A Phase 2 Study of IkT-148009 in Untreated Parkinson's Disease
Phase: PHASE2
Conditions: Parkinson Disease
Sponsor: ABLi Therapeutics, Inc.

 
 
 
 
 
 
 
 
Protocol Title: 
 
A Randomized, Double-Blind, Placebo-Controlled Trial of IkT-148009 in Untreated 
Parkinson’s Disease 
 
Protocol Number: IkT-148009-201 
 
Version 6.4 
 
Compound: IkT-148009 
 
Brief Title: A Phase 2 Study of IkT-148009 in Untreated Parkinson’s Disease 
 
 
Sponsor Name:  
Inhibikase Therapeutics, Inc. 
3350 Riverwood Pkwy SE, Suite 1900 
Atlanta, GA 30339 
Telephone: 678 392 3419 
 
 
Fax: 770 240 1401 
 
Regulatory Agency Identifier Number(s):  IND #138553 
 
 
 
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SPONSOR SIGNATURE PAGE 
 
Protocol Number: 
 
IkT-148009-201 
Product:  
 
 
IkT-148009  
IND No.:  
 
 
138553 
Study Phase: 
 
 
2 
Sponsor:  
 
 
Inhibikase Therapeutics, Inc. 
Date of Original Protocol: 
Version 3.3; 31 March 2022  
Date of Current Version: 
Version 6.4; 19 October 2023 
 
Sponsor Approval 
 
_______________________________________________                       _____________ 
Milton H. Werner, PhD 
 
 
 
 
 
         Date 
Title: President and CEO Inhibikase Therapeutics, Inc. 
 
           
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PROTOCOL SIGNATURE PAGE  
 
I have received and read the Investigator’s Brochure for IkT-148009. I have read the IkT-
148009-201 protocol and agree to conduct the study as outlined.  
The signature of the Principal Investigator constitutes an agreement that this study will be 
conducted according to all stipulations, clinically and administratively, as stated in the protocol, 
including all statements as to confidentiality.  It is agreed that the conduct and results of this 
study will be kept confidential and that the case report forms and other pertinent data will 
become the property of Inhibikase Therapeutics, Inc. 
It is agreed that the protocol contains all necessary information required to conduct the study as 
outlined in the protocol, and that the study will not be initiated without the approval of an 
appropriate Institutional Review Board or Ethics Review Committee.  
It is agreed that all participants in this study will provide written informed consent in 
accordance with International Council for Harmonisation (ICH) Guidelines for Good Clinical 
Practice and the requirements specified in the Code of Federal Regulations (21 CFR Parts 50, 
56, 312) and/or the Declaration of Helsinki.  All participants will also be informed that their 
medical records will be kept confidential except for review by authorized representatives of 
Inhibikase Therapeutics, Inc. and its associates, the U.S. Food and Drug Administration or 
other regulatory agencies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
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CONTACTS IN CASE OF EMERGENCY 
 
Table 1:  Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Sponsor Physician 
Andrew McGarry, MD 
2 North Tamiami Trail, Suite 308  
Sarasota, FL 34236  
 
(732) 330-8298 
  
Medical Monitor 
 
Bruce Rubin, MD 
Miami, Florida 
 
Mobile: (305) 299-6525 
Office: (910) 442-1402 
 
 
 
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Table of Contents 
1. PROTOCOL SUMMARY ....................................................................................................................... 9 
1.1  SYNOPSIS .................................................................................................................................................. 9 
1.2  SCHEMA .................................................................................................................................................. 11 
1.3  SCHEDULE OF ACTIVITIES (SOA) ............................................................................................................ 13 
2. INTRODUCTION ................................................................................................................................. 16 
2.1. STUDY RATIONALE ................................................................................................................................. 17 
2.2. BACKGROUND ......................................................................................................................................... 17 
3. OBJECTIVES AND ENDPOINTS ....................................................................................................... 17 
4. STUDY DESIGN ................................................................................................................................... 18 
4.1. OVERALL DESIGN ................................................................................................................................... 18 
4.2. JUSTIFICATION FOR DOSE ....................................................................................................................... 20 
4.3. END OF STUDY DEFINITION .................................................................................................................... 20 
5. STATISTICAL CONSIDERATIONS ................................................................................................... 20 
5.1. STATISTICAL HYPOTHESES ..................................................................................................................... 20 
5.2  MULTIPLICITY ADJUSTMENT ................................................................................................................... 20 
5.3  ANALYSIS SETS ....................................................................................................................................... 21 
5.4. STATISTICAL ANALYSES ......................................................................................................................... 22 
5.4.1. General Considerations .................................................................................................................. 22 
5.4.2. Primary Endpoint Analysis ............................................................................................................. 22 
5.4.3 
Secondary Endpoint Analysis (Efficacy) .................................................................................... 23 
5.4.4 
Exploratory Endpoint Analysis .................................................................................................. 24 
5.4.5 
Safety Analyses .......................................................................................................................... 24 
5.4.6 
Other Analyses ........................................................................................................................... 25 
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5.5. INTERIM ANALYSIS ................................................................................................................................. 25 
5.6. SAMPLE SIZE DETERMINATION ............................................................................................................... 26 
6. STUDY POPULATION ........................................................................................................................ 26 
6.1. INCLUSION CRITERIA .............................................................................................................................. 26 
6.2. EXCLUSION CRITERIA ............................................................................................................................. 27 
6.3 STOPPING RULES ..................................................................................................................................... 28 
6.4. SCREEN FAILURES .................................................................................................................................. 29 
7. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .................................................... 29 
7.1. STUDY INTERVENTION(S) ADMINISTERED .............................................................................................. 29 
7.2. PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ............................................................... 29 
7.3. MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................................... 30 
7.4. STUDY INTERVENTION COMPLIANCE ...................................................................................................... 31 
7.5. DOSE MODIFICATION AND CONTINUED ACCESS TO STUDY INTERVENTION AFTER THE END OF THE 
STUDY .................................................................................................................................................................. 32 
7.6. CONCOMITANT THERAPY ........................................................................................................................ 32 
7.6.1. Initiation of Dopaminergic Therapy ............................................................................................... 32 
8. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................................ 32 
8.1. DISCONTINUATION OF STUDY INTERVENTION ........................................................................................ 33 
8.2. PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ....................................................... 33 
8.3. LOST TO FOLLOW-UP .............................................................................................................................. 33 
9. STUDY ASSESSMENTS AND PROCEDURES .................................................................................. 34 
9.1. EFFICACY ASSESSMENTS ........................................................................................................................ 34 
9.1.1. Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) .............. 34 
9.1.2. Patient Global Impression – Severity (PGI-S) ................................................................................ 35 
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9.1.3. Clinician Global Impression of Severity (CGI-S) ........................................................................... 35 
9.1.4. Parkinson’s Disease Questionnaire (PDQ– 39) ............................................................................. 35 
9.1.5. Schwab and England Activities of Daily Living Scale (SE-ADL) ................................................... 35 
9.1.6. Non-Motor Symptom Scale (NMSS) ............................................................................................... 35 
9.1.7. Complete Spontaneous Bowel Movement Score (CSBM) ............................................................... 36 
9.1.8.  Patient Assessment of Upper GI Disorders Severity Index (PAGI-SYM) ...................................... 36 
9.1.9. Patient Assessment of Constipation Quality of Life (PAC-QoL) .................................................... 36 
9.1.10. Patient Assessment of GI Disorders Severity Quality of Life (PAGI-QoL) .................................. 36 
9.1.11. Epworth Sleepiness Scale (ESS) ................................................................................................... 36 
9.2. SAFETY ASSESSMENTS ............................................................................................................................ 36 
9.2.1. Physical Examinations.................................................................................................................... 36 
9.2.2. Vital Signs ....................................................................................................................................... 37 
9.2.3. Electrocardiograms ........................................................................................................................ 37 
9.2.4. Clinical Safety Laboratory Tests .................................................................................................... 37 
9.2.5. Pregnancy Testing .......................................................................................................................... 38 
9.2.6. 
Ophthalmic Exams ..................................................................................................................... 38 
9.2.7. Pharmacokinetics ........................................................................................................................... 38 
9.2.8. Suicidal Ideation and Behavior Risk Monitoring ........................................................................... 38 
9.3. ADVERSE EVENTS (AES) SERIOUS ADVERSE EVENTS (SAES), AND OTHER SAFETY REPORTING ........... 39 
9.3.1. Time Period and Frequency for Collecting AE and SAE Information ............................................ 40 
9.3.2. Method of Detecting AEs and SAEs ................................................................................................ 40 
9.3.3. Follow-up of AEs and SAEs ............................................................................................................ 40 
9.3.4. Regulatory Reporting Requirements for SAEs ................................................................................ 40 
9.3.5. Pregnancy ....................................................................................................................................... 41 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....................... 42 
10.1. APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .............................. 42 
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10.1.1. Regulatory and Ethical Considerations ........................................................................................ 42 
10.1.2. Financial Disclosure .................................................................................................................... 43 
10.1.3. Informed Consent Process ............................................................................................................ 43 
10.1.4. Data Protection ............................................................................................................................ 43 
10.1.5. Committees Structure ................................................................................................................... 44 
10.1.6. Dissemination of Clinical Study Data .......................................................................................... 44 
10.1.7. Data Quality Assurance ................................................................................................................ 45 
10.1.8. Source Documents ........................................................................................................................ 45 
10.1.9. Study and Site Start and Closure .................................................................................................. 46 
10.1.10. Publication Policy ...................................................................................................................... 47 
10.2. APPENDIX 2: CLINICAL LABORATORY TESTS ........................................................................................ 47 
10.3. APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING............................................................................................................................... 49 
10.3.1. Definition of AE ............................................................................................................................ 49 
10.3.2. Definition of SAE .......................................................................................................................... 50 
10.3.3. Recording and Follow-Up of AE and/or SAE ............................................................................... 51 
10.3.4. Reporting of SAEs ......................................................................................................................... 52 
10.4. APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ..................................................................... 53 
10.4.1. Definition ...................................................................................................................................... 53 
10.4.2. Contraception Guidance ............................................................................................................... 54 
10.5. APPENDIX 5: CONCOMITANT MEDICATIONS ......................................................................................... 54 
10.6. APPENDIX 6: ABBREVIATIONS AND DEFINITIONS .................................................................................. 55 
10.7. APPENDIX 7: PROTOCOL AMENDMENT HISTORY .................................................................................. 57 
11. REFERENCES .................................................................................................................................... 60 
 
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1. Protocol Summary 
1.1  Synopsis 
 
Protocol Title:  
A Randomized, Double-Blind, Placebo-Controlled Trial of IkT-148009 in Untreated 
Parkinson’s Disease 
 
Brief Title: 
A Phase 2 study of IkT-148009 in untreated Parkinson’s Disease 
 
Rationale: 
This is a Phase 2, double-blind, multi-center, randomized, placebo-controlled trial to evaluate 
the safety, tolerability, and exploratory efficacy of three different doses of IkT-148009 
self-administered once daily (QD) with food for 12 weeks in patients with untreated Parkinson’s 
Disease (PD).  
 
Objectives and Endpoints: 
 
 
Objectives 
Endpoints 
Primary 
 
To assess the safety and tolerability of three IkT-
148009 doses in Parkinson's Disease 
x 
Incidence 
and 
temporal 
profile 
of 
treatment-emergent 
adverse 
events 
(TEAEs) 
evaluated 
by 
type/nature, 
severity/intensity, 
seriousness, 
and 
relationship to study intervention 
x 
Proportion of those randomized in each 
dosing cohort who discontinued the 
assigned regimen 
Secondary 
 
To characterize the effects of three IkT-148009 
doses on Parkinson's Disease motor features, 
non-motor features, measures of function, and 
quality of life 
Change from Baseline to Week 12 in the following 
outcomes, arranged in hierarchical order: 
x 
Movement Disorder Society-
sponsored revision of the Unified 
Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Parts II + III 
x 
Patient Global Impression-Severity 
(PGI-S) 
x 
Clinician Global Impression of 
Severity (CGI-S) 
x 
MDS-UPDRS Part II 
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x 
MDS-UPDRS Part III 
x 
MDS-UPDRS Part I 
x 
Non-Motor Symptom Scale (NMSS) 
x 
Complete Spontaneous Bowel 
Movement score (CSBM) 
x 
ESS (Epworth Sleepiness Scale) 
x 
Schwab and England Activities of 
Daily Living (SE-ADL) Scale 
x 
Parkinson’s Disease Questionnaire 
(PDQ-39) 
x 
Patient Assessment of Upper 
Gastrointestinal Disorders Severity 
Index (PAGI-SYM) 
x 
Patient Assessment of Constipation 
Quality of Life (PAC-QoL) 
x 
Patient Assessment of 
Gastrointestinal Disorders Severity 
Quality of Life (PAGI-QoL) 
Exploratory 
 
 
x 
Analysis of phosphorylated alpha-
synuclein aggregates in skin and  
cerebrospinal fluid(CSF) 
x 
 
 
Study Design: 
 
This is a 12-Week, randomized, double-blind, multi-center, placebo-controlled dose-ranging 
clinical trial of three IkT-148009 doses in patients with untreated PD designed to assess safety, 
tolerability, and exploratory efficacy. It will enroll approximately 120 participants at up to 
40 sites across the USusing two randomization schemas.  First, participants will be randomized 
across the 50 mg, 100 mg or placebo groups.  Once 5 people have been randomized to each of 
the 50 mg, 100 mg or placebo groups, additional participants will be randomized as detailed in 
Section 7.3 to the 50 mg, 100 mg, 200 mg or placebo groups. 
After signing the informed consent form (ICF), participants will undergo screening to 
evaluate their eligibility. The screening period will last up to 28 days before enrollment and 
randomization. An Enrollment Authorization Committee (EAC) will be responsible for 
reviewing screening data and confirming the eligibility and suitability of participants. This 
process will be outlined in the EAC charter. Those selected will be enrolled and randomized to 
one of three active IkT-148009 arms (50, 100, or 200 mg) or a placebo arm using interactive 
voice/web response system (IVRS/IWRS) according to the table in section 7.3. All clinical staff, 
study investigators, and participants will be blinded to study assignments throughout the trial.  
Enrolled participants will have eaten within 2 hours prior to reporting to the site on Day 1 
(Baseline) and undergo protocol-mandated procedures. Meals should not include citrus fruits or 
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juice and they should not be consumed within 6 hours on either side of dosing.  Each participant 
will self-administer the study intervention on-site at the first treatment visit and then at home, as 
per treatment assignment. At home, enrolled participants should eat a meal within one hour prior 
to dosing.  Meals should not include citrus fruits or juice, and neither citrus fruits or juices should 
be consumed within 6 hours on either side of dosing.  The treatment period consists of outpatient 
visits at Weeks 1, 4, 8, and 12. A safety follow-up will occur at Week 14.  
Telephone contacts at Weeks 2, 6, and 10 will occur to review and document changes in 
concomitant medications, assess dosing compliance, and document and/or address any 
AEs/SAEs.  
ESS will be assessed at Weeks 1 and 12.  Gastrointestinal (GI) outcomes (PAGI-SYM, PAC-
QoL, PAGI-QoL, and CSBM, ) will be assessed at Baseline and Weeks 4, 8, and 12. PGI-S, CGI-
S, PDQ-39, Schwab and England ADL Scale will be assessed at Baseline and Weeks 4, 8, 12 and 
14. Optional exploratory skin biopsies will be obtained at Baseline and Week 4 and 12. Optional 
CSF collection will be obtained at Baseline and Week 12. 
CSSR-S, 
NMSS, 
MDS-UPDRS, 
vital 
signs, 
safety 
laboratory 
data, 
12-lead 
Electrocardiogram (ECG), concomitant medications, tolerability, and adverse events (AEs) will 
be obtained and documented throughout the study. The Columbia Suicide Severity Rating Scale 
(C-SSRS) will be assessed at each in-person visit. A safety follow-up visit will occur at two 
weeks after completion of the 12-week active treatment period. Data Safety Monitoring Board 
(DSMB) members will meet on a regular basis throughout the study to review safety data. They 
will have the authority to unblind upon request if deemed necessary and to stop the study if 
deemed appropriate, as outlined in the DSMB charter. 
1.2 Schema 
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Randomization Schema 1 
 
 
Randomization Schema 2 (implemented after 5 subjects have randomized in each of the placebo, 50mg, and 100mg cohorts) 
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1.3  Schedule of Activities (SoA) 
Procedures 
Screening 
Visit 
Baseline 
Treatment Period (12 Weeks ± 2 days) 
Safety 
Follow-up 
Study Visit 
SV 
1 
 
2 
 
3 
 
4 
EOS/EW 
5 
Week 
Day -28 
to -1 
Day 1 
2 
4 
6 
8 
10 
12 
14 ± 2 days 
Written informed consent 
X 
 
 
 
 
 
 
 
 
Enrollment Authorization 
Form 
X 
 
 
 
 
 
 
 
 
Outpatient visitsm 
X 
X 
 
X 
 
X 
 
X 
X 
Demographicsa 
X 
 
 
 
 
 
 
 
 
Vital signsb 
X 
X 
 
X 
 
X 
 
X 
X 
Height and weightc 
X 
X 
 
X 
 
X 
 
X 
X 
12-Lead ECG (triplicate)d 
X 
X 
 
X 
 
X 
 
X 
X 
Review concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
 
 
 
 
 
 
X 
X 
Modified Hoehn and 
Yahre 
X 
 
 
 
 
 
 
 
 
Montreal Cognitive 
Assessment 
X 
 
 
 
 
 
 
 
 
Telephone contactf 
Xk 
 
X 
 
X 
 
X 
 
 
C-SSRS 
X 
X 
 
X 
 
X 
 
X 
X 
Safety laboratory tests 
X 
X 
 
X 
 
X 
 
X 
X 
Pharmacokinetics 
(Blood)j 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy testg 
X 
X 
 
 
 
 
 
 
X 
MDS-UPDRS Parts I, II, 
and III 
X 
X 
 
X 
 
X 
 
X 
X 
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Procedures 
Screening 
Visit 
Baseline 
Treatment Period (12 Weeks ± 2 days) 
Safety 
Follow-up 
Study Visit 
SV 
1 
 
2 
 
3 
 
4 
EOS/EW 
5 
Week 
Day -28 
to -1 
Day 1 
2 
4 
6 
8 
10 
12 
14 ± 2 days 
Epworth Sleepiness Scale 
(ESS) 
 
X 
 
 
 
 
 
X 
 
PAGI-SYM, PAC-QoL, 
PAGI-QoL 
 
X 
 
X 
 
X 
 
X 
 
NMSS 
 
X 
 
X 
 
X 
 
X 
 
SE-ADL 
 
X 
 
X 
 
X 
 
X 
X 
PDQ-39 
 
X 
 
X 
 
X 
 
X 
X 
CGI-S 
 
X 
 
X 
 
X 
 
X 
X 
PGI-S 
 
X 
 
X 
 
X 
 
X 
X 
CSBM 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Dispense/collect (unused) 
investigational product 
 
Xh 
 
X 
 
X 
 
Xi 
 
Review dosing 
compliance 
 
X 
X 
X 
X 
X 
X 
X 
 
AEs/serious AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Skin biopsyn 
 
X 
 
X 
 
 
 
X 
 
CSF Collectionn 
 
X 
 
 
 
 
 
X 
 
Ophthalmic examsl 
X 
 
 
 
 
 
 
X 
 
AE=adverse event; BP=blood pressure; CGI-C=clinical global Impression of change; CSBM=Complete Spontaneous Bowel Movement Score; CSF=cerebrospinal 
fluid; C-SSRS=Columbia suicide severity rating scale; ECG=electrocardiogram; EOS=end of study; EW=early withdrawal; HR=heart rate; MDS-
UPDRS=Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; NMSS=Non-Motor Symptom Scale; QoL=quality of 
life; PAC-QoL=Patient Assessment of Constipation Quality of Life; PAGI-QoL=Patient Assessment of GI Disorders Severity Quality of Life; PAGI-SYM=Patient 
Assessment of Upper GI Disorders Severity Index; PDQ=Parkinson’s Disease Questionnaire; PGI-S=Patient Global Impression-Severity; RR=respiratory rate; 
SE-ADL=Schwab and England Activities of Daily Living Scale. 
a. 
Demographics include age, race, ethnicity, and sex. 
b. 
Vital Signs (Temperature, BP, HR, and RR) including orthostatic blood pressure measurements.  At Baseline only, vital signs must be measured 3 times 
over the course of an hour. 
c. 
Height measured at screening visit only. 
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d. 
12-lead ECGs will be read locally. 
e. 
Modified Hoehn and Yahr 
f. 
Telephone Visits: Participants will be contacted to review concomitant medications and dosing compliance and to assess tolerability and AEs. At screening, 
participants will be contacted to review the stool diary completion timelines. See k for more information. 
g. 
Serum testing at screening and urine testing at all other visits, for women of childbearing potential only. 
h. 
Only dispense investigational product. 
i. 
Only collect unused investigational product. 
j. 
Blood will be collected just prior to dosing at baseline visit and post dose (as patients are dosing at home prior to coming into the clinic) for the subsequent 
blood draws  
k. 
Patient stool diary to compute CSBM will be completed daily for the 7 days leading up to Day 1, the Week 4 visit, the Week 8 visit and the Week 12 visit.  
At the screening visit, participants will be given a copy of the diary. Once the EAF is approved, the site will call the participant to inform him/her what 
day they should begin recording in the diary.  The participant will bring the diary to the site for the Day 1 visit, at which time the CSBM assessment will 
be completed based upon the diary entries. Prior to the Weeks 4, 8, and 12 visits, the site will call the participant to remind him/her to start recording in 
the diary for the 7 days leading up to the visit date. The participant will bring the completed diary to the site for these  visits to be used for the CSBM 
assessment. 
l. 
Ophthalmic exams include: 
1. Best corrected visual acuity 
2. Slit lamp examination of the anterior segment, particularly cornea, aqueous and lens.  Slit lamp examination should determine the potential 
presence of dry eye, inflammatory cells in the aqueous and lens opacities. 
3. Wide-field photography 
4. Wide-field autofluorescence 
5. Wide-field fluorescein angiography (WF-FA) 
6. Spectral domain optical coherence tomography (SD-OCT) 
m. 
Participants should be advised by study staff to avoid alcohol for 24 hours prior to any in-person visit, including screening. 
n. 
At baseline, Skin Biospy and CSF collection must be completed prior to first dose. 
 
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2. Introduction 
Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disorder (Savitt et 
al., 2006). It affects approximately 1,000,000 persons in the United States, with 60,000 new cases 
and 38,000 deaths annually (Savitt et al., 2006; Dauer et al., 2003). PD is an inexorably 
progressive disorder that is characterized clinically by bradykinesia, rigidity, rest tremor, and gait 
disturbances with postural instability (Savitt et al., 2006; Dauer et al., 2003). Pathologically, PD 
is characterized by degeneration of dopaminergic (DA) neurons in the substantia nigra pars 
compacta (SNc), reduction in striatal dopamine, and accumulation of protein aggregates in cell 
bodies and terminals known as Lewy bodies (LBs) and Lewy neurites, respectively, collectively 
known as Lewy pathology (Goedert et al., 2001; Goedert et al., 2013; Lee and Trojanowski, 
2006). It is now appreciated that clinical and pathologic features are much more extensive than 
historically recognized. PD pathology affects serotonergic, cholinergic, and noradrenergic 
neurons and nerve cells in the olfactory system, cerebral hemisphere, brain stem, spinal cord, and 
peripheral autonomic nervous system in addition to SNc dopaminergic neurons (Jellinger, 2012). 
This non- dopaminergic pathology is associated with a variety of non-dopaminergic clinical 
features, none of which are adequately controlled with dopamine-replacement therapy (Schapira 
et al., 2014). These include falling, freezing, dysphagia, neuropsychiatric disorders, autonomic 
dysfunction, sensory problems, and cognitive impairment with dementia (Schapira et al., 2014). 
Indeed, non-dopaminergic features represent a major source of disability for PD patients. While 
numerous symptomatic therapies based on a dopamine replacement strategy have been developed 
over the past half century that provide meaningful motor benefits, non-motor therapies remain an 
unmet need (Schapira et al., 2014).  
Over the past 20 years, a number of studies have suggested that misfolding of alpha-synuclein 
plays a key role in the etiopathogenesis of PD; as such, therapies directed at preventing or clearing 
pathologic alpha-synuclein might be neuroprotective (Winner et al., 2011; Olanow and Brundin, 
2013; Polymeropoulos et al., 1997; Spillantini et al., 1997; Masliah et al., 2000; Kirik and 
Bjorklund, 2003; Jellinger, 2012). However, understanding of the precise toxic form of alpha-
synuclein is incomplete, complicating the proper targeting of toxic alpha-synuclein for a 
therapeutic purpose. Recent work has provided convincing evidence that a common pathway 
governs initiation and progression of the disease within the central nervous system (CNS) and in 
the periphery (Mao et al., 2016; Brahmachari et al., 2016 and 2017). At the core of this pathway 
is the cellular Abelson tyrosine kinase (c-Abl) which is believed to act as as a checkpoint and  
play a key role in the formation and accumulation of toxic alpha-synuclein that leads to disease 
progression. In addition, activation of c-Abl leads to inhibition of Parkin and exacerbation of the 
neurodegenerative process (Werner and Olanow). Indeed, c-Abl inhibitors protect against 
neuronal degeneration and are associated with clinical benefits in animal models of PD (Werner 
and Olanow). These studies suggest that inhibition of c-Abl will be neuroprotective and blunt the 
rate of disease progression in PD patients. 
 
 
 
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2.1. Study Rationale 
 
This is a Phase 2, double-blind, multi-center, randomized, placebo-controlled trial to evaluate 
the safety, tolerability, and exploratory efficacy of three different doses of IkT-148009 
self-administered once daily (QD) with food for 12 weeks in patients with untreated PD. 
2.2. Background 
 
Despite the success of anti-parkinsonian therapies for motor features of the disease, no 
intervention has been discovered that adequately controls the non-dopamine features of the 
illness, and no therapy has been demonstrated to slow or stop clinical progression in PD. These 
remain major unmet medical needs. 
Inhibikase Therapeutics Inc, is developing IkT-148009, a novel and potent inhibitor of the 
wild type c-Abl tyrosine kinase enzyme, for the treatment of PD. IkT-148009 is a chemical 
derivative of the anti-cancer agent imatinib (marketed as Gleevec®) with much higher potency 
for c-Abl kinase inhibition and greater likelihood of brain accumulation leading to effective c-
Abl inhibition. IkT-148009 will be administered as powder in capsule. 
A detailed description of the chemistry, pharmacology, efficacy and safety of IkT-148009 is 
provided in the Investigator’s Brochure (IB). 
3. Objectives and Endpoints 
 
Primary Objective 
Primary Endpoints 
To assess the safety and tolerability of three IkT-
148009 doses in Parkinson's Disease 
x 
Incidence and temporal profile of treatment-
emergent adverse events (TEAEs) evaluated 
by type/nature, severity/intensity, seriousness, 
and relationship to study intervention 
x 
Proportion of those randomized in each 
dosing cohort who discontinued the assigned 
regimen 
Secondary Objectives 
Secondary Endpoints 
To evaluate the effects of three IkT-148009 doses 
on Parkinson's Disease motor features, 
non-motor features, measures of function, and 
quality of life 
Change from Baseline to Week 12 in the 
following outcomes, arranged in hierarchical 
order: 
x 
Movement Disorder Society-
sponsored revision of the Unified 
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Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Parts II + III 
x 
Patient Global Impression-Severity 
(PGI-S) 
x 
Clinician Global Impression of 
Severity (CGI-S) 
x 
MDS-UPDRS Part II 
x 
MDS-UPDRS Part III 
x 
MDS-UPDRS Part I 
x 
Non-Motor Symptom Scale (NMSS) 
x 
Complete Spontaneous Bowel 
Movement score (CSBM) 
x 
ESS (Epworth Sleepiness Scale) 
x 
Schwab and England Activities of 
Daily Living (SE-ADL) Scale 
x 
Parkinson’s Disease Questionnaire 
(PDQ-39) 
x 
Patient Assessment of Upper 
Gastrointestinal Disorders Severity 
Index (PAGI-SYM) 
x 
Patient Assessment of Constipation 
Quality of Life (PAC-QoL) 
x 
Patient Assessment of 
Gastrointestinal Disorders Severity 
Quality of Life (PAGI-QoL) 
Exploratory 
 
 
 
x 
Analysis of phosphorylated alpha-
synuclein aggregates in skin and 
cerebrospinal fluid (CSF) 
4. Study Design 
 
This is a Phase 2, double-blind, multi-center, randomized, placebo-controlled trial of three 
IkT-148009 doses in patients with untreated PD. 
 
4.1. Overall Design  
 
This is a 12-Week, randomized, double-blind, multi-center, placebo-controlled dose-ranging 
clinical trial of three IkT-148009 doses in patients with untreated PD designed to assess safety, 
tolerability, and exploratory efficacy. It will enroll approximately 120 participants at up to 
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40 sites across the United States (US) using two randomization schemas.  First, participants will 
be randomized across the 50 mg, 100 mg or placebo groups.  Once 5 people have been 
randomized to each of the 50 mg, 100 mg or placebo groups, additional participants will be 
randomized as detailed in Section 7.3 to the 50 mg, 100 mg, 200 mg or placebo groups. 
After signing the informed consent form (ICF), participants will undergo screening to 
evaluate their eligibility. The screening period will last up to 28 days before enrollment and 
randomization. An Enrollment Authorization Committee (EAC) will be responsible for 
reviewing screening data and confirming the eligibility and suitability of participants. This 
process will be outlined in the EAC charter. Those selected will be enrolled and randomized to 
one of two active IkT-148009 arms (50/100 mg) or a placebo arm (1:1:1) using interactive 
voice/web response system (IVRS/IWRS) during the first part of the study, then randomized to 
one of three active IkT-148009 arms or a placebo arm according to the table in section 7.3 once 
the 200mg dose is impletemented. All clinical staff, study investigators, and participants will be 
blinded to study assignments throughout the trial.  
Enrolled participants will have eaten within 2 hours prior to reporting to the site on Day 1 
(Baseline) and undergo protocol-mandated procedures. Meals should not include citrus fruits or 
juice and they should not be consumed within 6 hours on either side of dosing.  Each participant 
will self-administer the study intervention on-site at the first treatment visit and then at home, as 
per treatment assignment. At home, enrolled participants should eat a meal within one hour prior 
to dosing.  The treatment period consists of outpatient visits at Weeks 1, 4, 8, and 12. A safety 
follow-up will occur at Week 14.  
Telephone contacts at Weeks 2, 6, and 10 will occur to review and document changes in 
concomitant medications, assess dosing compliance, tolerability, and document/address any 
adverse events.  
ESS will be assessed at Weeks 1 and 12.  Gastrointestinal (GI) outcomes (PAGI-SYM, PAC-
QoL, PAGI-QoL, and CSBM) will be assessed at Baseline and Weeks 4, 8, and 12. PGI-S, CGI-
S, PDQ-39, Schwab and England ADL Scale will be assessed at Baseline and Weeks 4, 8, 12 and 
14. Optional exploratory skin biopsies will be obtained at Baseline and Week 4 and 12. Optional 
CSF collection will be obtained at Baseline and Week 12. 
CSSR-S, 
NMSS, 
MDS-UPDRS, 
vital 
signs, 
safety 
laboratory 
data, 
12-lead 
Electrocardiogram (ECG), concomitant medications, tolerability, and adverse events (AEs) will 
be obtained and documented throughout the study. The Columbia Suicide Severity Rating Scale 
(C-SSRS) will be assessed at each in-person visit. A safety follow-up visit will occur at two 
weeks after completion of the 12-week active treatment period. Data Safety Monitoring Board 
(DSMB) members will meet on a regular basis throughout the study to review safety data. They 
will have the authority to unblind upon request if deemed necessary and to stop the study if 
deemed appropriate, as outlined in the DSMB charter. 
A participant will be considered to have completed the study if he/she completes all study 
periods followed by the safety follow-up visit in accordance with the schedule of activities (SoA, 
Section 1.3), or when end of study is declared. 
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See the SOA (Section 1.3) for the full list of study assessments and timings.  
 
4.2. Justification for Dose 
 
Based on the objectives to identify a minimum safe dose, maximum safe tolerated dose, and 
evaluate efficacy, the following three IkT-148009 doses are proposed for the study along with 
placebo: 50 mg QD, 100 mg QD and 200 mg QD IkT-148009. Data from the validated animal 
studies and clinical pharmacokinetics from prior trials were used to define the doses for this study. 
4.3. End of Study Definition 
 
The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the study globally.  
A participant is considered to have completed the study if he/she completes all visits in 
accordance with the SoA (Section 1.3). 
5. Statistical Considerations  
 
The statistical analysis plan (SAP) will be finalized prior to database lock and will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints including 
primary and secondary endpoints. 
5.1. Statistical Hypotheses 
 
The safety and tolerability of different dose levels of IkT-148009 will be assessed as an 
overall evaluation of all safety endpoints. No formal statistical hypothesis will be tested. 
5.2  Multiplicity Adjustment 
 
The safety and tolerability of different dose levels of IkT-148009 will be assessed as an 
overall evaluation of all safety endpoints. No formal statistical hypothesis will be tested. 
The efficacy endpoints will be tested in hierarchical order by endpoint and within each 
endpoint by dose. First, the primary endpoint will be compared to placebo for the primary 
endpoint. If the difference for the high dose is statistically significant, the middle dose will be 
compared to placebo for the primary endpoint. If the difference in both high and middle doses 
are statistically significant, the low dose will be compared to placebo for the primary endpoint. 
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Next, if there is a statistically significant difference in all dose levels for the primary endpoint, 
the testing will continue by comparison of high dose vs placebo for the secondary endpoint ranked 
highest, followed by comparisons of the same endpoint for the middle and low dose, as long as 
all previous comparisons have been statistically significant. The procedure will continue similarly 
for all remaining secondary endpoints. 
In case not all endpoints are compared as a part of the hierarchical testing procedure, the 
statistical tests will be reported for descriptive purposes and interpreted in an exploratory manner. 
The steps in the hierarchical testing procedure are as follows: 
 
1. MDS-UPDRS Parts II + III 
2. Patient Global Impression-Severity (PGI-S) 
3. Clinician Global Impression of Severity (CGI-S) 
4. MDS-UPDRS Part II 
5. MDS-UPDRS Part III 
6. MDS-UPDRS Part I 
7. Non-Motor Symptom Scale (NMSS) 
8. Complete Spontaneous Bowel Movement score (CSBM) 
9. ESS (Epworth Sleepiness Scale) 
10. SE-ADL Scale 
11. PDQ-39 
12. PAGI-SYM 
13. PAC-QoL 
14. PAGI-QoL 
5.3  Analysis Sets 
There are three analysis sets: 
 
Analysis Set 
Description 
Modified Intent to Treat 
(mITT) 
The mITT will include all participants who have been randomized, 
received at least one dose of study drug, and have at least one post-
baseline evaluation of the primary efficacy endpoints. Participants 
will be included in the analyses according to the intervention they 
were randomized to (intended to receive). This set will be used to 
analyze efficacy endpoints. 
Safety analysis set 
The Safety set will include all participants who are randomized and 
received at least one dose or study intervention. Participants will be 
included in the analyses according to the intervention that they 
received (actually received). 
Per-protocol Set (PP) 
Includes all participants who complete the study without a major 
protocol deviation. 
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5.4. Statistical Analyses 
5.4.1. General Considerations 
 
The below mentioned general principles will be followed throughout the study: 
 
A detailed description of the analysis methods to be performed in the study will be provided 
in the Statistical Analysis Plan (SAP). The SAP will be finalized and approved prior to unblinding 
and database lock. Descriptions in the SAP will predominate over protocol in case of any 
differences and any major change to the SAP will be reflected in a protocol amendment. 
Unless otherwise noted, the baseline value is defined as the last value observed prior to the 
first administration of study intervention on Day 1.  
Unless otherwise noted, missing data will not be imputed but will be analyzed as missing. 
Descriptive statistics will include the number of non-missing patients (n), mean, standard 
deviation (SD), median, minimum, and maximum values for continuous variables, and for 
categorical variables, the frequencies and percentages of patients will be presented.  
The number of Below the limit of quantitation (BLQ) values i.e., the n below lower limit of 
quantification (LLOQ) will be reported for each time point. 
All study data will be included in study data listings. In general, all data will be listed by time 
point within participants. All summary tables will present descriptive statistics for the parameters 
being analyzed. 
SAS® version 9.4 or higher will be used for all analyses. 
5.4.2. Primary Endpoint Analysis 
 
The primary objective is to assess the safety and tolerability of IkT-148009. 
 
The safety and tolerability will be assessed descriptively based on an overall evaluation of 
the following endpoints: 
 
x Incidence and temporal profile of TEAEs, evaluated by type/nature, severity/intensity, 
seriousness, and relationship to study intervention 
x Incidence of related TEAEs (including possibly- and probably-related TEAEs) of 
moderate or severe intensity 
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x Incidence of TEAEs leading to withdrawal of study drug 
x Incidence of serious adverse events (SAEs), including suicidality as measured by the C-
SSRS 
x Changes in physical examination, vital signs (blood pressure, heart rate, respiratory rate, 
and temperature), 12-lead ECG, and laboratory data (hematology and blood chemistry) 
x Safety analysis is described further in Section 5.4.3. Safety endpoints will be summarized 
with descriptive statistics. 
 
x Proportion of those randomized in each dosing cohort who discontinue the assigned 
regimen  
5.4.3 Secondary Endpoint Analysis (Efficacy) 
 
The efficacy endpoints (as changes from Baseline at Week 12) will be evaluated in 
hierarchical order (by endpoint and within each endpoint, by dose). The order of testing is defined 
in Section 9.1.1. The following endpoints will be evaluated: 
 
x MDS-UPDRS Parts II + III 
x PGI-S (proportion of patients who improved from baseline) 
x Clinician Global Impression of Severity (CGI-S) (proportion of patients who 
improved from baseline) 
x MDS-UPDRS Part II 
x MDS-UPDRS Part III 
x MDS-UPDRS Part I 
x Non-Motor Symptom Scale (NMSS) 
x Complete Spontaneous Bowel Movement score (CSBM) 
x ESS (Epworth Sleepiness Scale) 
x SE-ADL Scale 
x PDQ-39 
x PAGI-SYM 
x PAC-QoL 
x PAGI-QoL 
 
Descriptive statistics for each continuous endpoint will be presented as Change from Baseline 
by treatment group and visit. Furthermore, the differences between the dose levels versus placebo 
at Week 12 in the continuous secondary endpoints will be estimated using a Mixed Model for 
Repeated Measures (MMRM) using the mITT Set. The MMRM will include the observed 
changes from baseline from all post-baseline visits as the response values and the treatment 
group, visit and the interaction between the treatment group and visit as fixed factors. The 
baseline value will be used as a covariate in the model. 
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An unstructured covariance structure will be applied for MMRM. In case the model will not 
converge with the unstructured covariance structure, Heterogeneous Autoregressive (1) 
(ARH[1]), Heterogeneous Compound Symmetry (CSH), Autoregressive(1) (AR[1]) or 
Compound Symmetry (CS) covariance structure will be used instead in this order. The 
denominator degrees of freedom will be computed using the Kenward-Roger method. 
The least square (LS) means for each treatment group, SEM, and LS mean difference between 
different dose levels and placebo along with the 95% confidence intervals will be provided. The 
P-value for the hypothesis testing will also be provided. 
The categorical secondary endpoints (PGI-S and CGI-S) will be analyzed using the 
GLIMMIX procedure for binomial data with logic link. The model will include the observed 
binomial values from all post-baseline visits as the response values and the treatment group, visit 
and the interaction between the treatment group and visit as fixed factors. The baseline value will 
be used as a covariate in the model. 
5.4.4 Exploratory Endpoint Analysis 
Exploratory endpoints include the proportion of phosphorylated alpha-synuclein in skin and 
CSF. 
 
Descriptive statistics will be provided for each of the exploratory outcomes. 
5.4.5 Safety Analyses 
Safety assessments will include TEAEs tabulated by cohort; descriptive statistics for 
continuous variables and frequency counts for discrete variables. No inferential statistical 
analysis is planned for safety data. 
The number and percentage of subjects reporting TEAEs will be tabulated for the safety 
analyses set by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and 
system organ class (SOC) with a breakdown by treatment, and further by relationship to study 
drug, as well as by maximum severity. Listings of deaths, SAEs, and TEAEs that lead to 
discontinuation of a subject will be presented. 
For laboratory data, a treatment-emergent abnormal value is an abnormality that was not 
present before dosing, but was present after dosing, or one that represents an exacerbation of a 
pre-existing abnormal value. 
All clinical laboratory data will be listed by subject for the safety analysis set, with abnormal 
lab results presented by subject in another listing. Descriptive statistics will be provided for 
baseline, end of study and for other times during the study if appropriate. 
Vital signs will be listed at each time point for all subjects in the safety analysis set. Clinically 
significant findings on Safety ECG will be recorded as TEAEs, coded, listed and tabulated. 
Physical examination findings including neurological examination findings will be listed for all 
subjects in the safety analysis set. Clinically significant findings will be included as TEAEs. 
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No imputation of values for missing data will be performed. Standard clinical monitoring and 
data management practices will be used to ensure the integrity of data.  
For all safety analyses, the placebo dose group will be pooled across cohorts. AEs will be 
coded using MedDRA with the version used specified in the clinical study report. The overall 
incidence of AEs will be displayed by System Organ Class (SOC), preferred term, and dose 
group, as well as incidence of TEAEs: 
1. by maximum severity  
2. by relationship to study drug 
3. by seriousness 
4. related TEAEs of moderate or severe intensity 
5. Leading to withdrawal of study drug 
6. SAE 
7. Suicidality as measured by the C-SSRS 
 
Data from the physical exam, vital signs, clinical laboratory measures, and ECGs will be 
summarized using descriptive statistics by dose group and time point, where applicable. 
Continuous endpoints will be summarized with n, mean, SD, median, minimum and maximum. 
In addition, change from baseline values will be calculated at each time point and will be 
summarized using descriptive statistics. Out-of-range safety endpoints may be categorized as low 
or high, where applicable. For all categorical endpoints, summaries will include counts and 
percentages. Shift tables will be provided for clinical laboratory results. 
Changes in the physical examination involving new findings or aggravated existing 
abnormalities judged clinically significant by the investigator will be reported as an AE. 
5.4.6 Other Analyses 
 
Subgroup analyses of the primary endpoint will be made to assess consistency of the 
intervention effect across the following subgroups:  
 
x Above and below median UPDRS part III at baseline 
x Age group: < 65 vs ≥ 65 years 
x Sex: female vs male 
 
If the number of participants is too small (less than 10%) within a subgroup, then the subgroup 
categories may be redefined prior to unblinding the study. Further details on the statistical 
analysis will be provided in the SAP. 
5.5. Interim Analysis 
No interim analysis is planned for this study. 
 
 
 
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5.6. Sample Size Determination 
 
A group size of 30 patients per dose was deemed sufficient to evaluate the potential safety 
and tolerability of IkT-148009.  Secondary measures will use appropriate descriptive statistics to 
assess study outcomes. 
6. Study Population 
6.1. Inclusion Criteria 
 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Men and women ≥ 30 and ≤ 80  years of age at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
1. Participants who are diagnosed with PD consistent with UK Brain Bank criteria and 
MDS Research Criteria; must include bradykinesia with sequence effect and motor 
asymmetry.  
2. Receiving no anti-parkinsonian therapy  
3. Modified Hoehn/Yahr Stage < 3.0  
4. Montreal Cognitive Assessment ≥ 24 
5. Patient expected to be able to participate in trial without need for additional anti-
parkinsonian therapy 
Sex and Contraceptive/Barrier Requirements 
Male participants: 
1. Male participants must agree to practice an acceptable method of highly effective birth 
control from the screening visit, while on study and for 30 days after receiving the last 
dose of study drug. Highly effective methods of birth control include sexual abstinence, 
vasectomy, or a condom with spermicide (men) in combination with their partner’s 
highly effective method.  
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Female participants: 
1. Female participants of childbearing potential and male participants with female 
partners of childbearing potential must agree to either remain abstinent or use 
adequate and reliable contraception throughout the study and at least 30 days after the 
last dose of study drug has been taken. 
Informed Consent 
1. Capable of giving signed ICF as described in Appendix 1 which includes compliance 
with the requirements and restrictions listed in the ICF and in this protocol. 
Other Inclusions 
1.  Approved as an appropriate and suitable candidate by the EAC. 
 
 
6.2. Exclusion Criteria  
 
Participants are excluded from the study if any of the following criteria apply: 
 
Medical Conditions 
 
1. Diagnosis/suspicion of secondary or atypical parkinsonism 
2. Previous procedure or surgery for PD, or anticipation of these during the study 
3. High likelihood of needing anti-parkinsonian treatment over the study period, in the 
opinion of the investigator 
4. Clinically significant orthostatic hypotension 
5. Clinically significant hallucinations requiring antipsychotic use in the 12 months prior 
to Screening 
6. Clinically significant medical, surgical, psychiatric, or laboratory abnormalities in the 
judgement of the treating investigator or the EAC  
Prior/Concomitant Therapy 
 
1. Past treatment with levodopa, dopaminergic agonists, monoamine oxidase-B 
inhibitors, supplements containing levodopa (i.e. Mucana pruriens)or A2A 
antagonists for more than 28 days, or treatment with any of these medications or 
supplements within 28 days prior to screening 
2. Past treatment with irreversible monoamine oxidase-B inhibitors (e.g., selegiline) for 
more than 28 days; must be discontinued for at least 90 days before screening  
3. Currently receiving moderate or strong Cytochrome P450 (CYP) 3A4/5 inducers or 
CYP3A4/5 inhibitors (except for topical administration) 
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4. Currently receiving any antipsychotic, metoclopramide, reserpine, or amphetamine. 
Prior/Concurrent Clinical Study Experience 
 
1. Current participation in another investigational clinical trial and/or receipt of any 
investigational medication within 90 days prior to screening 
2. Previous randomization into this or another IkT-148009 study 
Diagnostic Assessments 
1. Active suicidal ideation within one year prior to screening visit, as determined by the 
Columbia Suicide Rating Scale (answer of “yes” on question 4 or 5) 
2. Current diagnosis or history of substance abuse (excluding nicotine or caffeine) by 
Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria 
3. Medical or recreational use of marijuana in the 3 months prior to the screening visit 
4. Any social or behavioral reason that would preclude completion of the study, in the 
judgement of the investigator  
5. Any skin condition that would interfere with obtaining adequate samples 
6. Evidence of advanced, age-related macular degeneration (neovascular or geographic 
atrophy) or intermediate macular degeneration as defined by Beckman classification 
(Large drusen > 125 um and/or any AMD pigmentary abnormalities).  Evidence of 
retina/choroid neovascularization from any cause. Evidence of central serous 
retinopathy. 
 
7. Abnormal amylase and/or lipase at screening (may be repeated during screening 
period) 
8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater 
than 2.5 times the upper limit of normal (ULN) 
9. Significant renal impairment as determined by the following criteria:  
x  Creatinine clearance (CrCL) less than or equal to 60 mL/min for subjects < 65 years 
of age 
x Creatinine clearance (CrCL) less than  55 mL/min or the presence of other evidence 
of chronic kidney disease such as proteinuria for subjects ≥ 65 years of age 
10. Currently lactating, pregnant or planning on becoming pregnant during the study 
 
6.3 Stopping Rules 
1.  Any participant that develops clinical abnormalities in the macula, retina, choroid or 
fundus that was not pre-existing must stop dosing unless it is clearly unrelated to the study 
medication. 
 
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2.  If two participants develop clinical abnormalities in the macula, retina, choroid or fundus 
that was not pre-existing, all participants at that dose must stop dosing unless it is clearly 
unrelated to the study medication. 
 
Sponsor must be alerted to these findings within 24 hours. 
6.4. Screen Failures 
A screen failure occurs when a participant who voluntarily consented to participate in the 
clinical study is subsequently not entered into the study. A minimal set of screen failure 
information is required to ensure transparent reporting on screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE. 
Laboratory test results that do not meet eligibility requirements may be repeated once within 
the 28-day screening period prior to designating the individual as a screen failure.  Individuals 
who do not meet the criteria for participation in this study (screen failure) may be rescreened 
once. Rescreened participants should sign a new ICF and be assigned a new participant number 
if the repeat screening visit falls outside of the 28-day screening period. 
7. Study Intervention(s) and Concomitant Therapy 
7.1. Study Intervention(s) Administered 
 
Three different doses (50/100/200 mg) of IkT-148009 or placebo capsules will be 
self-administered with food by the enrolled participants in this clinical trial. 
Dosage form: Capsule 
Strength: 50 mg/capsule 
Dosage frequency: Once daily 
Quantity: 4 capsules per day 
The double-blind dosing for the three treatment arms will be achieved using a blister pack 
configuration. Each participant will take a combination of active and placebo capsules once daily 
based on which group they are randomized to, to ensure the double blind is maintained.   
7.2. Preparation, Handling, Storage, and Accountability 
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The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current Good Manufacturing Practice (GMP) and Good clinical practice (GCP) 
guidelines and are available for review in the study intervention documentation.   
Upon receipt of the medication, the investigator or designee will inspect the medication and 
complete and return the Acknowledgment of Receipt Form enclosed with the parcel. A copy of 
the signed receipt will be kept in the study files.  
The study intervention must be carefully stored at 25°C (77°F); excursions permitted between 
15-30°C (59-86°F) [see United States Pharmacopeia Controlled Room Temperature]. It should 
be protected from moisture. 
The study intervention may not be used for any purpose other than the present study. After 
the study is completed, all unused study intervention must be retained, returned as directed or 
destroyed on site per the sponsor’s instructions. 
The investigator or designee will be responsible for ensuring appropriate storage, dispensing, 
inventory, and accountability of all clinical supplies. An accurate, timely record of the disposition 
of all clinical supplies must be maintained. The supplies and inventory must be available for 
inspection by the designated representatives of the sponsor or the sponsor’s representatives on 
request, and must include the information below: 
x the identification of the participant to whom the drug was dispensed; 
x the date(s) and quantity of the drug dispensed to the participant; 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented as directed. This documentation must include at least the information below 
or as agreed with the sponsor: 
x the number of unused units; 
x the number of units destroyed at the end of each outpatient study. 
7.3. Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally assigned to randomized study intervention using an 
IVRS/IWRS. Before the study is initiated, the telephone number and call-in directions for the 
IVRS and/or the log-in information and directions for the IWRS will be provided to each site. 
Study intervention will be dispensed at the study visits as summarized in the SoA (Section 
1.3). Returned study intervention should not be re-dispensed to the participants. 
This is a double-blind study in which participants/care providers/investigators/outcomes 
assessors, etc. are blinded to study intervention. The IVRS/IWRS will be programmed with 
blind-breaking instructions. In case of an emergency, the investigator should consult with the 
medical monitor (if/when possible) prior to unblinding.  Participant safety must always be the 
first consideration in making such a determination. If a participant’s intervention assignment is 
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unblinded, sponsor must be notified within 24 hours of this occurrence. The date and reason for 
the unblinding must be recorded. 
The study will begin with 50 mg, 100 mg and placebo groups. The 200 mg dose will be added 
at one of the defined enrollment timepoints defined in the table below: 
Randomization 
Schema 
# placebo 
subjects 
enrolled  
# 50 mg 
subjects 
enrolled 
# 100 mg 
subjects 
enrolled 
# 200 mg 
subjects 
enrolled 
Randomization 
Schema 1 
5 
5 
5 
0 
1:1:1:0 
Schema 2 
25 
25 
25 
30 
5:5:5:6 
 
 
 
 
 
 
Schema 1 
10 
10 
10 
0 
1:1:1:0 
Schema 2 
20 
20 
20 
30 
2:2:2:3 
 
 
 
 
 
 
Schema 1 
15 
15 
15 
0 
1:1:1:0 
Schema 2 
15 
15 
15 
30 
1:1:1:2 
 
 
 
 
 
 
Schema 1 
20 
20 
20 
0 
1:1:1:0 
Schema 2 
10 
10 
10 
30 
1:1:1:3 
 
If appropriate, the DSMB may unblind the intervention assignment for any participant with 
an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the participant’s intervention assignment, may be sent 
to investigators in accordance with local regulations and/or sponsor policy.  
7.4. Study Intervention Compliance 
Participants will self-administer the study intervention, as directed on a daily basis for the 
duration of the study, taken no more than one hour after a consumed meal.   On the first dosing 
day, the meal will be consumed no more than two hours prior to taking the first dose. 
Dosing compliance will be assessed by direct questioning and counting returned capsules 
during the site visits and documented in the source documents and relevant forms. Deviation(s) 
from the prescribed dosage regimen should be recorded. 
A record of the quantity of IkT-148009 capsules dispensed to and administered by each 
participant must be maintained. Intervention start and stop dates, including dates for intervention 
delays will also be recorded. 
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7.5. Dose Modification and Continued Access to Study Intervention After the 
End of the Study 
 
After completion of study period, no access will be provided to the study interventions. 
7.6. Concomitant Therapy 
Any medication, including over the counter or prescription medicines, recreational drugs, 
vitamins, herbal supplements, or other substances intended for therapeutic or beneficial purposes 
that the participant is receiving at the time of enrollment or receives during the study must be 
documented. For each, the following must be recorded: 
x Reason for use 
x Dates of administration including start and end dates 
x 
Dosage information including dose and frequency 
The medical monitor will review concomitant therapies for each patient in accordance with 
the Medical Monitoring Plan and the Medical Data Review Plan and document this review. Any  
findings or concerns will be discussed/reviewed and decisions documented.  
All participants will be questioned by the PI or research personnel about concomitant 
treatment at each telephone and clinic visit.  
The use of marijuana is not permitted from 3 months prior to screening through the end of 
the double-blind treatment period. For symptomatic treatment of nausea and/or emesis, the use 
of an anti-emetic may be considered. 
 
7.6.1. Initiation of Dopaminergic Therapy 
 
If medically necessary, participants may need to begin medications to treat the motor 
symptoms of PD during the study. This is not actively encouraged, but is permitted in the 
judgment of the participant, investigator, and in consultation with the medical monitor. 
Participants who start PD medication are encouraged to remain in the study and complete study 
activities as best as possible.  
8. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
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Discontinuation of specific sites or of the study as a whole is detailed in Appendix 1. 
8.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. If the 
study intervention is permanently discontinued, efforts will be made to encourage the participant 
to remain in the study for evaluation according to planned study procedures per SoA. See the 
SoA for data to be collected at the time of follow-up and for any further evaluations that need to 
be completed. 
8.2. Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or compliance 
reasons.  
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued from the study intervention and the study 
at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
8.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
x Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, three 
telephone calls, and if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
x Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
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x 
Site personnel, or an independent third party, will attempt to collect the vital status 
of the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get study intervention. Public sources may be searched 
for vital status information. If vital status is determined as deceased, this will be 
documented, and the participant will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts to collect vital status information. 
9. Study Assessments and Procedures 
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
 
x Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
x Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
x Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SoA. 
x Safety/laboratory results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will be outlined in the ICF. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
 
9.1. Efficacy Assessments 
 
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
9.1.1. Movement Disorder Society-Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) 
 
The MDS-UPDRS is a well-established tool for characterizing the signs and symptoms of PD 
(Goetz et al, 2008). The three parts used in this study are: Part I (Non-Motor Aspect of 
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Experiences of Daily Living), Part II (Motor Aspects of Experiences of Daily Living), and Part 
III (Motor Examination). Items in each domain are rated from 0-4, where 0 = normal, 1 = slight, 
2 = mild, 3 = moderate, and 4 = severe. 
9.1.2. Patient Global Impression – Severity (PGI-S) 
 
The PGI-S is a single-item tool used to determine how severe a person feels their symptoms 
are at the time of questioning. It is based on a 5-point scale (None, mild, moderate, severe, very 
severe).  
9.1.3. Clinician Global Impression of Severity (CGI-S) 
 
The CGI-S is a 7-point scale used to indicate how the clinician views the severity of the 
patients illness at the time of questioning (Guy, 1976). The range includes 1 (“normal”), 2 
(“borderline ill, not ill at all”), 3 (“mildly ill”), 4 (“moderately ill”), 5 (“markedly ill”), 6 
(“severily ill”), and 7 (“among the most extremely ill patients”).  
9.1.4. Parkinson’s Disease Questionnaire (PDQ– 39) 
 
The PDQ-39 is a self-administered questionnaire that assesses how often people affected by 
PD experience difficulties across 8 dimensions of daily living, including mobility (10 items), 
activities of daily living (6 items), emotional well-being (6 items), stigma (4 items), social support 
(3 items), cognition (4 items), communication (3 items), and bodily discomfort (3 items). (Peto 
et al 1995). It also assesses the impact of PD on specific dimensions of functioning and well-
being. The PDQ-39 is scored on a scale of 0 to 100, with lower scores indicating better health 
and higher scores more severe symptoms. 
 
9.1.5. Schwab and England Activities of Daily Living Scale (SE-ADL) 
 
The SE-ADL is a single item that assesses the difficulty that a patient has in completing daily 
activities. It ranges from 0% (bedridden) to 100% (completely independent). Scores are coded in 
increments of 10 (i.e., 100, 90, 80, 70, …). The rater column does not need to be completed. 
9.1.6. Non-Motor Symptom Scale (NMSS) 
 
The NMSS is a 30-item scale divided into 9 domains (cardiovascular, sleep/fatigue, 
mood/cognition, perceptual problems/hallucinations, attention/memory, GI, urinary, sexual 
function, miscellaneous) (Chaudhuri et al 2007). Each item is rated for frequency 
(rarely/often/frequent/very frequent) and severity (none/mild/moderate/severe) of symptoms.  
 
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9.1.7. Complete Spontaneous Bowel Movement Score (CSBM) 
 
The total number of spontaneous bowel movements and the stool types will be assessed at 
baseline, week 4, week 8, and week 12. A patient diary will be provided to record all bowel 
movements in the 7 days leading up to these timepoints. A spontaneous bowel movement is a 
stool not induced by rescue medication such as laxative, enema, or suppository use during the 
previous 24 hour period. “Complete” refers to the sensation of complete evacuation of the stool 
(Lacy et al, 2012).  
9.1.8.  Patient Assessment of Upper GI Disorders Severity Index (PAGI-SYM) 
 
The PAGI-SYM measures symptom severity in patients with upper GI disorders. The patient 
is asked to rate the severity of symptoms over the last 2 weeks. There are 20 items which are 
rated from 0 (none) to 5 (very severe). 
9.1.9. Patient Assessment of Constipation Quality of Life (PAC-QoL) 
 
The PAC-QoL assesses the effect that constipation has on daily life over the past 2 weeks. 
There are 28 items which are rated from 0 (not at all) to 4 (extremely). 
 
9.1.10. Patient Assessment of GI Disorders Severity Quality of Life 
(PAGI-QoL) 
 
The PAGI-QoL assesses the effect that GI problems have on daily life over the past 2 weeks. 
There are 30 items which are rated from 0 (none of the time) to 5 (all the time). 
9.1.11. Epworth Sleepiness Scale (ESS) 
 
The ESS assesses sleepiness over time. Patients and Caregivers are asked to rate (on a scale 
of 0 to 3) their likelihood of falling asleep during 8 daily activities, including reading, watching 
television, and driving.   
9.2. Safety Assessments 
 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
9.2.1. Physical Examinations 
 
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A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, lymphatic, musculoskeletal, GI, and neurological systems as well as 
assessment of general appearance, abdomen, skin, and extremities. Height and weight will also 
be measured and recorded. 
9.2.2. Vital Signs 
 
Vital signs (VS) for blood pressure and pulse are to be measured after subjects remain supine 
for 5 min and after 2 min standing. Baseline VS will be measured 3 times at baseline over the 
course  of an hour. Respiratory rate, pulse oximetry and temperature will also be collected. Vital 
signs measurements outside of the normal range (as per the CRU SOP) should be repeated. All 
time points are relative to the time of dosing. 
9.2.3. Electrocardiograms 
 
Standard (triplicate) 12-lead ECG(s) will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals.  Corrected QT interval should be done by Fredericia (QTcF). 
 
9.2.4. Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA (Section 
1.3) for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
x If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
the sponsor should be notified. 
x All protocol-required laboratory tests, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
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x 
If laboratory values from non-protocol-specified laboratory tests performed at 
the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
9.2.5. Pregnancy Testing 
 
All women of childbearing potential will take serum/urine pregnancy tests, per SoA 
(Section 1.3).  
9.2.6. Ophthalmic Exams 
Ophthalmic exams include: 
x Best corrected visual acuity 
x Slit lamp examination of the anterior segment, particularly cornea, aqueous and lens.  Slit 
lamp examination should determine the potential presence of dry eye, inflammatory cells 
in the aqueous and lens opacities. 
x Wide-field photography 
x Wide-field autofluorescence 
x Wide-field fluorescein angiography (WF-FA) 
x Spectral domain optical coherence tomography (SD-OCT) 
Opthalmic exams are performed at screening and at 12 weeks.  All images will be uploaded to a 
secure portal with patient-identifying information redacted.  Exam reports are required for all 
ophthalmic exams at screening and at 12 weeks. The exam reports at 12 weeks must compare 
observations at 12 weeks to what was observed at screening to determine if any changes occured. 
 
 
 
9.2.7. Pharmacokinetics   
 
Blood samples will be drawn either pre-dose (at baseline) or either pre-dose or post-dose  on 
the subsequent visit days (see SoA) to analyze steady-state pharmacokinetics for IkT-148009 and 
its primary metabolites. 
9.2.8. Suicidal Ideation and Behavior Risk Monitoring 
 
Patients with PD may occasionally develop suicidal ideation or behavior. 
Participants being treated with IkT-148009 should be monitored appropriately and observed 
closely for suicidal ideation and behavior (SIB) or any other unusual changes in behavior 
throughout the study. Participants who experience signs of SIB should undergo a risk assessment. 
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All factors contributing to SIB should be evaluated and consideration should be given to 
discontinuation of the study intervention.  
During the informed consent process, families and caregivers of participants being treated 
with IkT-148009 should be alerted about the need to monitor participants for the emergence of 
SIB and to report such symptoms immediately to the study investigator. 
Baseline assessment of SIB/intervention-emergent SIB will be monitored throughout the 
study period using the C-SSRS. The C-SSRS will be assessed by trained personnel only. The 
scale consists of 4 categories: suicidal ideation, intensity of suicidal ideation, suicidal behavior, 
and actual/potential lethality which can be answered by Yes or No. At the screening visit the 
questionnaire for the past 6 months will be used, and for all other visits the version “Since the 
last visit” will be administered. 
At each suicidality assessment, participants thought to have significant suicidal ideation with 
actual plan and intent or suicidal behavior must be evaluated by a clinician or mental health 
professional skilled in the evaluation of suicidality, who will determine if it is safe for the 
participant to continue in the trial. Specific criteria that indicate a need for further assessment 
include: 
x Suicidal ideation associated with actual intent and/or plan in the past 6 months; (a 
“YES” answer to C-SSRS questions 4 “some intent to act without specific plan” or 5 
“specific plan and intent”). 
x Previous history of suicide behaviors in the past 5 years (a “YES” answer to any of 
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 5 
years). 
x 
The investigator’s judgment that a risk assessment is warranted. 
 
Participants who respond “Yes” to items 4 or 5, or to any behavioral question of the C-SSRS 
on more than one occasion during the trial may be discontinued from the trial. 
9.3. Adverse Events (AEs) Serious Adverse Events (SAEs), and Other Safety 
Reporting 
 
The definitions of AEs and SAEs can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative [LAR]). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention/study. 
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The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
9.3.1. Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
timepoints specified in the SoA (Section 1.3). 
All AEs will be collected from the signing of the ICF until the follow-up visit at the timepoints 
specified in the SoA (Section 1.3). 
During the screening period baseline abnormalities (any sign or symptom present, such as 
abnormal screening laboratory value) will be assessed for clinical significance and captured in 
medical history as ongoing.  Any baseline abnormality that increases in severity or frequency 
should be captured as an adverse event if determined clinically significant by the investigator. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event 
to be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
9.3.2. Method of Detecting AEs and SAEs 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
 
 
9.3.3. Follow-up of AEs and SAEs 
 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 3. 
 
9.3.4. Regulatory Reporting Requirements for SAEs 
 
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Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it along with the IB and will notify the IRB/IEC, if appropriate, according to local requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
9.3.5. Pregnancy 
The risks of using the study drug during pregnancy are not known. It is possible that this 
study drug may cause harm to an unborn baby. This includes death, birth defects or other 
unforeseen health problems for the baby. 
Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study intervention and until the time period for postintervention 
contraception as determined in Section 6. 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the pregnancy of the 
female participant or female partner of male participant (after obtaining the necessary signed ICF 
from the female partner). 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant/pregnant female 
partner and the neonate, and the information will be forwarded to the sponsor. 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the sponsor as described in Section 9.3.5. While the 
investigator is not obligated to actively seek this information in former study 
participants/pregnant female partners, he or she may learn of an SAE through spontaneous 
reporting. 
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Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and will be withdrawn from the study.  
10. Supporting Documentation and Operational Considerations 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following: 
x Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
x Applicable International Council for Harmonisation (ICH) Good clinical practice 
(GCP) guidelines 
x Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), investigator’s brochure 
(IB), and other relevant documents (e.g., advertisements) must be submitted to an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
x Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety 
findings as required by IRB/IEC procedures 
x Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
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European regulation 536/2014 for clinical studies and all other applicable local 
regulations 
 
10.1.2. Financial Disclosure 
 
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
one year after completion of the study. 
 
10.1.3. Informed Consent Process 
 
x The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or their LAR and answer all 
questions regarding the study. 
x Participants must be informed that their participation is voluntary. Participants or 
their LARs will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy, and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
x The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
x Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
x A copy of the ICF(s) must be provided to the participant or their LAR. 
Participants who are rescreened are required to sign a new ICF. 
 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Exploratory research 
could include measurement of protein levels in vescicles that originated in the brain and are 
isolated from blood and/or plasma and/or urine. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s 
agreement to allow any remaining specimens to be used for exploratory research. Participants 
who decline to participate in this optional research will not provide this separate signature. 
10.1.4. Data Protection 
 
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Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. Committees Structure 
10.1.5.1. Enrollment Authorization Committee and Data Safety Monitoring 
Board 
 
Enrollment Authorization Committee is an independent group of medical experts 
responsible for ensuring that only those patients who met all eligibility criteria, as outlined in 
the final approved protocol, are suitable and appropriate for inclusion in the study. 
Participant safety will be continuously monitored by the sponsor’s external Data Safety 
Monitoring Board (DSMB), which monitors the safety and scientific integrity of a human 
research intervention and makes recommendations to the sponsor regarding the stopping of a 
study for harms. 
The DSMB is a group of independent scientists (at least two expert clinicians who are 
treating PD patients and a biostatistician). 
DSMB may request for unblinding of an individual participant or group of participants 
treatment, if the study intervention details plays a significant role in making certain decisions in 
participant’s best interest. 
10.1.6. Dissemination of Clinical Study Data 
 
Every research study involving human patients must be registered in a publicly accessible 
database before recruitment of the first patient. 
Researchers, authors, sponsors, editors, and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human patients and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
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interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
10.1.7. Data Quality Assurance 
 
All participant data relating to the study will be recorded on printed or electronic case report 
forms (eCRFs) unless transmitted to the sponsor or designee electronically (e.g., laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
Guidance on completion of eCRFs will be provided in electronic CRF completion guideline 
(eCCG). 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., contract 
research organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for two years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
 
10.1.8. Source Documents 
 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
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Definition of what constitutes source data, and its origin can be found in e.g., source data 
acknowledgment or monitoring guidelines. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the source documents and an eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9. Study and Site Start and Closure 
First Act of Recruitment: 
 
The trial start date is the date on which the clinical study will be open for recruitment of 
participants. The first site open is considered as the first act of recruitment. 
 
Study/Site Termination: 
 
The sponsor or designee reserves the right to close the trial site or terminate the trial at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but 
are not limited to: 
For study termination: 
 
x Discontinuation of further study intervention development 
 
For site termination: 
 
x Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
x Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
x Total number of participants included earlier than expected 
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If the trial is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any contract research organization(s) 
used in the trial of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
 
10.1.10. Publication Policy 
 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments. 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multi-center studies only in their entirety and not as individual site data. In this 
case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2. Appendix 2: Clinical Laboratory Tests 
 
The tests detailed in Table 1 will be performed by the central laboratory/local laboratory. 
 
x Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time. Additionally, if the local laboratory 
results are used to make either a study intervention decision or response evaluation, 
the results must be recorded. 
x Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol. 
x Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
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Laboratory 
Tests 
Parameters 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell (RBC) count 
Platelet count 
PT (in seconds)-International 
normalized ratio (INR) 
RBC indices: 
Reticulocyte count 
White blood cell 
(WBC) count with 
differential: 
Neutrophils, 
Lymphocytes, 
Monocytes, 
Eosinophils, 
Basophils 
Clinical 
chemistry 
Blood urea 
nitrogen (BUN) 
Sodium, 
triglycerides 
Urea and uric 
acid 
Bicarbonate 
Potassium 
Albumin 
Cholesterol 
Sodium 
Calcium 
Aspartate 
aminotransferase 
(AST) 
Alanine 
aminotransferase 
(ALT) 
Total and direct 
bilirubin 
(should be 
differentiated 
only when total 
bilirubin is 
above 1.5 X 
ULN) 
 
Creatinine 
Creatinine 
clearance 
Creatinine 
kinase 
Lactate 
dehydrogenase 
(LDH) 
inorganic 
phosphorus 
lipase 
Alkaline 
phosphatase2 
Gamma-glutamyl 
transferase 
(γ-GT) 
Total protein 
Amylase  
Potassium 
Magnesium 
Glucose 
(non-fasting) 
Lipase 
Pregnancy 
testing 
Highly sensitive [serum or urine] human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential) 
Routine 
urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, 
leukocyte esterase] by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other screening 
tests 
Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only), thyroid stimulating hormone (TSH), Luteinizing 
hormone (LH), Total Testosterone, and Inhibin B 
Investigators must document their review of each laboratory safety report. 
 
 
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10.3. Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
 
10.3.1. Definition of AE 
 
AE Definition 
x 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
x 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of Unsolicited and Solicited AE 
x 
An unsolicited adverse event is an adverse event that was not solicited using a 
participant diary and that is communicated by a participant/participant’s parent(s)/ 
LAR(s) who has signed the informed consent. Unsolicited AEs include serious and 
non-serious AEs. 
x 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The participants/participant’s parent(s)/LAR(s) will be instructed to contact 
the site as soon as possible to report medically attended event(s), as well as any events 
that, though not medically attended, are of participant/participant’s parent(s)/LAR(s) 
concern. Detailed information about reported unsolicited AEs will be collected by 
qualified site personnel and documented in the participant’s records. 
x 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant/participant’s parent(s)/LAR(s) will be collected during an interview with 
the participants/participant’s parent(s)/LAR(s) and by review of available medical 
records at the next visit. 
Events Meeting the AE Definition 
x 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., Electrocardiogram [ECG], radiological scans, vital 
signs measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease) 
x 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
x 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study 
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x 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction 
Events NOT Meeting the AE Definition 
x 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 
x 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
x 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE 
x 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
x 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
 
10.3.2. Definition of SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
Results in death 
Is life threatening 
x 
The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
x 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
x 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
Results in persistent or significant disability/incapacity 
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x 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
x 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Is a suspected transmission of any infectious agent via an authorized medicinal product 
Other situations: 
x 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias, convulsions or development of 
intervention dependency or intervention abuse. 
 
10.3.3. Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
x 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
x 
The investigator will then record all relevant AE/SAE information. 
x 
There may be instances when copies of medical records for certain cases are requested by 
sponsor/sponsor designee/local health authorities. In this case, all participant identifiers, 
with the exception of the participant number, will be redacted on the copies of the 
medical records before submission to sponsor/sponsor designee/local health authorities. 
x 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will assess intensity for each AE and SAE reported during the study and assign it to 
one of the following categories:  
x 
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
x 
Moderate: Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc.   
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x 
Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care 
ADL. Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the 
toilet, taking medications, and not bedridden.   
 
Assessment of Causality 
x 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
x 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
x 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
x 
The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
x 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
x 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to sponsor/local health authorities. However, it 
is very important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to sponsor/local health authorities. 
x 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
x 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
x 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
sponsor/sponsor designee/local health authorities to elucidate the nature and/or causality 
of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
x 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide his/her detailed report with a copy of any 
postmortem findings.  
x 
New or updated information will be recorded in the originally submitted documents. 
x 
The investigator will submit any updated SAE data to sponsor/sponsor designee within 
24 hours of receipt of the information. 
 
10.3.4. Reporting of SAEs 
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SAE Reporting to sponsor/sponsor designee via an Electronic Data Collection Tool 
x 
The primary mechanism for reporting an SAE to sponsor or sponsor’s designee will be 
the electronic data collection tool. 
x 
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
x 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
x 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
x 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
offline, then the site can report this information on a paper SAE form (see next section) or 
to the sponsor or sponsor’s designee/SAE coordinator by telephone. 
x 
Contacts for SAE reporting will be provided 
 
10.4. Appendix 4: Contraceptive and Barrier Guidance 
 
Study specific contraception requirements for women of childbearing potential are outlined 
in Section 10.4.2. 
Female participants of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk of the fetus if they become pregnant during treatment and for 30 days 
after the last dose of study intervention. 
10.4.1. Definition 
 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
x Premenopausal female with one of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
 
Note: Site staff documentation from the sources like participant’s medical records, medical 
examination, or medical history is acceptable. 
 
x Premenarchal female 
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x 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level; in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before trail enrollment. 
 
10.4.2. Contraception Guidance 
Contraception Methods for Female Participants 
 
Acceptable methods of effective contraception include:  
x Combined (estrogen and progestogen containing) or progestogen-only hormonal 
methods given oral, intravaginal, transdermal, injectable, or implantable route 
x Intrauterine device (IUD) 
x Intrauterine hormonal-releasing system (IUS) 
x Bilateral tubal ligation/occlusion 
x Vasectomized partner (provided that partner is the sole sexual partner of the female 
participant of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success). 
x Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associate with the study interventions; the reliability of sexual abstinence 
must be evaluated in relation to the duration of the trial and the preferred and usual 
lifestyle of the participant) 
x Male or female condom with or without spermicide 
x Cap, Diaphragm or sponge with spermicide 
x 
Double barrier method: the male uses a condom, and the female may choose either a 
cap, diaphragm, or sponge with spermicide (a female condom is not an option due to the 
risk of tearing when both parents use a condom) 
10.5. Appendix 5: Concomitant Medications 
 
All trial participants during the clinical trial period will be allowed to use concomitant 
medications, as needed. Particular scrutiny will be given to medications which are known to be  
Cytochrome P450 (CYP) 3A4/5 inhibitors and inducers and medications known to be MDR1 or 
BCRP inhibitors.  These concomitant medications will be noted and evaluated in accordance with 
the Medical Monitoring Plan and the Medical Data Review Plan to determine if any exclusions 
are warranted. 
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For the list of drugs falling under the CYP3A4/5, MDR1 and BCRP categories refer 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers. 
10.6. Appendix 6: Abbreviations and Definitions 
 
Abbreviation/Term 
ADL 
Activities of Daily Living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BLQ 
Below the limit of quantitation 
BUN 
Blood urea nitrogen 
c-Abl 
cellular Abelson tyrosine kinase 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT
Consolidated Standards of Reporting Trials 
CrCL 
Creatinine clearance 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSBM 
Complete Spontaneous Bowel Movement Score 
CYP 
Cytochrome P450 
eCCG 
electronic CRF completion guideline 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
FSH 
Follicle Stimulating Hormone 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
GMP 
Good manufacturing practice 
HbsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
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HRT 
Hormonal Replacement Therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormonal-releasing system 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LAR 
legally authorized representative 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
LLOQ 
Lower limit of quantification 
MDS-
Movement Disorder Society-sponsored revision of the Unified 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
NMSS 
Non-Motor Symptom Scale 
PAC-QoL 
Patient Assessment of Constipation Quality of Life 
PAGI-QoL 
Patient Assessment of GI Disorders Severity Quality of Life 
PAGI-
Patient Assessment of Upper GI Disorders Severity Index 
PD 
Parkinson’s Disease 
PDQ 
Parkinson’s Disease Questionnaire 
PGI-S 
Patient Global Impression-Severity 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
QD 
once daily 
QoL 
Quality of life 
QTc 
Corrected QT interval 
RBC 
Red blood cell 
SD 
Standard deviation 
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SD-OCT 
      Spectral domain optical coherence tomography 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SE-ADL 
Schwab and England Activities of Daily Living Scale 
SIB 
suicidal ideation and behavior 
SoA 
Schedule of Activities 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell count 
WF-FA 
         Wide-field fluorescein angiography  
 
10.7. Appendix 7: Protocol Amendment History 
 
Changes from protocol version 3.3: 
 
x Section 1.3 (SoA) Fluorescein dye angiography of the eye added as an additional 
assessment at baseline and end of study.  
x Section 9.1.2 (PGI-S) Description of assessment corrected as an error was identified 
in the text. 
x Section 9.1.3 (CGI-S) Description of assessment corrected as an error was identified 
in the text. 
x Section 9.1.5 (SE-ADL) Corrected error in description of scoring. 
x Section 9.1.8 (CSBM) Incorrect timepoints identified in description corrected. 
x Section 9.2.7 (Fluorescein dye angiography of the eye) Added to explain the rational 
for addition of this assessment.  
 
Changes from protocol version 4.0 
x Section 1.3 (SoA) Fluorescein dye angiography of the eye removed as an additional 
assessment at baseline as it was included in error. 
 
Changes from protocol version 4.1 
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x Section 1.3 (SoA) Footnote J added to define timing of blood draws for 
Pharmacokinetic assessments 
x Section 4.1 (Overall Design) Added details regarding eating pre-dose 
x Section 7.4 (Study Intervention Compliance) Added details regarding eating pre-dose 
x Section 7.6 (Concomitant Therapy) Added more detailed information regarding 
review of concomitant medications by medical monitor 
x Section 9.1.7 (Whole Gut Transit Time) Added that this assessment will not be 
conducted at all sites, but is required for patients at sites selected 
x Section 9.2.8 (Pharmacokinetics) Section added to explain the purpose and timing of 
blood sample draws for pharmacokinetic measures. 
x 10.5 (Appendix 5: Concomitant Medications) Additional detail added to describe 
concomitant medications that require additional medical review and monitoring  
 
     Changes from protocol version 4.2 
x Section 1.3 (SoA) Addition of SmartPill assessments and clarification of instructions 
x Section 4.1 (Overall Design) Clarification on the consumption of citrus fruits or juice 
with regards to dosing  
x Section 9.1.5 (SE-ADL) Clarification that rater column does not need to be completed 
x 9.1.7 (Whole Gut Transit Time) Additional information and clarification added to 
provide sites with clear instructions regarding SmartPill dosing and assessment 
x 9.2.3 (Electrocardiograms) Clarification to ensure triplicate ECGs are performed at 
all timepoints 
 
Changes from protocol version 5.0 
x Section 1.3 (SoA) Removal of Smartpill assessments throughout protocol and changes 
to definition of ophthalmic exams and the type of exams to be performed.  
x Section 1. (Protocol Summary) Change in number of dosing groups from 3 
(50/100/200) to 2 (50/100) plus placebo throughout protocol 
x Section 6.2 (Exclusion Criteria) Added exclusion criteria to diagnostic assessments 
for age-related macular degeneration 
x Section 6.3 (Stopping Rules) Added stopping rules for participants  
x Section 9.2.6 (Opthalmic exams) definition of these exams updated along with 
instructions for comparative analysis at 12 weeks. 
x Section 9.2.7 (Fluorescein Angiography) is eliminated and incorporated into the new 
section 9.2.6. 
 
Changes from protocol version 6.0 
x Section 10.1.3. (Informed Consent Process) Added more detail about potential 
exploratory research 
Changes from protocol version 6.1 
x Change in number of dosing groups from 2 (50/100) to 3 (50/100/200) plus placebo 
throughout protocol 
x Section 1.3 (SoA) addition of footnote advising patients to avoid alcohol prior to 
visits. 
Changes from protocol version 6.2 
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x Updated section 6.1 to modify age range for inclusion from ≥ 30 and ≤ 75 to ≥ 30 and 
≤ 80  
x Updated section 6.1 to modify the Montreal Cognitive Assessment inclusion criteria 
from ≥ 26 to ≥ 24  
x Updated section 6.2 to modify the creatinine clearance exclusion criteria from < 60 
mL/min for all participants to the following criteria: 
x Creatinine clearance (CrCL) less than or equal to 60 mL/min for subjects < 
65 years of age 
x Creatine clearance (CrCL) greater than or equal to 55 mL/min and the 
absence of proteinuria or hematuria for subjects ≥ 65 years of age 
x Updated section 6.2 to clarify that supplements containing levodopa like Mucuna 
pruriens are not permitted 
x Updated section 6.4 to clarify procedures regarding screen failures and rescreening 
activities 
Changes from protocol version 6.3 
x Fixed typographical error in section 6.2 Exclusion 9 language:  
 Corrected language: Creatinine clearance (CrCL) greater than or 
equal to less than 55 mL/min and the absence of proteinuria or 
hematuria or the presence of other evidence of chronic kidney disease 
such as proteinuria for subjects ≥ 65 years of age 
x Updated language in section 9.3.1 
 Removed: Medical occurrences that begin before the start of study 
intervention but after obtaining ICF will be recorded as medical 
history/current medical conditions, not as AEs. 
 Added: During the screening period baseline abnormalities (any sign 
or symptom present, such as abnormal screening laboratory value) will 
be assessed for clinical significance and captured in medical history as 
ongoing.  Any baseline abnormality that increases in severity or 
frequency should be captured as an adverse event if determined 
clinically significant by the investigator 
x Provided clarifying language regarding the QTcF calculation to section 9.2.3 
x Updated foot notes in SOA to clarify the following points:  
 Footnote b: At Baseline only, vital signs must be measured 3 times 
over the course of an hour. 
 Footnote n: At baseline, Skin Biospy and CSF collection must be 
completed prior to first dose. 
 
 
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