Clinical trial NCT05542576
Conditions: Parkinson Disease Amyotrophic Lateral Sclerosis
Keywords: Parkinsons ALS
Sponsor: Amydis Inc.
Start date: 2022-08-24; Completion date: 2023-03-15
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this research study is to assess safety and tolerability of a single intravenous (given through a vein) dose of the investigational retinal tracer AMDX-2011P in patients with neurodegenerative diseases (Parkinson's disease and ALS).

Detailed description:
The primary objective of this study is to evaluate the safety and tolerability of three different doses of AMDX-2011P (25mg, 50mg, or 100mg) given as a single intravenous dose in patients with neurodegenerative diseases (Parkinson's disease and ALS). The first cohort of participants taking part in the study will receive the lowest dose of AMDX-2011P (25mg). If no major side effects occur, the dose will be increased for the next group of participants to 50mg and then to 100mg.

Secondary objective of this study is to characterize the pharmacokinetic (PK) profile of AMDX-2011P and AMDX-2011.

Exploratory evaluations of the biological activity of AMDX-2011P in the retina will be performed by imaging.

Arms: arm 1: 25mg (1ml) single bolus injection intravenous for diagnostic review arm 2: AMDX2011P 50mg (2ml) single bolus injection intravenous for diagnostic review arm 3: AMDX2011P 100mg (4ml) single bolus injection intravenous for diagnostic review
Interventions: intervention 1: AMDX2011P
Intervention descriptions: intervention 1: AMDX2011P single bolus injection intravenous for diagnostic review

Protocol documents:
Prot_000.pdf: 
 
Study Drug: AMDX-2011P 
Protocol Number: AMDX-2011P-101 
 
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CLINICAL STUDY PROTOCOL 
 
Title:  
Prospective Randomized Open, Blinded Endpoint (PROBE) 
Study of AMDX-2011P as a Retinal Tracer in Subjects with 
Neurodegenerative Diseases Associated with Amyloidogenic 
Proteinopathy  
Protocol Number:  
AMDX-2011P-101 
Study Drug:  
AMDX-2011P 
Study Phase:  
Phase 1/2a 
Short Title: 
PROBE Study of AMDX-2011P in Neurodegenerative 
Diseases 
IND Sponsor: 
Amydis, Inc.  
1800 Century Park East Suite 600, Los Angeles, CA 90067 
Approval Date:  
24 January 2023 
Version: 
5.0, Amendment 5 
 
Confidentiality Notice 
This document contains confidential information of Amydis, Inc. the contents of which must not be disclosed to 
anyone other than the study staff and members of the respective Institutional Review Board/Ethics Committee. 
The information in this document cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Amydis, Inc. 


 
Study Drug: AMDX-2011P 
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SIGNATURE PAGE 
 
Protocol Title 
Prospective Randomized Open, Blinded Endpoint (PROBE) Study 
of AMDX-2011P as a Retinal Tracer in Subjects with 
Neurodegenerative Diseases Associated with Amyloidogenic 
Proteinopathy  
Protocol Number 
AMDX-2011P-101 
Version 
5.0, Amendment 5, 24 January 2023 
 
I have reviewed and approve the use of this protocol. 
Sponsor Representative: 
 
 
 
 
 
 
Masoud Mokhtarani, MD 
Chief Medical Officer 
 
Date 
 
 
 
 
24JAN2023


 
Study Drug: AMDX-2011P 
Protocol Number: AMDX-2011P-101 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Version 5.0, Amendment 5 
24 January 2023 
Version 4.0, Amendment 4 
16 September 2022 
Version 3.0, Amendment 3 
26 July 2022 
Version 2.0, Amendment 2 
01 July 2022 
Version 1.1, Amendment 1 
15 June 2022 
Original 
10 May 2022 
Amendment 5.0, 24 January 2023 
Overall Rationale for the Amendment: 
Changes are shown in order of appearance. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
2.1 Study Rationale 
2.2 Background 
3 Objectives and Endpoints 
4 Study Design  
5 Study Population 
9,1 Sample Size Determination 
10.4 Neurodegenerative 
Diseases Diagnosis Criteria 
• Add MSA indication 
• To examine additional 
patient population with 
alpha-synuclein deposits 
10.1.6 Clinical Monitoring 
• Update process for monitoring 
• For clarity 
Global 
• Update protocol to ensure 
consistency across protocol  
• Correct formatting and style 
• Move prior amendment to 
Section 10.6 
• Update footer, title page and 
signature page with 
date/amendment number 
• For clarity and 
consistency 
 


 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL .............................................................................................. 1 
SIGNATURE PAGE ..................................................................................................................... 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS ............................................................................................................. 4 
LIST OF TABLES .............................................................................................................................. 7 
STATEMENT OF COMPLIANCE ............................................................................................ 8 
1 
PROTOCOL SUMMARY ........................................................................................ 9 
1.1 
Synopsis ....................................................................................................................... 9 
1.2 
Schema ....................................................................................................................... 13 
1.3 
Schedule of Activities (SoA) ..................................................................................... 14 
2 
INTRODUCTION .................................................................................................... 16 
2.1 
Study Rationale .......................................................................................................... 16 
2.2 
Background ................................................................................................................ 17 
2.2.1 
Parkinson’s Disease ................................................................................................... 17 
2.2.2 
Multiple System Atrophy ........................................................................................... 18 
2.2.3 
Amyotrophic Lateral Sclerosis ................................................................................... 18 
2.2.4 
AMDX-2011P Product Development ........................................................................ 19 
2.3 
Risk/Benefit Assessment............................................................................................ 19 
2.3.1 
Known Potential Risks ............................................................................................... 19 
2.3.2 
Known Potential Benefits .......................................................................................... 21 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 21 
3 
OBJECTIVES AND ENDPOINTS ........................................................................ 22 
4 
STUDY DESIGN ...................................................................................................... 23 
4.1 
Overall Design ........................................................................................................... 23 
4.2 
Scientific Rationale for Study Design ........................................................................ 24 
4.3 
Justification for Dose ................................................................................................. 24 
4.4 
Study Duration ........................................................................................................... 26 
4.5 
End of Study Definition ............................................................................................. 26 
5 
STUDY POPULATION .......................................................................................... 27 
5.1 
Inclusion Criteria........................................................................................................ 27 
5.2 
Exclusion Criteria ...................................................................................................... 28 
5.3 
Lifestyle Considerations ............................................................................................ 29 
5.4 
Screen Failures ........................................................................................................... 29 
5.5 
Strategies for Recruitment and Retention .................................................................. 29 


 
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6 
STUDY DRUG ......................................................................................................... 30 
6.1 
Study Drug(s) Administration .................................................................................... 30 
6.1.1 
Study Drug Description ............................................................................................. 30 
6.2 
Preparation/Handling/Storage/Accountability ........................................................... 31 
6.2.1 
Acquisition and Accountability ................................................................................. 31 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................................... 31 
6.4 
Study Drug Compliance ............................................................................................. 31 
6.5 
Treatment of Overdose ............................................................................................... 32 
6.6 
Concomitant Therapy ................................................................................................. 32 
6.6.1 
Prohibited Medications .............................................................................................. 32 
6.6.2 
Rescue Medicine ........................................................................................................ 33 
7 
STUDY DRUG DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .............................................................. 34 
7.1 
Stopping Rules ........................................................................................................... 34 
7.1.1 
Pregnancy ................................................................................................................... 34 
7.2 
Discontinuation of Study Drug .................................................................................. 35 
7.3 
Subject Withdrawal from the Study ........................................................................... 35 
7.4 
Lost to Follow-Up ...................................................................................................... 35 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................. 36 
8.1 
Ophthalmological and Retinal Imaging Assessments ................................................ 36 
8.1.1 
Ophthalmological Exam ............................................................................................ 36 
8.1.2 
Triplicate Fundus Fluorescence (FF) Imaging ........................................................... 37 
8.1.3 
Optical Coherence Tomography (OCT) and OCT Angiography (OCT-A) Imaging 37 
8.1.4 
Central Retinal Image Center (CRIC) ........................................................................ 38 
8.2 
Safety and Other Assessments ................................................................................... 38 
8.2.1 
Physical Examinations ............................................................................................... 38 
8.2.2 
Vital Signs .................................................................................................................. 38 
8.2.3 
Electrocardiograms .................................................................................................... 39 
8.2.4 
Clinical Safety Laboratory Assessments .................................................................... 39 
8.3 
Pharmacokinetic Assessment ..................................................................................... 40 
8.4 
Adverse Events and Serious Adverse Events ............................................................ 42 
8.4.1 
Definition of Adverse Events (AE) ............................................................................ 42 
8.4.2 
Definition of Serious Adverse Events (SAE) ............................................................ 42 
8.4.3 
Classification of an Adverse Event ............................................................................ 42 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up .......................... 44 
8.4.5 
Adverse Event Reporting ........................................................................................... 44 
8.4.6 
Serious Adverse Event Reporting .............................................................................. 45 


 
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8.4.7 
Reporting Events to Subjects ..................................................................................... 46 
8.4.8 
Reporting of Pregnancy ............................................................................................. 46 
9 
STATISTICAL CONSIDERATIONS ................................................................... 47 
9.1 
Sample Size Determination and Statistical Hypotheses ............................................ 47 
9.2 
Populations for Analyses ........................................................................................... 47 
9.3 
Statistical Analyses .................................................................................................... 47 
9.3.1 
General Approach ...................................................................................................... 47 
9.3.2 
Safety Analyses .......................................................................................................... 48 
9.3.3 
Analysis of the Secondary Endpoint (Activity) ......................................................... 48 
9.3.4 
Pharmacokinetic Analysis .......................................................................................... 48 
9.3.5 
Sub-Group Analyses .................................................................................................. 49 
9.3.6 
Tabulation of Individual Subject Data ....................................................................... 49 
9.3.7 
Exploratory Analyses ................................................................................................. 49 
9.3.8 
Interim Analyses ........................................................................................................ 49 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 50 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ......................................... 50 
10.1.1 
Informed Consent Process ......................................................................................... 50 
10.1.2 
Study Discontinuation and Closure............................................................................ 51 
10.1.3 
Confidentiality and Privacy ....................................................................................... 51 
10.1.4 
Key Roles and Study Governance ............................................................................. 52 
10.1.5 
Safety Oversight – Safety Monitoring Committee .................................................... 52 
10.1.6 
Clinical Monitoring .................................................................................................... 52 
10.1.7 
Quality Assurance and Quality Control ..................................................................... 53 
10.1.8 
Data Handling and Record Keeping .......................................................................... 53 
10.1.9 
Protocol Deviations .................................................................................................... 54 
10.1.10 
Publication and Data Sharing Policy ......................................................................... 54 
10.1.11 
Conflict of Interest Policy .......................................................................................... 54 
10.2 
Clinical Laboratory Tests ........................................................................................... 56 
10.3 
Contraceptive Guidance and Collection of Pregnancy Information .......................... 57 
10.3.1 
Definitions .................................................................................................................. 57 
10.3.2 
Contraception Guidance ............................................................................................. 58 
10.3.3 
Collection of Pregnancy Information ......................................................................... 59 
10.4 
Neurodegenerative Diseases Diagnostic Criteria ....................................................... 61 
10.4.1 
Parkinson’s Disease Diagnostic Criteria .................................................................... 61 
10.4.2 
MSA Diagnostic Criteria ........................................................................................... 62 
10.4.3 
ALS Diagnostic Criteria............................................................................................. 64 


 
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10.5 
Abbreviations ............................................................................................................. 65 
10.6 
Protocol Amendment History .................................................................................... 67 
11 
REFERENCES ......................................................................................................... 70 
LIST OF TABLES 
Table 1 
Schedule of Activities (Subjects with Neurodegenerative Diseases, All Dose 
Cohorts) ................................................................................................................... 14 
Table 2 
Risk Assessment ...................................................................................................... 19 
Table 3 
Cohorts and Planned Doses ..................................................................................... 23 
Table 4 
Projected Human Dose Levels and Corresponding AUC and Cmax Exposures Based 
on Nonclinical Data ................................................................................................. 25 
Table 5 
Collection Timepoints for Fundus Fluorescence (FF) Imaging .............................. 37 
Table 6 
Pharmacokinetic Parameters ................................................................................... 40 
Table 7 
Adverse Event Reporting Periods ........................................................................... 44 
Table 8 
Protocol-Required Safety Laboratory Assessments ................................................ 56 
Table 9 
Movement Disorder Society (MDS) Diagnostic Criteria for Clinically Established 
Parkinson’s Disease ................................................................................................. 61 
Table 10 
Parkinson’s Disease Criteria per Hoehn and Yahr (1967) ...................................... 61 
Table 11 
ALS Diagnostic Criteria .......................................................................................... 64 
 


 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with International Council for Harmonization Good 
Clinical Practice (ICH-GCP) and the following:  
▪ United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)  
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the 
protocol and the consent form must be obtained before any subject is enrolled. Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented 
to the study, unless the protocol change is intended to eliminate an apparent immediate hazard to 
subjects. In addition, all changes to the consent form will be IRB-approved; a determination will 
be made regarding whether a new consent needs to be obtained from subjects who provided 
consent, using a previously approved consent form. 


 
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1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Prospective Randomized Open, Blinded Endpoint (PROBE) Study of 
AMDX-2011P as a Retinal Tracer in Subjects with Neurodegenerative 
Diseases Associated with Amyloidogenic Proteinopathy 
Study Phase: 
Phase 1/2a 
Study 
Description: 
AMDX-2011P is a novel retinal tracer in clinical development for the 
detection of neurodegenerative diseases associated with amyloidogenic 
proteinopathy by detecting alpha-synucleinopathies (α-syn) in Parkinson’s 
disease, and transactive response DNA-binding protein 43 (TDP-43) in 
amyotrophic lateral sclerosis (ALS). Nonclinical studies have 
demonstrated that AMDX-2011 binds selectively to protein with high beta 
sheet content, such as retinal α-syn and TDP-43 deposits, enabling 
visualization through conventional retinal imaging. There is currently a 
significant need for an accessible diagnostic measure to facilitate early 
diagnosis and patient management in these conditions. 
The current prospective randomized open, blinded endpoint (PROBE) 
study will evaluate the activity, safety, tolerability, and pharmacokinetics 
(PK) as well as detect amyloidogenic deposits through retinal imaging 
following escalating doses of bolus intravenous (IV) AMDX-2011P 
administration in subjects with Parkinson’s disease, multiple system 
atrophy (MSA) and ALS. Assessments of retinal images will be conducted 
by central masked assessors in a randomized fashion. 
Objectives and 
Endpoints: 
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
• To assess safety and 
tolerability of single IV dose of 
AMDX-2011P in subjects with 
neurodegenerative diseases 
(Parkinson’s disease, MSA and 
ALS).  
• Incidence, nature, and severity 
of adverse events (AEs) and 
serious adverse events (SAEs). 
Secondary 
• To assess the ability of 
AMDX-2011P to identify α-
syn in retina of subjects with 
Parkinson’s disease or MSA. 
• Detection of α-syn in the retina 
after AMDX-2011P 
administration. 


 
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• To assess the ability of 
AMDX-2011P to identify 
TDP-43 in retina of subjects 
with ALS. 
• Detection of TDP-43 in the 
retina after AMDX-2011P 
administration. 
• To characterize the PK profile 
of AMDX-2011P and 
AMDX-2011 following 
administration of a single IV 
dose of AMDX-2011P in 
subjects with 
neurodegenerative diseases 
(Parkinson’s disease, MSA 
and ALS). 
• PK parameters of 
AMDX-2011P and AMDX-
2011 calculated from 
concentrations in plasma.  
Overall Study 
Design 
This is a PROBE study designed to evaluate the safety, tolerability, and 
the ability of AMDX-2011P to detect amyloid deposits, α-syn and TDP-43 
(collectively called amyloidogenic deposits) through retinal imaging, as 
well as PK of single bolus IV of AMDX-2011P in subjects with 
Parkinson’s disease, MSA and ALS. Study schema is shown in 
Section 1.2. 
The study will enroll up to 4 dose cohorts as follows: 
Cohort 
Number of 
Subjects with neurodegenerative diseases 
(Parkinson’s Disease and/or MSA and/or 
ALS) a  
Proposed dose level 
1 
3-9 b 
25 mg (1 mL) 
2 
3-9 b 
50 mg (2 mL) 
3 
12 b 
100 mgc (4 mL) 
4 
12 b 
150 or 200 mgc (6-8 mL) 
Abbreviation: ALS, amyotrophic lateral sclerosis; SMC, Safety Monitoring Committee; 
TBD, to be determined. 
a. Additional subjects (from any subject population) may be enrolled into any cohort per 
SMC discretion. Approximately 12 ALS subjects will be enrolled in the study. 
b. All cohorts will include 1 sentinel subject who will be observed for 8 hours and 
evaluated at 24 hours for safety before enrolling the remaining subjects in that cohort. 
c. Tentative dose and will be confirmed by SMC based on emerging data from the prior 
cohorts; intermediate or higher dose level may also be explored in these cohorts 
 
A Safety Monitoring Committee (SMC), comprised of the Study Medical 
Monitor (or designee), neurologists with experience in these patient 
populations, an ophthalmologist with retinal imaging expertise, and the 
Sponsor’s clinical and technical representatives, will review safety data 
throughout the study. The SMC may recommend modifying the duration 


 
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of observation or timing of study procedures based on safety and other 
available data from the prior cohorts. 
All cohorts will include subjects with neurodegenerative diseases 
(Parkinson’s disease, MSA and/or ALS). The decision to escalate to the 
next dose level will be made based on review of all available safety and 
tolerability data collected including AEs, electrocardiograms (ECGs), vital 
signs, and laboratory safety results of the previous dose levels after single 
dose administration in at least 3 subjects from each cohort. Based on 
emerging data, additional cohort(s) and/or an intermediary dose may be 
investigated with prior approval by the SMC. The study may progress to 
the next cohort if approved upon satisfactory review of available safety 
data of the previous cohort(s) by the SMC. During each safety review, the 
SMC will make a decision to either continue enrollment to the next 
planned cohort, add additional subjects to the current cohort, or change the 
dose of the next cohort.  
Enrollment into each cohort will begin with 1 sentinel subject who will be 
observed for at least 8 hours at the clinic and evaluated by the investigator 
at 24 hours following dosing by the investigator. If no safety issues are 
observed, the remaining subjects will be enrolled into that cohort. Dosing 
of remaining subjects at the same center will be staggered by at least 
1 hour. Dosing within a cohort will continue unless stopping rules are met. 
For all dose cohorts, after signing the informed consent, subjects will be 
screened. If needed, the screening procedures may occur over a period of 
up to 42 days prior to dosing. On Day 1, subjects will be admitted to the 
clinical research unit for 8 hours confinement. Eye examination and retinal 
imaging will be conducted before administration of the study drug. 
AMDX-2011P will be administered through a single IV bolus injection 
followed by repeated retinal imaging and PK and safety assessments as 
outlined in the Schedule of Activities (SoA; Section 1.3). On Day 8 (end 
of study), there will be a follow-up visit for retinal imaging and safety 
assessments. 
All retinal images will be deidentified and sent in batches to a reading 
center for masked assessment. Assessors will be masked to type of 
subjects, their disease, dose, clinical status of subjects, and sequence of 
post-injection images. This provides an objective assessment of the ability 
of AMDX-2011P to identify amyloidogenic deposits. During the interim 
analysis, the SMC may also review representative images to confirm the 
optimum detection and the residence time and make potential 
recommendations to the retinal imaging time point(s) and/or potential 
safety assessment modifications. 


 
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Study 
Population: 
Adult subjects with neurodegenerative diseases: Up to 36 adult male and 
female subjects diagnosed with Parkinson’s disease, MSA or ALS. 
Description of 
Sites/Facilities 
Enrolling 
Subjects: 
The study will be conducted at 4-5 Phase 1 ophthalmology experienced 
sites located in the United States. 
Description of 
Study drug: 
AMDX-2011P is a novel retinal tracer indicated for the diagnosis of 
amyloid angiopathy. It is a phosphate prodrug hydrolyzed in vivo to the 
pharmacologically active molecule AMDX-2011. 
Study Duration: Estimated time to complete study from enrollment to completion of data 
analyses will be 7 months. 
Subject 
Duration: 
For each subject, study participation is expected to last up to 8 days: one 
day of dosing, 7 days of follow-up, and a window of up to 42 days to 
complete the screening procedures. 


 
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1.2 SCHEMA 
 
Abbreviations: SMC, Safety Monitoring Committee. 
 


 
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1.3 SCHEDULE OF ACTIVITIES (SOA) 
Table 1 
Schedule of Activities (Subjects with Neurodegenerative Diseases, All Dose Cohorts) 
Study Procedures 
Screening1 Treatment 
Follow-up 
Notes 
1. Note: Procedures such as diagnostic status 
determination and ophthalmological examinations 
performed by subject’s referring physicians can be used 
as screening procedures at the discretion of the 
investigator.  
Study Visit -42 to -1 
Day 1 
Day 8/EOS/ET 
Visit window (days) 
42 
 
+2  
Informed consent 
X 
 
 
 
Domiciled 
 
Xa 
 
a. Subjects will be admitted to the clinical research unit in 
the morning for 8 hours confinement  
Medical/ocular history/Physical exam 
X 
 
 
On Day 1, PE may be repeated if abnormalities are 
detected at screening. Relevant ocular and disease-
specific history will be captured up to date of diagnosis.  
Eligibility (inclusion/exclusion criteria) 
X 
 
 
 
Body weight and Height 
X 
 
 
 
Eye examination/  
X 
X 
X 
Refer to Section 8.1.1. 
Color fundus photography 
X 
 
 
 
Vital signs  
X 
Xb 
X 
b. To be collected predose, and at 0.25, 0.5, 1, 2, 8 hours 
postdose. A window of ±5 minutes will be allowed for 
measurements up to 2 hours, and ±10 minutes beyond 2 
hours.  
12-lead safety (ECG) 
X 
Xc 
X 
c. Triplicate at the following timepoints:  predose (within 
1 hour), and at 90 minutes (±15 minutes) and 8 hours (± 
60 minutes) postdose or before discharge 
Safety laboratories 
X 
Xd 
X 
Refer to Section 10.2. 
d. To be collected predose on Day 1 and before discharge  
Urinalysis 
X 
X 
X 
 
Pregnancy test  
S 
U (predose) 
U 
S = Serum; U = Urine 
Adverse event reporting 
X 
X 
X 
 


 
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Study Procedures 
Screening1 Treatment 
Follow-up 
Notes 
1. Note: Procedures such as diagnostic status 
determination and ophthalmological examinations 
performed by subject’s referring physicians can be used 
as screening procedures at the discretion of the 
investigator.  
Study Visit -42 to -1 
Day 1 
Day 8/EOS/ET 
Visit window (days) 
42 
 
+2  
Concomitant medications 
X 
X 
X 
 
Retinal fundus fluorescence (FF) imaging 
 
 
Xe 
 
X 
 
e. Refer to Section 8.1.2  
Retinal optical coherence tomography 
(OCT) and OCT angiography (OCTA)  
X 
 
X 
 
Blood PK sampling  
 
Xf 
 
f. On Day 1, PK blood samples will be collected at the 
following time points: 0 (predose), and at 3, 6, 15, and 30 
minutes postdose and 1, 2, 4, 6, and 8 hours postdose. A 
window of ±5 minutes will be allowed for samples 
collected from 30 minutes to 2 hours, and ±10 minutes 
beyond 2 hours. 
Study drug administration 
 
X 
 
 
Abbreviations: AE, adverse events; ECG, electrocardiogram; EOS, end of study; ET, early termination; FU, follow-up; PE, physical examination; 
PK, pharmacokinetics. 
 


 
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2 
 
INTRODUCTION 
2.1 STUDY RATIONALE  
There is currently a significant need for an accessible diagnostic measure to facilitate early 
diagnosis and treatment management of subjects with neurodegenerative diseases associated 
with amyloidogenic proteinopathy, such as Parkinson’s disease, multiple system atrophy (MSA), 
and amyotrophic lateral sclerosis (ALS). 
AMDX-2011P is a novel retinal tracer indicated for the detection of alpha-synucleinopathies 
(α-syn) in Parkinson’s disease and MSA, and transactive response DNA-binding protein 43 
(TDP-43) in ALS. AMDX-2011P is a phosphate prodrug hydrolyzed in vivo to the 
pharmacologically active molecule, AMDX-2011. 
Nonclinical studies have demonstrated that AMDX-2011 binds selectively to protein with high 
beta sheet content, such as retinal amyloid beta, α-syn, and TDP-43 deposits associated with 
human amyloid-related diseases. When AMDX-2011 binds to amyloid or amyloid-like peptides, 
it fluoresces with excitation and emission wavelengths, enabling visualization of amyloid 
deposits through conventional retinal imaging instruments widely available in ophthalmology 
clinics. 
Pharmacokinetic (PK) studies in rats and dogs demonstrated rapid and incomplete hydrolysis of 
AMDX-2011P to AMDX-2011 in plasma; and only AMDX-2011 (and not AMDX-2011P) was 
quantifiable in retinal tissues in rats after intravenous (IV) administration. After a bolus IV 
injection of 15 mg/kg, a pharmacologically active dose of AMDX-2011P in rats, peak 
AMDX-2011 concentrations were achieved in the retina by 2 minutes postdose and were below 
the level of detection within 30 minutes postdose. Similarly, in rabbits, after an IV injection of 
15 mg/kg AMDX-2011P, only AMDX-2011 was detected in the retina, and the majority of 
AMDX-2011 was cleared from the retina within 60 minutes. 
The safety of AMDX-2011P has been evaluated in a program of Good Laboratory Practice 
(GLP) toxicology and safety pharmacology studies, conducted using a single bolus IV injection 
of AMDX-2011P to mimic the clinical dosing regimen. In the definitive GLP single-dose rat 
study, no adverse target organ toxicity and no evidence of ocular or cutaneous phototoxicity 
were identified at up to 50 mg/kg. Injection site reactions occurred in rats after administration 
into the tail vein, which were considered adverse at 50 mg/kg and not adverse at ≤ 15 mg/kg. 
Therefore, in rats, the dose showing no adverse systemic toxicity was 50 mg/kg, and the overall 
study no-observed-adverse-effect level (NOAEL) was 15 mg/kg. In safety pharmacology studies 
conducted in rats, there were no acute neurobehavioral changes or effects on respiratory function 
at up to 50 mg/kg. In the definitive GLP single-dose dog study, reversible clinical ophthalmic 
signs, including mydriasis, minimal hyperemic conjunctiva and minimal to mild chemosis, 
occurred in male dogs within 24 hours postdose at 60 mg/kg. Other non-adverse clinical signs at 
60 mg/kg included intermittent emesis and soft feces, which resolved by Day 2 and were not 
considered adverse. There was histologic evidence of injection site reactions in dogs at all doses, 
which were not considered adverse. There was no adverse target organ toxicity in dogs at 
60 mg/kg, which was considered the NOAEL in females; the NOAEL in males was 20 mg/kg 


 
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based on ophthalmic changes at 60 mg/kg. In a dog cardiovascular safety study, transient 
reductions in blood pressure (systolic, diastolic, and mean arterial pressure) and heart rate 
occurred at 15-30 minutes after a single bolus injection of 30 mg/kg, but not at ≤ 10 mg/kg, and 
there were no effects on electrocardiogram (ECG) profile at any dose. In vitro, AMDX-2011 
caused a dose-dependent inhibition of the human Ether-à-go-go-related gene (hERG) cardiac 
potassium channel of up to 44% at a concentration of 10 µM. This concentration is expected to 
be at least 10-fold above human peak plasma concentration (Cmax) values of the 
pharmacologically relevant doses; therefore, a risk for QTc prolongation in humans is 
considered low. Overall, the nonclinical safety studies support the safe administration of 
AMDX-2011P in this study. 
The current prospective randomized open, blinded endpoint (PROBE) study is designed to 
evaluate the ability of AMDX-2011P to assess safety, tolerability, and PK, as well as detect 
amyloid deposits, α-syn and TDP-43 through retinal imaging following escalating doses of bolus 
IV AMDX-2011P administration in subjects with Parkinson’s disease, MSA and ALS. 
2.2 BACKGROUND  
2.2.1 
Parkinson’s Disease 
Parkinson’s disease is a neurodegenerative disorder that mostly presents in later life with 
generalized slowing of movements (bradykinesia) and at least one other symptom of resting 
tremor or rigidity (Zafar, 2021). The prevalence of Parkinson’s disease increases with age and is 
more common in males than females (de Lau, 2006; Dorsey, 2018; GBD, 2018). The 
neuropathological hallmarks of Parkinson’s disease are neuronal loss in the basal ganglia, 
specifically the substantia nigra and globus pallidus (Prakash, 2016), which leads to striatal 
dopamine deficiency, and intracellular inclusions containing aggregates of α-syn. Therefore, 
Parkinson’s disease belongs to the group of α-synucleinopathies (including Parkinson’s disease, 
dementia with Lewy bodies and multiple system atrophy) that share the abnormal aggregation of 
α-syn as their key-molecular hallmark (Malfertheiner, 2021). 
Currently, there are no specific tests to detect Parkinson’s disease. Diagnosis is determined with 
a clinical evaluation by identifying and monitoring symptoms associated with the disease. 
Recent advances in brain imaging (magnetic resonance imaging [MRI], computed tomography 
[CT], dopamine transport scan [DaTscan]) can only be used to rule out structural and other 
causes of parkinsonian symptoms (Nemade, 2021). 
α-syn is an abundant neuronal protein that is primarily found in the presynaptic nerve 
terminals (Lashuel, 2013). Under pathological conditions α-syn is phosphorylated and 
accumulates and forms insoluble aggregates (Heras-Garvin, 2020). Pathological aggregates of α-
syn has been reported in retinal layers of Parkinson’s disease patients in postmortem 
examination and levels of a-syn deposition in retina may provide an in vivo indicator of disease 
severity (Ortuño-Lizarán, 2018). Furthermore, 80% of Parkinson’s disease patients report at 
least one visual symptom that often occurs in early disease stages preceding cardinal Parkinson’s 
disease symptoms and correlates with disease progression (Veys, 2019). However, there are 
currently no positron emission tomography (PET) ligands that can selectively label -syn 


 
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deposits, and detection is thus far only possible by histological examination of postmortem brain 
tissue (Korat, 2021). 
2.2.2 
Multiple System Atrophy 
MSA is a fatal progressive neurodegenerative disease characterized by the variable combination 
of autonomic dysfunction, parkinsonian and cerebellar features  (Fanciulli, 2015a; Jellinger, 
2018).  The dominant display of specific symptomatology is used to stratify cases of disease into 
two subtypes: a parkinsonian variant (MSA-P) associated with features such as bradykinesia, 
muscle rigidity, tremors, and postural instability, and a cerebellar variant (MSA-C) characterized 
by cerebellar ataxia, speech difficulties and problems controlling eye movement (Fanciulli, 
2015b). Movement Disorder Society (MDS) criteria for MSA diagnosis were recently updated 
(Wenning, 2022); however, MSA and Parkinson’s disease can be difficult to differentially 
diagnose due to large overlaps in presenting symptoms and the lack of specific tests for either 
condition  (Stankovic, 2019).  
MSA is characterized by inclusions of abnormal α-syn protein that, for unknown reasons, build 
up in cells in many parts of the brain and spinal cord (Koga, 2021). There are key differences in 
the nature of a-syn deposition in MSA and Parkinson’s disease, and how these manifests in 
retina. At the cellular level, MSA is distinguished from Parkinson’s disease in that -syn 
deposits occur almost exclusively as cytoplasmic inclusions in oligodendrocytes – so called 
“glial cytoplasmic inclusions” (Koga, 2018; Schweighauser, 2020).  Oligodendrocytes are 
excluded from the retina (presumably to avoid light scattering effects of myelination) but line the 
retrolaminar aspect of the optic nerve. In addition, recent data indicate that amyloid 
configurations of a-syn may differ among synucleinopathies (Meade, 2019), which may yield 
different fluorescence emission profiles for each disease. Detecting a-syn early (before 
symptoms arise) and being able to determine whether it represents Parkinson’s or MSA would 
be a tremendous advance in the field. It would enable earlier and more accurate therapeutic 
intervention, and greatly facilitate the clinical testing of novel, disease-modifying therapeutics 
(Osaki, 2009; Stankovic, 2019; Wenning, 2022). 
2.2.3 
Amyotrophic Lateral Sclerosis 
ALS is the most common adult-onset motor neuron disease, clinically and pathologically 
characterized by degeneration of upper and lower motor neurons leading to progressive paralysis 
and death within 3–5 years of diagnosis (Dhasmana, 2021). The estimated prevalence of ALS in 
the United States (US) and Europe is 5 cases per 100,000 population (Chiò, 2013; Mehta, 2018). 
TDP-43 inclusions occur in neurons and glia in approximately 97% of ALS cases (de Boer, 
2020). TDP-43 is a DNA/RNA-binding protein that has various roles in RNA metabolism, 
including trafficking, splicing, and degradation. Misfolding of TDP-43 into an “amyloid-like” or 
true amyloid configuration promotes aggregate assembly and prion-like spread (McAlary, 2019; 
Jo, 2020). 
Currently, there are no specific tests to detect ALS. The diagnosis is determined by excluding 
other conditions and utilizing clinical examinations, laboratory and genetic tests and nerve 
conduction/needle electromyography studies. Needle electromyography records abnormal 


 
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activities at rest and looks for neurogenic patterns during muscle contraction. Motor evoked 
potentials after transcranial magnetic stimulation remain the test of choice to identify impairment 
of upper motor neurons (Štětkářová, 2021). Recent advances in brain imaging (MRI and PET) 
can only be used to rule out other neurodegenerative diseases. There are no PET ligands that can 
selectively label TDP-43 deposits (Young, 2020; Rao, 2021). 
2.2.4 
AMDX-2011P Product Development 
AMDX-2011P is a small molecule intended for IV administration. AMDX-2011P is a prodrug 
and rapidly converts to AMDX-2011, its active moiety, after injection. In vitro and in vivo 
pharmacology studies have demonstrated that AMDX-2011 binds to human brain and α-syn 
associated with Parkinson’s disease and MSA, and TDP-43 in ALS. 
In vivo studies in mice indicated that amyloidogenic deposits in the retina can be visualized as 
hyper-fluorescent signals after systemic doses of AMDX-2011P. The principle for the sensitive 
and selective detection of amyloid-like peptides by AMDX-2011 and other molecules sharing 
the same molecular core is the enhanced fluorescence occurring after binding (Cao, 2018). 
Compound binding to the beta-pleated sheet structure of the peptide increases fluorescence by 
restricting the torsional rotation of the sigma bond between the piperidine and naphthalene rings 
and enhancing the electronic transition upon photoexcitation. The primary de-excitation 
mechanism of enhanced fluorescence can then be detected visually. 
A detailed description of the chemistry, pharmacology, efficacy (activity), and safety of 
AMDX-2011P is provided in the Investigator’s Brochure (IB). 
2.3 RISK/BENEFIT ASSESSMENT 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of AMDX-2011P may be found in the IB. 
2.3.1 
Known Potential Risks  
This is the first-in-human (FIH) study with AMDX-2011P. Though similar and higher doses of 
AMDX-2011P have been tested in multiple animal studies and results support the dose level to 
be tested in humans, this will be the first clinical exposure of the study drug; thus, there may be 
risks that are currently unknown. 
There are no identified or potential risks of particular severity or seriousness anticipated on the 
basis of the mechanism of action of AMDX-2011P. The potential risks are based on theoretical 
considerations and findings (Table 2) from completed GLP nonclinical safety studies. 
Table 2 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential Risks which may be associated with Study Drug 
Phototoxicity 
Both AMDX-2011P and AMDX-2011 were 
suspected of being phototoxic in the in vitro 
Subjects will be instructed to 
avoid direct sunlight and wear 


 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
3T3 neutral red uptake phototoxicity test; 
however, there was no evidence of ocular or 
cutaneous phototoxicity after IV administration 
of AMDX-2011P to pigmented rats at doses of 
up to 50 mg/kg followed by exposure to 
ultraviolet B, ultraviolet A, and visible light 
from a xenon lamp. 
protective gear (e.g., 
sunglasses) for 24 hours after 
dosing.  
Ophthalmologic examinations 
will be conducted throughout 
the study. 
Effect on eye  
In male dogs, single IV bolus injections of 
60 mg/kg AMDX-2011P resulted in mydriasis, 
minimal hyperemic conjunctiva and minimal to 
mild chemosis within 24 hours postdose, which 
was reversible within 6 days. 
Ophthalmologic examinations 
will be conducted throughout 
the study. 
Effect on 
cardiovascular 
function 
In dogs, single IV bolus injections of 30 mg/kg 
AMDX-2011P resulted in transient reductions 
in systolic, diastolic, and mean arterial pressure 
and heart rate 15-30 min after injection. In 
vitro, inhibition of hERG channel was seen at 
high concentrations of AMDX-2011P. 
Vital sign assessments, 
triplicate ECG recording  
Mutagenicity 
AMDX-2011P and AMDX-2011 were mutagenic 
in bacteria only in the presence of an exogenous 
metabolic system, suggesting a metabolite was the 
mutagenic and not the parent drugs. AMDX-2011P 
and AMDX-2011 did not cause chromosomal 
aberrations in mammalian cells with or without 
metabolic activation. 
Healthy volunteers are excluded 
from clinical studies until 
additional information on human 
risk is obtained.  
Potential Risks which may be associated with Study Procedures 
Injection site reactions 
(ISRs) such as redness, 
swelling, itching and 
tenderness 
As with any IV administration procedure, ISR 
is possible. 
ISRs were seen in nonclinical studies (rats) 
IV administration will be done 
by trained personnel. 
In the case of ISRs, observe 
and treat as needed. 
Retinal imaging. 
Potential mild discomfort, fatigue and 
temporary dry eyes 
For temporary dry eyes, 
artificial tears may be used to 
alleviate the symptoms. 
Retinal imaging will be 
performed by trained 
personnel to minimize the time 
of data acquisition.  
Abbreviations: ECG, electrocardiogram; hERG, human Ether-à-go-go-related gene; ISR, injection site 
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2.3.2 
Known Potential Benefits  
The results from completed nonclinical studies with AMDX-2011P suggest a potential benefit of 
AMDX-2011P as a novel compound to facilitate diagnosis and patient management in these 
conditions. 
2.3.3 
Assessment of Potential Risks and Benefits  
Considering the measures taken to minimize risk to subjects participating in this study, the 
potential risks identified in association with AMDX-2011P are justified, given the significant 
need for an accessible diagnostic measure for patients with neurodegenerative diseases.  


 
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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
• To assess safety and tolerability of 
single intravenous (IV) dose of AMDX-
2011P in subjects with 
neurodegenerative diseases (Parkinson’s 
disease, MSA and ALS).  
• Incidence, nature, and severity of adverse 
events (AEs) and serious adverse events 
(SAEs). 
Secondary 
 
• To assess the ability of AMDX-2011P 
to identify α-syn in retina of subjects 
with Parkinson’s disease or MSA. 
• To assess the ability of AMDX-2011P to 
identify TDP-43 in retina of subjects 
with ALS. 
• Detection of α-syn in the retina after 
AMDX-2011P administration. 
• Detection of TDP-43 in the retina after 
AMDX-2011P administration. 
• To characterize the PK profile of 
AMDX-2011P and AMDX-2011 
following administration of a single IV 
dose of AMDX-2011P in subjects with 
neurodegenerative diseases (Parkinson’s 
disease, MSA and ALS). 
• The PK parameters of AMDX-2011P and 
AMDX-2011 calculated from concentrations 
in plasma.  


 
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4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
This is a PROBE study designed to evaluate safety, tolerability, and the ability of AMDX-2011P 
to detect amyloid deposits, α-syn and TDP-43 (collectively called amyloidogenic deposits) 
through retinal imaging, as well as PK of single bolus IV of AMDX-2011P in subjects with 
Parkinson’s disease, MSA and ALS. Study schema is shown in Section 1.2. 
The study will enroll up to 4 dose cohorts, as shown in Table 3: 
Table 3 
Cohorts and Planned Doses 
Cohort 
Number of 
Subjects with neurodegenerative diseases 
(Parkinson’s Disease and/or MSA and/or 
ALS)a 
Proposed dose level 
1 
3-9b 
25 mg (1 mL) 
2 
3-9 b 
50 mg (2 mL) 
3 
12 b 
100 mgc (4 mL) 
4 
12 b 
150 or 200 mgc (6-8 mL) 
Abbreviation: ALS, amyotrophic lateral sclerosis; SMC, Safety Monitoring Committee; TBD, to be determined. 
a. Additional subjects (from any subject population) may be enrolled into any cohort per SMC discretion. 
Approximately 9 ALS subjects will be enrolled in the study. Approximately 9 MSA subjects will be enrolled.  
b. All cohorts will include 1 sentinel subject who will be observed for 8 hours and evaluated at 24 hours for safety 
before enrolling the remaining subjects in that cohort. 
c. Tentative dose and will be confirmed by SMC based on emerging data from the prior cohorts; intermediate or 
higher dose level may also be explored in these cohorts. 
 
A Safety Monitoring Committee (SMC), comprised of the Study Medical Monitor (or designee), 
neurologists with experience in these diseased populations, an ophthalmologist with retinal 
imaging expertise, and the Sponsor’s clinical and technical representatives, will review safety 
data throughout the study. The SMC may recommend modifying the duration of observation or 
timing of study procedures based on safety and other available data from the first cohort. For 
additional details, refer to Section 10.1.5. 
All cohorts will include subjects with neurodegenerative diseases (Parkinson’s disease, MSA 
and/or ALS). The decision to escalate to the next dose level will be made based on review of all 
available safety and tolerability data collected, including AEs, ECGs, vital signs, and laboratory 
safety results of the previous dose levels after single dose administration in at least 3 subjects 
from each cohort. Based on emerging data, additional cohort(s) and/or an intermediary dose may 
be investigated with prior approval by the SMC. The study may progress to the next cohort if 
approved upon satisfactory review of available safety data of the previous cohort(s) by the SMC. 
During each safety review, the SMC will make a decision to either continue enrollment to the 
next planned cohort, add additional subjects to the current cohort, or change the dose of the next 
cohort. 


 
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Enrollment into each cohort will begin with 1 sentinel subject who will be observed for at least 8 
hours at the clinic and evaluated by the investigator at 24 hours following dosing by the 
investigator. If no safety issues are observed, the remaining subjects will be enrolled into that 
cohort. Dosing of remaining subjects at the same center will be staggered by at least 1 hour. 
Dosing within a cohort will continue unless stopping rules are met. 
For all dose cohorts, after signing the informed consent, subjects will be screened. If needed, the 
screening procedures may occur over a period of up to 42 days prior to dosing. On Day 1, 
subjects will be admitted to the clinical research unit for 8 hours confinement. Eye examination 
and retinal imaging will be conducted before administration of the study drug. AMDX-2011P 
will be administered through a single IV bolus injection followed by repeated retinal imaging 
and PK and safety assessments as outlined in the Schedule of Activities (SoA; Section 1.3). On 
Day 8 (end of study), there will be a follow-up visit for retinal imaging and safety assessments. 
All retinal images will be deidentified and sent in batched to a reading center for masked 
assessment. Assessors will be masked to type of subjects, their disease, dose, clinical status of 
subjects, and sequence of post-injection images. This provides an objective assessment of the 
ability of AMDX-2011P to identify amyloidogenic deposits. During the interim analysis (see 
Section 9.3.8), the SMC may also review representative images to confirm the optimum 
detection and the residence time and make potential recommendations to the retinal imaging 
timepoint(s) and/or potential safety assessment modifications. 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This is a FIH study of AMDX-2011P and the study aims to recruit subjects with a diagnosis of 
neurodegenerative diseases (Parkinson’s disease, MSA or ALS) to assess the activity, safety, 
tolerability, and PK of AMDX-2011P and AMDX-2011 in the target population. AMDX-2011, 
formed from AMDX-2011P, is intended to visualize the amyloidogenic deposits not abundantly 
present in healthy individuals. 
The PROBE design (Hansson, 1992) provides an objective assessment of the ability of 
AMDX-2011P to identify α-syn (Parkinson’s disease and MSA) and TDP-43 (ALS).  
Conducting a FIH study in a target patient population provides essential information to establish 
the amyloidogenic deposits visualization and fluorescence residence time in the retina after 
administration of study drug. As an older population (40 to 90 years old) may have undiagnosed 
amyloidogenic proteinopathy associated diseases of up to ~28%. 
4.3 JUSTIFICATION FOR DOSE 
The proposed starting dose is based on recommendations from an FDA Guidance for Industry: 
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers, July 2005 (FDA, July 2005). Table 4 shows NOAEL doses and systemic 
AUC and Cmax exposures from the pivotal rat and dog toxicity studies, as well as projected 
human exposures at proposed clinical dose levels. Clinical PK parameters (clearance and volume 
of distribution) for AMDX-2011P were projected by model fitting of dog PK data, then scaling 
to human values. AMDX-2011 parameters were projected based on rates of formation and 


 
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observed metabolite/parent ratios in animals. Human PK profiles were then simulated at various 
doses based on projected parameter values. 
The lowest NOAEL for dogs (20 mg/kg, males) equates to a human equivalent dose (HED) for a 
60-kg adult male of 667 mg, and the NOAEL for systemic toxicity in rats (50 mg/kg) equates to 
a HED of 484 mg. Using an ~20-fold safety margin, the starting dose in the proposed clinical 
study will be 25 mg. The escalating doses will be 25 mg, 50 mg, 100 mg, and either 150 mg or 
200 mg. 
The doses proposed for this study will cover the anticipated pharmacologically active dose range 
and are predicted to be significantly below AUC and Cmax exposures for AMDX-2011 and 
AMDX-2011P achieved at NOAEL doses in rats and dogs. 
Table 4 
Projected Human Dose Levels and Corresponding AUC and Cmax Exposures 
Based on Nonclinical Data 
AUC (hr •∙ng /mL) 
Cmax (ng/mL) 
Dose 
AMDX-2011Pa 
AMDX-2011a 
AMDX-2011Pa 
AMDX-2011a 
Human (mg) 
25 
49.0 
19.1 
135 
43.8 
50 
97.8 
38.2 
269 
87.5 
75 
144 
57.4 
403 
131 
100 
192 
76.6 
539 
175 
150 
288 
115 
806 
263 
200 
383 
153 
1070 
350 
Dog NOAELb 
20 mg/kg (Male) 
(HED 667 mg) 
400  
182  
 2270  
 937  
60 mg/kg (Female) 
(HED 2000 mg) 
13,700   
2200  
45,500   
 5930  
Rat NOAELc 
   
   
   
   
15 mg/kg (injection site 
reaction) 
(HED 145 mg) 
923   
138   
 7,175  
 1,019  
50 mg/kg (Systemic) 
(HED 484 mg) 
17,900 
1,345   
 141,500  
 8,930  
a human AUC and Cmax values are estimated from projected PK at each dose level 
b NOAEL in dogs based on ophthalmic clinical observations at 60 mg/kg in males and no adverse toxicity in 
females. AUC values are AUClast 


 
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c NOAEL in rats based on adverse injection site reactions at 50 mg/kg, but no adverse target organ (systemic) 
toxicity at up to 50 mg/kg . AUClast and Cmax are means of male and female values. 
Abbreviation: AUC, area under the curve; HED, human equivalent dose; NOAEL, no observed adverse 
effect level. 
4.4 STUDY DURATION 
For each subject, the study is expected to last up to 8 days: one day of dosing, 7 days of follow-
up, and a window of up to 42 days to complete the screening procedures. 
4.5 END OF STUDY DEFINITION 
A subject is considered to have completed the study if he or she has completed the study, 
including the last visit or the last scheduled procedure shown in the SoA, Section 1.3. 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the study globally. 


 
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5 
STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Subjects are eligible to be included in the study only if they meet the criteria relevant to their 
disease status: 
Type of Subject and Disease Characteristics 
Subjects with Parkinson’s Disease 
1. Clinically established Parkinson’s disease based on Movement Disorder Society (MDS) 
Clinical Diagnostic Criteria for Parkinson's disease (Table 9) and a modified Hoehn & 
Yahr scale of 1-3 (Table 10). 
2. No suspected atypical parkinsonian syndromes due to drugs, metabolic disorders, 
encephalitis, or degenerative diseases. 
Subjects with ALS 
3. Confirmed diagnosis of ALS with both upper and lower motor neuron involvement 
(Table 11). 
Subjects with MSA 
4. Diagnosis of clinically established MSA according to MDS 2022 Criteria (Wenning, 
2022); refer to Appendix 4, Section 10.4.2. 
Age, Gender, Informed Consent, Pregnancy and Contraception 
5. Male and female subjects 18 years and older at the time of signing the informed consent. 
6. Ability to undergo retinal imaging. 
7. Subject or legally authorized representative must provide signed informed consent (or 
signed assent form) prior to study entry and have the ability and willingness to attend and 
comply with the necessary study procedures and visits at the study site. For subjects 
unable to physically sign the informed consent, a guardian or trusted care giver can sign 
on their behalf in presence of an independent witness. 
Contraception 
8. Contraception use by study subjects of childbearing potential (male and female) and 
female partners of childrearing potential male subjects should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies. For details, refer to Section 10.2. 
9. Female subjects of childbearing potential and female partners of childbearing potential 
male subjects must refrain from oocyte donation for up to 30 days after study drug 
administration. 


 
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10. Male subjects must  refrain from sperm donation for 90 days after study drug 
administration. 
11. Females of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on Day 1 (predose). Females not of 
childbearing potential must be surgically infertile or postmenopausal (defined as 
cessation of regular menstrual periods for at least 12 months) at Screening. 
 
5.2 EXCLUSION CRITERIA 
Subject meeting ANY of the following exclusion criteria are NOT eligible to be enrolled into the 
study: 
Medical Conditions  
1. Presence of any underlying physical or psychological medical condition that, in the 
opinion of the investigator, would make it unlikely that the subject will complete the 
study per protocol. 
2. Clinically significant laboratory abnormalities assessed by the investigator. 
3. Active malignancy and/or history of malignancy in the past 5 years, with the exception of 
completely excised non-melanoma skin cancer or low-grade cervical intraepithelial 
neoplasia. 
4. Prolonged QTcF (>450 ms for males and >470 ms for females), cardiac arrhythmia, or 
any clinically significant abnormality in the resting ECG, as judged by the investigator. 
5. Presence of any ocular condition that, in the opinion of the investigator, would 
significantly hinder the ability to detect and quantify hyper-fluorescent puncta (e.g., eyes 
with significant hyper-autofluorescence that would mask the ability to detect, quantify, 
and discern post-injection hyper-fluorescent signal from pre-injection hyper-
autofluorescence signal). These conditions may include, but are not limited to; age-
related macular degeneration, central serous chorioretinopathy, diabetic retinopathy, 
macular dystrophies such as Stargardt disease, retinitis pigmentosa, choroideremia, white 
dot syndromes, and drug toxicities such as hydroxychloroquine toxicity.  
Prior/Concomitant Prohibited Therapy  
6. Use of any new prescription therapies or vaccines within 7 days prior to the study drug 
administration.  
7. Drugs with potential phototoxicity per Package Insert are prohibited within 48 hours or 
5 half-lives, whichever is longer, prior to first study drug until End-of-study (EOS) visit, 
except for those required for treatment of underlying disease. Examples of such drugs 
include the following: Chloroquine (Aralen), hydroxychloroquine (Plaquenil), 
Thioridazine (Mellaril), Topiramate (Topamax), vemurafenib, voriconazole, 


 
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doxycycline, hydrochlorothiazide, amiodarone, furosemide, allopurinol, phenothiazine, 
and chlorpromazine. 
Prior/Concurrent Clinical Study Experience  
8. Administration of investigational product in another study within 30 days prior to the 
first study drug administration, or five half-lives, whichever is longer. 
Other Exclusions 
9. Females who are pregnant or breastfeeding. 
 
5.3 LIFESTYLE CONSIDERATIONS 
Not applicable. 
5.4 SCREEN FAILURES 
Subjects will be assigned a subject number upon entry of data into the Electronic Data Capture 
(EDC) system. 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently assigned to a cohort. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects 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 not met, and any SAE. 
Potential candidates who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
The Sponsor (or designee) will identify clinical sites with: 
• Access to subjects with neurodegenerative diseases (Parkinson’s disease, MSA and 
ALS).  
• Ability to perform ophthalmological procedures. 
The clinical study is designed to recruit subjects through a network of physicians who routinely 
manage patients with neurodegenerative diseases and make referrals to study sites. The 
investigator will perform qualification assessments including confirmed diagnosis of 
neurodegenerative diseases. 


 
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6 
STUDY DRUG 
6.1 STUDY DRUG(S) ADMINISTRATION 
6.1.1 
Study Drug Description 
AMDX-2011P, a retinal tracer (small molecule), is a phosphate prodrug hydrolyzed in vivo to 
the pharmacologically active molecule AMDX-2011. 
 
Active 
Study Drug Name (INN) 
AMDX-2011P 
Type  
Retinal tracer (small molecule) 
Dose Formulation 
Solution for injection 
Unit Dose Strength(s) 
mg 
Dosage Level(s) 
• 
Cohort 1 – 25 mg (1 mL)  
• 
Cohort 2 – 50 mg (2 mL) 
• 
Cohort 3 – tentative 100 mg (4 mL) 
• 
Cohort 4 – tentative 150 or 200 mg (6-8 mL) 
 
For Cohorts 3-4, doses to be confirmed by SMC based on emerging data 
from prior cohorts. Intermediate and/or higher dose levels may be 
explored. 
Route of Administration 
IV bolus injection over 2 minutes 
Use 
Experimental  
Sourcing 
The drug product is manufactured by Pace (Salem, NH), and provided 
centrally by the Sponsor or subsidiary, or designee. 
Preparation 
Individual doses of AMDX-2011P will be prepared by pharmacy staff and 
will be provided to study personnel for administration. Procedures relating 
to study drug preparation will be outlined in the Pharmacy Manual. 
AMDX-2011P will be provided frozen (at -20℃) in a 10 mL amber vial 
containing 5.5 mL of solution at a concentration of 25 mg/mL. It is a 
single dose vial. Vials must not be shared between subjects. The solution 
is light sensitive and must be protected from light at all times. AMDX-
2011P must be thawed to room temperature prior to administration; once 
thawed, it must be used within 3 hours. 
Post administration 
instructions 
Subjects to be instructed to avoid direct sun and wearing light protective 
eye gear such as sunglasses for 24 hours after the dose. Subjects will be 
evaluated for signs and symptoms of phototoxicity.  
Packaging and Labeling 
The study drug will be dispensed in single administration vials. Study 
drug will be labeled as required per local regulations. All packaging and 
labeling operations for the study drug will be performed according to 


 
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Active 
current Good Manufacturing Practices and the relevant regulatory 
requirements. 
Storage Condition 
Study drug is to be stored in a secure freezer (-20℃) and monitored 
(manual or automated) in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff. 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 
Acquisition and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported and 
resolved before use of the study drug. Only subjects enrolled in the study may receive study 
drug, and only authorized site staff may administer study drug. 
The investigator, or designee is responsible for study drug accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). A record will be 
maintained by the investigational site staff member that will account for all dispensing and 
return of any used and unused study drug. Study drug administration will be at the clinical site. 
At the end of the study, the study drug will be reconciled, and a copy of the record given to the 
study monitor. 
Clinical supplies, including study drug and inventory records, must be made available upon 
inspection by Sponsor or regulatory agency upon request. The study monitors will review the 
records along with other study records during monitoring visits. 
Upon completion of the study, and after completion of study drug accountability by the study 
monitor, any surplus supplies will be destroyed upon receipt of written approval from the 
Sponsor (following the site’s destruction Standard Operating Procedures) and evidence of 
destruction supplied to the study monitor. 
Further guidance and information for the final disposition of unused study drugs are provided in 
the relevant manuals. 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This study is open-label, assessor masked. All retinal images will be sent in batches to a central 
reading center for masked assessment. Assessors will be masked to type of subjects, their disease 
status, dose, and sequence of post-injection images. Investigators will not be masked to study 
drug. Please see Section 8.1.4 for further details on the central reading center procedures. 
6.4 STUDY DRUG COMPLIANCE 
Study drug will be administered at the study site by the investigator or designee, as per the SoA 
(Section 1.3). 


 
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A record of the dose of AMDX-2011P administered to each subject must be maintained and 
reconciled with study drug and compliance records. Study drug start time will also be recorded 
in the electronic case report form (eCRF). 
6.5 TREATMENT OF OVERDOSE 
For this study, any dose of AMDX-2011P greater than the assigned dose will be considered an 
overdose. 
There is no specific treatment recommended to treat an overdose of study drug, and the subject 
should receive treatment directed towards any symptoms manifested. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the Study Medical Monitor immediately. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities until 
AMDX-2011P can no longer be detected systemically (at least 48 hours). 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
6.6 CONCOMITANT THERAPY 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements, taken during the 7 days prior to the study drug administration will be 
recorded and reviewed by the investigator (or designee) to determine whether the subject is 
suitable for inclusion. 
Treatment with another study drug, investigational device, or approved therapy for 
investigational use within 30 days (or five half-lives, whichever is longer) before anticipated 
dosing is prohibited. 
The Study Medical Monitor (or designee) should be contacted if there are any questions 
regarding concomitant medications. 
6.6.1 
Prohibited Medications  
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
study this include: 
• Use of any new prescription therapies and vaccines within 7 days prior to study drug 
administration. 
• Use of drugs with potential phototoxicity per Package Insert are prohibited within 48-hrs 
or 5-half-lives, whichever is longer, prior to first study drug until EOS visit, except for 
those required for treatment of underlying disease and/or AEs. Examples of such drugs 
include the following: Chloroquine (Aralen), hydroxychloroquine (Plaquenil), 
Thioridazine (Mellaril), Topiramate (Topamax), vemurafenib, voriconazole, 


 
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doxycycline, hydrochlorothiazide, amiodarone, furosemide, allopurinol, phenothiazine, 
and chlorpromazine.  
The investigator is expected to discuss any questions regarding prohibited medications with the 
Study Medical Monitor (or designee) and/or referring physician if applicable. The final decision 
on any supportive therapy rests with the investigator. 
6.6.2 
Rescue Medicine 
Not applicable. 


 
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7 
STUDY DRUG DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1 STOPPING RULES 
The SMC will monitor safety throughout the study. The SMC will meet periodically to review 
available safety data to make decisions regarding continuation, modification, suspension, or 
termination of the study. 
Study Stopping Rules 
Dose escalation or administration of study drug in a dose cohort may be stopped and additional 
subjects will not receive study drug until a consultation has taken place among the investigator, 
the Study Medical Monitor (or designee), and SMC if one of the following circumstances occurs 
in subjects treated with AMDX-2011P unless it is determined by the SMC in consultation with 
investigator and the Study Medical Monitor that the occurrence is not related to the 
administration of the study drug: 
• Two or more subjects in a cohort experience a Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 or higher clinical or laboratory abnormality that is 
considered to be related to study drug by the investigator. 
• An AE or group of AEs that singularly or in aggregate suggests to the investigator or 
Sponsor that the study drug is poorly tolerated and further treatment per protocol may not 
be safe. 
• If one or more subject(s) in a cohort experience any treatment-related, 
treatment-emergent SAEs, dose escalation will be stopped to re-evaluate the dose in 
question. 
If any of these criteria occur, the SMC will review all available data; if an event is determined to 
be related to a specific dose level, doses in subsequent cohorts may be modified or dose 
escalation may be terminated. Prior to any required dose level adjustment, the clinical and 
laboratory safety parameters from the previous dosing cohort(s) will be reviewed and discussed 
by the SMC to allow a recommendation on advancing to the next dose level. The suggested next 
doses may be the protocol-defined escalation dose, an equivalent dose, an intermediate dose, or 
an adjusted-downward dose based on evaluation of safety and tolerability data from previous 
cohorts. 
The Sponsor, investigator, and the IRBs reserve the right to terminate or suspend the study at 
any time; the reason for such decision must be recorded. Should this occur, all data available will 
also be recorded in eCRFs. The investigator should notify the IRB in writing of the study’s 
completion or early termination. 
7.1.1 
Pregnancy 
A female subject or a female partner of a male subject who becomes pregnant will be followed 
as described in Section 10.3. 


 
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7.2 DISCONTINUATION OF STUDY DRUG 
Not applicable; this is a single dose study. 
7.3 SUBJECT WITHDRAWAL FROM THE STUDY 
• A subject 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 withdrawing from the study, if possible, an early termination visit 
should be conducted, as shown in the SoA (Section 1.3). 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 subject will be permanently discontinued from the study drug and the study at 
that time. 
• If the subject 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 subject 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. 
7.4 LOST TO FOLLOW-UP 
A subject will be considered lost to follow-up if he or she repeatedly fails to engage for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical 
record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management (e.g., 
diagnostic status determination, ophthalmological examinations, blood count) and 
obtained before signing of the informed consent form 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. 
• Where study procedures coincide at the same time point, order of collection should be 
retinal imaging, ECGs, vital signs, blood draws where possible, provided that PK 
samples are collected within permitted windows. When ECG and vital signs occur at the 
same time, the rest time may be shared by the assessments. 
8.1 OPHTHALMOLOGICAL AND RETINAL IMAGING ASSESSMENTS 
8.1.1 
Ophthalmological Exam 
Eye exam (both eyes) will include: 
• Slit lamp examination of the anterior segment of the eye 
• Refraction (manual, autorefractor, lensometer, or historical) 
• Visual acuity with Snellen eye chart 
• Ophthalmoscopy examination, which may include OCT imaging as part of routine 
clinical care 
• Intraocular pressure (contact or non-contact tonometry) 
• Color fundus photograph 
 


 
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8.1.2 
Triplicate Fundus Fluorescence (FF) Imaging 
FF imaging enables visualization of fluorescent signals in the retina. Conventional and routinely 
used FF retinal cameras have the appropriate technical specifications to detect the 
hyper-fluorescent signal generated by AMDX-2011P–bound amyloidogenic proteins.  
Predose images will be captured using fundus autofluorescence (FAF) imaging. Immediately 
after IV injection with study drug, FAF images and/or videos will be continuously captured until 
2 minutes post-injection to assess the influx of the dye into the retina. After that, the remainder 
of the static images will be captured using FAF imaging. FF images (excluding conventional 
fundus photos) at all time points will be captured with the Heidelberg Spectralis 55-degree lens 
and the FAF settings of the device, using the central fixation target. Additional FF images may 
also be captured using the Optos UWF imaging modality or offset (no central fixation target) 55-
degree Heidelberg FAF modality at select time points. Complete instructions information will be 
provided in the imaging section of the Study Reference Manual. Images will be quality checked 
and exported per the respective retinal imaging device User Manual. All FF images will be 
prepared and transferred to a central reading center for review. Each FF image will be reviewed 
by the masked reading center assessors using the respective retinal imaging device’s native 
review software. The images will be assessed for image quality based on the respective devices 
image quality criteria.  
On Day 1, retinal imaging will be performed with both Spectralis and Optos devices in triplicate 
as shown in Table 5. Due to intensity of imaging, images taken outside the windows will not be 
considered protocol deviation. 
Table 5 
Collection Timepoints for Fundus Fluorescence (FF) Imaging 
Day 1 Time point 
Window 
Spectralis 
Optos 
Predose  
 
X 
X 
0-1 min  
 
Video 
 
2 min 
 
X 
 
5 min 
 
X 
 
10 min 
±2 
X 
X 
30 min 
±5 
X 
X 
1hr 
±10  
X 
X 
2hr 
±10  
X 
X 
4hr 
±10  
X 
X 
8hr 
±10  
X 
X 
 
 
8.1.3 
Optical Coherence Tomography (OCT) and OCT Angiography (OCT-
A) Imaging 
OCT is a non-contact imaging technique which generates high resolution cross-sectional images 
of the retina and its corresponding layers. OCT images will be acquired as specified in the SoA 
(Section 1.3). The Heidelberg Spectralis device will be used to capture volumetric structural 


 
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OCT and OCT-A images. The combination of FF and OCT/OCT-A images will enable for 
detection and mapping of amyloidogenic protein distribution across the fundus and across 
different retinal layers and retinal plexuses. For each imaging modality, OCT and OCT-A, the 
images will be assessed for image quality based on the respective device’s image quality criteria. 
8.1.4 
Central Retinal Image Center (CRIC) 
All acquired images will be checked for quality, and subjects’ identifiers will be removed by 
study personnel at investigational site. Deidentified images will be sent to a central imaging 
center specialized in assessing retinal images for detection and quantification of hyper-
fluorescent puncta. Each assessor at the CRIC will be masked to the subject’s disease status and 
sequence of post-injection images. Images will be batched and read at time of the interim 
analysis and final analysis, or more frequently at the request of SMC. Upon receiving 
deidentified images from the clinical site, quality assurance (QA) officer at the CRIC will review 
all images to confirm that the images sent meet the quality, quantity, and image acquisition 
criteria defined in the protocol. The QA officer will confirm that the images are labeled 
appropriately and that they were obtained by a certified imager. Once the QA officer reviews 
and confirms the integrity of each image batch, the images will be randomized and submitted to 
the masked assessors for grading. At the time of the interim and final analyses, the randomized 
masked images submitted to the assessors will be evaluated for image quality and for the number 
of distinct hyper-fluorescent puncta. Additional information will be provided in the imaging 
section of the Study Reference Manual.  
8.2 SAFETY AND OTHER ASSESSMENTS 
Safety assessments will include physical examination, ophthalmologic examination, vital signs, 
electrocardiogram (ECG), and laboratory assessments. Adverse events and concomitant 
medications will be monitored throughout the study.  
8.2.1 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems.  
• Height and body weight will be measured and recorded at screening. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 
Vital Signs 
• Systolic and diastolic blood pressure, heart rate, oral temperature, respiratory rate, and 
oximetry will be assessed. 
• Blood pressure and heart rate measurements will be assessed using a completely 
automated device, with cuff wrapped around the non-dominant arm. Manual techniques 
will be used only if an automated device is not available. 


 
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• Subjects should be resting in a supine or semi-reclined position for at least 5 minutes 
prior to and during vital signs measurement obtained. When ECG and vital signs occur 
at the same time, the rest time may be shared by the assessments. 
• Vital signs should be checked prior to blood draws when blood draws and vital signs 
occur at the same time. 
• Additional vital signs may be performed at other times if deemed necessary. 
• If deemed appropriate by the investigator, clinically significant findings in the vital 
signs will exclude a subject from study participation. Any abnormal finding related to 
vital signs that the investigator considers to be clinically significant must be recorded as 
an AE. 
8.2.3 
Electrocardiograms 
• 12-lead ECGs will be obtained at the time points indicated in the SoA (Section 1.3) with 
the following parameters: HR, PQ (PR), QRS, QT, RR and QTcF along with 
information on T- and U-waves. Triplicate ECGs will be conducted on Day 1; single 
ECGs at all other time points. 
• Subject to be resting in a supine position for at least 5 minutes prior to ECG. When ECG 
and vital signs occur at the same time, the rest time may be shared between the 
assessments. 
• Investigator to record in eCRF if ECG is normal, abnormal (not clinically significant) or 
abnormal (clinically significant, with description of findings). 
• In all cases in which an ECG has a potentially clinically significant finding, it will be 
repeated in triplicate within about 30 minutes and reviewed by the investigator or 
designee prior to subsequent dosing or study disposition decisions that do not constitute 
a subject emergency. 
• Clinically significant findings in the ECG obtained at screening should exclude a subject 
from study participation (as deemed appropriate by the investigator). Any clinically 
significant change will be reported as an AE. 
• Original paper tracings and tracing copies of the ECGs, including the interpretation, 
should be stored in the source documents. If ECG is thermal paper, it should be 
photocopied and then signed and dated since it fades over time. 
8.2.4 
Clinical Safety Laboratory Assessments 
• See Section 10.2 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 relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 


 
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significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the subject's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or Study 
Medical Monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the Medical 
Monitor notified. 
− All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
− If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the investigator (e.g., SAE 
or AE), then the results must be recorded in the eCRF.  
8.3 PHARMACOKINETIC ASSESSMENT 
Blood samples for determination of plasma concentrations of AMDX-2011P and AMDX-2011 
will be collected as detailed in the SoA (Section 1.3). The timings of sample collection may be 
amended during the study conduct on the basis of emerging data to allow optimal 
characterization of the PK profile of AMDX-2011P and AMDX-2011. 
Plasma concentrations of AMDX-2011P and AMDX-2011 will be measured by a specific and 
validated liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method.  
The following pharmacokinetic parameters (where appropriate) will be calculated by 
noncompartmental analysis from plasma concentrations of AMDX-2011P and for AMDX-2011 
as defined in Table 6. 
Table 6 
Pharmacokinetic Parameters  
Parameter 
Definition 
C0 
Back-extrapolated concentration at time = 0 hr (AMDX-2011P only) 
Cmax 
Maximum observed drug concentration 
Tmax 
Time of the maximum drug concentration 
AUC0-last 
Area under the drug concentration-time curve from time zero to the last measurable 
concentration 
AUC(inf) 
Area under the drug concentration-time curve from time zero to infinity 
AUC(0-t) 
Area under the drug concentration-time curve from time zero to time t 
t½ 
Apparent terminal half-life 
z 
Apparent terminal elimination rate constant 
CL 
Systemic clearance (AMDX-2011P only) 


 
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Parameter 
Definition 
Vss 
Steady-state volume of distribution (AMDX-2011P only) 
 
 


 
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8.4 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.4.1 
Definition of Adverse Events (AE) 
An AE means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.4.2 
Definition of Serious Adverse Events (SAE)  
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or Sponsor, it results in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or 
a congenital anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
8.4.3 
Classification of an Adverse Event 
8.4.3.1 
Severity of Event 
AE severity will be evaluated by the investigator in accordance with the National Cancer 
Institute (NCI) CTCAE v5.0 1. For AEs that are not adequately addressed in the NCI CTCAE, 
the investigator should classify the intensity of the AE using the following guidelines: 
• Grade 1: Mild: Aware of sign or symptom, but easily tolerated; no intervention needed 
• Grade 2: Moderate: Discomfort enough to cause interference with usual activity, minimal 
non-invasive intervention indicated (e.g., short course of antibiotics) 
• Grade 3: Severe: Medically significant but not immediately life-threatening; 
incapacitation with inability to work or do usual activity 
• Grade 4: Life-threatening: Refers to an event in which the subject was at risk of death at 
the time of the event, as judged by the investigator; urgent/emergent intervention 
indicated. This category should not be used for an event that hypothetically might have 
caused death if it were more severe. 
• Grade 5: Fatal outcome. 
 
 
1 Please refer to the CTCAE v5 at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. 
Accessed March 30, 2022 


 
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It will be left to the investigator’s clinical judgment to determine whether an AE is of sufficient 
severity to require the subject’s removal from treatment or from the study. A subject may also 
voluntarily withdraw consent from treatment due to what she/he perceives as an intolerable AE. 
If either of these situations arises, the subject should be strongly encouraged to undergo an EOS 
assessment and be under medical supervision until symptoms cease or the condition becomes 
stable. An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
8.4.3.2 
Relationship to Study Drug 
All AEs must have their relationship to study drug assessed by the clinician who examines and 
evaluates the subject based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. In a clinical study, the study 
product must always be suspect.  
Relationship 
Scale  
Definition 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the 
study drug or in which the study drug level has been established in body fluids or 
tissue; that follows a known or expected response pattern to the suspected study 
drug; and that is confirmed by improvement on stopping or reducing the dosage of 
the study drug, and reappearance of the reaction on repeated exposure. 
Probable 
A reaction that follows a reasonable temporal sequence from administration of the 
study drug; that follows a known or expected response pattern to the suspected study 
drug; that is confirmed by stopping or reducing the dosage of the study drug; and 
that could not be reasonably explained by the known characteristics of the subject’s 
clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from administration of the 
study drug; that follows a known or expected response pattern to the suspected study 
drug; but that could readily be produced by a number of other factors. 
Unlikely 
An event that does not follow a reasonable temporal sequence from administration of 
the study drug; that does not follow a known or suspected response pattern to the 
suspected study drug; and that could reasonably be explained by known 
characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
 
8.4.3.3 
Expectedness  
The investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information provided in the IB. 


 
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8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study subject presenting for medical care, or upon review by a study 
monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate eCRF. Information to be collected includes event description, time 
of onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and will be reported in the Medical History eCRF page, not as an AE. However, if 
the study subject’s condition deteriorates at any time during the study, it will be recorded as an 
AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The investigator will record all events with start dates occurring any time after informed consent 
is obtained until 7 days after the study drug administration for non-serious AEs or 30 days after 
the study drug administration for SAEs. At each study visit, the investigator will inquire about 
the occurrence of AE/SAEs since the last visit. Events will be followed for outcome information 
until resolution or stabilization. 
8.4.5 
Adverse Event Reporting  
Table 7 below summarizes the different reporting periods for AEs, SAEs, and pregnancy. 
Table 7 
Adverse Event Reporting Periods 
Type of Event 
Adverse Event 
Serious Adverse Event / 
SUSAR 
Pregnancy 
Reporting 
period 
From consent until 7 days after study 
drug administration or until AE is 
resolved or no further follow-up is 
required. 
(from consent to dosing, only collect 
AEs related to study procedures) 
From consent until: 30 days 
after study drug administration 
or until SAE is resolved or no 
further follow-up is required 
From dosing until 30 
days after study drug 
administration 
Reporting 
Timelines to the 
Sponsor  
Entered into the clinical database on 
an ongoing basis  
Within 24 hours of the 
investigator’s knowledge 
Within 24 hours of 
the investigator’s 
knowledge 
Reporting 
Method 
AE eCRF 
AE eCRF and SAE form 
Pregnancy Form 
Abbreviation: AE, adverse event (AE); eCRF, electronic case report form; SAE, serious adverse event ; SUSAR, 
serious unexpected suspected adverse reaction. 


 
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Events  that begin before the start of study drug but after obtaining informed consent will be 
recorded on the AE section of the eCRF and will be identified in the analysis as non-TEAEs. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from site awareness. The investigator will submit any 
updated SAE data to the Sponsor or designee within 24 hours of it becoming available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of a subject’s study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a subject has completed the study, and he/she considers the event to be related to the study drug 
or study participation, the investigator must promptly notify the Sponsor or designee. 
8.4.6 
Serious Adverse Event Reporting  
The investigator will immediately report to the Sponsor any SAE, whether or not considered 
study drug-related, including those listed in the protocol or investigator brochure and must 
include an assessment of whether there is a reasonable possibility that the study drug caused the 
event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a causal relationship between 
the study drug and the event (e.g., death from anaphylaxis). In that case, the investigator must 
immediately report the event to the Sponsor. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic or the subject is stable. Other supporting documentation of the event may be 
requested by Sponsor and should be provided as soon as possible. 
The Sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the Sponsor's initial receipt of the information. In addition, the 
Sponsor must notify FDA and all participating investigators in an Investigational New Drug 
(IND) safety report of potential serious risks, from clinical studies or any other source, as soon 
as possible, but in no case later than 15 calendar days after the Sponsor determines that the 
information qualifies for reporting. 
SAE reporting procedures 
• The primary mechanism for reporting an SAE to the Sponsor will be the EDC 
system. 
• Investigators will report all SAEs occurring during the study to the contract research 
organization (CRO) within 24 hours following the site’s knowledge of the SAE. All 
SAEs will be reported using the Serious Adverse Event Report form (SAE Report) in 
the electronic data system, Medrio. In case that the outcome is death, the investigator 
will also contact the Medical Monitor via telephone as soon as possible. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 


 
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• If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information via contact to the Medical Monitor. 
• If the electronic system is unavailable, then within 24 hours, the site will contact the 
Medical Monitor to report the event or email or fax the SAE form as detailed below. 
• Contacts for SAE reporting: Safety@TrialRunners.com 
8.4.7 
Reporting Events to Subjects  
Subjects will be informed about new risks and safety information through updated informed 
consent during the study. 
8.4.8 
Reporting of Pregnancy  
 
• Details of all pregnancies in female subjects and of female partners of male subjects will 
be collected as outlined in Section 10.2. 
• If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.3.3. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 


 
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9 
STATISTICAL CONSIDERATIONS  
9.1 SAMPLE SIZE DETERMINATION AND STATISTICAL HYPOTHESES 
This clinical study is designed to explore safety and preliminary activity of AMDX-2011P. A 
total sample size of ~36 subjects and assuming approximately 10% subjects are false negative, 
the study will provide test sensitivity and test specificity of approximately 0.8 for each 
individual subject population and the pooled populations. The study will enroll up to 36 subjects 
with confirmed diagnosis of Parkinson’s disease, MSA or ALS (approximately 12 subjects); the 
prevalence of disease is assumed at 0.5 for each individual disease population. 
 
9.2 POPULATIONS FOR ANALYSES 
Analysis Population 
Definition 
Safety Population 
All enrolled subjects who receive any amount of study drug 
comprise the Safety Population for safety and exposure analyses. 
Imaging Population 
 
All enrolled subjects who received any amount of study drug and 
who have at least one set of acceptable color fundus photographs 
and OCT scans predose and at least 3 acceptable quality fundus 
autofluorescence images during each of the following imaging 
sessions: predose, postdose: 5 minutes to 1 hour.  
Pharmacokinetic (PK) 
Population 
All enrolled subjects who receive any amount of study drug and 
who have at least one post-baseline PK sample will comprise the 
PK Population. 
Abbreviations: OCT, optical coherence tomography. 
9.3 STATISTICAL ANALYSES 
9.3.1 
General Approach 
A formal statistical analysis plan (SAP) and data management plan will be developed and 
finalized before study database lock. The following is a summary of statistical approach:  
• Variables used for sample size calculation will be calculated and presented for pooled 
populations and each subject population. 
• All disposition, demographic, baseline characteristic and concomitant 
medication summaries will be presented by arm. 
• Continuous variables: Descriptive statistics will include the number of non-missing 
values (n), arithmetic mean, standard deviation (SD), median, minimum and maximum 


 
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values. 90% Confidence Intervals (CIs), least-square (LS Means) values and Ratio for 
Geometrics LS means will also be displayed when appropriate. 
• Categorical variables: Descriptive statistics will include counts and percentages per 
category. The denominator in all percentage calculations will be the number of subjects 
in the relevant analysis population with non-missing data, unless specifically stated 
otherwise. Percentages will be displayed to one decimal place. Proportions will be 
displayed to 3 decimal places. 
9.3.2 
Safety Analyses 
Continuous safety data will be summarized with descriptive statistics (arithmetic mean, standard 
deviation [SD], median, minimum, and maximum) overall, by treatment, and by nominal 
visit/time point (where applicable).  
Categorical safety data will be summarized with frequency counts and percentages overall and 
within dose level. Adverse events will be coded by system organ class and preferred term using 
the most current Medical Dictionary for Regulatory Activities (MedDRA) version available. The 
number of subjects experiencing treatment-emergent adverse events as well as maximum 
severity and relationship to study drug will be summarized. 
Laboratory evaluations, vital signs assessments, and ECG parameters will be summarized at 
protocol-specified collection time point. A summary of change-from-baseline at each protocol-
specified time point will also be presented. 
Concomitant medications will be listed by subject and coded using the most current World 
Health Organization drug dictionary. 
Medical history will be listed by subject and coded using MedDRA. 
Further details will be provided in the SAP. 
9.3.3 
Analysis of the Secondary Endpoint (Activity) 
The number, diameter, and area of post-injection hyper-fluorescent puncta detected on fundus 
fluorescence images upon injection of AMDX-2011P that were not present prior to injection will 
be summed and descriptive statistics will be presented for each study eye per cohort. 
A positive diagnosis is defined as detection of hyper-fluorescent puncta on fundus fluorescence 
imaging that were not present prior to injection of AMDX-2011P. 
A false negative is defined as an eye from a subject with definite diagnosis and no new 
hyper-fluorescent puncta detected post-injection of AMDX-2011P via fundus fluorescence 
imaging that were not present prior to injection. 
9.3.4 
Pharmacokinetic Analysis 
The actual blood sampling dates and times will be listed by subject and nominal sampling time, 
with time deviation calculated, for all subjects with available plasma concentration data, 
including subjects excluded from the PK population. Individual (for each subject) and arithmetic 


 
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mean concentrations over time will be displayed graphically on linear and semi-
logarithmic axes, by treatment group. For individual subjects, the latter will include line 
segments indicating the range of data used to estimate the elimination rate constant (lz). The 
actual collection time will be used for individual plasma concentration curves, and the nominal 
time will be used for the plots of mean plasma concentration curves. 
For PK concentration data, the arithmetic mean, standard deviation, median, minimum, 
maximum, and coefficient of variation (CV%) values will be presented. For the calculation of 
summary statistics, unrounded data will be used and reported to 3 significant figures except for n 
and CV%, which will be presented to the nearest integer and one decimal place, respectively. 
For PK parameter data, the number of non-missing values, arithmetic mean, standard deviation, 
median, minimum and maximum, coefficient of variation (CV%), geometric mean and 
geometric coefficient of variation (geo CV%) values will be presented. Individual PK 
parameters will be presented to a minimum of 3 significant figures. 
9.3.5 
Sub-Group Analyses 
Each disease will be analyzed as a subgroup in an exploratory manner. Further details will be 
provided in the SAP. 
9.3.6 
Tabulation of Individual Subject Data 
All data collected on the eCRF will be presented in the data listings and will be listed, sorted by 
subject number and visit, where applicable. 
9.3.7 
Exploratory Analyses 
Exploratory analyses will be defined in the SAP. 
9.3.8 
Interim Analyses 
An exploratory interim analysis will be performed after the end of the 2nd cohort or when 12 
subjects have been enrolled to assess safety, PK, and retinal image quality by SMC. Additional 
information will be provided in the SAP. 


 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/assent and Other Informational Documents Provided to 
Subjects 
Consent forms describing in detail the study drug, study procedures, and risks are given to the 
subject and written documentation of informed consent is required prior to starting 
intervention/administering study drug. Master informed consent will be submitted with this 
protocol. 
10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved, and the subject will be asked to read and review the document. The investigator 
(or designee) will explain the research study to the subject and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the subject’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research subjects. 
Subjects will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The subjects should have the opportunity to discuss the study with their family 
or surrogates or think about it prior to agreeing to participate. The subject will sign the informed 
consent document prior to any procedures being done specifically for the study. Subjects must 
be informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. A copy of the signed informed consent document will be given to the 
subjects for their records. The informed consent process will be conducted and documented in 
the source document (including the date), and the form signed, before the subject undergoes any 
study-specific procedures. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
Cognitively impaired subjects will sign an assent form; their legally authorized representative 
will also sign this form.  
In the event a subject is unable to physically sign the informed consent form, an independent 
witness should be present for the entire consent discussion. The subject should read the consent; 
if this is not possible due to disability, the consent should be read to the subject. The discussion 
should allow ample time for the subject to ask questions and for the person obtaining informed 
consent to assess subject understanding. The subject may verbally provide consent; such verbal 
consent must be noted in the subject’s source documents and by hand on the consent document. 
The independent witness signs and personally dates the consent form. By doing so, the witness 
attests that the consent information was accurately explained and that the subject apparently 
understood and informed consent was given freely.  


 
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10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the Sponsor to investigator, funding agency, and the IND. If the 
study is prematurely terminated or suspended, the investigator will promptly inform study 
subjects, the IRB, and Sponsor and will provide the reason(s) for the termination or suspension. 
Study subjects will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB and/or FDA. 
10.1.3 
Confidentiality and Privacy  
Subject confidentiality and privacy are strictly held in trust by the participating investigators, 
their staff, and the Sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to subjects. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the Sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this 
study. The clinical study site will permit access to such records. 
The study subject’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or Sponsor 
requirements. 
Study subject research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the CRO. This will not include the subject’s contact or 
identifying information. Rather, individual subjects and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used 


 
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by clinical sites and by the CRO research staff will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived at the CRO. 
10.1.4 
Key Roles and Study Governance 
Refer to the Study Reference Manual. 
10.1.5 
Safety Oversight – Safety Monitoring Committee 
An SMC, appointed by the Sponsor and comprised of the Study Medical Monitor (or designee), 
neurologists with experience in these diseased populations, an ophthalmologist with retinal 
imaging expertise, and the Sponsor’s clinical and technical representatives, will be established 
before start of screening in the study. Details for the SMC will be outlined in a separate SMC 
Charter, the governing document that will supersede this section of the protocol. Composition of 
the SMC, meeting structure, schedule, and procedures, the content and format of SMC reports, 
and other relevant details will be determined in consultation with SMC members and detailed in 
a separate SMC charter. 
Safety data to be reviewed by the SMC will be shared in the format of a Safety Data Review 
Summary. The summary will include details on any clinically significant events experienced on 
study related to safety parameters, with a table listing of the aggregate of AEs reported on the 
study. The SMC authorizes escalating the dose and continued enrolment in subsequent cohorts 
based on all available safety, PK and/or imaging data during the safety review.  
At each decision stage, the SMC will review the Safety Data Review Summary and PK data (if 
available), and together make one of the following recommendations: 
• To continue the study as planned, e.g. enroll the next cohort at the planned dose. 
• To continue the study with modifications, e.g. modify the next dose, enroll additional 
subjects into current cohort, or add additional cohorts to the study 
• To temporarily suspend or terminate the study. If at any time the study is terminated, a 
written statement fully documenting the reasons for study termination will be provided to 
the IRB. 
10.1.6 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of study subjects 
are protected, that the reported study data are accurate, complete, and verifiable, and that the 
conduct of the study is in compliance with the currently approved protocol/amendment(s), with 
ICH-GCP, and with applicable regulatory requirement(s).  
• Monitoring for this study will be performed by the CRO. 
• The electronic database will be 100% source verified.  
• Monitoring visits will be onsite or remote at the discretion of the Sponsor and monitor 
dependent on enrollment and risk-based metrics.  


 
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• Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. 
• Independent audits will be conducted by the CRO to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the 
CMP. 
10.1.7 
Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion. An individualized quality management 
plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical study is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and applicable 
regulatory requirements (e.g., GLP, Good Manufacturing Practices [GMP]). 
The investigational site will provide direct access to all study related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, and 
inspection by local and regulatory authorities. 
10.1.8 
Data Handling and Record Keeping 
10.1.8.1 
Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each subject enrolled in the study. Data recorded in the eCRF 
derived from source documents should be consistent with the data recorded on the source 
documents.  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into EDC, a 21 CFR Part 11-compliant data capture 
system provided by the CRO. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 


 
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10.1.8.2 
Study Records Retention  
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be retained 
for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the Sponsor, if applicable. It is the responsibility of the Sponsor to 
inform the investigator when these documents no longer need to be retained. 
10.1.9 
Protocol Deviations  
A protocol deviation is any noncompliance with the clinical study protocol or International 
Council for Harmonisation Good Clinical Practice (ICH GCP) requirements. The noncompliance 
may be either on the part of the subject, the investigator, or the study site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH-GCP:  
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 5.1 Quality Assurance and Quality Control, section 5.1.1  
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations in a timely manner. All deviations must be addressed in study source documents, 
reported to Sponsor. Protocol deviations must be sent to the reviewing IRB per their policies. 
The site investigator is responsible for knowing and adhering to the reviewing IRB requirements. 
Further details about the handling of protocol deviations will be included in the study manuals. 
10.1.10 
Publication and Data Sharing Policy 
All information supplied by the Sponsor or their representative in association with this study and 
not previously published, is considered confidential information. Any data collected during the 
study are also considered confidential. This confidential information shall remain sole property 
of the Sponsor, shall not be disclosed to others without the written consent of the Sponsor, and 
shall not be used except in the performance of this study. 
The Sponsor follows local regulatory requirements relating to clinical study registration and 
results disclosure. Thus, this study will be registered on the ClinicalTrials.gov, and results from 
this study will be submitted to ClinicalTrials.gov. In addition, any other presentation/publication 
of complete/partial study data by the investigators or any other party is stipulated by written 
authorization from the Sponsor. 
10.1.11 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 


 
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have a role in the design, conduct, analysis, publication, or any aspect of this study will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this study. The study leadership has established policies and procedures 
for all study group members to disclose all conflicts of interest and will establish a mechanism 
for the management of all reported dualities of interest. 
 


 
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10.2 CLINICAL LABORATORY TESTS 
• The tests detailed in Table 8 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report in subject’s 
source records. 
Table 8 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Parameters 
Serum Chemistry 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and 
conjugated bilirubin, alkaline phosphatase (ALP), gamma-glutamyl-
transferase (g-GT), creatine phosphokinase (CPK), albumin, creatinine, urea, 
total protein, sodium, chloride, calcium, phosphate, potassium, triglycerides, 
total cholesterol, glucose (fasting) 
Hematology  
Hemoglobin, hematocrit, erythrocytes (RBC), reticulocytes, platelets, 
leukocytes (WBC), differential (counts): neutrophils, basophils, eosinophils, 
lymphocytes, and monocytes 
Coagulation 
International normalized ratio (INR), activated partial thromboplastin time 
(aPTT), prothrombin time (PT)  
Urinalysis 
Protein, glucose ketones, bilirubin, urobilinogen, hemoglobin, pH, specific 
gravity, appearance, color, leukocyte esterase, nitrite 
Microscopic tests (bacteria, erythrocytes, leucocytes, crystals, casts, 
epithelial cells, yeast, oval fat bodies, fat, mucous, sperm, trichomonas) 
Other laboratory 
assessments 
Human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) 
 
 
 
 


 
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10.3 CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY INFORMATION 
10.3.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female 
• 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, confirmation with more than one FSH measurement 
is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen 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 study enrollment. 


 
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10.3.2 
Contraception Guidance 
Male Subjects 
Male subjects are eligible to participate if they agree to the following from informed consent 
through 90 days after study drug administration: 
• Refrain from donating sperm, except for the purpose of fertility analysis as part of 
this protocol 
PLUS, either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use double barrier contraception (a male condom with spermicide) 
Female Subjects 
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
− Is not a woman of childbearing potential (WOCBP) 
OR 
− Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency (see table 
below), from consent through 30 days after study drug administration, and agrees 
not to donate eggs (ova, oocytes) for the purpose of reproduction during this 
period. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study drug. 
− A WOCBP must have negative serum pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 
72 hours prior to receiving the first administration of study drug and a negative 
urine pregnancy test before first administration of study drug. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test is required 
and results must be negative. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical studies. 


 
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Highly Effective Methodsa That Have Low User Dependency  
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) (hormonal and non-hormonal) 
• Surgical sterilization 
• Bilateral tubal occlusion or ligation 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsa That Are User Dependent  
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
− injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the subject.) 
a Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
b If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction). 
 
10.3.3 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 


 
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pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Subjects who become pregnant 
• The investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a subject's pregnancy. 
• The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• 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. 
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
drug by the investigator will be reported to the Sponsor as described in Section 8.4.8. 
While the investigator is not obligated to actively seek this information in former 
study subjects, he or she may learn of an SAE through spontaneous reporting. 
• Any female subject who becomes pregnant while participating in the study will 
discontinue study drug or be withdrawn from the study. 
 
 


 
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10.4 NEURODEGENERATIVE DISEASES DIAGNOSTIC CRITERIA 
Below are diagnostic criteria for neurodegenerative diseases evaluated in this study. 
10.4.1 
Parkinson’s Disease Diagnostic Criteria 
Table 9 
Movement Disorder Society (MDS) Diagnostic Criteria for Clinically 
Established Parkinson’s Disease 
Parkinsonism consist of bradykinesia plush either rigidity or rest tumor, as defined below 
Bradykinesia: slowness of movement 
AND decrement in amplitude or speed 
(or progressive hesitations/halts) as 
movements are continued  
Rigidity: velocity-independent 
resistance to passive movement not 
solely reflecting failure to relax 
(i.e., distinct from spasticity or 
paratonia) 
Rest tremor: a 4- to 6-Hz 
tremor in the fully resting limb, 
which is suppressed during 
movement initiation 
Clinical established Parkinson’s disease is defined as: 
Absence of absolute exclusion criteria; at least 2 supportive criteria; no ‘red flags’ (as defined below) 
Absolute Exclusion Criteria 
Red Flags 
Supportive Criteria 
• 
Cerebellar signs 
• 
Supranuclear gaze palsy 
• 
Established diagnosis of BVFTD 
• 
Parkinsonism restricted to the 
lower limbs only for >3 years 
• 
Treatment with an 
antidopaminergic,  
or with dopamine-depletion agents 
• 
Absence of response to levodopa 
• 
Sensory–cortical loss  
• 
No evidence for dopaminergic 
deficiency on functional imaging 
• 
Other parkinsonism-inducing 
condition 
• 
Rapid deterioration of gait 
• 
Absence of motor symptom 
progression over 5 years 
• 
Early bulbar dysfunction 
• 
Respiratory dysfunction 
• 
Early severe autonomic failure 
• 
Early recurrent falls due to 
misbalance 
• 
Disproportionate anterocollis 
• 
Absence of common non-motor 
features of disease during 
>5 years 
• 
Pyramidal tract signs 
• 
Bilateral symmetric presentation 
• 
A clear and dramatic 
positive response to 
dopaminergic therapy 
• 
Levodopa-induced 
dyskinesia 
• 
Documentation of resting 
tremor of a limb 
• 
A positive diagnostic test of 
either olfactory loss or 
cardiac sympathetic 
denervation on scintigraphy 
Abbreviation: BVFTD, behavioral variant frontotemporal dementia. 
Source: (Postuma, 2015) 
Table 10 Parkinson’s Disease Criteria per Hoehn and Yahr (1967) 
Stage 
Hoehn and Yahr Scale  
1 
Unilateral involvement only usually with minimal or no functional disability  
2 
Bilateral or midline involvement without impairment of balance  
3 
Bilateral disease: mild to moderate disability with impaired postural reflexes; physically 
independent  
4 
Severely disabling disease; still able to walk or stand unassisted  
5 
Confinement to bed or wheelchair unless aided  
Source: (Hoehn, 1967) 


 
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10.4.2 
MSA Diagnostic Criteria 
 


 
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24 January 2023 
Continued 
 
Source:  (Wenning, 2022) 
 


 
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24 January 2023 
10.4.3 
ALS Diagnostic Criteria 
Table 11 ALS Diagnostic Criteria 
 
Source: (Brooks, 2000) 
 
 


 
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24 January 2023 
 
10.5 ABBREVIATIONS 
Term 
Description 
α-syn 
alpha-synucleinopathies 
AE 
Adverse event 
ALS 
Amyotrophic lateral sclerosis 
AUC 
Area under the curve 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Peak plasma concentration 
CMP 
Clinical Monitoring Plan 
CONSORT 
Consolidated Standards of Reporting Trials 
CRIC 
Central Retinal Image Center 
CRO 
Clinical Research Organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DaTscan 
Dopamine transport scan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End-of-study 
ET 
Early termination 
FAF 
Fundus autofluorescence 
FDA 
Food and Drug Administration 
FF 
Fundus fluorescence  
FIH 
First-in-human 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
geo CV 
geometric coefficient of variation 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HED 
Human equivalent dose 
hERG 
Human Ether-à-go-go-related gene 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
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Term 
Description 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
OCT 
Optical coherence tomography  
OCT-A 
OCT angiography 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PROBE 
Prospective Randomized Open, Blinded Endpoint 
QA 
Quality assurance 
QC 
Quality control 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SMC 
Safety Monitoring Committee 
SoA 
Schedule of activities 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TDP-43 
Transactive response DNA-binding protein 43 
US 
United States 
WOCBP 
Woman of childbearing potential  
 
 
 


 
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10.6 PROTOCOL AMENDMENT HISTORY 
Prior amendments are listed below in order of occurrence. Current amendment is provided in 
section above table of contents. 
 
Original 
10 May 2022 
 
Amendment 1.0, 15 June 2022 
Overall Rationale for the Amendment: 
Changes are shown in order of appearance. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 SoA 
• Add vital signs measurements 
on Day 1 at 15 and 30 minutes 
postdose 
• Per request of the IRB 
5.1 Inclusion criteria 
10.1.1 Informed Consent 
Process 
• Clarify that legally authorized 
representative will also sign 
assent form for cognitively 
impaired subjects  
• Per request of the IRB 
Global 
• Ensure consistency across 
protocol including typo 
corrections 
• Correct formatting and style 
• Add summary of changes page 
• Update footer and title page 
with date/amendment number 
• For clarity and 
consistency 
 
Amendment 2.0, 01 July 2022 
Overall Rationale for the Amendment: 
Changes are shown in order of appearance. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema 
4 Study Design 
9.1 Sample Size Determination 
• Add 2 sentinel healthy 
volunteers to cohorts 1-4 
• Adjust sample size 
• To enhance the safety of 
participants at each cohort 
and  maintain the blind at 
the imaging center. 
8.1.1 
• Indicate that visual acuity will 
be done by Snellen eye chart 
• For clarification 
10.2 Clinical Laboratory Tests 
• Replace central laboratory with 
local laboratory  
• For logistical and 
operational reasons 


 
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Section # and Name 
Description of Change 
Brief Rationale 
Global 
• Ensure consistency across 
protocol including typo 
corrections 
• Correct formatting and style 
• Move prior amendment to 
Section 10.6 
• Update footer, title page and 
signature page with 
date/amendment number 
• For clarity and 
consistency 
 
Amendment 3.0, 26 July 2022 
Overall Rationale for the Amendment: 
Changes are shown in order of appearance. 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol title 
1.1 Synopsis 
1.2 Schema 
1.3 Schedule of Activities 
2. Introduction 
3 Objectives and Endpoints 
4 Study Design 
5 Study Population 
6 Study Drug 
9 Statistical Considerations 
10.1.5 Safety Oversight – Safety 
Monitoring Committee 
• Remove healthy volunteers 
participation in the study  
 
• As a safety precaution per 
FDA request based on 
preliminary nonclinical 
finding requiring 
additional in vitro testing 
2.3.1 Known potential risks 
6.1.1 Study Drug Description 
• Add that due to potential 
phototoxicity, subjects will be 
instructed to avoid direct sun 
and wear protective gear for 24 
hours after dosing. 
• Add mutagenicity as a potential 
risk 
• As a safety precaution per 
FDA request 
6.1.1 Study Drug Description 
• Clarify study drug is a single 
dose vial not to be shared 
between subjects. 
• To align with the 
investigator’s brochure 


 
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24 January 2023 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
• Update protocol to ensure 
consistency across protocol  
• Correct formatting and style 
• Move prior amendment to 
Section 10.6 
• Update footer, title page and 
signature page with 
date/amendment number 
• For clarity and 
consistency 
Amendment 4.0, 16 September 2022 
Overall Rationale for the Amendment: 
Changes are shown in order of appearance. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
8.1.2 Retinal fundus 
fluorescence (FF) imaging  
• Clarify timing of when 
assessments will be performed 
• For clarity 
1.1 Synopsis 
4.1 Study design 
9.1 Sample Size Determination 
• Indicate that approximately 12 
ALS subjects will be enrolled 
• For clarity 
10.2 Clinical Laboratory Tests 
• Delete urine test for drugs of 
abuse 
• This assessment is not 
conducted in the studied 
subject population 
Global 
• Update protocol to ensure 
consistency across protocol  
• Correct formatting and style 
• Move prior amendment to 
Section 10.6 
• Update footer, title page and 
signature page with 
date/amendment number 
• For clarity and 
consistency 
 
 
 


 
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24 January 2023 
11 REFERENCES  
Brooks, B. R., Miller, R. G., Swash, M., Munsat, T. L. and World Federation of Neurology 
Research Group on Motor Neuron, D. (2000). "El Escorial revisited: revised criteria for the 
diagnosis of amyotrophic lateral sclerosis." Amyotroph Lateral Scler Other Motor Neuron 
Disord 1(5): 293-299. 
 
Cao, K. J. and Yang, J. (2018). "Translational opportunities for amyloid-targeting fluorophores." 
Chem Commun (Camb) 54(66): 9107-9118. 
 
Chiò, A., Logroscino, G., Traynor, B. J., Collins, J., Simeone, J. C., Goldstein, L. A., et al. 
(2013). "Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the 
published literature." Neuroepidemiology 41(2): 118-130. 
 
de Boer, E. M. J., Orie, V. K., Williams, T., Baker, M. R., De Oliveira, H. M., Polvikoski, T., et 
al. (2020). "TDP-43 proteinopathies: a new wave of neurodegenerative diseases." J Neurol 
Neurosurg Psychiatry 92(1): 86-95. 
 
de Lau, L. M. and Breteler, M. M. (2006). "Epidemiology of Parkinson's disease." Lancet Neurol 
5(6): 525-535. 
 
Dhasmana, S., Dhasmana, A., Narula, A. S., Jaggi, M., Yallapu, M. M. and Chauhan, S. C. 
(2021). "The panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological 
disorder." Life Sci 288: 120156. 
 
Dorsey, E. R. and Bloem, B. R. (2018). "The Parkinson Pandemic-A Call to Action." JAMA 
Neurol 75(1): 9-10. 
 
Fanciulli, A. and Wenning, G. K. (2015a). "Multiple-system atrophy." N Engl J Med 372(3): 
249-263. 
 
Fanciulli, A. and Wenning, G. K. (2015b). "Multiple-system atrophy." N Engl J Med 372(14): 
1375-1376. 


 
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24 January 2023 
 
FDA (July 2005). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers.  Center for Drug Evaluation and 
Research. Pharmacology and Toxicology, from https://www.fda.gov/media/72309/download. 
 
GBD (2018). "Global, regional, and national burden of Parkinson's disease, 1990-2016: a 
systematic analysis for the Global Burden of Disease Study 2016." Lancet Neurol 17(11): 939-
953. 
 
Hansson, L., Hedner, T. and Dahlöf, B. (1992). "Prospective Randomized Open Blinded End-
point (PROBE) Study. A novel design for intervention trials." Blood Pressure 1(2): 113-119. 
 
Heras-Garvin, A. and Stefanova, N. (2020). "From Synaptic Protein to Prion: The Long and 
Controversial Journey of α-Synuclein." Front Synaptic Neurosci 12: 584536. 
 
Hoehn, M. M. and Yahr, M. D. (1967). "Parkinsonism: onset, progression and mortality." 
Neurology 17(5): 427-442. 
 
Jellinger, K. A. (2018). "Multiple System Atrophy: An Oligodendroglioneural 
Synucleinopathy1." J Alzheimers Dis 62(3): 1141-1179. 
 
Jo, M., Lee, S., Jeon, Y. M., Kim, S., Kwon, Y. and Kim, H. J. (2020). "The role of TDP-43 
propagation in neurodegenerative diseases: integrating insights from clinical and experimental 
studies." Exp Mol Med 52(10): 1652-1662. 
 
Koga, S. and Dickson, D. W. (2018). "Recent advances in neuropathology, biomarkers and 
therapeutic approach of multiple system atrophy." J Neurol Neurosurg Psychiatry 89(2): 175-
184. 
 
Koga, S., Sekiya, H., Kondru, N., Ross, O. A. and Dickson, D. W. (2021). "Neuropathology and 
molecular diagnosis of Synucleinopathies." Mol Neurodegener 16(1): 83. 
 


 
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Korat, Š., Bidesi, N. S. R., Bonanno, F., Di Nanni, A., Hoàng, A. N. N., Herfert, K., et al. (2021). 
"Alpha-Synuclein PET Tracer Development-An Overview about Current Efforts." 
Pharmaceuticals (Basel) 14(9). 
 
Lashuel, H. A., Overk, C. R., Oueslati, A. and Masliah, E. (2013). "The many faces of α-
synuclein: from structure and toxicity to therapeutic target." Nat Rev Neurosci 14(1): 38-48. 
 
Malfertheiner, K., Stefanova, N. and Heras-Garvin, A. (2021). "The Concept of α-Synuclein 
Strains and How Different Conformations May Explain Distinct Neurodegenerative Disorders." 
Front Neurol 12: 737195. 
 
McAlary, L., Plotkin, S. S., Yerbury, J. J. and Cashman, N. R. (2019). "Prion-Like Propagation 
of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis." Frontiers in 
Molecular Neuroscience 12(262). 
 
Meade, R. M., Fairlie, D. P. and Mason, J. M. (2019). "Alpha-synuclein structure and 
Parkinson’s disease – lessons and emerging principles." Molecular Neurodegeneration 14(1): 29. 
 
Mehta, P., Kaye, W., Raymond, J., Punjani, R., Larson, T., Cohen, J., et al. (2018). "Prevalence 
of Amyotrophic Lateral Sclerosis - United States, 2015." MMWR Morb Mortal Wkly Rep 
67(46): 1285-1289. 
 
Nemade, D., Subramanian, T. and Shivkumar, V. (2021). "An Update on Medical and Surgical 
Treatments of Parkinson's Disease." Aging Dis 12(4): 1021-1035. 
 
Ortuño-Lizarán, I., Beach, T. G., Serrano, G. E., Walker, D. G., Adler, C. H. and Cuenca, N. 
(2018). "Phosphorylated α-synuclein in the retina is a biomarker of Parkinson's disease 
pathology severity." Mov Disord 33(8): 1315-1324. 
 
Osaki, Y., Ben-Shlomo, Y., Lees, A. J., Wenning, G. K. and Quinn, N. P. (2009). "A validation 
exercise on the new consensus criteria for multiple system atrophy." Mov Disord 24(15): 2272-
2276. 
 


 
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Postuma, R. B., Berg, D., Stern, M., Poewe, W., Olanow, C. W., Oertel, W., et al. (2015). "MDS 
clinical diagnostic criteria for Parkinson's disease." Mov Disord 30(12): 1591-1601. 
 
Prakash, K. G., Bannur, B. M., Chavan, M. D., Saniya, K., Sailesh, K. S. and Rajagopalan, A. 
(2016). "Neuroanatomical changes in Parkinson's disease in relation to cognition: An update." J 
Adv Pharm Technol Res 7(4): 123-126. 
 
Rao, P. P. N., Shakeri, A., Zhao, Y. and Calon, F. (2021). "Strategies in the design and 
development of (TAR) DNA-binding protein 43 (TDP-43) binding ligands." European Journal of 
Medicinal Chemistry 225: 113753. 
 
Schweighauser, M., Shi, Y., Tarutani, A., Kametani, F., Murzin, A. G., Ghetti, B., et al. (2020). 
"Structures of α-synuclein filaments from multiple system atrophy." Nature 585(7825): 464-469. 
 
Stankovic, I., Quinn, N., Vignatelli, L., Antonini, A., Berg, D., Coon, E., et al. (2019). "A 
critique of the second consensus criteria for multiple system atrophy." Mov Disord 34(7): 975-
984. 
 
Štětkářová, I. and Ehler, E. (2021). "Diagnostics of Amyotrophic Lateral Sclerosis: Up to Date." 
Diagnostics (Basel) 11(2). 
 
Veys, L., Vandenabeele, M., Ortuno-Lizaran, I., Baekelandt, V., Cuenca, N., Moons, L., et al. 
(2019). "Retinal alpha-synuclein deposits in Parkinson's disease patients and animal models." 
Acta Neuropathol 137(3): 379-395. 
 
Wenning, G. K., Stankovic, I., Vignatelli, L., Fanciulli, A., Calandra-Buonaura, G., Seppi, K., et 
al. (2022). "The Movement Disorder Society Criteria for the Diagnosis of Multiple System 
Atrophy." Mov Disord 37(6): 1131-1148. 
 
Young, P. N. E., Estarellas, M., Coomans, E., Srikrishna, M., Beaumont, H., Maass, A., et al. 
(2020). "Imaging biomarkers in neurodegeneration: current and future practices." Alzheimer's 
Research & Therapy 12(1): 49. 
 


 
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Zafar, S. and Yaddanapudi, S. S. (2021). Parkinson Disease. StatPearls. Treasure Island (FL), 
StatPearls Publishing 
Copyright © 2021, StatPearls Publishing LLC. 
 
 

SAP_001.pdf: 
Amydis 
AMDX-2011P 
 
Statistical Analysis Plan 
Version V1.0 – 31JAN2023 
 
 
 
Page 1 of 15 
 
 
 
Statistical Analysis Plan 
 
 
Prospective Randomized Open, Blinded Endpoint (PROBE) Basket Design Study of AMDX-2011P as a 
Retinal Tracer in Subjects with Neurodegenerative Diseases Associated with Amyloidogenic 
Proteinopathy  
 
 
Prepared for:  Amydis, Inc 
 
 
1800 Century Park East Suite 600 
 
 
Los Angeles, CA 90067 
 
 
Protocol details: 
 
Name:   
AMDX-2011P-MASTER 
 
Version:  
1.0 
 
Date:   
31 October 2022 
 
 
Author details: 
 
Version:  
1.0 
 
Version Date:  31-JAN-2023 
 
Author(s):  
Andrew Mao 
 
 


Amydis 
AMDX-2011P 
 
Statistical Analysis Plan 
Version V1.0 – 31JAN2023 
 
 
 
Page 2 of 15 
 
 
Review and Approval 
The undersigned have approved this Statistical Analysis Plan for use in this study.  
 
Trial Runners, LLC Approval: 
 
 
 
Andrew Mao 
 
Date 
Biostatistician 
 
 
 
 
 
 
Stephanie Poe 
 
Date 
Project Manager 
 
 
 
 
 
 
Linet Bolar 
 
Date 
Safety Physician 
 
 
 
 
 
 
Amydis, Inc Approval: 
 
 
 
Masoud Mokhtarani, MD 
 
Date 
Chief Medical Officer 
 
 
 
 


Amydis 
AMDX-2011P 
 
Statistical Analysis Plan 
Version V1.0 – 31JAN2023 
 
 
 
Page 3 of 15 
 
 
Table of Contents 
 
1 
INTRODUCTION ..................................................................................................................................... 5 
1.1 
Changes from Protocol ................................................................................................................. 5 
2 
STUDY OBJECTIVES ................................................................................................................................ 5 
2.1 
Primary Objective.......................................................................................................................... 5 
2.2 
Secondary Objective ..................................................................................................................... 5 
3 
STUDY DESIGN....................................................................................................................................... 5 
3.1 
Sample Size Considerations .......................................................................................................... 6 
3.2 
Randomization .............................................................................................................................. 6 
3.3 
Schedule of Evaluations and Analysis Visit Windows ................................................................... 6 
4 
ANALYSIS POPULATIONS ....................................................................................................................... 7 
4.1 
Safety Population .......................................................................................................................... 7 
4.2 
Imaging Population ....................................................................................................................... 7 
4.3 
Pharmacokinetic (PK) Population ................................................................................................. 7 
5 
STUDY VARIABLES/PARAMETERS .......................................................................................................... 7 
5.1 
Primary (Safety) Endpoints ........................................................................................................... 7 
5.2 
Secondary Endpoints .................................................................................................................... 7 
5.3 
Pharmacokinetic Endpoints .......................................................................................................... 7 
6 
STATISTICAL ANALYSIS METHODS ......................................................................................................... 8 
6.1 
Subject Disposition ........................................................................................................................ 8 
6.2 
Protocol Deviations ....................................................................................................................... 8 
6.3 
Missing Data and Imputation ........................................................................................................ 8 
6.4 
Demographics and Baseline Characteristics ................................................................................. 8 
6.5 
Prior and Concomitant Medications ............................................................................................. 9 
6.6 
Medical History ............................................................................................................................. 9 
6.7 
Primary (Safety) Analysis .............................................................................................................. 9 
6.7.1 
Electrocardiogram (ECG) ....................................................................................................... 9 
6.7.2 
Physical Exam ...................................................................................................................... 10 
6.7.3 
Vital Signs ............................................................................................................................ 10 
6.7.4 
Clinical Laboratory Assessments ......................................................................................... 10 
6.7.5 
Intraocular Pressure ............................................................................................................ 10 
6.8 
Secondary Analysis ...................................................................................................................... 10 


Amydis 
AMDX-2011P 
 
Statistical Analysis Plan 
Version V1.0 – 31JAN2023 
 
 
 
Page 4 of 15 
 
 
6.9 
Pharmacokinetic Analysis ........................................................................................................... 11 
6.10 
Exploratory Analyses ................................................................................................................... 12 
6.11 
Other Assessments ..................................................................................................................... 13 
6.11.1 
ALS/Parkison’s/CAA Disease History ................................................................................... 13 
6.11.2 
Ophthalmoscopy ................................................................................................................. 14 
6.11.3 
Slit Lamp Biomicroscopy ..................................................................................................... 14 
6.11.4 
Mini-mental state exam (MMSE) for CAA group ................................................................ 14 
7 
INTERIM ANALYSIS .............................................................................................................................. 14 
8 
REFERENCES ........................................................................................................................................ 14 
9 
APPENDICES ........................................................................................................................................ 14 
9.1 
Glossary of Abbreviations ........................................................................................................... 14 
10 
VERSION HISTORY LOG ................................................................................................................... 15 
 
 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of analyses and 
reporting of data for study protocol AMDX-2011P-101P Version 1.0-Master containing sub-study 
protocols: AMDX-2011P-001 Version 1.0 and AMDX-2011P-101 Version 5.0, Amendment 5.0.  The 
purpose of the SAP is to ensure the credibility of the study findings by pre-specifying the statistical 
approaches to the analysis of study data prior to data base lock. 
 
1.1 
Changes from Protocol 
The visit window for analysis was changed from +2 days to +6 days.  
 
2 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
The primary study objective is: 
• 
to assess safety and tolerability of single IV dose of AMDX-2011P in subjects with 
neurodegenerative diseases (Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), multiple 
system atrophy (MSA), and Cerebral Amyloid Angiography (CAA)). 
 
2.2 
Secondary Objective 
The secondary study objectives are: 
• 
to assess the ability of AMDX-2011P to identify α-syn in retina of subjects with Parkinson’s 
disease and MSA. 
• 
to assess the ability of AMDX-2011P to identify TDP-43 in retina of subjects with ALS. 
• 
to assess the ability of AMDX-2011P to identify Amyloid Beta in the retina of CAA subjects. 
• 
to characterize the PK profile of AMDX-2011P and AMDX-2011 following administration of a 
single IV dose of AMDX-2011P in subjects with neurodegenerative diseases (Parkinson’s Disease, 
ALS, MSA, and CAA). 
 
3 
STUDY DESIGN 
This is a Phase I PROBE basket design study to evaluate safety, tolerability, and the ability of AMDX-
2011P to detect amyloid deposits, α-syn, TDP-43, and Amyloid Beta through retinal examination, as well 
as PK of single bolus IV of AMDX-2011P in subjects with Parkinson’s disease, Amyotrophic Lateral 
Sclerosis (ALS), Cerebral Amyloid Angiopathy (CAA), and multiple system atrophy (MSA). The study 
contains two sub-studies under separate protocols.    
 
List of sub-studies included in Master Protocol Basket Design: 
 
Study Protocol 
Study Population 
Protocol 
Appendix for 
further details 
Dose Levels 
Number of 
Cohorts 
Subjects 
Per Cohort 


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Study AMDX-
2011P-001 
Version 1.0 
Cerebral Amyloid 
Angiopathy (CAA) 
Section 7.1 
50 mg (2mL), 
100 mg, 150 
or 200 mg 
(tentative), 
Cohort 4 
(TBD) 
4 
3-5 
Study AMDX-
2011P-101 
Version 5.0, 
Amendment 5.0 
Amyotrophic 
Lateral (ALS) / 
Parkinson’s 
Disease, Multiple 
System Atrophy 
(MSA) 
Section 7.2 
25 mg (1mL), 
50 mg (2mL), 
100 mg (4 
mL), 150 mg 
or 200 mg (6-
8 mL) 
4 
3-9 for 
cohorts 1-
2, 12 for 
cohorts 3-
4 
 
Approximately 9 subjects will be enrolled in each of the ALS and MSA studies.  Additional subjects may 
be enrolled into any cohort per DSMB recommendation for CAA sub-study and all sub-study cohorts will 
include 1 sentinel subject who will be observed for 8 hours and evaluated at 24 hours for safety before 
enrolling the remaining subjects into that cohort.  Tentative doses will be determined and confirmed by 
DSMB based on emerging data from prior cohorts.  Additional cohorts may be explored per DSMB 
recommendations.   
 
3.1 
Sample Size Considerations 
A total sample size of approximately 36 subjects and assuming approximately 10% subjects are false 
negative, the sub-study will provide test sensitivity of at least 0.8 for each individual subject population 
and the pooled populations in protocol AMDX-2011P-101 Version 5.0, Amendment 5.0. The study will 
enroll approximately 36 subjects with confirmed diagnosis of Parkinson’s disease, ALS, or MSA; the 
prevalence of disease is assumed at 0.75 for pooled population and 0.5 for each individual disease 
population.  For the CAA group, a total sample size of up to 20 subjects with confirmed diagnosis of CAA, 
and assuming approximately 10% subjects are false negative, the sub-study will provide test sensitivity 
of approximately 0.8 for the target population in protocol AMDX-2011P-001.   
 
3.2 
Randomization 
The study is open-label and cohort assignment will be based on current dose level and disease status.  
 
3.3 
Schedule of Evaluations and Analysis Visit Windows 
The schedule of visits and procedures are provided in the study protocol AMDX-2011P-101, Version 5.0, 
Amendment 5, Section 1.3 and AMDX-2011P-001, Version 1.0, Section 1.3. The study consists of a 
screening visit, treatment day, and 1 follow-up visit.  For purposes of analysis, nominal time points will 
be used in data summarizations. The following target windows are expected for each visit: 
 
Visit 
Target Day of Visit 
Visit Window (Days) for Analysis 
Screening 
-42 to -1 
-42 to -1 
Treatment (Day 1) 
1 
1 
Follow-up (Day 8) 
8 
8-14 
 


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4 
ANALYSIS POPULATIONS 
4.1 
Safety Population 
The Safety (SAF) Population includes all enrolled subjects who receive any amount of study drug. The 
Safety Population will be used for the safety and exposure analyses.  
 
4.2 
Imaging Population 
The Imaging (IMG) Population includes all enrolled subjects who receive any amount of study drug and 
who have at least one set of acceptable color fundus photographs and OCT scans pre-dose and at least 3 
acceptable quality fundus autofluorescence images during each of the following imaging sessions: pre-
dose, post-dose: 5 minutes to 1 hour.  Acceptability of the images will be determined as defined in the 
Imaging Manual.  
 
4.3 
Pharmacokinetic (PK) Population 
The Pharmacokinetic (PK) Population includes all enrolled subjects who receive any amount of study 
drug and who have at least one post-baseline PK measurable samples.  
 
5 
STUDY VARIABLES/PARAMETERS 
5.1 
Primary (Safety) Endpoints 
The primary endpoint is defined to be: 
• 
Incidence, nature, and severity of treatment-emergent adverse events (TEAEs) 
• 
Incidence, nature, and severity of serious adverse events (SAEs) 
 
5.2 
Secondary Endpoints 
The secondary endpoints are defined to be: 
• 
Detection of α-syn (numbers per field) in the retina after AMDX-2011P administration by 
OCT/OCT A and Fundus Fluorescence 
• 
Detection of TDP-43 (numbers per field) in the retina after AMDX-2011P administration by 
OCT/OCT A and Fundus Fluorescence 
• 
Detection of Amyloid Beta (numbers per field) in the retina after AMDX-2011P administration by 
OCT/OCT A and Fundus Fluorescence 
• 
The PK parameters of AMDX-2011P and AMDX-2011 calculated from concentrations in plasma 
through blood sampling 
 
5.3 
Pharmacokinetic Endpoints 
The following PK parameters will, where possible, be determined (to a precision minimum of 3 
significant figures): 
Parameter 
Definition 
C0 (ng/mL) 
Extrapolated concentration at time equal to zero 
Cmax (ng/mL) 
Maximum observed drug concentration 
Tmax (hr) 
Time of the maximum drug concentration 


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Parameter 
Definition 
AUC0-last (hr*ng/mL) 
Area under the drug concentration-time curve (AUC) from time zero to the 
last measurable concentration. 
AUCINF (hr*ng/mL) 
AUC from zero extrapolated to infinity 
AUC(0-t) 
AUC from time zero to time t 
CL/F (L) 
Apparent total body clearance following IV administration 
t½ (hr) 
Apparent terminal half-life 
λz (1/hr) 
Apparent terminal elimination rate constant 
Vss (L) 
Steady-state volume of distribution 
 
6 
STATISTICAL ANALYSIS METHODS 
No formal statistical tests or inference will be performed. All summaries will be presented using 
descriptive statistics for each cohort, and overall.  Data processing, summarization, and analyses will be 
performed using SAS Version 9.4 or higher.  Unless otherwise discussed, continuous variables will be 
summarized by the number of available data points (N), mean, standard deviation, median, minimum, 
and maximum. 90% confidence intervals, least-square means, and ratio for geometrics LS means will be 
displayed when appropriate.  The mean, median, minimum, and maximum will be displayed with the 
same number of decimals as raw data, and the standard deviation will be displayed with two more 
decimals than raw data.  Categorical variables will be summarized by the number and percentage of 
subjects in each level, where the denominator for each percentage is the number of subjects in the 
relevant population and specified cohort.  Percentages will be displayed to one decimal place and 
proportions will be displayed to three decimal places.  Data listings of all data collected on the eCRF will 
be presented, sorted by subject number and visit, where applicable.  
 
6.1 
Subject Disposition 
The number and percentage of subjects screened, enrolled, cohort assignment, completed treatment, 
completed study, and analysis populations will be summarized for each cohort, by neurodegenerative 
disease population, and overall.  The time in study (in days) and follow-up time will also be summarized 
for each cohort and overall.  
 
6.2 
Protocol Deviations 
The number and percentage of protocol deviations will be presented by cohort and overall.  
 
6.3 
Missing Data and Imputation 
There will be no imputation of missing data.  
 
6.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for each cohort and overall, including age 
(years), sex (male, female), child-bearing potential? (Yes, No: bilateral oophorectomy, bilateral tubal 
ligation, hysterectomy, post-menopausal, and other), contraception (Yes, No), ethnicity (Hispanic or 


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Latino, Not Hispanic or Latino), Race (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Other), height (inches), weight (lbs), and iris 
color (Blue, Green, Brown, Black, Grey, Hazel, Other).  
 
6.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be listed by subject and coded using the Word Health 
Organization (WHO) drug dictionary, Version September 2021, for the Safety (SAF) Population.  Any 
medication or vaccine taken 7 days prior to study drug administration will be recorded.  The number and 
percentage of subjects who reported taking prior and/or concomitant medications will be summarized 
overall.  Individual subject prior and concomitant medications data will be listed. 
 
6.6 
Medical History 
Medical history will be listed by subject and coded using the MedDRA, Version 25.0, using System Organ 
Class and Preferred Term for the Safety Population.  Individual subject medical history data will be listed. 
 
6.7 
Primary (Safety) Analysis 
The primary analysis for this study will assess the safety of study drug, AMDX-2011P. Adverse Events will 
be coded by System Organ Class and Preferred Term using MedDRA, Version 25.0. The number and 
percentage of subjects experiencing treatment-emergent adverse events, serious adverse events, 
maximum severity to study drug, and highest relationship to study drug will be summarized by cohort 
and listed by subject ID for both eyes.  Treatment emergent adverse events and serious adverse events 
leading to discontinuation will also be presented by count.  Treatment emergent adverse events are 
defined as any AEs with an onset date on or after the date of the first dose of the investigational product 
or is pre-existing and worsens after administration.  TEAEs severity will be measured by the severity 
scale: mild, moderate, severe, life-threatening, and fatal.  The degree of certainty of causality will be 
graded using the following categories: definite, probable, possible, unlikely, and not related.  A line 
listing of all treatment emergent adverse events will be provided including as reported verbatim term, 
SOC, PT, onset date, end date, severity, seriousness, causality, dose level, outcome and action taken 
with investigational product.  Subjects with 1 or more than one TEAE per system organ class and 
preferred term will be counted once and be reported with the highest severity.  In cases where severity 
or relationship are missing, the most conservative approach will be taken (i.e., highest severity and 
assumed to be related).  Laboratory evaluations, vital sign assessments, and ECG parameters will be 
summarized using appropriate statistics at protocol-specified time points, as well as change-from-
baseline at all protocol-specified post-baseline timepoints.  Non-ocular adverse events will be 
summarized separately and listed by subject ID for both eyes.  
 
6.7.1 
Electrocardiogram (ECG) 
Baseline, post-dose, and change from baseline for ECG parameters (heart rate (HR), RR interval, QRS 
interval, PR interval, QT interval, and QTcF) along with clinically significant abnormalities on T and U 
waves will be presented by cohort and overall.  Triplicate ECGs will be conducted on Day 1 (at pre-dose, 
90 minutes post-dose, and 8 hours post dose) and single ECGs at other timepoints.  Results will also be 
listed by subject ID. 


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Clinically significant findings will be presented based on the following categories:  
• The proportion of patients obtaining a heart rate change from baseline > 25% decrease resulting in a 
heart rate < 50 beats per minute (bpm) and heart rate change from baseline > 25% increase resulting in 
a heart rate > 100 bpm.  
• The proportion of patients obtaining a QRS change from baseline > 25% increase resulting in QRS > 120 
ms.  
• The proportion of patients obtaining a PR interval change from baseline > 25% increase reaching a 
value of > 220 ms.  
• The proportion of patients obtaining a QTcF increase from baseline values > 30 ms and ≤ 60 ms; and > 
60 ms.  
• The proportion of patients obtaining treatment emergent absolute QTcF values > 450 ms and ≤ 480 
ms; > 480 ms and ≤ 500 ms; and > 500 ms.  
 
6.7.2 
Physical Exam 
Complete physical exam at screening includes assessment of height (in/cm), weight (lb/kg) at screening. 
General appearance, cardiovascular, respiratory, head, eyes, ears, nose, throat, neurologic, abdomen 
will be assessed on a scale of normal, abnormal (NCS), abnormal (CS), and not done.   
 
6.7.3 
Vital Signs 
Vital signs assessment include systolic blood pressure (mmHG), diastolic blood pressure (mmHG), 
temperature (F), heart rate (beats/min), and respiration (per/minute) for each protocol specified 
timepoint.   
 
6.7.4 
Clinical Laboratory Assessments 
Clinical laboratory assessments including hematology, chemistry, coagulation, and urinalysis will be 
summarized by cohort and overall for each protocol specified timepoint.   
 
6.7.5 
Intraocular Pressure 
Intraocular pressure (mmHG) using contact or non-contact tonometry will be assessed and summarized 
for both eyes for each protocol specified timepoint. 
 
6.8 
Secondary Analysis 
The number, diameter, and area of post-injection hyper-fluorescent puncta detected on fundus 
fluorescence images upon injection of AMDX-2011P that were not present prior to injection will be 
summed and descriptive statistics will be presented for each study eye per neurodegenerative disease 
population (e.g PD, ALS, MSA, CAA) and dose levels. 
• 
Detection of α-syn in the retina after AMDX-2011P administration, defined as the number of 
distinct new spots that are visible to the naked eye post-injection only.  
• 
Detection of TDP-43 in the retina after AMDX-2011P administration, defined as the number of 
distinct new spots that are visible to the naked eye post-injection only.  


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• 
Detection of Amyloid Beta in the retina after AMDX-2011P administration, defined as the 
number of distinct new spots that are visible to the naked eye post-injection only. 
• 
PK parameters of AMDX-2011P and AMDX-2011 calculated from concentrations in plasma. 
 
Diagnostic test summary statistics will be presented overall. Calculated values will include: 
• 
A true positive diagnosis is defined as detection of hyper-fluorescent puncta on fundus 
fluorescence imaging that were not present prior to injection of AMDX-2011P.  
• 
A false negative is defined as an eye from a subject with definite diagnosis and no new hyper-
fluorescent puncta detected post-injection of AMDX-2011P via fundus fluorescence imaging that 
were not present prior to injection.  
 
6.9 
Pharmacokinetic Analysis 
PK Data Reporting and BLQ Imputation: 
Individual plasma concentration data will be listed and summarized by cohort and dose levels / nominal 
time point with descriptive statistics (sample size [N], arithmetic mean, standard deviation [SD], median, 
minimum, maximum, geometric mean, and percent coefficient of variation [CV%]).  Only concentration 
data collected within window of the scheduled timepoint will be included in summary tables and figures, 
however all data will be provided in data listings.  Individual concentration data and descriptive statistics 
will be presented to 3 significant figures, except N, which will be reported as whole number CV% will be 
reported to one decimal place.  For the purpose of descriptive statistics on the plasma concentration 
values and for PK analysis, all non-numerical values reported as being below the lower limit of 
quantification (BLQ) will be imputed as follows: 
• 
Any BLQ value will be presented as ‘BLQ’ in the concentration table listings and footnoted 
accordingly.  
• 
Any BLQ value prior to Cmax will be set equal to zero.  Any BLQ post Cmax will be kept as “BLQ” 
and treated as a non-numerical value and excluded from descriptive statistics and PK analysis. 
• 
In the event that two BLQ values are followed by a value within the quantification limit, the 
quantifiable value may be excluded from the analysis.  
 
PK Parameter Estimation: 
The PK parameters will be estimated by non-compartmental analysis (NCA) using Phoenix WinNonlin 
(v8.3 or later) using the data imputations described above.  Actual sampling time points relative to 
dosing will be used for the NCA.  There will be no imputation for missing data.  No formal “outlier” 
analysis is planned.  A profile must include at least consecutive quantifiable concentrations to be 
included in PK analysis.  Subject profiles that are excluded from PK analysis (e.g. missing more than 2 
samples, etc.) will be included in the concentration tables only and the reason for exclusion will be 
provided in the PK report.   
 
Peak plasma concentrations (Cmax) post dose administration and the corresponding Tmax will be 
determined by direct assessment (no calculations) of the concentration vs time data. 
 
All AUC calculations will be performed using the linear trapezoidal rule.   
 


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If the data permit, the terminal rate constant (λz) will be calculated.  The value of λz will be determined 
by the slope of the regression line of the natural log transformed concentrations vs time with the 
following constraints: 
1. At least 3 data points post the Cmax should be used in the regression; and 
2. The correlation coefficient (R2) of regression should be > 0.80. 
To optimize the reliability of the identified terminal phase (λz), where possible, the data points used to 
define the λz will be manually selected.  The λz profiles that do not meet the guidelines stated above will 
not report the AUCINF, t1/2, CL or Vz parameters for that subject profile. 
 
When possible, AUCINF will be calculated as: AUClast + (Clast / λz).  CL will be calculated as: Dose / (AUCINF) 
and Vz will be calculated as: Dose / (AUCINF * λz).  Terminal half-life (t1/2) will be calculated as: loge(2) / 
λz.  If the lambda z range is not at least 2-fold greater than the calculated half-life value, the half-life 
value will be flagged and excluded from summary descriptive statistics. 
 
If there any deviations from the planned treatment, then the analysis model specified or methods of 
analysis may be re-evaluated, as appropriate.  Details of any deviations from the planned analysis will be 
documented in the PK report. 
 
Individual subject PK parameters will be listed and summarized by cohort / dose levels with descriptive 
statistics (e.g. N, arithmetic mean, SD, median, minimum, maximum, geometric mean and CV%).  
Individual parameters and descriptive statistics will be presented to 3 significant figures, except N, which 
will be reported as whole number, while individual Tmax and half-life values will be reported to two 
significant figures. 
 
PK Figures: 
Mean ± SD Concentration vs nominal time profiles will be generated on log/linear scales by cohort.  
Overlay plots of all individual plasma concentration by actual time (or nominal time) for each cohort will 
be generated on log/linear axis, with each subject data represented with a different symbol and 
included in a legend.  Individual subject concentration by time plots will also be produced on log/linear 
axis. 
 
Mean ± SD AUClast versus dose plots will also be generated to assess dose proportionality / linearity. 
 
6.10 Exploratory Analyses 
The following endpoints will be considered in the exploratory analysis, to be performed at the time of 
final analysis.  
• 
time to clearance of all puncta, 
• 
determining the residence time, defined as the time of injection to complete resolution of all 
identified puncta 
• 
the number of post-injection spots 
• 
distribution and total area of hyperfluorescent between cohorts  
• 
peripheral puncta vs central, estimated number and size within the Macula and outside of the 
macula as reported by the grading center 
• 
relationship between puncta and blood concentrations and residence time,  


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• 
time to maximum number of puncta detected 
 
6.11 Other Assessments 
6.11.1 ALS/Parkison’s/CAA Disease History 
Disease history assessment will capture diagnostic criteria for each disease and also describes disease 
state for each subject.   
• 
ALS Diagnostic Criteria 
1 - Definite ALS 
2 - Probable ALS 
3 - Probable ALS w/ Lab Result Supported 
4 - Possible ALS 
• 
ALSRFS-R Score (0-10) 
• 
Parkinson MDS Diagnostic Criteria:  
1 – Bradykinesia 
2 – Rigidity 
3 – Resting Tremor 
4 – Positive response to dopaminergic therapy 
5 – Levodopa – induced Dyskinesia 
6 – Documentation of resting tremor of a limb 
7 – Positive diagnostic test for olfactory loss 
8 – Positive diagnostic test of cardiac sympathetic denervation on scintigraphy 
• 
Hoehn and Yahr Scale for Parkinson’s subjects  
1 – Unilateral only 
2 – Bilateral or midline without impairment of balance 
3 – Bilateral 
4 – Severely disabling 
5 – Confinement 
• 
MSA Diagnostic Criteria 
Established MSA 
 
MSA-C – Atrophy of: Putamen (and signal decrease on iron-sensitive 
sequences), infratentorial structures (pons and middle cerebellar pedundle).  Hot cross 
bun sign. 
 
MSA-P – Atrophy of Putamen (and signal decrease on iron-sensitive sequences), 
middle cerebellar pedundle, pons, and cerebellum.  Hot cross bun sign. 
Probable MSA 
MSA-C – Atrophy of: Putamen (and signal decrease on iron-sensitive 
sequences), infratentorial structures (pons and middle cerebellar pedundle).  Hot cross 
bun sign. 
 
MSA-P – Atrophy of Putamen (and signal decrease on iron-sensitive sequences), 
middle cerebellar pedundle, pons, and cerebellum.  Hot cross bun sign. 
• 
CAA Diagnostic Criteria 
1 – Definite CAA 
2 – Probable CAA with evidence 
3 – Probable CAA 
4 – Possible CAA 


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6.11.2 Ophthalmoscopy 
Measurements will be taken of the vitreous, macula, peripheral retina, choroid, optic nerve for both 
eyes and assessed on a scale of normal, abnormal (NCS), abnormal (CS), and not done.   
 
6.11.3 Slit Lamp Biomicroscopy 
Measurements will be taken of the subject’s lids/lashes, conjunctiva/sclera, iris/pupil, cornea, anterior 
chamber, and lens at each protocol specified timepoint for both eyes and assessed on a scale of normal, 
abnormal (NCS), abnormal (CS), and not done.   
 
6.11.4 Mini-mental state exam (MMSE) for CAA group 
Short screening tool to provide overall measure of cognitive impairment in clinical research and will be 
conducted at screening for the CAA group.  The MMSE is a score-based 30-question assessment with a 
maximum of 30 points possible (PubMed, 2015).  MMSE scores will be assessed as a continuous 
variable. 
7 
INTERIM ANALYSIS 
An exploratory interim analysis will be performed after the end of the 2nd cohort, or when 12 subjects 
have been enrolled to assess safety, PK, and retinal image quality by SMC.  
 
Individual subject listings will be provided by Trial Runners for the following: 
• 
subject disposition 
• 
number of hyperfluorescent puncta pre and post dose for each subject 
• 
TEAEs 
• 
Clinically significant laboratory results  
• 
Vital signs  
 
No formal statistical analysis will be performed as the nature of the interim analysis is descriptive, to 
evaluate the quality of images obtained, and to inform the selection of the optimum dose.  There will be 
no interim analysis for the MSA and Glaucoma groups. 
 
8 
REFERENCES 
Rodriguez, Ingrid-Arevalo, et. al. (2015, Mar). Mini-Mental State Examination (MMSE) for the detection 
of Alzheimer’s disease and other dementias in people with mild cognitive impairment (MCI) PubMed. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464748/ 
 
9 
APPENDICES 
9.1 
Glossary of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 


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ALS 
Amyotrophic lateral sclerosis 
AUC 
Area under the curve 
CAA 
Cerebral Amyloid Angiopathy 
CS 
Clinical Signs 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
EOS 
End of Study 
IMG 
Imaging population 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Exam 
MSA 
Multiple Systems Atrophy 
NCS 
No Clinical Signs 
OCT 
Optical Coherence Tomography 
OCT A 
Optical Coherence Tomography Angiography 
OD 
Right Eye 
OS 
Left Eye 
OU 
Both Eyes 
PK 
Pharmacokinetic 
PROBE 
Prospective Randomized Open Blinded Endpoint 
SAE 
Serious adverse event 
SAF 
Safety population 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
TDP-43 
TAR DNA-binding protein 43 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
α-syn 
Alpha-synuclein 
 
10 VERSION HISTORY LOG 
Version Date 
Implemented Changes 
Author 
1.0 
31-JAN-2023 
First approved version 
Andrew Mao