurological Exam 
X 
 
X 
 
Concomitant Medications  
X 
X 
X 
X 
Columbia Suicide Severity Rating Scale (C-SSRS)- 
Baseline/Screening version 
X 
 
 
 
Columbia Suicide Severity Rating Scale (C-SSRS)- 
Since last visit version 
 
X 
X 
X 
Montreal Cognitive Assessment (MoCA) 
X 
 
 
 
Beck Depression Inventory-II 
X 
 
 
 
QUIP-RS - Screening version 
X 
 
 
 
QUIP-RS - Since last visit version 
 
X 
X 
X 
UPDRS Part III and dyskinesia rating in the OFF state 
X4 
X5 
 
 
UPDRS Part III and dyskinesia rating in the ON state 
X4 
X5 
 
 
Modified Hoehn and Yahr scale in the ON state 
X 
 
 
 
12 lead ECG 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
 
 
 

BlackThorn Therapeutics, Inc. 
Protocol NEP-PD-201 v4.0 
CONFIDENTIAL 
 
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Appendix 2 Examples of Inhibitors and Inducers of CYP3A4 
Per exclusion criteria: Are currently taking or have taken within 5 half-lives of Screening 
any medications or supplements that are strong inhibitors or inducers of CYP3A4. The 
listed moderate inhibitors/inducers below are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm
093664.htm. 
Table 1.a         Inhibitors of CYP3A4 
Strong inhibitors a 
Moderate inhibitors b 
boceprevir 
amprenavir 
clarithromycin 
aprepitant 
conivaptan 
atazanavir 
erythromycin 
ciprofloxacin 
grapefruit juice 
darunavir 
indinavir 
diltiazem 
itraconazole 
erythromycin 
ketoconazole 
fluconazole 
lopinavir 
fosamprenavir 
mibefradil 
imatinib 
nefazodone 
verapamil 
nelfinavir 
 
posaconazole 
  
ritonavir 
  
saquinavir 
  
telaprevir 
  
telithromycin 
  
voriconazole 
  
a    Increases the area under the curve (AUC) of the substrate by ≥ 5-fold. 
b     Increases the AUC of the substrate by 2- to 5-fold.  

BlackThorn Therapeutics, Inc. 
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Table 1.b 
 Inducers of CYP3A4 
Strong inducers a 
Moderate inducers b 
avasimibe 
bosentan 
carbamazepine 
efavirenz 
enzalutamide 
etravirine 
phenytoin 
modafinil 
rifampin 
nafcillin 
St John’s wort 
 
a     Decreases the AUC of the substrate by ≥ 80%. 
b     Decreases the AUC of the substrate by 50–80%.