Conditions: Healthy Participants
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 3
Healthy volunteers: yes

Brief summary:
This is a phase 1, open-label, positron emission tomography (PET) study in healthy adult participants to determine the relationship between plasma concentration and brain target occupancy of ASN51 following a single oral dose.

Detailed description:

Arms:
arm 1: Participants received low, medium, and high doses of ASN51, orally on Day 1 of imaging sessions 2 and 3 before the PET scan during the study.

Interventions: intervention 1: ASN51
Intervention descriptions: intervention 1: Oral

Protocol document:
Prot_000.pdf: 


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 CLINICAL TRIAL PROTOCOL 
 
 
 
A Phase 1, Open-Label, Positron Emission Tomography Study in Healthy Adult Subjects to 
Determine the Relationship Between Plasma Concentration and Brain Target Occupancy of 
ASN51 Following a Single Oral Dose 
Protocol Number: 
ASN51-102 
Original Protocol: 
Version 2.0, 19 May 2021  
Investigational Product: 
ASN51 (O-linked-β-N-acetylglucosaminidase inhibitor) 
Indication: 
Alzheimer’s Disease 
IND Number: 
TBD 
Trial Registration: 
ClinicalTrials.gov:   not yet assigned 
EudraCT:  
2021-001918-10 
Sponsor: 
Asceneuron S.A. 
EPFL Innovation Park  
Bâtiment B, CH-1015 Lausanne, SWITZERLAND 
Primary Medical Officer (EU): 
Name:  
 M.D., M.Sc., Ph.D. 
Title:    
 Early Clinical Development 
Email:  
  
Phone (Switzerland Cell): 
Secondary Medical Officer (US): 
Name:  
 M.D. 
Title:    
 Clinical Development and Translational 
Medicine 
Email:  
  
Phone (U.S. Cell): 
 
Emergency On-Call Physician: 
  
Compliance Statement: 
This clinical trial is to be performed in compliance with the protocol, Good Clinical Practices (GCP), and 
applicable regulatory requirements. 
Confidentiality Statement: 
This document contains confidential and proprietary information; the information contained within may 
only be used for the purpose of conducting the trial. The information is intended solely for the use of the 
Investigator, trial personnel, and applicable Research Ethics Committee (REC) and Medicines Healthcare 
and products Regulatory Agency (MHRA).  Information in this document shall not be otherwise disclosed 
without prior written consent from Asceneuron SA.  


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SPONSOR SIGNATURE PAGE 
 
Protocol Title: 
A Phase 1, Open-Label, Positron Emission Tomography Study in Healthy 
Adult Subjects to Determine the Relationship Between Plasma 
Concentration and Brain Target Occupancy of ASN51 Following a Single 
Oral Dose 
 
Protocol Number:   ASN51-102 
Original Protocol: 
Version 2.0, 19 May 2021 
 
As the Sponsor representative, I confirm that the Sponsor will comply with all Sponsor obligations 
as detailed in all applicable regulations and guidelines.  I will ensure the Investigator is informed 
of all relevant information that becomes available during the conduct of this trial.   
 
 
 
Date 
 
 
May 20, 2021




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INVESTIGATOR AGREEMENT  
 
Protocol Title: 
A Phase 1, Open-Label, Positron Emission Tomography Study in Healthy 
Adult Subjects to Determine the Relationship Between Plasma 
Concentration and Brain Target Occupancy of ASN51 Following a Single 
Oral Dose 
 
Protocol Number:   ASN51-102 
Original Protocol: 
Version 2.0, 19 May 2021 
 
As an Investigator, I agree to comply with all protocol specifications and ensure the safety of 
subjects enrolled at my site. I agree to conduct the trial in accordance with applicable regulations, 
Research Ethics Committee (REC)/Medicines Healthcare and products Regulatory Agency 
(MHRA)specifications, and ICH GCP guidance.  I will ensure site personnel understand their 
obligations in the conduct of this trial and will provide site personnel with all relevant information 
that becomes available during the conduct of this trial.   
 
Principal Investigator Name: 
  
Institution Address: 
  
 
 
Principal Investigator Signature: _
_________________________________ 
                        
 
Date:  
 
21 May 2021


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2.0 
STUDY SYNOPSIS 
Title 
A Phase 1, Open-Label, Positron Emission Tomography Study in Healthy Adult 
Subjects to Determine the Relationship Between Plasma Concentration and 
Brain Target Occupancy of ASN51 Following a Single Oral Dose 
Development Phase 
Phase 1 
Sites 
Single center  
Indication 
ASN51 is indicated for the treatment of adults with Alzheimer’s Disease (AD) 
Investigational 
Drug and Dosage 
Form 
Investigational drug: 
ASN51 (
 ASN51) 
Route of 
Administration 
Oral 
Study Design  
ASN51-102 is an open phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics study of 
oral ASN51 in healthy adult subjects.  
 
Open-label single oral doses of ASN51 will be administered to up to 10 (aged 25-55 years, inclusive) 
healthy adult male or female subjects to investigate the target brain occupancy of O-GlcNAcase by 
ASN51. 
Each subject will have up to 3 imaging sessions, with one scan in each session.  In the first imaging 
session, subjects will have a baseline PET scan.  In the second and third imaging sessions, subjects will 
receive a single oral dose of ASN51, followed by an on-treatment PET scan.  Subjects will receive an 
intravenous dose of the radiolabeled tracer, [18F]-IMA601, at the start of each PET scan. 
Selection of the dose levels to be administered and the timing of the PET scans relative to the time of 
study drug administration will be made by the safety review committee (SRC) depending on the results 
of the single ascending dose tolerability study ASN51-101 in healthy young adult subjects and the results 
of the previous study drug administrations in study ASN51-102.  


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Study Objectives 
Primary Objective: 
• 
To assess the brain O-GlcNAcase occupancy using [18F] IMA601 PET, following a single oral 
dose of ASN51 
Secondary Objectives: 
• 
To assess the relationship between the plasma concentration of ASN51, and the time-course of 
brain O-GlcNAcase occupancy using [18F]-IMA601 PET, following a single oral dose of 
ASN51 
• 
To assess the single dose safety and tolerability of ASN51 in healthy adult subjects under 
fasted conditions 
Study Population 
 
Inclusion Criteria: 
Individuals meeting all the following inclusion criteria and none of the exclusion criteria will be 
eligible to participate None of the inclusion criteria are eligible for re-screening. No waivers will be 
granted and any deviation from below will get recorded as a major protocol deviation. An exception can 
apply for subjects who meet the inclusion and exclusion criteria, but then miss a cohort that is filled and 
so they are no longer eligible due to lapse of the 3-week screening window; these subjects may be 
rescreened. Screening period duration is 3 weeks. 
1. Healthy as determined by the Investigator, based on a medical evaluation including medical 
history physical examination, neurological examination, laboratory tests and cardiac monitoring.  
2. Men or women aged 25-55 years, inclusive (age range was selected on grounds of radiation 
burden). 
3. Women of child-bearing potential with partners of child-bearing potential (see Section 9.10.7 
for definitions) must agree to use highly effective contraception (per CTFG 2020; bilateral 
tubal occlusion, hormonal contraception associated with inhibition of ovulation except oral 
contraception, intra-uterine device with or without intrauterine hormone-releasing system, 
sexual abstinence in relation to the preferred and usual lifestyle of the subject) from at least 28 
days before first tracer dosing through 30 days after last dose of IMP. All women of child-
bearing potential must have a negative pregnancy test result before administration of test 
article. Vasectomized partner is also an accepted a highly effective birth control method 
provided that partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomized partner has received medical assessment of the surgical success. 
4. Women of non-childbearing potential must be postmenopausal [the last menstrual period was at 
least 12 months ago, and FSH at screening confirms postmenopausal status, or have no uterus, 
ovaries, or fallopian tubes). Women who are surgically sterile must provide documentation of 
the procedure by an operative report or by ultrasound. 
5. Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female 
partner of childbearing potential must use a male condom plus spermicide from 1 day prior to 
the first tracer administration throughout the total duration of the treatment period and 90 days 


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after the last dose of IMP.  Periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of contraception.  Male subjects should refrain from sperm donation 
throughout this period. 
6. Body weight > 50.0 kg for men and > 45.0 kg for women and Body Mass Index within the range 
18.5-30.0 kg/m2 (inclusive). 
7. Subjects must understand the nature of the study and must provide signed and dated written 
informed consent in accordance with local regulations before the conduct of any study-related 
procedures. 
8. Subjects must be, in the opinion of the Investigator, able to participate in all scheduled 
evaluations, likely to complete all required tests, and likely to be compliant. 
9. Subjects must be fluent in the local language. 
10. Subjects must agree not to post any personal medical data related to the study or information 
related to the study on any website or social media site (e.g., Facebook, Twitter, etc.) until the 
trial has completed. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate: 
1. A positive urine drug screen/alcohol test at Screening or Day -1. 
2. Any history of psychiatric disorders, including substance use disorders, according to the 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria. 
3. A diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation. 
4. Significant suicide risk as assessed by C-SSRS. 
5. A positive Hepatitis B surface antigen or positive Hepatitis C antibody result at Screening. 
6. A positive test for human immunodeficiency virus (HIV) antibody at Screening. 
7. Alanine aminotransferase or aspartate aminotransferase levels greater than 1.5 times the upper 
limit of normal (ULN) at Screening or between Screening and first dose of tracer. 
8. Frequently used any tobacco-containing (e.g., cigar, cigarette, or snuff) or nicotine-containing 
product (e.g., nicotine chewing gum, nicotine plasters, or other product used for smoking 
cessation) within 3 months prior to first dose of tracer.  Frequent use is defined as 3 or more 
days per week.  Use of any tobacco- or nicotine-containing product is prohibited within 1 week 
of first dose of tracer. 
9. History of regular alcohol consumption within 12 months of the study defined as an average 
weekly intake of >21 alcoholic units/week for men or >14 alcoholic units/week for women. 
10. Regularly consumed (e.g., more days than not) excessive quantities of xanthine-containing 
beverages (e.g., more than five cups of coffee or the equivalent per day) within 30 days prior to 
Screening or between Screening and first dose of tracer. 
11. Received or used an investigational product (including placebo) or device within the following 
time period prior to the first tracer dosing day in the current study: 90 days, 5 half-lives or twice 
the duration of the biological effect of the investigational product (whichever is longer). 
12. Other than exceptions outlined in Section 9.10, use of prescription or non-prescription drugs, 
vitamins, herbal, and dietary supplements (including St John’s Wort) within 7 days (or 28 days 
if the drug is a potential hepatic enzyme inducer) or 5 half-lives (whichever is longer) prior to 
the first dose of study tracer medication. 


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13. History of clinically significant sensitivity to any of the study medications, or components 
thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical 
Monitor, contraindicates their participation. 
14. Loss of more than 400 mL of blood within 3 months prior to first dose of tracer, i.e., blood donor. 
15. A positive serum pregnancy test or lactation. 
16. A history or presence of any disease, condition, or surgery likely to affect drug absorption, 
distribution, metabolism, or excretion. Subjects with a history of cholecystectomy should be 
excluded. 
17. A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, 
endocrine, pulmonary, ophthalmologic, immunologic, hematologic, dermatologic, or neurologic 
abnormality. 
18. A clinically significant abnormality on physical examination, neurological examination, ECG, 
or laboratory evaluations at screen or between screen and first tracer dose administration. 
19. A corrected QT interval measurement corrected according to the Fridericia rule (QTcF) > 450 
msec for males and 470 msec for females during controlled rest at screen or between screen and 
first tracer dose administration, or family history of long QT syndrome. 
20. Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting 
ECG and any abnormalities in the 12-lead ECG that, in the judgement of the Investigator or 
Medical Monitor, may interfere with the interpretation of QTc interval changes, including 
abnormal ST-T-wave morphology or left ventricular hypertrophy. 
21. PR (PQ) interval shortening < 120 msec (PR < 120 msec but > 110 msec is acceptable if there 
is no evidence of ventricular pre-excitation). 
22. PR (PQ) interval prolongation (>220 msec), intermittent second- (Wenckebach block while 
asleep or in deep rest is not exclusionary) or third-degree AV block. 
23. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block 
(IBBB), or intraventricular conduction delay (IVCD) with QRS > 120 msec. 
24. A clinically significant vital signs abnormality at screening This includes, but is not limited to, 
3 measurements (each 5 minutes apart) in the seated position: (a) systolic blood pressure < 90 
or >140 mmHg, (b) diastolic blood pressure <50 or > 95 mmHg, or (c) heart rate < 45 or >100 
beats per minute. The average of the 3 measurements should be used to assess eligibility at 
screening.  
25. Significant (> 10%) weight loss or gain within 30 days prior to Screening and first tracer dose 
administration. 
26. A history of seizure. History of a single benign febrile convulsion of childhood is permitted. 
27. A history of head trauma, including closed head injury with loss of consciousness. 
28. A history of symptomatic orthostatic hypotension (i.e., postural syncope). 
29. A history of neuroleptic malignant syndrome. 
30. A history of chronic urinary tract infections. 
31. The subject is, in the opinion of the Investigator or Medical Monitor, unlikely to comply with 
the protocol or is unsuitable for any reason. 


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32. Currently employed by Asceneuron SA or by a clinical trial site participating in this study, or a 
first-degree relative of an Asceneuron SA employee or of an employee at a participating clinical 
trial site. 
33. Unsatisfactory venous access 
34. Significant exposure to ionizing radiation as part of research (defined as ICRP category IIb or 
above:  no more than 10 mSv in addition to natural background radiation including this trial), 
within the previous 12 months prior to first tracer dose administration. 
35. Unsuitable or unwilling to undergo the imaging procedures, as determined by an MRI safety 
questionnaire.  Reasons for exclusion include but are not limited to presence of a cardiac 
pacemaker or other implanted electronic device; ferromagnetic metal foreign bodies, intracranial 
aneurysm clips or other metallic objects; non-MRI compatible heart valves; inner ear implants; 
or a history of claustrophobia. 
36. Significant structural brain abnormality, as determined by MRI. 
37. Contraindication for arterial cannulation: Allen’s test indicating potential risk in placement of 
the arterial cannula. 
38. Subjects with a COVID-19 vaccination within two weeks of screening or due to receive second 
dose of COVID-19 vaccine while participating in the study. 
 
Trial Procedures and Assessments 
After assessing eligibility during a 3‐week screening period, up to 10 healthy male subjects or female 
subjects will participate in the study. Subjects will be admitted to the study center on Day -1, the day 
before (first) tracer administration for baseline assessments and to (re‐)confirm eligibility. Subjects will 
stay in the clinical unit for 5 days (4 nights) for imaging sessions 2 and 3. For the baseline PET scan, 
subjects may leave the unit in the evening. Blood samples for PK analysis will be collected pre‐dose and 
at specified time points up to Day 4 post‐dose (sessions 2 and 3). Physical examinations, vital signs, 
ECG, will be performed at specified times. Adverse events will be recorded throughout the study. A 
follow-up visit will take place 7 days (±3 days) after receiving the last tracer dose. For details regarding 
the timing of specific procedures, see Table 1. 
Safety Review Committee (SRC): 
The study will be monitored by an SRC. The SRC is intended to ensure the treatment does not pose 
undue risk to subjects. Safety and pharmacokinetic data will be assessed by the SRC prior to start of the 
study to determine the first dose level to be administered. For details regarding study safety oversight 
and SRC, see Section 7.5.  The SRC will be composed of the following core individuals: 
• 
Principal Investigator (PI) or delegate 
• 
Asceneuron SA medical monitor or delegate (must be a physician). 
Endpoints 
. 
Primary Outcome Measures 
• 
Pharmacodynamic (PD): [18F]-IMA601 regional total volume of distribution (VT) at each brain 
scan. 


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Secondary Outcome Measures 
• 
Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) up to 
follow-up 
• 
Serious Adverse Events (SAEs) up to 4 weeks after last administration 
• 
Laboratory tests 
• 
Vital signs  
• 
ECG 
• 
Physical examination 
• 
Pharmacokinetic (PK): plasma concentration of ASN51at the time of each post-dose PET scan. 
• 
PK/PD: relationship between ASN51 exposure and receptor occupancy. 
Statistical 
Considerations 
A full description of the statistical evaluations, general considerations, and 
procedures for handling missing data will be provided in the Statistical Analysis 
Plan (SAP) and, if applicable, in the data management plan (DMP). The SAP 
will provide full details of the analyses, the data displays and the algorithms to 
be used for data derivations. 
In general, trial data will be reported using summary tables, figures, and data 
listings. Descriptive statistics will be used to summarize the data. For continuous 
variables, the mean, standard deviation, median, minimum, and maximum will 
be provided. For discrete data, incidence and percentages will be provided. 
Statistical tests will be 2-sided at the alpha level of 0.05, unless stated otherwise. 
For the analysis of the PET data, O-GlcNAcase occupancy will be quantified for 
each post-dose PET scan as the fractional change from the subject’s baseline 
PET scan. Decreases in regional total volume of distribution (VT) from baseline 
to post-dose scans will be interpreted as an effect of O-GlcNAcase occupancy 
by ASN51. The Lassen plot will be used to estimate the target occupancy by 
calculating the changes of VT between baseline and post-dose against baseline 
VT for 14 brain regions of interest. The non-displaceable volume of distribution 
(VND) will be constrained to be equal for all scans within a subject. 
Occupancy estimates will be plotted against plasma concentrations of ASN51, 
corresponding to the start of each post-dose PET scan. The following model will 
be fitted to the occupancy data set. 
𝑅𝑂 = 100 × (𝐶𝑝 / (𝐶𝑝 + 𝐸𝐶50)) 
Where 𝑅𝑂 is the estimated receptor/target occupancy (%), 𝐶𝑝 is the measured 
plasma concentration of ASN51 (ng/mL) and 𝐸𝐶50 is the plasma concentration 
of ASN51 that corresponds to 50% receptor/target occupancy. 
Treatment-emergent AEs will be tabulated and summarized by Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and 
Preferred Term (PT). The number and percentage of patients who experienced 
AEs coded with the same PT and SOC will be summarized by treatment group 
(in descending order according to the incidence in the investigational study drug 


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group). Adverse events will also be tabulated by severity and by relationship to 
study drug. Summary tables will be accompanied by individual subject listings 
broken down by treatment group, including pre-dose events. SAEs will be listed 
and summarized similarly to AEs. Reasons for death will only be listed. Reasons 
for premature discontinuation of study drug will be listed and summarized by 
frequency tables. ECG variables, vital sign measurements and laboratory 
measurements will be summarized at each time point using mean, median, 
standard deviation, min, max, number of available observations, and change 
from baseline. Individual patient listings of ECG data, vital signs data and 
laboratory measurements will be provided.  
For PK and PD secondary endpoints, individual subject listings will be provided. 
Mean and individual plasma concentration-time profiles for ASN51 will be 
presented graphically for each group. PK variables will be summarized using 
arithmetic mean, STD, geometric mean, median, minimum, maximum, and 
%CV. 
Exploratory data-driven analyses will be performed with the caveat that any 
statistical inference will not have any confirmatory value. 
Listings of all individual subject data will be produced.  
Determination of 
Sample Size 
The trial is hypothesis generating, so no formal calculation of sample size is 
appropriate. The sample size of at most 10 subjects is considered adequate to 
allow modelling of the relationship between ASN51 plasma concentrations and 
the occupancy of O-GlcNAcase and is within the range generally accepted for 
PET studies. Enrolment of subjects into the study will be stopped as soon as 
the brain O-GlcNAcase occupancy versus ASN51 plasma concentrations is 
sufficiently characterized in opinion of the SRC. 






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7. 
MRI Scan: Screening MRI will occur once all other screening results are available.  If a subject is being re-screened (i.e. missed cohort) and there is 
already a recent MRI scan available within 3 months from their first screening period (ie if subjects were a reserve subject for a previous group but were not 
dosed and are no longer within the screening window) they do not need to have a repeat MRI scan.    
8. 
Venous cannulation: One for administration of [18F]-IMA601 (all imaging sessions) and one PK sampling (imaging sessions 2 and 3) (two venous 
cannulae be used).   
9. 
[18F]-IMA601 Administration: At the start of each PET scan. 
10. PET Scan: Subjects will have one baseline PET scan during imaging session 1, and two on-treatment PET scans during imaging sessions 2 and 3. For 
session 1, subjects will receive dosing water after a minimum of 10 hours fast (no food or drink except water) and will fast for a further 4 h after their dose 
with the PET scan done approximately 2 h after taking the dosing water.  Other than the dosing water, water is not allowed from 2 h before until 2 h after 
dosing. The times of on-treatment PET scans for all subsequent groups will be selected based on review of emerging data.  Subjects will have no more than 
3 PET scans in total during the study.   
11. ASN51 Administration: Subjects will receive an oral dose of ASN51 following a minimum 10 h fast (no food or drink except water) and will fast for a 
further 4 h after their dose.  Other than the water required to take the study medicine, water is not allowed from 2 h before until 2 h after dosing.   
12. Inpatient Discharge: Subjects will be inpatient until after their baseline PET in imaging session 1, and until at least 72 h after their dose of study drug in 
imaging sessions 2 and 3.    
13. Physical Examination: A full physical and neurological examination will be done at screening visit 1 and at the follow-up visit (or Early Termination 
visit).  All other indicated physical examinations (Day -1 for sessions 2 and 3) should be symptom-directed, and include neurological assessment of cranial 
nerves, motor, sensation, coordination, reflexes, and gait. 
14. Pregnancy and FSH: Pregnancy tests in WOCBP only:  serum at all timepoints except urine pregnancy test at the MRI visit.  FSH at screening only in 
post-menopausal women.  Urine pregnancy test at MRI screening visit to be done at PET site.  
15. Height, Weight, BMI: BMI and height will be measured at screening visit 1 only.  
16. Vital Signs: Vital signs consist of systolic and diastolic blood pressure, heart rate, tympanic temperature, and respiratory rate.  Assessments will be done at 
screening, on Day –1 at imaging session 1, pre-dose on Day 1 in imaging sessions 2 and 3, and at follow-up.  Single measurements will be made at all time 
points except screening. At screening, 3 measurements will be made, each 5 minutes apart.  Measurements should begin with subjects in a seated position, 
after they have rested for 5 min.  Additional unscheduled assessments may be done at the discretion of the Investigator.  
17. 12-Lead ECG: During the period of residence, ECGs will be recorded at the timepoints indicated.  Assessments will be done at screening visit 1, Day -1 of 
imaging session 1, and pre-dose on Day 1 in imaging sessions 2 and 3, and at the follow-up visit.  Single recordings will be done at all time points.  
Recordings should be made with subjects in a supine position, after resting for 10 min.  Additional unscheduled assessments may be done at the discretion 
of the Investigator. 
18. PK Sampling: Plasma samples for assay of the ASN51 will be collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 h post-
dose.  Samples scheduled immediately before the PET scan should be taken as close as possible to the planned start of the PET scan samples scheduled for 
the end of the PET scan should be taken as soon as possible after the PET scan is finished; and samples scheduled during the PET scan should be taken 
either before or after the PET scan, as close to the scheduled timepoint as possible. 
19. Hematology, biochemistry, coagulation, and urinalysis  to be taken 72 h post-dose in sessions 2 and 3. 
20. Timing of Assessments: If more than one assessment is foreseen for a timepoint, PET procedures prevail. All assessments should be staggered in the same 
order throughout the study with the PK sampling point closest to the scheduled timepoint. 


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3.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .....................................................................................................................1 
2.0 
STUDY SYNOPSIS ...........................................................................................................4 
3.0 
TABLE OF CONTENTS ................................................................................................14 
4.0 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................18 
5.0 
INTRODUCTION AND RATIONALE .........................................................................21 
5.1 
Background: O-GlcNAcylation and Protein Aggregation in 
Neurodegenerative Disease ....................................................................................22 
5.2 
ASN51 Mechanism of Action and Rationale in Alzheimer’s Disease ..................23 
5.3 
Nonclinical Studies ................................................................................................25 
5.4 
Clinical Experience ................................................................................................27 
5.5 
Summary of Overall Risks and Potential Benefits ................................................27 
6.0 
OBJECTIVES ..................................................................................................................28 
7.0 
INVESTIGATIONAL PLAN .........................................................................................29 
7.1 
Study Design ..........................................................................................................29 
7.2 
Treatment Assignment and Blinding .....................................................................30 
7.2.1 
Number of Subjects ...............................................................................30 
7.2.2 
Method of Assigning Subject Numbers to Treatment Groups ..............30 
7.2.3 
Blinding .................................................................................................31 
7.2.4 
Unblinding ............................................................................................31 
7.3 
Sites ........................................................................................................................31 
7.4 
Study Duration .......................................................................................................31 
7.5 
Study Safety Oversight ..........................................................................................31 
7.5.1 
Safety Review Committee.....................................................................31 
7.5.2 
Stopping Criteria Based on Urgent Safety Events ................................31 
7.5.3 
Criteria for Dose Level Selection ..........................................................32 
7.6 
Subject Discontinuation .........................................................................................32 
7.6.1 
Removal of Subjects .............................................................................32 
7.6.2 
Early Termination Procedure ................................................................33 
7.6.3 
Replacement of Subjects .......................................................................33 
7.7 
Study Completion ..................................................................................................33 
7.8 
Scientific Rationale for Study Design....................................................................34 
8.0 
POPULATION .................................................................................................................35 
8.1 
Use of Healthy Young Volunteers .........................................................................35 
8.2 
Inclusion/Exclusion Criteria ..................................................................................35 
8.3 
Subject Withdrawal ................................................................................................38 


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9.0 
STUDY DRUGS ...............................................................................................................39 
9.1 
Investigational Drug...............................................................................................39 
9.2 
Study Drug Preparation..........................................................................................39 
9.3 
Study Drug Packaging ...........................................................................................39 
9.4 
Study Drug Labeling ..............................................................................................39 
9.5 
Study Drug Administration ....................................................................................39 
9.6 
Concomitant Medications and Therapy .................................................................40 
9.7 
Treatment Compliance ...........................................................................................40 
9.8 
Non-Investigational Medicinal Product (non-IMP) ...............................................40 
9.9 
Storage and Return of Study Drug .........................................................................40 
9.10 
Diet, Activities, and Other Restrictions .................................................................41 
9.10.1 
Concomitant Medications .....................................................................41 
9.10.2 
Caffeine .................................................................................................42 
9.10.3 
Alcohol ..................................................................................................42 
9.10.4 
Physical Activities .................................................................................42 
9.10.5 
Dietary Aspects .....................................................................................42 
9.10.6 
Smoking ................................................................................................42 
9.10.7 
Definitions of Women of child-bearing potential .................................42 
10.0 
STUDY PROCEDURES AND ASSESSMENTS ..........................................................42 
10.1 
Structural MRI .......................................................................................................43 
10.2 
PET scan ................................................................................................................43 
10.3 
Clinical Safety Assessments ..................................................................................43 
10.3.1 
Informed Consent ..................................................................................43 
10.3.2 
Medical History and Demographics .....................................................43 
10.3.3 
FSH tests ...............................................................................................43 
10.3.4 
Drugs of abuse, urine alcohol and cotinine tests ...................................43 
10.3.5 
Weight and Height ................................................................................44 
10.3.6 
Physical and Neurological Examination ...............................................44 
10.3.7 
Vital Signs .............................................................................................44 
10.3.8 
Electrocardiogram .................................................................................44 
10.3.8.1 
ECG Parameters .............................................................................44 
10.3.9 
Prior and Concomitant Medications......................................................44 
10.3.10 
Adverse Events......................................................................................45 
10.4 
Clinical Laboratory Assessments ...........................................................................45 
10.4.1 
Serum Chemistry ...................................................................................45 
10.4.2 
Hematology ...........................................................................................45 


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10.4.3 
Urinalysis ..............................................................................................46 
10.4.4 
Coagulation Panel/(s) ............................................................................46 
10.4.5 
Pregnancy Testing .................................................................................46 
10.4.6 
Serum Hormone Markers ......................................................................46 
10.5 
Pharmacokinetic Assessments ...............................................................................46 
10.5.1 
Timing for Sampling .............................................................................46 
10.5.2 
Procedures for PK Blood Sampling ......................................................46 
10.5.3 
Shipping and Labeling ..........................................................................46 
10.5.4 
Bioanalysis ............................................................................................46 
10.5.5 
Pharmacokinetic Parameters .................................................................47 
10.6 
Total volume of blood removed .............................................................................47 
10.7 
Instructions for PET Scans.....................................................................................48 
10.7.1 
General Procedures ...............................................................................48 
10.7.2 
Assessment and management of risk ....................................................48 
11.0 
ADVERSE EVENT DEFINITIONS, REPORTING, AND FOLLOW-UP ................50 
11.1 
Definitions..............................................................................................................50 
11.1.1 
Adverse Event Associated with Study Procedures ...............................50 
11.1.2 
Adverse Event .......................................................................................50 
11.1.3 
Serious Adverse Event ..........................................................................50 
11.2 
Assessment of Adverse Events ..............................................................................50 
11.2.1 
Severity .................................................................................................51 
11.2.2 
Causality ................................................................................................51 
11.2.3 
Outcome ................................................................................................51 
11.3 
Adverse Event Reporting and Follow Up ..............................................................52 
11.4 
Procedures for Dealing with Severe Adverse Events ............................................52 
11.5 
Procedures for Handling Withdrawals Due to Adverse Events .............................53 
11.6 
Procedures for Reporting Pregnancies ...................................................................53 
11.7 
Trial Conduct .........................................................................................................54 
12.0 
STATISTICAL METHODS ...........................................................................................54 
12.1 
Statistical Analysis Plan (SAP) ..............................................................................54 
12.2 
Analysis Populations ..............................................................................................54 
12.3 
Sample Size ............................................................................................................55 
12.4 
Procedure for Accounting for Missing, Unused, and Spurious Data .....................55 
12.5 
Discontinuations ....................................................................................................55 
12.6 
Pharmacokinetic Statistical Analysis .....................................................................55 
12.7 
Safety and Tolerability Parameters ........................................................................56 


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12.8 
Exposure to Study Drug .........................................................................................57 
12.9 
Baseline Parameters and Concomitant Medications ..............................................57 
12.10 Exploratory Analyses .............................................................................................57 
12.11 PET Image Data Analysis ......................................................................................57 
12.11.1 
Image processing ...................................................................................58 
12.11.2 
Arterial blood data processing ..............................................................58 
12.11.3 
Signal change evaluation.......................................................................59 
12.11.4 
PET Data Reporting ..............................................................................59 
12.12 Clinical Study Report .............................................................................................59 
13.0 
TRIAL CONDUCT AND OVERSIGHT .......................................................................59 
13.1 
Ethics......................................................................................................................59 
13.1.1 
Research Ethics Committee or Medicines Healthcare and Products 
Regulatory Agency................................................................................60 
13.1.2 
Informed Consent ..................................................................................60 
13.2 
Investigator Responsibilities ..................................................................................60 
13.2.1 
Investigational Product Accountability .................................................61 
13.3 
Quality and Recordkeeping....................................................................................61 
13.3.1 
Quality ...................................................................................................61 
13.3.2 
Record Retention ...................................................................................62 
13.4 
Disruption Due to Coronavirus Disease 2019 Pandemic (COVID-19), 
Considerations for COVID-19 Vaccination, and COVID-19 Risk Mitigation......63 
13.5 
Publications ............................................................................................................63 
14.0 
REFERENCES .................................................................................................................65 
 
LIST OF TABLES 
Table 1: 
Visit and Assessment Schedule for Each Dose Level20 .............................11 
Table 2: 
Expected maximal radioactive exposure of each subject ..........................49 
 
 
 


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4.0 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or Term 
Definition/Explanation 
AChEI 
Acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADAS-Cog 
Alzheimer’s Disease (AD) Assessment Scale-Cognitive Subscale 
AE 
Adverse Event 
Ae 
Amount excreted 
ALT (SGPT) 
Alanine aminotransferase (Serum Glutamic Pyruvic Transaminase) 
ALP 
Alkaline phosphatase 
ANOVA 
Analysis of Variance 
AST (SGOT) 
Aspartate aminotransferase (Serum Glutamic Oxaloacetic Transaminase) 
ATC 
Anatomical Therapeutic Chemical Classification 
AUC 
Area Under the Curve 
AUC0-∞ 
Area under the curve from time zero to infinity 
AUC0-t 
Area under the curve from time zero to last concentration above LOQ 
BID 
Bis in die, twice a day dosing (or QD [once daily] 
BLQ 
Below Limit of Quantification 
BMI 
Body mass index 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CDR 
Clinical Dementia Rating: numeric scale used to quantify the severity of symptoms 
of dementia 
Cmax 
Maximum concentration 
CRF 
Case Report Form 
CNS 
Central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Computed tomography 
dL 
Deciliter 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ERP 
Event related potential 


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Abbreviation or Term 
Definition/Explanation 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials is the European Clinical 
Trials Database of all clinical trials of investigational medicinal products 
FDA 
Food and Drug Administration 
Fe 
Fraction (%) of amount excreted 
FSH 
Follicle stimulating hormone 
g 
Gram 
GFR 
Glomerular Filtration Rate 
GlcNAc 
β-D-N-acetylglucosamine 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
HIPAA 
Health Information Portability and Accountability Act of 1996 
ICH 
International Conference on Harmonization 
IEC 
Institutional ethics committee 
IMP 
Investigational Medical Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IU 
International unit 
IV 
Intravenous 
IWRS 
Interactive Web Response System, 
kg 
Kilogram 
L 
Liter 
LLOQ 
Lower limit of quantification 
λZ 
Rate elimination constant 
µg 
Microgram 
MAD 
Multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 


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Abbreviation or Term 
Definition/Explanation 
MMSE 
Mini-Mental State Examination 
MOA 
Mode of action 
MRI 
Magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
N 
Normal 
ng 
Nanogram 
NFTs 
Neurofibrillary tangles 
NOAEL 
Non observable adverse effect level 
OGA 
O-linked-β-N-acetylglucosaminidase 
O-GlcNAcase 
O-linked-N-acetylglucosaminyltransferase or OGA 
OGT 
O-linked-N-acetylglucosaminyltransferase 
PBMC 
Peripheral blood mononuclear cell 
PD 
Parkinson’s disease 
PET 
Positron emission tomography 
pH 
Hydrogen ion concentration 
PHF 
Paired helical filament 
PR 
ECG: time from the beginning of the P wave to the beginning of the QRS complex 
Pre 
Before 
QD 
Quaque die, once daily 
QRS 
ECG: The QRS complex represents the electrical impulse as it spreads through the 
heart ventricles 
PSP 
Progressive Supranuclear Palsy 
PT 
Preferred Term 
QT 
measurement that represents the total time interval from ventricular depolarization to 
complete repolarization 
QTcB 
heart rate-corrected QT interval according to Bazett’s formula 
QTcF 
heart rate-corrected QT interval according to Fridericia’s formula 
RBC 
Red Blood Cell 
ROI 
Region of interest 
SAD 
Single ascending dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 


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Abbreviation or Term 
Definition/Explanation 
SD 
Standard Deviation 
SF 
Straight filament 
SGOT (AST) 
Serum Glutamic Oxaloacetic Transaminase 
SGPT (ALT) 
Serum Glutamic Pyruvic Transaminase 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
t½ 
Terminal elimination phase half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
US 
United States 
WBC 
White Blood Cell 
VND 
Non-displaceable volume of distribution 
VT 
Regional total volume of distribution 
 
5.0 
INTRODUCTION AND RATIONALE 
ASN51 
 
 
 is under development for the treatment of 
neurodegenerative diseases caused by intracellular protein aggregates (proteinopathies) in the 
brain. ASN51 is indicated for the treatment of adults with Alzheimer’s Disease (AD). 
 
 
 
 
This single dose open study is a human Phase 1 trial in healthy adult (HA) subjects investigating 
the target receptor brain occupancy of ASN51 by means of PET scans. Establishing the target brain 
occupancy is important for dose selection because it has been shown 
 
 
 These data will serve as a basis for the dosing and dosing regimen in further 
clinical studies. The safety of ASN51 has been evaluated and there were no findings in non-clinical 
studies to date which would preclude the initiation of the planned Phase 1 study.  


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5.1 
Background: O-GlcNAcylation and Protein Aggregation in Neurodegenerative 
Disease  


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5.2 
ASN51 Mechanism of Action and Rationale in Alzheimer’s Disease 


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5.3 
Nonclinical Studies 
Nonclinical findings of potential clinical significance and relevance to this protocol are 
summarized briefly below; additional information is provided in the IB.  


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5.4 
Clinical Experience 
This study will be conducted in parallel to a separate Phase 1 single ascending dose (SAD) 
tolerability study in healthy young adult subjects (ASN51-101). Safety and pharmacokinetic data 
for each SAD cohort will be determined in ASN51-101 and will be reviewed by the safety 
review committee (SRC) prior to dosing in ASN51-102 at each respective dose level (Section 
7.5.1). Safety, pharmacokinetic and pharmacodynamic PET data will be assessed by the SRC 
prior to any further dosing in this study to determine the next dose level to be administered as 
well as the timing of the next PET scan in relation to the time of the study drug administration. 
Any dose level set by the SRC will not exceed 85% of the highest well-tolerated dose level in the 
single rising dose tolerability study ASN51-101. 
5.5 
Summary of Overall Risks and Potential Benefits 


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Risks attributable to the COVID-19 pandemic: To address these specific risks, a risk mitigation 
plan for staff, volunteers, and visitors will be followed throughout the study see also Section 13.4.  
6.0 
OBJECTIVES  
Primary Objective 
• To assess the brain O-GlcNAcase occupancy using [18F] IMA601 PET, following a 
single oral dose of ASN51 


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Secondary Objectives 
• To assess the relationship between the plasma concentration of ASN51, and the time-
course of brain O-GlcNAcase occupancy using [18F]-IMA601 PET, following a single 
oral dose of ASN51 
• To assess the single dose safety and tolerability of ASN51 in healthy adult subjects under 
fasted conditions 
 
7.0 
INVESTIGATIONAL PLAN 
7.1 
Study Design 
This is an open-label, adaptive-design PET study to investigate the occupancy of O-GlcNAcase 
by ASN51 after single oral doses in healthy adult male and female subjects (aged 25-55 years, 
inclusive). The study schema is depicted in Figure 2.  
Figure 2: 
Phase 1a ASN51-102 Study Schema 
 
Up to 10 subjects will be enrolled. Each subject will have up to 3 imaging sessions, with one scan 
in each session. In the first imaging session, subjects will have 240 ml of water followed by a 
baseline PET scan approximately 2 h later. In the second and third imaging sessions, subjects will 
receive a single oral dose of ASN51 with 240 ml of water, followed by an on-treatment PET scan. 
Safety and pharmacokinetic data of the SAD study ASN51-101 will be assessed by the SRC prior 
to the dosing of the first subject(s) to determine the first dose level to be administered in session 2 
after the baseline session 1 and the timing of the PET scans in relation to the study drug 
administration time. At most 2 subjects will be dosed on the same study day. For subsequent 
sessions, the dose level and the time of the PET scan in all imaging session 2 and 3 will be 
determined after review of the results from the first on-treatment PET scan, including the PK data. 
Subjects will receive an intravenous dose of the radiolabelled tracer, [18F]-IMA601, at the start of 
each PET scan.  
This study will have an adaptive design: to adequately evaluate the exposure versus receptor 
occupancy (RO) relationship, various doses of ASN51 of up to 85% of the highest well-tolerated 
dose level in the preceding SAD study ASN51-101, and the timing of on-treatment PET scans may 


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be altered based on emerging data or study logistical requirements. On-treatment PET scans may 
be scheduled up to 48 h post-dose. 
After each on-treatment PET scan, the SRC will review available RO, PK, safety and tolerability 
data, before selecting the dose and PET scan timings for imaging session 3. Arterial blood 
sampling will be done during each PET scan to quantify the parent tracer related radioactivity over 
the course of the PET scan, and to establish a tracer metabolite corrected plasma input function. 
The total arterial blood volume required for each tracer injection will not exceed 145 mL. Arterial 
cannulation and arterial blood sampling may be reduced or removed if analysis of PET data from 
previous subjects indicates that noninvasive analysis of the PET scan data can be done. If a non-
invasive analysis is not possible, the use of an arterial cannula with each PET scan will continue 
through the study.   
Subjects will be screened within 21 days before their baseline PET scan. Their on-treatment PET 
scans will be within 7 days of their baseline scan with an interval of 7–14 days between imaging 
sessions 2 and 3. Subjects will be confined for 72 h after the study drug administration in sessions 
2 and 3. After the baseline scan in session 1 without study drug administration, subjects may leave 
the unit in the evening. In the case of a technical failure (such as unsuccessful tracer synthesis), 
subjects may be asked to attend an additional on-treatment imaging session, in which they will 
receive a third oral dose of ASN51. There will be at least 7 days between each dose of ASN51. 
Subjects will not have more than 3 PET scans or 3 doses of ASN51 during the study. Subjects will 
have a follow-up visit at the research unit 7 days (± 3 days) after imaging session 3 (Day 8). 
7.2 
Treatment Assignment and Blinding 
7.2.1 
Number of Subjects 
Up to 10 healthy adult subjects will be enrolled.  All subjects will receive ASN51. 
Subjects who withdraw or are removed from the trial after receiving investigational medicinal 
product (IMP) and prior to completion of the Treatment Period may be replaced on a case-by-case 
basis, at the discretion of the Sponsor. 
7.2.2 
Method of Assigning Subject Numbers to Treatment Groups 
Subjects will be sequentially assigned a screening identification number upon signing of informed 
consent. Once eligibility is confirmed (Day 1 of imaging session 1), subjects will receive a 4-digit 
number on Day 1 before the start of the day’s study procedures. Subjects who replace discontinuing 
subjects who have started procedures/assessments on Day 1 will receive the number of this subject 
+1000, e.g., subject 2411 will replace subject 1411, subject 2211 will replace subject 1211, etc. 
The substitute subject will receive the treatment assigned to the withdrawn subject. The following 
subject numbers are assigned: 
Subject numbers 1411 – 1420, replacement subject numbers 2411 – 2420 


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7.2.3 
Blinding 
Not applicable 
7.2.4 
Unblinding 
Not applicable  
7.3 
Sites 
ASN51-102 is a single-center study.  
7.4 
Study Duration 
The estimated duration of subject participation for the four parts of the study is as follows: 
From Screening (3 weeks) to study conduct to follow-up (3 weeks) to telephone follow-up for 
potential SAEs (6 weeks): approximately 12 weeks for each subject.   
7.5 
Study Safety Oversight 
7.5.1 
Safety Review Committee 
The study will be monitored by an SRC. The SRC is intended to ensure that treatment does not 
pose undue risk to subjects and to determine the individual dose levels to be administered in the 
study as well as the timing of the PET scans in relation to the time point of the study drug 
administration. The SRC will review RO data (ASN51-102 study only) and all available PK, 
safety, and tolerability data at each dose level from the planned, parallel Phase 1 SAD/MAD study 
ASN51-101 prior to initiating dosing in ASN51-102 and prior to each dose within this study 
(ASN51-102).  
The SRC will be composed of the following core individuals: 
• Principal Investigator (PI) or delegate 
• Asceneuron SA medical monitor or delegate (must be a physician) 
 
7.5.2 
Stopping Criteria Based on Urgent Safety Events 
The study (including dose escalation) will be halted if any of the following occur: 
• One (1) serious adverse event (SAE) that is considered to be at least possibly related to 
study treatment; or  
• Two (2) or more severe non-serious or clinically significant AEs that are considered to be 
at least possibly related to study treatment irrespective of whether they occur in the same 
system organ class (SOC) or not. 


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If following an internal safety review, it is appropriate to restart the trial, a substantial amendment 
will be submitted to the MHRA and REC.  The trial will not restart until the amendment has been 
approved by the MHRA and REC. 
7.5.3 
Criteria for Dose Level Selection 
Safety and pharmacokinetic data will be assessed by the SRC prior to  
a) The first study drug administration   
b) All subsequent study drug administrations 
 
After each on-treatment PET scan, the SRC will review available RO, PK, safety and tolerability 
data, before selecting the dose and PET scan timings for the next imaging session.  
The SRC may stop dosing at any time if the SRC determines that the next dose would pose an 
undue risk to subjects.  
The safety and PK data will be reviewed by the SRC in an unblinded manner (e.g., with subject 
identifiers). For each meeting, the Investigator will prepare a report outlining a summary analysis 
of the safety data of the previous cohort. 
7.6 
Subject Discontinuation 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the trial 
at any time for any reason. The Sponsor must be notified of all subject withdrawals as soon as 
possible. 
7.6.1 
Removal of Subjects 
The Investigator and Sponsor also have the right to remove subjects from the trial. The Sponsor 
also reserves the right to discontinue participation of an individual subject. 
Subjects may be removed from the trial for the following reasons: 
• Occurrence of an AE or SAE that precludes further participation  
• Serious adverse event (SAE) considered related to study treatment. 


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• Any condition that, in the judgment of the Investigator or Sponsor, might place the subject 
at risk or invalidate the trial  
• Pregnancy in subject  
• At the request of the subject, Investigator, or Sponsor, for administrative or other reasons 
• Protocol deviation or noncompliance 
• One or more study drug administrations are missed 
• Alanine aminotransferase (ALT) ≥ 5 x upper limit of normal (ULN). 
• ALT ≥ 3 x ULN and total bilirubin ≥ 2 x ULN or international normalised ratio (INR) 
> 1.5.  (If a subject meets that withdrawal criterion, serum bilirubin fractionation 
should be performed.) 
• ALT ≥ 3 x ULN if associated with the appearance or worsening of rash or hepatitis 
symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash or eosinophilia).  Subjects who have -ALT  ≥ 3 x ULN and < 5 x ULN, total 
bilirubin < 2 x ULN or INR < 1.5, who do not exhibit hepatitis symptoms or rash, can 
continue in the study (and continue receiving trial medication) as long as they can be 
monitored at least weekly until abnormal results are within the reference range or 
close to pre‑treatment values. 
Subjects that experience an AE or SAE as defined above will be followed-up by the Investigator 
until the AE/SAE has resolved. If a subject discontinues from the trial prematurely, reasonable 
efforts should be made to perform the Early Termination Visit procedures, within four weeks of 
discontinuation. 
7.6.2 
Early Termination Procedure 
The early termination procedures are noted in the Schedule of Events, in any case the procedures 
foreseen for the follow-up visit must be completed (Table 1).  
7.6.3 
Replacement of Subjects 
Subjects who withdraw or are removed from the trial after receiving IMP and prior to completion 
of the Treatment Period may be replaced on a case-by-case basis, at the discretion of the Sponsor. 
7.7 
Study Completion  
The end of the trial is defined as the date of protocol-specified visit/assessment for the last subject 
participating in the trial. If the trial ends before all subjects are enrolled because the study 
objectives have been met, it will not be considered an early study termination. 


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7.8 
Scientific Rationale for Study Design 
ASN51 is a reversible and substrate competitive inhibitor of O-GlcNAcase that is currently being 
developed by Asceneuron S.A for the treatment of AD.  
The primary objective of this study is to investigate the occupancy of O-GlcNAcase using PET 
and the O-GlcNAcase ligand [18F]-IMA601, and to characterize the relationship between plasma 
concentration of ASN51 and the occupancy of O-GlcNAcase. These data will serve as a basis for 
the planning of the dosing and dosing regimen in further clinical studies.  
 
 
 


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8.0 
POPULATION 
8.1 
Use of Healthy Young Volunteers 
The ASN51-102 study will dose healthy young volunteers (HYV) for following reasons. HYVs 
have no confounding pathology or medication use that could interfere with this early phase study, 
are not expected to have vascular disease that would interfere with arterial cannulation, are unlikely 
to be taking concomitant medications (e.g., aspirin) that would contraindicate arterial cannulation, 
are better able to tolerate arterial cannulation, are better suited for obtaining a total of about 600mL 
of blood for full PK analysis and are better able to tolerate repeated PET scans. 
8.2 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
Individuals meeting all the following inclusion criteria and none of the exclusion criteria will be 
eligible to participate. None of the inclusion criteria are eligible for re-screening. No waivers will 
be granted and any deviation from below will get recorded as a major protocol deviation. An 
exception can apply for subjects who meet the inclusion and exclusion criteria, but then miss a 
cohort that is filled and so they are no longer eligible due to lapse of the 3-week screening window; 
these subjects may be rescreened.   
1. Healthy as determined by the Investigator, based on a medical evaluation including medical 
history physical examination, neurological examination, laboratory tests and cardiac 
monitoring.  
2. Men or women aged 25-55 years, inclusive (age range was selected on grounds of 
radiation burden). 
3. Women of child-bearing potential with partners of child-bearing potential (see Section 
9.10.7 for definitions) must agree to use highly effective contraception (per CTFG 2020; 
bilateral tubal occlusion, hormonal contraception associated with inhibition of ovulation 
except oral contraception, intra-uterine device with or without intrauterine hormone-
releasing system, sexual abstinence in relation to the preferred and usual lifestyle of the 
subject, ) from at least 28 days before first tracer dosing through 30 days after last dose of 
IMP. All women of child-bearing potential must have a negative pregnancy test result 
before administration of test article. Vasectomised partner is also an accepted a highly 
effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomised partner has received medical 
assessment of the surgical success. 
4.  Women of non-childbearing potential must be postmenopausal [the last menstrual period 
was at least 12 months ago, and FSH at screening confirms postmenopausal status], or have 
no uterus, ovaries, or fallopian tubes). Women who are surgically sterile must provide 
documentation of the procedure by an operative report or by ultrasound. 


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5. Non-sterilized male subjects who are not abstinent and intend to be sexually active with a 
female partner of childbearing potential must use a male condom plus spermicide from 1 
day prior to the first tracer administration throughout the total duration of the treatment 
period and 90 days after the last dose of IMP.  Periodic abstinence, the rhythm method, and 
the withdrawal method are not acceptable methods of contraception.  Male subjects should 
refrain from sperm donation throughout this period. 
6. Body weight > 50.0 kg for men and >45.0 kg for women and Body Mass Index within the 
range 18.5-30.0 kg/m2 (inclusive). 
7. Subjects must understand the nature of the study and must provide signed and dated written 
informed consent in accordance with local regulations before the conduct of any study-
related procedures. 
8. Subjects must be, in the opinion of the Investigator, able to participate in all scheduled 
evaluations, likely to complete all required tests, and likely to be compliant. 
9. Subjects must be fluent in the local language. 
10. Subjects must agree not to post any personal medical data related to the study or 
information related to the study on any website or social media site (e.g., Facebook, 
Twitter, etc.) until the trial has completed. 
Exclusion Criteria: 
Individuals who meet any of the following exclusion criteria will not be eligible to participate. 
1. A positive urine drug screen/alcohol test at Screening or Day -1. 
2. Any history of psychiatric disorders, including substance use disorders, according to the 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria. 
3. A diagnosis of intellectual disability (intellectual developmental disorder) or mental 
retardation. 
4. Significant suicide risk as assessed by C-SSRS. 
5. A positive Hepatitis B surface antigen or positive Hepatitis C antibody result at Screening. 
6. A positive test for human immunodeficiency virus (HIV) antibody at Screening. 
7. Alanine aminotransferase or aspartate aminotransferase levels greater than 1.5 times the 
upper limit of normal (ULN) at Screening or between Screening and first dose of tracer 
administration. 
8. Frequently used any tobacco-containing (e.g., cigar, cigarette, or snuff) or nicotine-
containing product (e.g., nicotine chewing gum, nicotine plasters, or other product used for 
smoking cessation) within 3 months prior to first dose of tracer.  Frequent use is defined as 
3 or more days per week.  Use of any tobacco- or nicotine-containing product is prohibited 
within 1 week of first dose of tracer. 
9. History of regular alcohol consumption within 12 months of the study defined as an 
average weekly intake of >21 alcoholic units/week for men or >14 alcoholic units/week 
for women. 


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10. Regularly consumed (e.g., more days than not) excessive quantities of xanthine-containing 
beverages (e.g., more than five cups of coffee or the equivalent per day) within 30 days 
prior to Screening or between Screening and first dose of tracer. 
11. Received or used an investigational product (including placebo) or device within the 
following time period prior to the first tracer dosing day in the current study: 90 days, 5 
half-lives or twice the duration of the biological effect of the investigational product 
(whichever is longer). 
12. Other than exceptions outlined in Section 9.10, use of prescription or non-prescription 
drugs, vitamins, herbal, and dietary supplements (including St John’s Wort) within 7 days 
(or 28 days if the drug is a potential hepatic enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study tracer medication. 
13. History of clinically significant sensitivity to any of the study medications, or components 
thereof or a history of drug or other allergy that, in the opinion of the Investigator or 
Medical Monitor, contraindicates their participation. 
14. Loss of more than 400 mL of blood within 3 months prior to first dose of tracer, i.e., blood 
donor. 
15. A positive serum pregnancy test or lactation. 
16. A history or presence of any disease, condition, or surgery likely to affect drug absorption, 
distribution, metabolism, or excretion. Subjects with a history of cholecystectomy should 
be excluded. 
17. A history or presence of a clinically significant hepatic, renal, gastrointestinal, 
cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic, 
dermatologic, or neurologic abnormality. 
18. A clinically significant abnormality on physical examination, neurological examination, 
ECG, or laboratory evaluations at screen or between screen and first tracer dose 
administration. 
19. A corrected QT interval measurement corrected according to the Fridericia rule (QTcF) > 
450 msec for males, 470 msec for females during controlled rest at screen or between 
screen and first tracer dose administration, or family history of long QT syndrome. 
20. Any clinically significant abnormalities in rhythm, conduction, or morphology of the 
resting ECG and any abnormalities in the 12-lead ECG that, in the judgement of the 
Investigator or Medical Monitor, may interfere with the interpretation of QTc interval 
changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy. 
21. PR (PQ) interval shortening < 120 msec (PR < 120 msec but > 110 msec is acceptable if 
there is no evidence of ventricular pre-excitation). 
22. PR (PQ) interval prolongation (>220 msec), intermittent second- (Wenckebach block while 
asleep or in deep rest is not exclusionary) or third-degree AV block. 
23. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch 
block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 120 msec. 


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24. A clinically significant vital signs abnormality at screening or between screening and first 
tracer dose administration.  This includes, but is not limited to, 3 measurements (each 5 
minutes apart) in the seated position: (a) systolic blood pressure < 90 or >140 mmHg, (b) 
diastolic blood pressure <50 or > 95 mmHg, or (c) heart rate < 45 or >100 beats per 
minute. The average of the 3 measurements should be used to assess eligibility.  
25. Significant (> 10%) weight loss or gain within 30 days prior to Screening and first tracer 
dose administration. 
26. A history of seizure. History of a single benign febrile convulsion of childhood is 
permitted. 
27. A history of head trauma, including closed head injury with loss of consciousness. 
28. A history of symptomatic orthostatic hypotension (i.e., postural syncope)  
29. A history of neuroleptic malignant syndrome. 
30. A history of chronic urinary tract infections. 
31. The subject is, in the opinion of the Investigator or Medical Monitor, unlikely to comply 
with the protocol or is unsuitable for any reason. 
32. Currently employed by Asceneuron SA or by a clinical trial site participating in this study, 
or a first-degree relative of an Asceneuron SA employee or of an employee at a 
participating clinical trial site. 
33. Unsatisfactory venous access 
34. Significant exposure to ionising radiation as part of research (defined as ICRP category IIb 
or above:  no more than 10 mSv in addition to natural background radiation including this 
trial), within the previous 12 months prior to first tracer dose administration.  
35. Unsuitable or unwilling to undergo the imaging procedures, as determined by an MRI 
safety questionnaire.  Reasons for exclusion include but are not limited to presence of a 
cardiac pacemaker or other implanted electronic device; ferromagnetic metal foreign 
bodies, intracranial aneurysm clips or other metallic objects; non-MRI compatible heart 
valves; inner ear implants; or a history of claustrophobia. 
36. Significant structural brain abnormality, as determined by MRI. 
37. Contraindication for arterial cannulation: Allen’s test indicating potential risk in 
placement of the arterial cannula.  
38. Subjects with a COVID-19 vaccination within two weeks of screening or due to receive 
second dose of COVID-19 vaccine while participating in the study. 
 
8.3 
Subject Withdrawal 
Please see Section 7.6.1. 
 


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9.0 
STUDY DRUGS  
9.1 
Investigational Drug 
Asceneuron SA will provide ASN51 for clinical trial use in the form of 
. ASN51 is 
provided in an immediate release 
 supplied in 
 dosage strengths. 
Investigational Medicinal Product (IMP) will be administered under the supervision of the 
Investigator or designee under fasted conditions. Each dose incl. date, time, witness will be 
recorded. 
9.2 
Study Drug Preparation 
All study drugs will be prepared (i.e., packaged and labeled in individual doses) by a pharmacist, 
or his/her designee. All study drugs will be dispensed by the Investigator or a person under his/her 
supervision together with another witness.  
9.3 
Study Drug Packaging 
Asceneuron SA will be responsible for the supply of the following drugs: 
• 
 containing 
 of ASN51 
The study drug will be packed and dispatched in containers. A batch release certificate will be 
provided, stating that the batches have been manufactured according to GMP. Study drugs are 
provided as 
 and supplied to the study center as a bulk shipment. Under the supervision of 
the pharmacist, the study drug will be packed per subject for each dosing occasion, according to 
the dosing specifications of the SRC. 
9.4 
Study Drug Labeling 
The trial medication will be packaged and labelled by the 
 Pharmacy, in accordance with 
The Rules Governing Medicinal Products in the EU (European Union), Volume 4: Good 
Manufacturing Practice (GMP), and with 
’s Manufacturing Authorisation for IMPs 
(MIA(IMP)). The IMP labels will include all the information required by Annex 13 to GMP 
9.5 
Study Drug Administration 
While in the study clinic, subjects are not allowed to consume any food and beverages not provided 
by the institution. Standardized meals will be provided. An extra amount of tap water will be given 
if it is required for the intake of the study drug, that will be recorded. 
The study drug will be administered together with 240 ml of tap water in fasted state following a 
minimum 10 h fast (no food or drink except water) and will fast for a further 4 h after their dose.  
Other than the water required to take the study medicine, water is not allowed from 2 h before until 
2 h after dosing. These restrictions also apply to the session 1 baseline PET scan such that all PET 
scans are carried out under the same conditions.  


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9.6 
Concomitant Medications and Therapy 
Investigators may prescribe any concomitant medications or treatments deemed necessary to 
provide adequate supportive care.  All concomitant medications taken during the trial will be 
recorded with indication, dose information, and dates of administration.   
9.7 
Treatment Compliance 
Site personnel will maintain a record of all IMP dispensed to each subject.  
For this trial, treatment compliance is defined as completion of 100% of scheduled doses, because 
the study drug administration is under direct control of the Investigator or designee. 
9.8 
Non-Investigational Medicinal Product (non-IMP) 
The radioligand [18F]-IMA601 (non-IMP) will be prepared by the PET site. 
Product name: [18F]-IMA601 (also known as [18F]OGA1) 
Dosage form: Solution 
Effective dose: maximum 2.46 mSv each PET scan, as it includes components from PET (2.1 mSv) 
and CT scans (0.36 mSv)  
Injected activity: Will not exceed 100 MBq for each PET scan 
Route of administration:  intravenous bolus 
Manufacturer/source of procurement: PET site§ 
§ cGMP grade precursor will be procured from an external commercial source 
9.9 
Storage and Return of Study Drug 
Upon receipt of the study drugs, the responsible pharmacist will inspect all study drugs for 
completeness. Subsequently, he/she must immediately return the enclosed acknowledgement of 
receipt form; duly completed and signed (the date of receipt must be noted). 
The pharmacist is responsible for storage of the study drug at the study site in an appropriate 
lockable room at refrigerated temperature (2-8 C). The drug will be stored according to the 
instructions provided by Asceneuron SA. Only the pharmacist or his/her assistant, who are 
otherwise not involved in the study, will handle the study drug. 
A dispensing record (or similar document) as well as a Drug Accountability Record must be kept 
current and should contain the following information: 
• Subject number for whom the drug was prepared 


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• Initials and date of the person who prepared the study drug 
• Dates on which drug was prepared and quantity of the drug prepared 
• The inventory must be available for inspection by the monitor 
After sponsor confirmation, all unused investigational material (drugs and packaging) must be 
destroyed by the site on termination of the study and after a drug accountability check by the 
monitor, listing the following: 
• All ASN51 administered 
• All unused ASN51  
• All ASN51 destructed by the site 
Alternatively, upon request of Asceneuron SA, the pharmacist may send back the unused 
investigational drug. The pharmacist will be responsible for the inventory and accountability of all 
Clinical Trial Material, exercising accepted pharmaceutical practices. An accurate, timely record 
of the Clinical Trial Material will be maintained. Only after completion of the study, the Clinical 
Trial Material and the inventory will be available for inspection by the designated representatives 
of Asceneuron SA upon request. The original dispensing records and Drug Accountability Record 
are considered as source data and will be archived at the site. 
9.10 
Diet, Activities, and Other Restrictions 
9.10.1 
Concomitant Medications 
Use of prescription or non-prescription drugs, vitamins, herbal, and dietary supplements 
(including St John’s Wort) within 7 days (or 28 days if the drug is a potential hepatic enzyme 
inducer) or 5 half-lives (whichever is longer) prior to the first dose of study tracer medication 
and until the Follow-up visit.   
The use of other types of concomitant medication is not allowed from 1 week prior to the first 
dose of study tracer medication until the Follow-up, except for paracetamol (at most 2g /day) or 
medication that is required for the treatment of AEs. If concomitant medication is needed during 
the study, this medication must be recorded on the eCRF, stating its generic name, time of 
administration, dose, route and duration, as well as the reason for administration. 
Subjects who received a COVID-19 vaccination within two weeks of screening will be excluded 
from the study. Concomitant administration of a COVID-19 vaccination during the course of 
study participation will not be permitted. 
An exception applies to the use of hormonal contraceptives as follows: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o intravaginal 


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o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o injectable 
o implantable  
• intrauterine hormone-releasing system (IUS) 
9.10.2 
Caffeine 
Subjects will abstain from ingesting caffeine- or xanthine- containing products (e.g. coffee, tea, 
cola drinks and chocolate) from 24 hours prior to first tracer dose administration until 72 hours 
after each study drug administration.  
9.10.3 
Alcohol 
Subjects will abstain from alcohol for 48 hours prior to first tracer dose administration until the 
follow up visit.  
9.10.4 
Physical Activities 
 
Subjects will abstain from strenuous exercise from 7 days prior to first tracer dose administration 
until the last follow up visit. Subjects may participate in light recreational activities during the 
study. 
9.10.5 
Dietary Aspects  
Consumption of Seville oranges or grapefruit (or their juices) is not allowed from 7 days prior to 
the first dose of the tracer medication until 72 hours after the last study drug administration. 
9.10.6 
Smoking 
Use of any tobacco- or nicotine-containing product is prohibited from 1 week prior to first tracer 
administration until 72 hours after the last study drug administration. 
9.10.7 
Definitions of Women of child-bearing potential 
A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
 
10.0 
STUDY PROCEDURES AND ASSESSMENTS  
The Schedule of Events, including allowed visit windows, assessments, and procedures to be 
conducted at each visit are detailed in Table 1. Guidelines for study procedures and assessments 
are discussed briefly in the following sections. 


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10.1 
Structural MRI 
Structural MRI acquisition will be performed at 
 and will consist of a structural scanning 
protocol. MRI scans will be evaluated by a radiologist to exclude any subjects with major 
pathology or abnormalities. A radiologist’s report will be provided for each MRI scan to the 
Investigator at 
 
10.2 
PET scan 
Dynamic PET scans will be performed at 
 using a Siemens Biograph 6 PET/computed 
tomography (CT) scanner (Siemens Healthcare, Erlangen, Germany). The subjects will be placed 
in the PET scanner during the scan. A low dose CT scan will be performed to correct for the 
attenuation of emitted radiation. Subjects will then receive an intravenous bolus injection of up 
to 100 MBq of the [18F]-IMA601 radioligand. Dynamic emission data will be recorded for up to 
about 90 min after injection of the radioligand. 
10.3 
Clinical Safety Assessments 
Assessments to characterize safety and tolerability of ASN51 are described below; associated 
planned analyses are described Section 12.7.  
10.3.1 
Informed Consent 
Informed consent will be obtained as outlined in Section 13.1.2. 
10.3.2 
Medical History and Demographics 
Medical history includes active conditions, and any medical illnesses, diagnoses, and surgeries 
considered clinically relevant by the Investigator.  
Demographic information (year of birth, sex, race, ethnicity) will be recorded at Screening (as 
allowed by local regulations). 
10.3.3 
FSH tests 
Serum FSH tests will be done using a chemiluminescent immunoassay method. 
10.3.4 
Drugs of abuse, urine alcohol and cotinine tests 
Urine will be tested for drugs of abuse, urine alcohol and cotinine according to the 
laboratory’s SOP. Tests will include: amphetamines, cocaine, opiates, cannabis, barbiturates, 
benzodiazepines, and cotinine 


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10.3.5 
Weight and Height 
Weight (measured in kilograms) and height (in meters) will be measured and recorded as noted in 
the Schedule of Events. Subjects may remain in clothes (without shoes). A standing height will be 
measured and recorded using a stadiometer at the Screening Visit only.  
10.3.6 
Physical and Neurological Examination  
Complete physical examinations will be performed by a licensed professional at Screening, at 
follow-up, and at early termination, when applicable. A complete physical examination includes 
general appearance; head, eyes, ears, nose, and throat; and cardiovascular, dermatologic, 
respiratory, gastrointestinal, musculoskeletal, and neurologic systems.  
All other indicated physical examinations should be symptom-directed, and include neurological 
assessment of cranial nerves, motor, sensation, coordination, reflexes, and gait. 
Findings will be recorded as normal/abnormal for each parameter with additional description as 
indicated. 
10.3.7 
Vital Signs 
Vital signs include systolic and diastolic blood pressure (mm Hg), heart rate (beats per minute), 
respiration rate (breaths per minute), and temperature (°C; tympanic). Measurements will be 
obtained as noted in the Schedule of Events. At screening, obtain triplicate blood pressure 
measurements (5-minute intervals) while the subject is seated; use the average to assess eligibility. 
During the study, blood pressure may be assessed as single recording in seated  position after a 
rest of 5 minutes. 
 
 
10.3.8 
Electrocardiogram 
Routine single 12-lead ECGs will be performed after the subject has rested for a minimum of 10 
minutes. All ECGs will be stored digitally. ECGs may be repeated once to rule out a technical 
error with new lead placement; only the values of the second recording will be entered into the 
data base. Perform additional assessments as clinically indicated. 
10.3.8.1 
ECG Parameters  
ECG Parameters include PR interval, QRS duration, QT interval, QTcB, and QTc-Fredericia’s 
correction (QTcF). ECGs will be interpreted as normal, abnormal clinically not significant (ncs), 
or abnormal-clinically significant (cs). 
10.3.9 
Prior and Concomitant Medications   
Investigators may prescribe any concomitant medications or treatments deemed necessary to 
provide adequate supportive care. 


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All concomitant medication and concurrent therapies will be documented at Screening and at all 
subsequent visits. Medications (investigational, prescription, over-the-counter, and herbal) and 
nutritional supplements taken during the 30 days prior to Day 1 of imaging session 1 will be 
reviewed and recorded as prior medications. Change in concomitant medication since the previous 
visit will be recorded. Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured.  
If subject is taking high dose biotin supplements (found in multivitamins, biotin supplements, and 
supplements for hair, skin, and nail growth), site personnel is to advise on the potential for 
laboratory test interference with certain safety labs.  
10.3.10 
Adverse Events 
All events meeting the definition for AE, SAE, and pregnancy will be assessed and reported 
following guidelines provided in Section 11.0. At Day -1, during the confinement period at regular 
intervals, and at follow-up, subjects will be asked about any new or ongoing AEs since the previous 
inquiry. Four weeks after last dose of tracer administration, an inquiry via phone will be done for 
the identification of potential SAEs. 
Clinically significant changes from baseline in any safety or clinical laboratory parameter will be 
recorded as AEs or SAEs, if deemed appropriate by the Investigator. 
Subjects who discontinue due to a treatment-emergent SAE will be followed-up by the Investigator 
until the SAE has resolved (Section 7.6.1). 
 
10.4 
Clinical Laboratory Assessments 
Laboratory assessments will be used routinely to assess IMP safety in all subjects. After first 
administration of IMP, clinically significant abnormal laboratory findings must be documented as 
an AE. Samples will be collected as noted in the Schedule of Events (Table 1). Clinical laboratory 
parameters to be assessed for safety are listed in Appendix A.  
Fasting for a minimum of 4 hours prior to each blood draw is required and fasting status will be 
recorded. All clinical laboratory assessments will be conducted by the local laboratory unless 
otherwise specified. Communicate to the laboratory if the subject is receiving biotin supplements 
as high-dose biotin may interfere with certain laboratory assessments.  
10.4.1 
Serum Chemistry 
Blood samples will be obtained for serum chemistry (Appendix A). 
10.4.2 
Hematology  
Blood sample will be obtained for hematology (complete blood count with differential; Appendix 
A).  


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10.4.3 
Urinalysis 
A urinalysis panel (dipstick with microscopic examination on positives; Appendix A) will be 
obtained. 
10.4.4 
Coagulation Panel/(s) 
A coagulation panel will be obtained (Appendix A).  
10.4.5 
Pregnancy Testing  
A negative serum pregnancy test is required from WOCBP within 24 hours before the first dose 
of IMP. Additional serum pregnancy tests (or urine pregnancy tests for MRI visit at 
) will 
be obtained from females (WOCBP) at all subsequent clinic visits as noted in the Schedule of 
Events (Table 1).  
All pregnancy tests will be performed at the site’s local laboratory 
. Pregnancy 
in subject or partner must be reported (Section 11.6); pregnant subjects will be discontinued from 
the trial.   
10.4.6 
Serum Hormone Markers 
See Appendix A 
10.5 
Pharmacokinetic Assessments 
10.5.1 
Timing for Sampling 
See Table 1. 
10.5.2 
Procedures for PK Blood Sampling 
About 2.0 mL blood for the PK samples will be collected via vena puncture or via an intravenous 
(i.v.) cannula placed following the local standard procedures. Information on equipment and 
further details on the procedures on the sampling are documented in a separate instruction 
manual. 
10.5.3 
Shipping and Labeling 
Labeling and shipping instructions are provided in the Study Laboratory Manual. 
10.5.4 
Bioanalysis 
The concentrations of ASN51 in plasma will be determined using a validated LC-MS/MS assay. 
In addition, urine samples may be analyzed for occurrence of metabolites of ASN51 with an 
exploratory method if warranted. 
 


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10.5.5 
Pharmacokinetic Parameters 
 The plasma PK parameters for ASN51 will be derived by non-compartmental analysis of the 
plasma concentration-time profiles at the end of study only. 
The following pharmacokinetic parameters are defined: 
 
• The area under the plasma concentration-time curve from time zero to time t of the last 
measured concentration above the limit of quantification (AUC0-t). 
• The area under the plasma concentration-time curve from zero to infinity (AUC0-). 
• The maximum plasma concentration (Cmax). 
• The time to reach maximum plasma concentration (tmax). 
• The terminal elimination rate constant (λZ) with the respective half-life (t½) 
• The percentage of the extrapolated AUC. 
AUC0-t will be calculated according to the linear up/log down trapezoidal method using the 
measured concentration-time values above the limit of quantification (LOQ). AUC0- will be 
calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained 
by Ct/λZ, where Ct is the last plasma concentration measured above the LOQ and λZ represents the 
terminal elimination rate constant determined by log-linear regression analysis of the measured 
plasma concentrations of the terminal elimination phase. The half-life will be calculated as 
follows: t½ = ln 2 / λZ. 
The Cmax, and time to peak concentration (tmax) will be directly determined from the observed 
plasma concentrations data. AUC0-t will be calculated using linear up/log down trapezoidal method 
using the measured concentration-time values above the limit of quantification (LOQ). 
All PK parameters will be based on actual blood sampling times [h] (relative to the corresponding 
administration time) rounded to two digits and negative pre-dose times will be set to zero. 
10.6 
Total volume of blood removed 
Hematology: 7 x 2mL = 14 mL 
 
Clinical Chemistry: 7 x 3.5mL = 24.5 mL 
Coagulation: 7 x 3mL = 21 mL 
 
FSH, Serology: 1 x 3.5 mL = 3.5 mL 
Pregnancy Test*: 4 x 3.5 mL =14mL  
PK: 32 x 2 mL = 64 mL 
 
Arterial blood: 3 x 145 mL = 435mL  
Total: 576 mL within about 4-6 weeks 
*included in serology sample at screening 


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If a study session is repeated because of a PET scan failure, an extra 53 mL of blood may be 
taken during the whole study.  
No more than an extra 50 mL of blood will be taken from any subject.  
10.7 
Instructions for PET Scans 
10.7.1 
General Procedures 
If arterial cannulation will be used, the patency of subjects’ ulnar and radial arteries in both wrists 
will be checked, at screening and before insertion of the arterial cannula on scanning days (Allen’s 
test). Up to 10 subjects will be enrolled. At most 2 subjects will be dosed in parallel. Each subject 
will have up to 3 imaging sessions, with one scan in each session. In the first imaging session, 
subjects will have 240 ml of water followed by a baseline PET scan approximately 2 h later. In the 
second and third imaging sessions, subjects will receive a single oral dose of ASN51 with 240 ml 
of water, followed by an on-treatment PET scan. 
  
The study will have an adaptive design: to adequately evaluate the exposure versus RO 
relationship, various doses of ASN51 up to 85% of the highest well-tolerated dose in the SAD 
study ASN51-101 may be tested, and the timing of on-treatment PET scans may be altered based 
on emerging data or study logistical requirements. On-treatment PET scans may be scheduled up 
to 48 h post-dose. Before each on-treatment PET scan, the SRC will review available RO, PK, 
safety and tolerability data, before selecting the dose and PET scan timings for all on-treatment 
imaging sessions. Subjects will receive an intravenous dose of the radiolabelled tracer, [18F]-
IMA601, at the start of each PET scan.  
 
  
Arterial blood sampling will be done during each PET scan to quantify the parent tracer related 
radioactivity over the course of the PET scan, and to establish a tracer metabolite corrected plasma 
input function. The total arterial blood volume required for each tracer injection will not exceed 
145 mL. Arterial cannulation and arterial blood sampling may be reduced or removed if analysis 
of PET data from previous subjects indicates that noninvasive analysis of the PET scan data can 
be done. If a non-invasive analysis is not possible, the use of an arterial cannula with each PET 
scan will continue through the study.  
 
Subjects will be screened within 21 days before their baseline PET scan. Their on-treatment PET 
scans will be within 28 days of their baseline scan with an interval of 7–14 days between imaging 
sessions 2 and 3. Subjects will be confined from Day -1 until about 72 h after drug intake in on-
treatment sessions 2 and 3. In session 1, subjects will be confined from day -1 and may leave the 
clinical unit in the evening of the PET scan on Day 1. In the case of a technical failure (such as 
unsuccessful tracer synthesis), subjects may be asked to attend an additional on-treatment imaging 
session, in which they will receive a third oral dose of ASN51. There will be at least 7 days between 
each dose of ASN51. Subjects will not have more than 3 PET scans or no more than 3 doses of 
ASN51 during the study. 
10.7.2 
Assessment and management of risk 
Risk associated with the imaging techniques 


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Subjects in this study will be exposed to an additional dose of ionising radiation as a result of their 
participation. The majority of the radiation dose comes from the administered radioligand, while 
a smaller portion comes from a low dose computed tomography (CT) scan performed to estimate 
tissue attenuation. To mitigate this risk, the study will exclude subjects who have had previous 
exposure to ionising radiation such that, their exposure would be > 10mSv for the previous year. 
A maximum of 100 MBq of [18F]-IMA601 will be injected for each PET scan and the maximal 
effective dose from ionising radiation for an individual will not exceed 7.4 mSv from the PET and 
low-dose CT scans. The maximal radiation exposure for each subject over the whole study is 
presented in Table 2. 
Table 2: 
Expected maximal radioactive exposure of each subject 
Assessment 
Number 
of scans 
Effective dose per 
injected activity 
(mSv/MBq) 
PET tracer 
Activity (MBq) 
Effective dose 
per scan (mSv) 
Total exposure 
(mSv) 
PET emission scan 
3 
0.021 
100 
2.1 
6.3 
Low-dose CT scan 
3 
 
 
0.36 
1.08 
TOTAL 
 
 
 
 
7.4 
A maximal study exposure of 7.4 mSv for a participant, places this study towards the top of 
Category IIb (< 10 mSv) of the guidance published by the International Commission for Radiation 
Protection (ICRP). Following the ICRP 62 guidance that provides a guideline of ≤10 mSv per 
study 
where 
research 
subjects 
are 
not 
expected 
to 
benefit 
personally.  
 
Magnetic resonance images delineating brain anatomy will be acquired in this study to aid PET 
image analysis. There are no known risks to subjects associated with MRI scanning, provided that 
they have no contraindications to MRI as listed in the exclusion criteria. Potential risks associated 
with metallic implants will be mitigated by administration of a questionnaire and careful screening. 
At all times while subjects are on the ward, registered nurses will provide care and supervision. 
Risk associated with arterial cannulation 
Before the PET-CT scan, subjects will have a cannula inserted into the radial artery by qualified 
staff using aseptic technique under local anaesthesia. That insertion may be uncomfortable, cause 
minor local bleeding and bruising, and can rarely lead to complications (e.g., a blood clot could 
form around the cannula). Most people have no after-effects of cannulation. However, very 
occasionally, it may cause a small scar. Very rarely, more serious complications can occur, 
although these usually occur when the radial artery is cannulated in sick people for therapeutic 
purposes, rather than in healthy subjects for research purposes. 
 


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11.0 
ADVERSE EVENT DEFINITIONS, REPORTING, AND FOLLOW-UP 
All AEs, SAEs, SARs, and pregnancies occurring during the protocol-specified timeframes 
(Table 1) will be assessed and reported per guidelines provided in the following sections. 
11.1 
Definitions 
11.1.1 
Adverse Event Associated with Study Procedures 
A procedure-related AE is an AE considered by the Investigator to be related to a procedure 
required by the protocol (i.e., temporally associated or known risk of the procedure).  
11.1.2 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. The term “adverse event” could include any of the following events 
that develop or increase in severity during the course of the trial. Examples include: 
• Any sign, symptom, or physical examination finding that worsens in nature, severity, or 
frequency compared to baseline irrespective of association with the condition under study 
• Any clinically significant laboratory abnormality or laboratory abnormality that requires 
medication or hospitalization 
• Reactions to study drug(s) including those occurring as a result of an overdose, abuse, 
withdrawal phenomena, sensitivity, or toxicity 
• Concurrent illness 
• Injury or accident 
Conditions present prior to enrollment are considered Medical History. Pre-existing conditions 
should be reported as a TEAE if there is a change in the frequency, intensity, or the character of 
the condition.  
11.1.3 
Serious Adverse Event 
A SAE is an AE that: 
• results in death 
• is considered life threatening 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent/significant disability/incapacity 
• results in a congenital anomaly/birth defect; or  
• other medially important serious medical event 
11.2 
Assessment of Adverse Events 
For each AE, the Investigator will assess the severity, causality, and outcome. 


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11.2.1 
Severity  
AEs should be graded as mild, moderate, severe, life-threatening, or death using the following 
definitions:  
• Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention generally not indicated 
• Moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
• Severe: interrupts normal daily activities and generally requires systemic drug therapy or 
other treatment; usually incapacitating. 
• Life-threatening: urgent intervention indicated 
• Death: events that results in death 
Severity is not considered a guide for defining regulatory reporting obligations. 
11.2.2 
Causality 
The Investigator should consult the IB when assessing relationship to study drug and consider all 
possible etiologies for the AE. The Investigator will assess the causality of the AE to study 
procedure or study drug as follows: 
1) Attributions for “Unrelated” events: 
• Unrelated:  the AE is clearly not related to the study drug/procedure, beyond a reasonable 
doubt 
• Unlikely Related:  the AE is doubtfully related to the study drug/procedure 
2) 
Attributions for “Related” events: 
• Possibly Related: the AE may be related to the study drug/procedure 
• Probably Related: the AE is likely related to the study drug/procedure 
• Definitely Related: the AE is clearly related to the study drug/procedure 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related will 
be considered Unrelated. 
AEs listed as related are considered to have a suspected “reasonable causal relationship” to the 
study drug/intervention (ICH E2A). The expression "reasonable causal relationship" is meant to 
convey in general that there are facts (evidence) or arguments to suggest a causal relationship. 
11.2.3 
Outcome 
The outcome of an AE associated will be assessed as follows: 


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• Recovered/Resolved: the event has improved or recuperated 
• Not recovered/Not Resolved: the event has not improved or recuperated 
• Recovered/resolved with sequelae: the participant recuperated but retained pathological 
conditions resulting from the prior disease or injury 
• Fatal: termination of life as a result of an AE  
• Unknown: not known, not observed, not recorded 
11.3 
Adverse Event Reporting and Follow Up 
All AEs (i.e., any new or worsening in severity or frequency of a preexisting condition) with onset 
after the subject signs consent for trial participation must be promptly documented on the AE 
electronic case report form (eCRF). Details of the AE must include severity, relationship to study 
drug, duration, and outcome. Serious Adverse Events Reporting 
SAEs must be reported to the Sponsor (or designee) within 24 hours of the knowledge of the 
occurrence.  
An SAE report will be completed as thoroughly as possible including all available details about 
the event and the signature of the Investigator. The SAE form will be updated when additional 
information is received. 
A death occurring during the trial must be reported to Sponsor or its designee within 24 hours of 
knowledge of the death whether or not it is considered treatment-related.   
The Investigator also must notify the IRB/IEC of the occurrence of the SAE, in writing, as soon 
as is practicable and in accordance with IRB/IEC requirements and local law. A copy of this 
notification must be provided to Sponsor or its designee. 
Subjects will be instructed to contact the Investigator site and report any adverse events that 
develop after being discharged from the clinical unit. The Investigator will advise the subject on 
appropriate treatment, if necessary, and will follow the subject up until the adverse event resolves 
or the subject is lost to follow-up. If, in the investigator’s opinion, the adverse event could be 
related to sterility issues with [18F]-IMA601, the investigator will inform 
 In the event of a 
positive sterility result, 
 Quality Assurance department will be informed and an 
investigation following the process as outlined in 
 standard operating procedures will be 
initiated. 
11.4 
Procedures for Dealing with Severe Adverse Events 
In the event of any SAE which, in the investigator’s opinion, justifies termination or modification 
of the trial (see Section 7.5.2), dosing will be stopped and the sponsor’s medical monitor will be 
informed immediately (within 24 h of the investigator becoming aware of the event) by telephone 
or email, as follows. 
 MD, MSc, PhD  
Tel: 
 


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Email: 
  
Mobile: 
 
For all SAEs, the investigator will complete a SAE form and provide it to the sponsor’s 
pharmacovigilance department immediately (within 24 h of the investigator becoming aware of 
the event), as follows. 
 MD, MSc, PhD  
Tel: 
 
Email: 
  
Mobile: 
 
The 
sponsor 
will 
also 
be 
notified 
by 
email 
 
The investigator will notify the REC of SAEs that occur during this trial, if applicable, in 
accordance with the SOPs issued by the Research Ethics Service (RES). 
The sponsor is responsible for determining the expectedness of the event, using the reference safety 
information in the Investigator’s Brochure. The sponsor will notify the MHRA of all suspected 
unexpected serious adverse reactions (SUSARs), and will be responsible for ensuring that the REC 
is notified of SUSARs, if applicable. 
SUSARs that are fatal or life-threatening must be notified to the MHRA and REC within 7 days 
after the sponsor has learned of them. Other SUSARs must be reported to the REC and MHRA 
within 15 days after the sponsor has learned of them. 
11.5 
Procedures for Handling Withdrawals Due to Adverse Events 
The investigator will assess the reason for withdrawal as far as possible and will fully record the 
circumstances and medical details. Provided that subjects give written informed consent, they will 
undergo the standard medical examination and laboratory tests at withdrawal from the trial which 
they would have undergone had they completed it (see also Section 7.6.1). 
11.6 
Procedures for Reporting Pregnancies 
Subjects will be asked to follow the contraception guidance in Section 8.1. 
If, during the study, the investigator becomes aware of a pregnancy in a subject, or a partner of a 
subject, they will inform the sponsor’s pharmacovigilance department immediately (within 24 h 
of the investigator becoming aware of the event), as follows. 
 MD, MSc, PhD  
Tel: 
 
Email: 
  


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Mobile: 
 
The investigator will follow-up the pregnancy according to 
 SOPs, provided the subject’s 
partner consents to that. A pregnancy will not constitute an SAE unless it meets one of the criteria 
in Section 11.3. 
11.7 
Trial Conduct 
This study will be conducted in compliance with the protocol approved by the Research Ethics 
Committee (REC) and the Medicines Healthcare and Products Regulatory Agency (MHRA), and 
according to Good Clinical Practice standards.  No deviation from the protocol will be 
implemented without the prior review and approval of the REC/MHRA except where it may be 
necessary to eliminate an immediate hazard to a research subject.  In such case, the deviation will 
be reported to the REC/MHRA as soon as possible. 
12.0 
STATISTICAL METHODS 
The completeness of the data affects the integrity and accuracy of the final trial analysis. Therefore, 
every reasonable effort will be made to ensure complete, accurate, and timely data collection, and 
to avoid missing data. In general, missing data will be treated as missing and no statistical 
imputation method will be used unless stated otherwise.  The procedures for handling missing, 
unused, or spurious data will be presented in the Statistical Analysis Plan (SAP). 
12.1 
Statistical Analysis Plan (SAP) 
A SAP (and data management plan (DMP), if appropriate) will be written and finalized before the 
database closure. The SAP will provide full details of the analyses, the data displays and the 
algorithms to be used for data derivations.  
The SAP will include the definition of major and minor protocol deviations/violations and the link 
of major protocol deviations/violations to the analysis sets. 
Any deviations from the original statistical plan will be described and justified in the final report. 
12.2 
Analysis Populations 
Three different analysis sets are defined. Subjects who withdraw from the study, or who have 
missing data, will be included in the statistical analyses provided that they are eligible for 
inclusion in the analysis population as described below. 
All-treated set: This analysis set includes all randomized subjects who received study drug (at 
least one dose). 
Safety set: This analysis set includes subjects from the all-treated set who had at least one safety 
assessment post-baseline. The safety set will be employed in the analysis of tolerability and 
safety variables.  


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PET population: The PET population will consist of randomised subjects who receive study 
medication, have a baseline PET scan, at least one post-baseline PET scan, and a PK result 
immediately preceding PET scan. 
PK analysis population: The PK analysis population will consist of the subjects who provide 
evaluable data for the comparisons of interest. These subjects should have at least one 
quantifiable plasma concentration, should not have violated any major entry criterion likely to 
confound the PK analysis, and should not have deviated significantly from the protocol between 
enrolment and successful study completion 
In all populations, treatment will be assigned based upon the treatment subjects actually 
received. 
The primary endpoint will be analyzed using the PET population. 
12.3 
Sample Size 
The trial is hypothesis generating, so no formal calculation of sample size is appropriate. The 
sample size of at most 10 subjects is considered adequate to allow modelling of the relationship 
between ASN51 plasma concentrations and the occupancy of O-GlcNAcase and is within the range 
generally accepted for PET studies. Enrolment of subjects into the study will be stopped as soon 
as the brain O-GlcNAcase occupancy versus ASN51 plasma concentrations is sufficiently 
characterized in opinion of the SRC.  
12.4 
Procedure for Accounting for Missing, Unused, and Spurious Data 
All analyses will be performed on data available at the time point considered. In summary tables, 
the number of subjects with missing data will be presented unless otherwise specified. In 
calculation of percentages, subjects with missing data will not be considered in numerator or 
denominator unless otherwise specified. 
12.5 
Discontinuations 
The number of subjects randomized who complete the treatment period (through each interim 
analysis time point) and who discontinue the trial will be summarized. Reasons for 
discontinuation will be summarized.  
12.6 
 Pharmacokinetic Statistical Analysis 
A definition of the PK parameters is described in Section 10.5. PK parameters will be described 
descriptively. 
The PK analysis population will be used for all PK analyses. Individual subject listings will be 
provided. Mean and individual plasma concentration-time profiles for ASN51 will be presented 
graphically for each group. 


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PK variables will be summarized using arithmetic mean, STD, geometric mean, median, 
minimum, maximum, and %CV and by means of scatterplots, dose-normalized scatterplots versus 
dose and means plots versus the dose. 
12.7 
Safety and Tolerability Parameters 
Definitions of the safety and tolerability parameters are described in Section 10.3. The safety set 
is used to perform all safety analyses. 
The medical history is coded using the most recent MedDRA version and listed. All AEs and 
SAEs are coded using the most recent MedDRA version. 
The treatment-emergent AEs are tabulated by system organ class (SOC), and individual preferred 
terms within each SOC by treatment group. The number and percentage of patients who 
experienced AEs coded with the same preferred term and SOC will be summarized by treatment 
group (in descending order according to the incidence in the investigational study drug group). 
Adverse events will also be tabulated by severity and by relationship to study drug. Summary 
tables will be accompanied by individual subject listings broken down by treatment group, 
including pre-dose events. Separate summary tables of adverse events for related/all AEs will be 
provided including severity and percentages. 
SAEs will be listed and summarized similarly to AEs. Reasons for death will only be listed. 
Reasons for premature discontinuation of study drug will be listed and summarized by frequency 
tables. 
ECG variables, vital sign measurements and laboratory measurements will be summarized at each 
time point using mean, median, standard deviation, min, max, number of available observations, 
and change from baseline. Individual patient listings of ECG data, and laboratory measurements 
will be provided. 
In addition, ECG parameters will be analyzed as follows (data listings): 
• 450 ms < QTcF/ QTcB <= 480 ms 
• 480 ms < QTcF/ QTcB <= 500 ms 
• 500 ms < QTcF/ QTcB 
• 30 ms < QTcF/ QTcB change from baseline <= 60 ms 
• 60 ms < QTcF/ QTcB change from baseline 
The mean +/- SD and median over time for ECGs will be plotted by line graphs. An analysis will 
be provided for the concentration versus ECG parameters based on a linear regression model 
(numerical and graphical analysis). The regression model will contain the change from baseline of 


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QT/QTcB/QTcF as the dependent variable and include the corresponding plasma concentrations 
of ASN51 (i.e., the plasma concentration taken at the closest timepoint to the ECG recording) as 
the independent variables and the subject as a random effect. Pre-dose and follow-up ECGs will 
not be included in this analysis. 
Abnormal ECG observations will be listed.  
Listings for each laboratory, ECG and vital sign parameter out of normal range will be provided, 
separately for above/below normal range per time point. Standard numeric laboratory parameters 
are presented in the units supplied. If needed, a conversion will be made to standard units. 
12.8 
Exposure to Study Drug 
A listing with information about the drug administration will be provided. 
12.9 
Baseline Parameters and Concomitant Medications 
Summary statistics (mean, median, standard deviation, min, max, number of available 
observations) will be provided for continuous demographic variables (e.g., age, height, weight). 
Individual patient listings of demographic data will be provided. 
Qualitative demographic characteristics (gender, race) will be summarized by counts and 
percentages. Other baseline patient characteristics (medical history, physical examination clinical 
findings, previous medications, inclusion/exclusion checklist) will only be listed. 
Distributions of these parameters will be compared between the treatment groups only 
descriptively. No statistical inference will be performed. 
Previous and concomitant medications will be coded by the sponsor according to the WHO drug 
code and the ATC class code. 
12.10 Exploratory Analyses 
Exploratory data-driven analyses can be performed with the caveat that any statistical inference 
will not have any confirmatory value. 
12.11 PET Image Data Analysis 
PET data analysis will be performed using PET site’s in-house MIAKATTM software package. 
MIAKATTM is implemented using MATLAB (The Mathworks Inc., Natick, MA, USA), and 
makes use of SPM (Wellcome Trust Centre for Neuroimaging, http://www.fil.ion.ucl.ac.uk/spm) 
for image segmentation and registration. MIAKATTM implements a robust and consistent analysis 
pipeline with built-in audit trail and pre-specified QC points whereby the analyst is required to 
inspect results of intermediate stages (for example checking the success of automated corrections 
for subject motion or assessing the quality of model fits). 


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12.11.1 
Image processing 
Each subject’s structural MRI image will undergo grey matter segmentation and registration to a 
standard reference space (MNI152, (Grabner et al. 2006). The MNI152 template brain image and 
associated atlas (CIC atlas, (Tziortzi et al. 2011) will be nonlinearly warped to the subject’s MR 
image to enable automated definition of regions of interest (ROIs). 
The set of ROIs to be considered and reported will be selected based on previous studies (Paul et 
al. 2018), and the signal observed in these human PET scans and may include (but not be limited 
to) the frontal, parietal and occipital lobes, insular cortex, posterior cingulate gyrus, anterior 
cingulate, caudate nucleus, putamen, nucleus accumbens, thalamus, amygdala, hippocampus and 
cerebellum. 
Dynamic PET images (90-minute duration) will be generated on the PET scanners using the 
manufacturer’s recommended reconstruction settings which include corrections for scatter, 
randoms and attenuation. These will then be registered to each subject’s MRI scan and corrected 
for motion using a frame-to-frame registration process with a normalised mutual information cost 
function. ROIs defined on the MRI images will be applied to the dynamic PET data to derive 
regional time-activity curves (TACs), with activity concentrations expressed as standardised 
uptake values (SUV), given by: 
𝑆𝑈𝑉=
𝐴𝑐𝑡
𝐼𝐴𝐵𝑊
⁄
 
where 𝐴𝑐𝑡 is the measured radioactivity concentration (kBq/ml), 𝐼𝐴 is the injected radioactivity 
(MBq) and 𝐵𝑊 is the subject’s bodyweight (kg). 
12.11.2 
Arterial blood data processing 
Continuous blood data will be scaled (i.e., calibrated) to match overlapping discrete whole blood 
samples, and then merged with the remaining discrete whole blood data to form a whole blood 
activity curve covering the duration of the scan. Activity measurements from the discrete plasma 
samples will be divided by the corresponding whole blood data to form plasma-over-blood (POB) 
data. The POB data will be fitted to a simple model in order to smooth and interpolate the 
relationship. The POB model fit curve will be multiplied by the whole blood curve to give an 
estimated total plasma curve. 
Parent fraction (metabolite) data will be fitted to an appropriate simple model, to be determined 
empirically. The resulting fitted parent fraction profile will be multiplied by the total plasma curve 
(calculated as described above) and then smoothed post-peak using a multi-exponential fit to give 
the required parent plasma input function. For each scan, a time delay will be fitted and applied to 
the input function to account for any delay between blood sampling measurements and tissue data 
from the PET tomograph. The resulting parent plasma input function will be used as input for the 
kinetic modelling processes described in Section 12.11.3. 


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12.11.3 
Signal change evaluation 
Decreases in VT from baseline to post-dose scans will be interpreted as an effect of O-GlcNAcase 
occupancy by ASN51. Target occupancy estimates may be directly calculated from scan data via 
methods including a ‘Lassen plot’ (Cunningham et al. 2010). Alternatively, the relationship 
between exposure and occupancy may be explored by direct fitting of a saturation model to pooled 
(across subjects and scans) VT data, to obtain for example an estimate of EC50 for occupancy by 
ASN51. It is anticipated that data from the first subjects will be sufficient to enable a definitive 
selection of an appropriate analysis method to support the fulfilment of the study objectives. Data 
and analysis will be explored on an ongoing basis for the first four (completing) subjects. 
Following analysis of data from these four subjects, the data analysed to that point will be 
reviewed. An updated Image Analysis Plan will then be generated if appropriate, with the intention 
of fixing the image analysis methodology to be used for data form subsequent subjects and the 
dataset as a whole. 
12.11.4 
PET Data Reporting 
The PET site 
 will produce a separate Imaging Analysis Report on the PET scans and the 
PET scan data. A STDM dataset of the report will be generated by the PET site. The RO values 
will be listed in both reports for sessions 2 and 3, respectively, together with the plasma 
concentration of ASN51 at the time of the start of each post-dose PET scan; which will be 
calculated by log-linear interpolation from the two closest pk data points by subject and treatment 
(data will come from the sponsor). 
These concentration data will be transferred to the PET site for the PK-RO analysis. Three PK-RO 
analyses will be done: for session 2, for session 3 and for pooled data of session 2 and session 3.  
12.12 Clinical Study Report 
Safety and tolerability parameters as well as PK parameters will be evaluated in a Clinical Study 
Report. 
13.0 
TRIAL CONDUCT AND OVERSIGHT  
13.1 
Ethics 
The trial will be conducted in accordance with the consensus ethical principles derived from 
international guidelines including the Declaration of Helsinki, applicable ICH Good Clinical 
Practice Guidelines, and applicable local laws and regulations. Should a conflict arise, the 
Investigator will follow whichever law or guideline affords the greater protection to the individual 
subject.   
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an REC/MHRA by the Investigator and reviewed and approved by the 
REC/MHRA before the trial is initiated. 


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Protocol amendments require REC/MHRA approval before implementation of changes to the trial 
design, except for changes necessary to mitigate an immediate hazard to subjects. 
13.1.1 
Research Ethics Committee or Medicines Healthcare and Products Regulatory 
Agency 
The trial proposal will be reviewed by a recognised REC, and by the MHRA. The trial will not 
proceed unless the sponsor obtains from the MHRA a clinical trial authorisation, and the REC 
approves the trial. No subject will have a PET scan without approval from the Administration of 
Radioactive Advisory Committee (ARSAC).  The protocol, any protocol amendments, and the 
associated ICFs must be reviewed and approved by the REC/MHRA prior to screening of any 
potential subject.  
All subject recruitment information must be submitted to the REC and Sponsor or its designee for 
review and approval prior to implementation. REC/MHRA approval of any protocol amendments 
must be received before any of the changes outlined in the amendments are put into effect, except 
when the amendment has been enacted to protect subject safety.  In such cases, the chair of the 
REC/MHRA should be notified immediately, and the amendment forwarded to the REC/MHRA 
for review and approval. 
13.1.2 
Informed Consent 
Appropriate forms for documenting written informed consent will be reviewed and approved by 
the Sponsor or its designee prior to Investigator submission to the REC/MHRA. The Sponsor or 
its designee must receive a copy of the REC/MHRA approval of the ICF before the shipment of 
IMP to the trial site. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, and all other applicable regulatory requirements.     
The Investigator is responsible for obtaining written informed consent from each potential trial 
subject prior to the conduct of any trial procedures. The signed ICF must be retained in each 
subject's trial file and be accessible to the trial monitor. Subjects will be given a copy of the signed 
ICF and will be provided any new information during the course of the trial that might affect their 
continued participation in the trial. 
If the protocol is amended and the ICF is revised, each subject will be required to provide written 
informed consent again using the revised ICF as applicable. 
13.2 
Investigator Responsibilities 
• Providing oversight of trial conduct at the site 
• Adhering to 21 CFR, ICH guidelines, REC/MHRA requirements, European Clinical 
Trials Directive (if applicable), and all other applicable local regulations 
• Promptly notifying the REC/MHRA of significant safety findings 
• Providing trial status updates to the REC/MHRA as required  


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• Provide the Sponsor with required information to complete financial certification or 
disclosure statement as required by regulatory authorities 
A coordinating Investigator will be selected based on level of participation in the trial, therapeutic 
area expertise, and ability to interpret data. The coordinating Investigator will read and approve 
the final clinical study report and participate in publication of trial results. 
Financing and insurance for this clinical trial will be addressed in clinical trial agreements with 
each Investigator/trial site. 
13.2.1 
Investigational Product Accountability 
The Investigator is responsible for ensuring IMP is stored in a secure limited access location at 
controlled temperature as described in the IB and according to product packaging. The storage 
facility must be available for inspection by the trial monitor at any time during the trial. 
A drug accountability record must be maintained for all IMP received, dispensed, returned, and/or 
lost during the trial. This record must be kept current and made available to the trial monitor for 
inspection. Following the close-out of the trial, all unused IMP must be returned to Sponsor and/or 
its designee unless other instructions have been provided for final disposition of the IMP. 
13.3 
Quality and Recordkeeping 
13.3.1 
Quality 
Monitoring and auditing procedures developed by Sponsor and/or its designee will be 
implemented to ensure compliance with FDA and ICH GCP guidelines. The following principles 
will be set forth to ensure quality of trial data: 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations) 
• The Sponsor or designee is responsible for the management of trial data including 
quality control 
• The Sponsor (or designee) will develop a monitoring plan to detail methods, 
responsibilities, and requirements (including handling of noncompliance issues)  
• All subject data relating to the trial will be recorded on the electronic CRF unless 
electronically transmitted directly to the Sponsor or designee (e.g., laboratory data) 
• Any changes to the data will be made only by Sponsor-authorized users; changes will 
be captured in an electronic audit trail 
• The Investigator is responsible for verifying the accuracy of data entered at the trial site 
• The Investigator will maintain accurate documentation (source data) that supports 
information entered in the eCRF 
• The Investigator must permit trial-related monitoring, audits, REC/MHRA review, and 
regulatory agency inspections, and provide direct access to source data documents 


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• Monitors will verify source data to confirm data entered into the eCRF by authorized 
site personnel are accurate, complete, and verifiable 
• Monitors will evaluate the site to assure the safety and rights of subjects are being 
protected; and the trial is being conducted in accordance with the current protocol, trial 
agreements, ICH GCP, and all applicable regulatory requirements 
13.3.2 
Record Retention 
Records and documents pertaining to the conduct of this trial (including original signed ICFs), 
must be retained by the Investigator for 25 years after trial completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. Written notification to the Sponsor 
is required prior to any transfer of records to another location or party. 
 
 


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13.4 
Disruption Due to Coronavirus Disease 2019 Pandemic (COVID-19), Considerations 
for COVID-19 Vaccination, and COVID-19 Risk Mitigation 
If a clinical site or Investigator experiences disruption due to COVID-19 (or other natural disaster), 
a shortened list of assessments may be implemented as an immediate safety measure to ensure at 
least safety, primary, and key secondary endpoints are captured for any dosed subject. Travel 
services will be provided as needed for subjects to continue participation in the trial. 
Based on various guidelines (e.g., MHRA Guidance on Coronavirus [COVID-19]), COVID-19 
vaccination should be prioritized for elderly patients and patients with underlying conditions. 
Subjects eligible for enrollment into this study shall be healthy adult male or female subjects (age 
15 – 55 years old) (Section 8.1). Every effort should be made to vaccinate subjects prior to being 
considered for this study based on the Investigator’s risk/benefit analysis for each subject. As with 
any vaccine, COVID-19 vaccines may cause side effects in some patients. The overwhelming 
majority of adverse effects to the vaccines relate to injection-site reactions and generalized 
symptoms such as ‘flu-like’ illness, headache, chills, fatigue, nausea, fever, dizziness, weakness, 
myalgia, and heart rate increased (MHRA Guidance on Coronavirus [COVID-19]). Generally, 
these occur shortly after vaccination and are not associated with more serious or lasting illness. No 
interactions or overlapping toxicities between the IMP and COVID-19 vaccines are anticipated. 
For this study, subjects who received a COVID-19 vaccination within two weeks of screening or 
due to receive the second dose of COVID-19 vaccine while participating in the study will be 
excluded (Section 8.1). Concomitant administration of a COVID-19 vaccine is not permitted 
during participation in the study (Section 9.10.1). 
This clinical trial will be done in accordance with 
COVID-19 risk mitigation plan (RMP), 
which documents 
 COVID-19 virus testing strategy for volunteers and staff, social 
distancing measures, and management of COVID-19-like symptoms.  
 RMP was first 
notified to the Medicines and Healthcare products Regulatory Agency (MHRA) and Health 
Research Authority (HRA) on 22 May 2020, and applies across all 
 trials.  The mitigation 
measures specified in the 
 COVID-19 RMP are deemed adequate for this trial.  Any 
deviations from the RMP will be documented in a separate COVID-19 trial-specific risk 
assessment, prepared by the Principal Investigator (PI).  Any deviations from the protocol that 
result from the COVID-19 pandemic will be documented. 
If a subject develops COVID-19, this will be reported and followed as an AE per Section 11.0. 
The Investigator will follow the standard operating procedures for the site as well as local, regional, 
and national guidelines for COVID-19. Investigators should use clinical judgement as to whether 
a subject should continue, temporarily stop, or permanently withdraw from the trial. 
13.5 
Publications 
Participation as an Investigator does not confer any rights to authorship of publications. The 
Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This 
allows the Sponsor to protect proprietary information and review content for accuracy. 


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Page 64 of 69 
 
 
The Sponsor will comply with the requirements for publication of trial results. In accordance with 
standard editorial practice, the Sponsor will generally support publication of multicenter studies in 
their entirety, irrespective of outcome.  
 


ASN51-102 
Asceneuron SA 
Version 2.0, 19 May 2021 
 
Confidential Information 
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14.0 
REFERENCES 


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Version 2.0, 19 May 2021 
 
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ASN51-102 
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Version 2.0, 19 May 2021 
 
Confidential Information 
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Version 2.0, 19 May 2021 
Confidential Information 
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ASN51-102 
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Version 2.0, 19 May 2021 
 
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APPENDIX A:  LABORATORY PARAMETERS 
Clinical Labs for Safety 1 
Central Laboratory2 
Serum Chemistry (basic metabolic panel-14) 
• alanine aminotransferase (ALT); albumin:globulin (A:G) 
ratio; 
albumin; 
alkaline 
phosphatase; 
aspartate 
aminotransferase (AST); bilirubin* (total; differentiate into 
direct and indirect if total > 1.5 × ULN), total; urea ; urea: 
creatinine ratio; calcium; carbon dioxide, total; chloride; 
creatinine; eGFR calculation (CKD-Epi formula); globulin, 
total; glucose (fasting required; note status); potassium; 
protein, total; sodium 
Drug concentration (plasma) 
• ASN51  
Serum Hormone Markers (for post-menopausal female subjects) 
• 
FSH 
Hematology (complete blood count with differential) 
• Hematocrit; hemoglobin; mean corpuscular volume (MCV); 
mean corpuscular hemoglobin (MCH); mean corpuscular 
hemoglobin concentration (MCHC); red cell distribution 
width (RDW) 
• Percentage and absolute differential counts: white blood cells 
(WBC) 
• platelets; red cell counts (RBC);  
 
Urinalysis panel (dipstick w/microscopic examination on 
positives) 
• Color; appearance; specific gravity, pH, protein, glucose, 
ketones, occult blood, leukocyte esterase, nitrite, bilirubin, and 
urobilinogen 
• If protein, leukocyte, occult blood, and nitrites negative, 
microscopic examination is not performed 
Coagulation panel  
• Prothrombin time (PT), partial thromboplastin time (PTT), 
international normalized ratio (INR) 
Pregnancy testing (WOCPB only; local laboratory) 
• Serum (to be confirmed before Day 1 IMP) 
• Urine (MRI visit) 
 
Serology 
• HBsAg, HCV, HIV 
 
Urine drug and cotinine screen and Alcohol Tests 
• DOA 
• Cotinine 
• Urine Alcohol 
 
1 Note on laboratory forms if subject is taking high dose biotin supplements given potential for biochemical interference in certain 
assays. 
2 Consult manual and protocol for instructions on collection, processing, and shipping to Central Laboratory 



SAP_001.pdf: 


HMR code: 21-001 
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Page 1 of 49 
Statistical Analysis Plan 
Clinical trial protocol title: 
A Phase 1, Open-Label, Positron Emission Tomography 
Study in Healthy Adult Subjects to Determine the 
Relationship Between Plasma Concentration and Brain 
Target Occupancy of ASN51 Following a Single Oral 
Dose 
HMR code: 
21-001 
Sponsor code: 
ASN51-102 
EudraCT no: 
2021-001918-10 
CRO details: 
HMR 
Cumberland Avenue 
London NW10 7EW 
Sponsor details: 
Asceneuron S.A. 
EPFL Innobation Part 
Bâtiment B, CH-1015 Lausanne, SWITZERLAND 
Issued: 
17 November 2021 
Version: 
1 
Based on: 
Protocol version 2.0, 19 May 2021 
Prepared by: 
 


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Table of Contents 
1 
LIST OF ABBREVIATIONS .............................................................................. 4 
2 
SIGNATURES ...................................................................................................... 6 
3 
INTRODUCTION ................................................................................................ 7 
4 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ................................................. 7 
4.1 
Study objective(s) ....................................................................................... 7 
4.1.1 
Primary objective(s) ................................................................................. 7 
4.1.2 
Secondary objective(s) ............................................................................. 7 
4.2 
Study endpoint(s) ....................................................................................... 8 
4.2.1 
Primary endpoint(s) .................................................................................. 8 
4.2.2 
Secondary endpoint(s) ............................................................................. 8 
4.3 
Statistical hypotheses ................................................................................. 8 
5 
STUDY DESIGN .................................................................................................. 8 
6 
TIME AND EVENTS TABLE .......................................................................... 10 
7 
PLANNED ANALYSES .................................................................................... 10 
7.1 
Interim analyses ....................................................................................... 10 
7.2 
Final analysis ........................................................................................... 10 
7.2.1 
Persons responsible for analysis ........................................................... 10 
8 
SAMPLE SIZE CONSIDERATIONS .............................................................. 10 
8.1 
Sample size assumptions .......................................................................... 10 
9 
ANALYSIS POPULATIONS ............................................................................ 10 
9.1 
Analysis datasets ...................................................................................... 11 
10 
DATA DISPLAY TREATMENT AND OTHER SUBGROUP DESCRIPTORS 
11 
10.1 
Conventions for summary statistics and data displays ............................. 11 
11 
DATA HANDLING CONVENTIONS ............................................................. 12 
11.1 
Premature withdrawal and missing data .................................................. 12 
11.2 
Derived and transformed data .................................................................. 12 
11.3 
Assessment windows ............................................................................... 12 
11.4 
Vital signs reference ranges ..................................................................... 13 
12 
STUDY POPULATION ..................................................................................... 13 
12.1 
Disposition of subjects ............................................................................. 13 
12.2 
Protocol deviations ................................................................................... 13 
12.3 
Demographic and baseline characteristics ............................................... 14 
12.4 
Treatment compliance .............................................................................. 14 


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13 
SAFETY ANALYSES ........................................................................................ 14 
13.1 
Extent of exposure ................................................................................... 14 
13.2 
Adverse events ......................................................................................... 14 
13.3 
Deaths, serious adverse events and other significant adverse events ...... 15 
13.4 
Adverse events leading to withdrawal from the study ............................. 15 
13.5 
Clinical laboratory evaluations ................................................................ 15 
13.6 
Other safety measures .............................................................................. 15 
13.6.1 Vital signs ............................................................................................... 15 
13.6.2 ECG ....................................................................................................... 15 
13.6.3 Physical examination ............................................................................. 15 
13.6.4 Columbia-Suicide Severity Rating Scale (C-SSRS) ............................... 15 
14 
PHARMACOKINETIC ANALYSES .............................................................. 16 
14.1 
Pharmacokinetic concentration data ........................................................ 16 
14.2 
Pharmacokinetic parameters .................................................................... 16 
15 
PHARMACODYNAMIC ANALYSES ............................................................ 16 
15.1 
PET analysis data ..................................................................................... 16 
16 
REFERENCES ................................................................................................... 17 
17 
ATTACHMENTS ............................................................................................... 17 
17.1 
Table of contents for data display specifications ..................................... 17 
17.2 
Data display specifications ....................................................................... 22 
17.2.1 Table outlines .................................................................................................... 22 
17.2.2 Figure outlines .................................................................................................. 33 
17.2.3 Listing outlines ................................................................................................. 36 
APPENDIX A: PHARMACOKINETIC ANALYSIS ............................................... 45 
1 
CALCULATION METHODS .......................................................................... 45 
1.1 
Data handling conventions ....................................................................... 45 
1.1.1 
Missing and BLQ concentrations ...................................................................... 45 
1.2 
AUC calculations ..................................................................................... 45 
1.3 
Lambda-z calculations ............................................................................. 45 
1.4 
Observed v predicted values .................................................................... 46 
2 
PARAMETER DEFINITIONS ......................................................................... 47 
2.1 
Plasma parameters ................................................................................... 47 
APPENDIX B: SAMPLE PAGE LAYOUT ............................................................... 49 


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1 
List of abbreviations 
 
λz 
Terminal rate constant 
AE 
Adverse event 
AUC 
Area under concentration-time curve 
AUCinf 
AUC from time zero to infinity 
AUCt 
AUC from time zero to time t 
AUClast 
AUC from time zero to last measurable concentration 
BMI 
Body mass index 
BQL 
Below the limit of quantification 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
HR 
Heart rate 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of subjects 
n 
Number of observations used in analysis 
PCI 
Potential clinical importance 
PD 
Pharmacodynamic(s) 
PET 
Positron emission tomography 
PK 
Pharmacokinetic(s) 
PR 
Portion of the ECG from the beginning of the P wave to the beginning of 
the QRS complex, representing atrioventricular node function. 
Q1 
Lower quartile 
Q3 
Upper quartile 
QRS 
The QRS complex of the ECG reflects the rapid depolarization of the right 
and left ventricles. 
QT 
Portion of the ECG between the onset of the Q wave and the end of the T 
wave, representing the total time for ventricular depolarization and 
repolarization. 
QTc 
Corrected portion of the ECG between the onset of the Q wave and the end 
of the T wave, representing the total time for ventricular depolarization and 
repolarization. 
QTcB 
QTc interval with Bazett’s correction method 
QTcF 
QTc interval with Fridericia's correction method 
RO 
Receptor occupancy 
RR 
Portion of the ECG between consecutive R waves, representing the 
ventricular rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SEM 
Standard error of mean 
SRC 
Safety Review Committee 
t½ 
Terminal elimination half-life 


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TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma concentration 
VT 
Regional total volume of distribution 
WHO 
World Health Organisation 




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3 
Introduction 
 
This statistical analysis plan (SAP) is based on the current trial protocol (version 2.0, 19 May 
2021). Where statistical methods differ substantially between this SAP and the protocol, that 
will be identified in this document. 
This SAP describes the datasets and the statistical methods to be used for the reporting and 
analysis of all data collected during the trial except the analysis of the PK-RO which will be 
done by Invicro. 
If a future protocol amendment necessitates a substantial change to the statistical analysis of 
the trial data, this SAP will be amended accordingly. If, after database lock, additional 
analyses are required to supplement the planned analyses described in this SAP, those 
unplanned analyses will not be described in an amended SAP, but they will be identified in 
the integrated clinical study report (CSR). Any deviations from this SAP will be documented 
in the CSR. 
This SAP has been written in consideration of the following guidelines: 
• 
International Conference on Harmonization (ICH) E9, Guidance for Industry: Statistical 
Principles for Clinical Trials (ICH E9 1998)1; and 
• 
ICH E3, Guidance for Industry: Structure and Content of Clinical Study Reports (ICH E3 
1995)2. 
Pharmacokinetic (PK) analysis will be done using WinNonlin v8.3 or higher on a Windows 
PC. Statistical analysis will be done using SAS  9.4 or higher on a Windows PC. 
4 
Study objective(s) and endpoint(s) 
 
4.1 
Study objective(s) 
 
4.1.1 Primary objective(s) 
• To assess the brain O-GlcNAcase occupancy using [18F] IMA601 PET, following a 
single oral dose of ASN51 
4.1.2 Secondary objective(s) 
• To assess the relationship between the plasma concentration of ASN51, and the time- 
course of brain O-GlcNAcase occupancy using [18F]-IMA601 PET, following a single 
oral dose of ASN51 
• To assess the single dose safety and tolerability of ASN51 in healthy adult subjects 
under fasted conditions 


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4.2 
Study endpoint(s) 
 
4.2.1 Primary endpoint(s) 
• Pharmacodynamic (PD): [18F]-IMA601 regional total volume of distribution (VT) at 
each brain scan. 
4.2.2 Secondary endpoint(s) 
• Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) up 
to follow-up 
• Serious Adverse Events (SAEs) up to 4 weeks after last administration 
• Laboratory tests 
• Vital signs 
• ECG 
• Physical examination 
• Pharmacokinetic (PK): plasma concentration of ASN51 at the time of each post-dose 
PET scan. 
• PK/PD: relationship between ASN51 exposure and receptor occupancy. 
 
4.3 
Statistical hypotheses 
 
The trial is an exploratory one, and there are no null hypotheses to be tested. 
5 
Study design 
 
This is an open-label, adaptive-design PET study to investigate the occupancy of O-GlcNAcase 
by ASN51 after single oral doses in healthy adult male and female subjects (aged 25-55 years, 
inclusive). The study schema is depicted in Figure 2 of the protocol. 
Up to 10 subjects will be enrolled. Each subject will have up to 3 imaging sessions, with one 
scan in each session. In the first imaging session, subjects will have 240 ml of water followed 
by a baseline PET scan approximately 2 h later. In the second and third imaging sessions, 
subjects will receive a single oral dose of ASN51 with 240 ml of water, followed by an on- 
treatment PET scan. Safety and pharmacokinetic data of the SAD study ASN51-101 will be 
assessed by the Safety Review Committee (SRC) prior to the dosing of the first subject(s) to 
determine the first dose level to be administered in session 2 after the baseline session 1 and the 
timing of the PET scans in relation to the study drug administration time. At most 2 subjects 
will be dosed on the same study day. For subsequent sessions, the dose level and the time of 
the PET scan in all imaging session 2 and 3 will be determined after review of the results from 


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the first on-treatment PET scan, including the PK data. Subjects will receive an intravenous 
dose of the radiolabelled tracer, [18F]-IMA601, at the start of each PET scan. 
This study will have an adaptive design: to adequately evaluate the exposure versus receptor 
occupancy (RO) relationship, various doses of ASN51 of up to 85% of the highest well- 
tolerated dose level in the preceding SAD study ASN51-101, and the timing of on-treatment 
PET scans may be altered based on emerging data or study logistical requirements. On- 
treatment PET scans may be scheduled up to 48 h post-dose. 
After each on-treatment PET scan, the SRC will review available RO, PK, safety and 
tolerability data, before selecting the dose and PET scan timings for imaging session 3. Arterial 
blood sampling will be done during each PET scan to quantify the parent tracer related 
radioactivity over the course of the PET scan, and to establish a tracer metabolite corrected 
plasma input function. The total arterial blood volume required for each tracer injection will 
not exceed 145 mL. Arterial cannulation and arterial blood sampling may be reduced or 
removed if analysis of PET data from previous subjects indicates that noninvasive analysis of 
the PET scan data can be done. If a non-invasive analysis is not possible, the use of an arterial 
cannula with each PET scan will continue through the study. 
Subjects will be screened within 21 days before their baseline PET scan. Their on-treatment 
PET scans will be within 7 days of their baseline scan with an interval of 7–14 days between 
imaging sessions 2 and 3. Subjects will be confined for 72 h after the study drug 
administration in sessions 2 and 3. After the baseline scan in session 1 without study drug 
administration, subjects may leave the unit in the evening. In the case of a technical failure 
(such as unsuccessful tracer synthesis), subjects may be asked to attend an additional on- 
treatment imaging session, in which they will receive a third oral dose of ASN51. There will 
be at least 7 days between each dose of ASN51. Subjects will not have more than 3 PET scans 
or 3 doses of ASN51 during the study. Subjects will have a follow-up visit at the research unit 
7 days (± 3 days) after imaging session 3 (Day 8). 


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6 
Time and events table 
 
Please refer to Table 1 of the protocol, version 2.0, dated 19 May 2021 
 
7 
Planned analyses 
 
7.1 
Interim analyses 
 
No interim analyses are planned. 
7.2 
Final analysis 
 
The database will be locked once all subjects have completed the study, data have been 
entered, and queries resolved. The final analysis will be carried out following database lock. 
7.2.1 Persons responsible for analysis 
 
Statistician 
8 
Sample size considerations 
 
8.1 
Sample size assumptions 
 
The trial is hypothesis generating, so no formal calculation of sample size is appropriate. The 
sample size of at most 10 subjects is considered adequate to allow modelling of the relationship 
between ASN51 plasma concentrations and the occupancy of O-GlcNAcase and is within the 
range generally accepted for PET studies. Enrolment of subjects into the study will be stopped 
as soon as the brain O-GlcNAcase occupancy versus ASN51 plasma concentrations is 
sufficiently characterized in opinion of the SRC. 
9 
Analysis populations 
 
The following populations will be identified 
All-treated set: 
This analysis set includes all randomised subjects who 
received study drug (at least one dose). 
Safety set: 
This analysis set includes subjects from the all-treated set who 
had at least one safety assessment post-baseline. The safety set 
will be employed in the analysis of tolerability and safety 
variables. 
PET population: 
The PET population will consist of randomised subjects who 
receive study medication, have a baseline PET scan, at least 
one post-baseline PET scan, and a PK result immediately 
preceding PET scan. 


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PK analysis population: 
The PK analysis population will consist of the subjects who 
provide evaluable data for the comparisons of interest. These 
subjects should have at least one quantifiable plasma 
concentration, should not have violated any major entry 
criterion likely to confound the PK analysis, and should not 
have deviated significantly from the protocol between 
enrolment and successful study completion. 
In all populations, treatment will be assigned based upon the treatment subjects actually 
received. 
The primary endpoint will be analysed using the PET population. 
 
9.1 
Analysis datasets 
 
All analysis datasets will be based on observed data, except as outlined in Section 11.2. 
10 
Data display treatment and other subgroup descriptors 
 
The treatment groups will be sorted in ascending dose order. When a total column is 
included, it immediately follows the treatment groups which it aggregates. 
Listings of data will be sorted and displayed by treatment group, subject number, and also by 
date and time if applicable. 
The treatment descriptions to be used on all tables and listings are: 
 
Treatment Groups 
 xx mg ASN51 
 
 
10.1 Conventions for summary statistics and data displays 
 
The minimum set of summary statistics for numeric variables will be: n, mean, standard 
deviation (or standard error mean [SEM]), median, minimum, and maximum. 95% 
confidence intervals (CI) will be presented where appropriate for data interpretation. 
Categorical data will be summarised in frequency tables with n and percentage. Summaries 
of a categorical variable will include all recorded values. 
The minimum and maximum values will be presented with the same number of decimal 
places as the raw data collected on the CRF (or to 3 significant figures for derived parameters 
less than 100 and as integers for values more than 99). The mean and percentiles (eg median, 
Q1, and Q3) will be presented using one additional decimal place. The standard deviation 
and standard error will be presented using two additional decimal places. 


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11 
Data handling conventions 
 
11.1 Premature withdrawal and missing data 
 
All subjects who withdraw prematurely from the study or study drug will be included in the 
statistical analyses. 
If a subject completes the treatment period but has missing data, then this will be made 
apparent in the subject listings. Missing data will not be imputed except for as outlined in 
Section 11.2. 
If the study is prematurely discontinued, all available data will be listed and a review will be 
carried out to assess which statistical analyses are still considered appropriate. 
Data collected at unscheduled time points during the study will not be used in the summaries 
or data analyses. They will be included in the listings. 
If time information (ie hours and/or minutes) for adverse events (AEs) or concomitant 
medication is missing, but the day is present, then the time will be calculated in days. If date 
information is partial or missing, then any derived times (eg AE start time from last study 
medication) will be listed as missing. 
Conventions for handling missing plasma concentrations are given in Appendix A: 
Pharmacokinetic Analysis. 
11.2 Derived and transformed data 
 
Baseline will be considered to be the latest value obtained before study drug administration 
(eg Day 1, pre-dose; or Day –1 if not recorded at pre-dose; or screening if not recorded at 
pre-dose or on Day –1). 
Laboratory data will be reported in standard units. Out-of-range laboratory tests may be 
repeated. If a test is out of-range at baseline and repeated before dosing, the latest repeat 
value before dosing will be used as baseline. However, if a test is out-of-range and repeated 
at any other time during the study, the out-of-range value (not the repeat value) will be 
included in statistical summaries. 
Triplicate vital sign measurements will be made at screening and the mean of the three 
measurements for each subject will be used for analysis. 
The PK parameters to be derived are given in Appendix A: Pharmacokinetic Analysis. 
11.3 Assessment windows 
 
No assessment windows are defined for this report. 


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11.4 Vital signs reference ranges 
 
The following vital signs ranges will be used: 
 
Vital Sign 
Range 
Seated systolic blood pressure 
90–140 mm Hg 
Seated diastolic blood pressure 
50–95 mm Hg 
Seated heart rate 
45–100 beats/min 
Respiration rate 
10–16 breaths/min 
Tympanic temperature 
35.5–37.8°C 
 
 
12 
Study population 
 
12.1 Disposition of subjects 
 
The disposition of all subjects in the safety population will be summarised including: number 
of subjects randomised; number completing the study, by treatment; and number withdrawn 
from the study. 
All subjects who withdraw or are withdrawn from the study will be listed, by treatment, with 
the reason for withdrawal. 
A listing of analysis populations will be provided. 
12.2 Protocol deviations 
 
Before closing the database, data listings will be reviewed to identify any significant 
deviations and determine whether the data should be excluded from any analysis populations. 
Major protocol deviations include subjects who: 
• Entered the study even though they did not satisfy the entry criteria. 
• Met the criteria for withdrawal from the study but were not withdrawn. 
• Received the wrong treatment or incorrect dose. 
• Received an excluded concomitant therapy. 
• Received investigational product(s) past the expiration date. 
In addition, subjects with minor time deviations (measurements taken outside the allowable 
windows) will be identified. Allowable time windows for pharmacokinetic samples and other 
procedures are given in HMR Trial Procedures Summary. 


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12.3 Demographic and baseline characteristics 
 
Demographic and baseline characteristics (eg physical examination, vital signs and ECGs) 
will be listed and summarised. 
Subjects who take concomitant medication will be listed. All non-trial medication will be 
coded using the latest version of the World Health Organisation (WHO) Drug Global 
dictionary current at the time of the database lock (version September 2021 or higher). 
Medical and surgical history will also be listed. 
12.4 Treatment compliance 
 
Dates and times of dosing will be listed. 
13 
Safety analyses 
 
Summaries and listings of safety data will use the safety population. 
13.1 Extent of exposure 
 
The dates and times of treatment dosing will be listed to indicate exposure to the study 
medication. 
13.2 Adverse events 
 
AEs will be coded using the version of the Medical Dictionary for Regulatory Activities 
(MedDRA) which is current at the time of database lock (version 24.0 or higher). 
All AEs will be listed. 
The number of subjects with at least one treatment-emergent adverse event (TEAE) per 
treatment will be tabulated by actual treatment and MedDRA system organ class. A TEAE is 
defined as an event emerging during treatment (having been absent pre-treatment) or that 
worsens after treatment1. 
For each of the following, the number of TEAEs and the number of subjects with TEAEs will 
be summarised by treatment group: 
• TEAEs, by system organ class and preferred term 
• Drug-related (“related” as recorded by the investigator) TEAEs, by system organ class and 
preferred term 
Subjects with more than one TEAE will be counted only once, at the greatest severity or 
causality, for each system organ class/preferred term. Multiple TEAEs in a subject will be 
counted once per system organ class and preferred term. AEs with missing severity and/or 
causality will be treated as severe and definitely related, respectively. 
Summaries will be sorted by system organ class and decreasing total incidence of preferred 
term. 


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13.3 Deaths, serious adverse events and other significant adverse 
events 
 
Deaths and serious adverse events (SAEs) will be listed separately (fatal events separate from 
non-fatal events). Other significant AEs, as identified by the investigator in the CRF, will be 
listed separately. 
13.4 Adverse events leading to withdrawal from the study 
 
AEs leading to withdrawal will be listed separately. 
13.5 Clinical laboratory evaluations 
 
Data from haematology, coagulation, urinalysis and clinical chemistry will be summarised by 
treatment. 
Data from haematology, coagulation and clinical chemistry outside the normal range will be 
listed separately and summarised. 
13.6 Other safety measures 
 
13.6.1 Vital signs 
Vital signs evaluation at each planned assessment will be summarised by actual treatment. 
Vital signs data outside of the normal range will be listed and summarised. 
A separate listing of vital sign findings, classified as clinically significant by the investigator 
will also be provided. 
13.6.2 ECG 
QT interval data will be presented using Fridericia's (QTcF) and Bazett (QTcB) corrections. 
ECG variables will be summarised by treatment and time point. 
QTcF and QTcB values > 450 msec, PR interval shortening < 120 msec, and PR interval 
prolongation >220 msec will be listed by treatment and timepoint and summarised. A 
separate listing of ECG findings classified as abnormal by the investigator will also be 
provided. 
13.6.3 Physical examination 
Abnormal physical examination findings will be listed. 
 
13.6.4 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Positive C-SSRS data will be listed. 


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14 
Pharmacokinetic analyses 
 
The PK parameters to be derived are given in Appendix : Pharmacokinetic analysis. 
PK concentration data and PK parameter data will be summarised using the PK analysis 
population. 
14.1 Pharmacokinetic concentration data 
 
The plasma concentrations and dose-normalised plasma concentrations of ASN51 will be 
listed and summarised by treatment. 
 
Using actual sample times, linear and semi-logarithmic plasma concentration-time plots will 
be prepared by treatment and synoptic linear and semi-logarithmic dose-normalised plasma 
concentration-time plots of ASN51 will be prepared. Both Session 2 and Session 3 profiles 
will be included on the same plot. The same linear and logarithmic scales will be used for 
each subject. The linear and semi-logarithmic plots for a given subject will be presented on 
the same page. 
 
Mean plasma concentration versus time plots will be presented for ASN51 per treatment 
(synoptic plot) (normal scale and log-linear scale). 
 
Mean dose normalised plasma concentration versus time plots will be presented for 
ASN51 per treatment (synoptic plot) (normal scale and log-linear 
scale). 
 
 
14.2 Pharmacokinetic parameters 
 
The pharmacokinetic parameters of ASN51 will be listed and summarised by treatment. 
If there is a quantifiable plasma concentration of the baseline PK sample of session 3, that 
value will be used in addition for the calculation of the PK parameters for session 2. 
15 
Pharmacodynamic analyses 
 
15.1 PET analysis data 
 
Start and end date of each PET scan will be listed together with the scan start/stop time and 
the Dose drawn up, Dose administered, Residual 1, and Residual 2. 
 
[18F]-IMA601 regional total volume of distribution (VT) at each brain scan will be listed for 
each session and for change from baseline. 


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The RO values will be listed for sessions 2 and 3, respectively, together with the plasma 
concentration of ASN51 at the time of the start of each post-dose PET scan; which will be 
calculated by log-linear interpolation from the two closest PK data points by subject and 
treatment. 
 
These concentration data will be transferred to Invicro for the PK-RO analysis. The PK-RO 
analysis will be provided by Invicro and sent to HMR for the inclusion in the CSR. 
 
16 
References 
 
1. International Conference on Harmonization, 1998. Statistical Principles for Clinical 
Trials – ICH Harmonised Tripartite Guideline. Guidance for Industry, E9, FDA federal 
register, Vol 63, 1998, p49583. Available at: http://www.fda.gov/cder/guidance. 
2. International Conference on Harmonization, 1995. Structure and Content of Clinical Study 
Reports – ICH Harmonised Tripartite Guideline. Guidance for Industry, E3, FDA federal 
register, Vol 61, 1996, p37320. Available at: http://www.fda.gov/cder/guidance. 
3. International Conference on Harmonisation, 2005. Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Concept paper, 
Guidance for Industry, E14, Center for Drug Evaluation and Research (CDER). Available 
at: http://www.fda.gov/cder/guidance/6922fnl.htm. 
4. Julious, SA & Debarnot, CAM (2000) “Why are Pharmacokinetic Data Summarised by 
Arithmetic Means?”, Journal of Biopharmaceutical Statistics, 10 (1), p55-71 
 
 
17 
ATTACHMENTS 
 
17.1 Table of contents for data display specifications 
 
For overall page layout refer to Appendix B: Sample page . 
The numbering in the tables below will take precedence over the numbering in the shells. 
The following tables and figures will be produced (templates provided in Section 17.2.1 and 
17.2.2): 








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Listing 
Description 
Template (Shells 
below) 
16.2.9.6 
Listing of positive Columbia-Suicide Severity Rating Scale data 
L_CSS_PG 
 
Complete listings of all data collected in this study will also be produced. 


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17.2 Data display specifications 
 
17.2.1 Table outlines 
Note: Summary statistics for continuous data will only be provided for treatments where n>1 
 
Template T_SD1 
Table 10.1 
Summary of subject disposition 
 
Population 
Status 
Reason for Withdrawal 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Etc 
All Subjects 
(N=xx) 
n (%) 
n (%) 
n (%) 
All-treated 
Included 
xx (xx) 
xx (xx) 
xx (xx) 
Safety 
Included 
xx 
xx 
xx 
Completed 
xx (xx) 
xx (xx) 
xx (xx) 
Withdrawn 
Death 
xx (xx) 
xx (xx) 
xx (xx) 
Adverse Events 
xx (xx) 
xx (xx) 
xx (xx) 
Withdrawal by subject 
xx (xx) 
xx (xx) 
xx (xx) 
Study terminated by 
Sponsor 
xx (xx) 
xx (xx) 
xx (xx) 
Lost to follow-up 
xx (xx) 
xx (xx) 
xx (xx) 
Other 
xx (xx) 
xx (xx) 
xx (xx) 
Alternative 1 (if applicable) 
Included 
Alternative 2 (if applicable) 
Included 
 
Source: Listing 16.2.xx 
Programming notes: 
Continued with all treatment groups 
Remove column “Reason for Withdrawal” if no subject withdrew 
Add a footnote about n=4 for the 
 dose group 


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Template T_DM1 
 
Table 14.1 
Summary of demographic characteristics 
 
Variable 
Statistics 
All Subjects (N=xx) 
 
Age (y) 
n 
Mean 
SD 
Median 
Min 
Max 
Sex (%) 
Female 
Male 
Race (%) 
American Indian or Alaskan 
Native 
Asian 
Black 
Native Hawaiian or other 
Pacific Islander 
White 
Other 
Ethnicity (%) 
Hispanic or Latino 
Not Hispanic or Latino 
Height (cm) 
n 
Mean 
SD 
Median 
Min 
Max 
Weight (kg) 
n 
Mean 
SD 
Median 
Min 
Max 


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Variable 
Statistics 
All Subjects (N=xx) 
 
BMI (kg/m2) 
n 
Mean 
SD 
Median 
Min 
Max 
Smoker 
History (%) 
Former 
Never 
Alcohol* 
(units/week) 
n 
Mean 
SD 
Median 
Min 
Max 
Caffeine* 
(cups daily) 
n 
Mean 
SD 
Median 
Min 
Max 
Optional 
(units) 
 
Source: Listing 16.2.xx 
*includes only those subjects who drink caffeine/alcohol 
 
Programming notes: 
Continued with all treatment groups and additional demographic characteristics 


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Template T_PK1 
 
Table 14..2.xx 
Summary of derived ASN51 plasma pharmacokinetic concentration-time data [units] by treatment 
 
Treatment 
{Add. 
time 
var.} 
Planned 
Relative 
Time 
n 
No. 
Imputed 
Mean 
95% CI 
(Lower,Upper) 
SD 
%CVb 
Median 
Min 
Max 
Treatment 1 
(N=xx) 
Pre-dose 
x 
x 
xxxx.x 
(xxxx.x,xxxx.x) 
xx.x 
xxxx.x 
xxxx 
xxxx 
30 min 
x 
x 
xxxx.x 
(xxxx.x,xxxx.x) 
xx.xx 
xx.x 
xxxx.x 
xxxx 
xxxx 
1 hr 
x 
x 
xxxx.x 
(xxxx.x,xxxx.x) 
xx.xx 
xx.x 
xxxx.x 
xxxx 
xxxx 
Treatment 2 
(N=xx) 
Pre-dose 
x 
x 
xxxx.x 
(xxxx.x,xxxx.x) 
xx.xx 
xx.x 
xxxx.x 
xxxx 
xxxx 
30 min 
x 
x 
xxxx.x 
(xxxx.x,xxxx.x) 
xx.xx 
xx.x 
xxxx.x 
xxxx 
xxxx 
1 hr 
x 
x 
xxxx.x 
(xxxx.x,xxxx.x) 
xx.xx 
xx.x 
xxxx.x 
xxxx 
xxxx 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all dose levels and timepoints 
 
 
 
Template T_PK3 
 
Table 14..2.xx 
Summary of derived ASN51 plasma pharmacokinetic parameters by treatment 
 
Parameter 
Treatment 
{Additional 
time 
variables} 
n 
Mean 
95% CI 
(Lower,Upper) 
SD 
%CVb 
Median 
Min 
Max 
AUCt (units) 
Treatment 1 (N=xx) 
xx 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.x 
xxxx.xx 
xxxx.x 
xxxx.x 
Treatment 2 (N=xx) 
xx 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.x 
xxxx.xx 
xxxx.x 
xxxx.x 
Cmax (units) 
Treatment 1 (N=xx) 
xx 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.x 
xxxx.xx 
xxxx.x 
xxxx.x 
Treatment 2 (N=xx) 
xx 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.x 
xxxx.xx 
xxxx.x 
xxxx.x 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all dose levels, timepoints and parameters 


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Template T_PK4 
Table 14..2.xx 
Summary of log-transformed derived ASN51 plasma pharmacokinetic parameters by treatment 
 
Parameter 
Treatment 
{Additional 
time 
variables} 
n 
Geom 
Mean 
95% CI 
(Lower,Upper) 
SD (logs) 
%CVb 
AUClast (units) 
Treatment 1 (N=xx) 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.xx 
Treatment 2 (N=xx) 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.xx 
Cmax (units) 
Treatment 1 (N=xx) 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.xx 
Treatment 2 (N=xx) 
xxxx.xx 
(xxxx.xx,xxxx.xx) 
xx.xxx 
xx.xx 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all dose levels, timepoints and parameters 


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Template T_AE1 
 
Table 14.3.3.xx 
Summary of treatment-emergent adverse events 
 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
Etc 
All Subjects 
(N=xx) 
System Organ Class 
Preferred Term 
n (%) 
n (%) 
Number of subjects with TEAEs 
x (xx.x) 
x (xx.x) 
Gastrointestinal disorders 
Total number of subjects 
x (xx.x) 
x (xx.x) 
Abdominal discomfort 
x (xx.x) [xx] 
x (xx.x) [xx] 
Abdominal pain 
x (xx.x) [xx] 
x (xx.x) [xx] 
↓ 
Nervous system disorders 
Total number of subjects 
Dizziness 
Headache 
↓ 
↓ 
↓ 
 
Source: Listing 16.2.xx 
n = number of subjects (subjects with >1 TEAE are counted only once per system organ class and preferred term) 
[ ] = number of TEAEs 
Coded using MedDRA v xx.x 
 
Programming notes: 
Continued with all treatment groups 
SOCs and PTs are sorted in decreasing order of frequency 
Presented for all applicable MedDRA system organ classes and terms. 


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Template T_LB1 
 
Table 14.3.4.xx 
Summary of laboratory values outside the normal range by treatment, planned relative time 
 
Laboratory Test (units) 
Treatment 
Planned Relative 
Time 
m 
H 
L 
Treatment 1 (N=xx) 
 
Source: Listing 16.2.xx 
H = Above reference interval, L = Below reference interval 
m = number of subjects with results for that parameter 
 
 
 
Programming notes: 
Continued with all tests, treatment groups and time points. 
 
 
Template T_LB3 
 
Table 14.3.4.xx 
Summary of laboratory values outside the normal range by treatment 
 
Laboratory Test (units) 
Treatment 
m 
H 
L 
Overall* 
Treatment 1 (N=xx) 
 
Source: Listing 16.2.xx 
H = Above reference interval, L = Below reference interval 
Subjects only counted once per treatment per double flag 
*Subjects only counted once per treatment 
m = total number of results for that parameter 
 
 
Programming notes: 
Continued with all tests, treatment groups and time points. 


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Template T_LB2 
 
Table 14.3.5.xx 
Summary of chemistry laboratory values 
 
 
Change from Baseline 
Laboratory Test 
(units) 
Treatment 
Planned 
Relative Time 
n 
Mean 
SD 
Median Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
 Treatment 1 (N=xx) 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatments and time points 
 
 
Template T_UR1 
Table 14.3.5.xx 
Summary of urinalysis results 
 
Planned Relative 
Time 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
Laboratory Test 
Result 
n 
(%) 
n 
(%) 
Time 1 
Positive 
X 
x 
Negative 
X 
X 
Not Done 
x 
Time 2 
Positive 
Negative 
Not Done 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Results recorded as received, e.g. Negative, Trace, etc; urine pH summarised as <5, 5-8, >8; specific gravity summarised as <=1.005, 1.006 - 
1.010, 1.011 - 1.015, 1.016 - 1.020, 1.021 - 1.025, 1.026 - 1.029, >=1.030 Continued with all treatment groups and time points 


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Template T_VS1 
 
Table 14.3.6.xx 
Summary of vital signs 
 
Variable (units) 
Treatment 
Planned 
Relative Time 
n 
Mean 
SD 
Median 
Min 
Max 
Systolic BP (mmHg) 
Treatment 1 (N=xx) 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all variables, treatments and time points 
 
Template T_VS2 
 
Table 14.3.6.xx 
Summary of vital signs outside the normal range by treatment, planned relative time and parameter 
 
Planned Relative 
Time 
Systolic Blood 
Pressure (mmHg) 
Diastolic Blood 
Pressure (mmHg) 
Heart Rate 
(beats/min) 
Temperature (C) 
etc 
Treatment 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Treatment 1 
(N=xx) 
Time 1 
Time 2 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatments and parameters. n = total number of results for that parameter 


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Template T_EG2 
 
Table 14.3.7.xx 
Summary of ECG values 
 
 
Variable (units) 
Treatment 
Planned Relative 
Time 
n 
Mean 
SD 
Median 
Min 
Max 
Heart Rate (bpm) 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
 
PR Interval (msec) 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and time points 
Do not summarise RR or QRS axis 


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Template T_EG3 
 
Table 14.3.7.xx 
Summary of QTcF, QTcB and PR interval values outside the normal range by treatment, planned relative time and category 
 
 
 
 
 
 
QTcF (msec) 
QTcB (msec) 
PR int. (msec) 
Planned 
Relative 
Time 
 
451 – 480 
481 – 500 
> 500 
451 – 480 
481 – 500 
> 500 
<120 
>220 
Treatment 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Treatment 1 
(N=xx) 
Time 1 
Time 2 
Time 3 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all variables, treatments and time points. n = total number of results for that parameter 








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17.2.3 Listing outlines 
Template L_SD1_PG 
 
Listing 16.2.x.xx 
Listing of study dates 
 
Subject 
Sequence* 
Screening 
Period 1 
Period 2 
Period 3 
Follow Up 
 
 
xxx 
 
 
Programming notes: 
Lists dates for screening, each dosing period and follow up 
Add footnotes for the sequences 
 
 
Template L_SD2_PG 
 
Listing 16.2.x.xx 
Listing of reasons for withdrawal 
 
Treatment 
Subject 
Date of 
Withdrawal 
Study 
Day 
Reason 
 
 
Programming notes: 
Reason for withdrawal is concatenation of reason and details 
 
 
Template L_DV1_PG 
 
Listing 16.2.x.xx 
Listing of subjects with inclusion/exclusion criteria deviations 
 
Treatment 
Subject 
Type 
Criterion 
Inclusion 
Exclusion 


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Template L_TD1_PG 
 
Listing 16.2.x.xx 
Listing of subjects with time deviations 
 
 
Treatment 
Subject 
Planned 
Relative 
Time 
Procedure 
Allowed 
deviation 
(h:min) 
Actual 
deviation 
(h:min) 
Time outside the 
deviation window 
(h:min) 
 
 
Programming notes: 
Only include time deviations which exceed the allowed deviation 
 
 
Template L_DV2_PG 
 
Listing 16.2.x.xx 
Listing of subjects with other protocol deviations 
 
Treatment 
Subject 
Protocol Deviation 
Type of Deviation 
Category 
 
 
 
 
Template L_AN1_PG 
 
Listing 16.2.x.xx 
Listing of analysis populations 
 
Treatment 
Subject 
Safety 
Population 
Population 1 
Population 2 
Etc. 


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Template L_DM1_PG 
 
Listing 16.2.x.xx 
Listing of demographic characteristics 
 
Subject 
Sequence* 
Date of visit 
Year of birth 
Age 
(y) 
Sex 
Race 
Ethnic origin 
Height 
(cm) 
Weight 
(kg) 
BMI (kg/m2) 
Etc (units) 
 
 
 
*A = 0 mg ASN51, B = xx mg ASN51, C = xx mg ASN51, D = xx mg ASN51, 
Programming notes: 
A by-subject listing of demographic characteristics including: 
Treatment 
Subject 
Date of visit 
Year of birth 
Age 
Sex 
Race / Ethnic Origin 
Height (if collected only once during the study) 
Weight (if collected only once during the study) 
Smoking History 
Alcohol Consumption 
Additional study-specific demography characteristics included on the CRF 


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Template L_CM1_PG 
 
Listing 16.2.x.xx 
Listing of concomitant medications 
 
Treatment 
Subject 
ATC Class/ 
Medication Code* 
Drug Name/ 
Indication 
Dose/ 
Freq/Route 
Date/Time Started/ 
Date Stopped 
Study Day 
Started/ 
Time Since Last 
Dose 
Started Pre- 
Trial? 
Ongoing 
Medication? 
 
*Coded using WHODrug Global vXX.X 
 
 
Programming notes: 
* only include this column and the footnote if coding used 
Include dose and units (e.g. 
 
 
Template L_MH1_PG 
 
Listing 16.2.x.xx 
Listing of medical and surgical history 
 
Treatment 
Subject 
Category 
System organ 
class*/Preferred 
term 
Verbatim text 
Clinical 
significance 
Date 
Started 
Date 
Stopped 
End relative 
to Screening 
 
*Coded using MedDRA vXX.X 
 
Template L_EX1_PG 
 
Listing 16.2.x.xx 
Listing of exposure data 
 
Treatment 
Subject 
Start Date/ 
Start Time of Dose 
Dose 
Dose 
Unit 
Formulation/ 
Route 
Frequency 
Treatment 1 
 
 
 
 
 
2xday 
 
 


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Template L_PK1_PG 
Listing 16.2.6.xx 
Listing of ASN51 plasma pharmacokinetic concentration-time data 
 
Treatment 
Subject 
{Add. 
time 
var.} 
Date 
Study Day 
Planned 
Relative Time 
Actual time 
(hh:mm) 
Time Deviation 
(min) 
Actual Relative 
Time 
( h) 
Concentration (units) 
 
 
Below the Limit of Quantification (BLQ) is < xx units (e.g. 1 ng/mL) 
Programming notes: 
Values below LLOQ are shown as BLQ. Check LLOQ value in final PK spreadsheet for each analyte. 
Template L_PK4_PG 
 
Listing 16.2.xx 
Listing of derived ASN51 plasma pharmacokinetic parameters 
 
Treatment 
Subject 
Imaging 
Session 
AUCinf 
(units) 
AUCt 
(units) 
Cmax 
(units) 
t1/2 
(units) 
tmax 
(units) 
 
Programming notes: 
Continue with all parameters 
 
Template L_PD1 
 
Listing 16.2.xx 
Listing of [18F]-IMA601 data regional total volume of distribution 
 
 
Treatment 
Subject 
Scan 
number 
{Add. 
time 
var.} 
Start Date/ 
Start Time of PET 
scan 
Stop Date/ 
Stop Time of 
PET scan 
Dose 
drawn 
up 
Residual 1 
Residual 2 
Brain Region 
VT 
(units) 
Change from 
baseline VT 
(units) 
 
 
 
 


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Template L_PD2 
 
Listing 16.2.xx 
Listing of receptor occupancy and plasma concentration data of ASN51 
 
 
Treatment 
Subject 
Scan 
number 
{Add. 
time 
var.} 
Start Date/ 
Start Time of PET 
scan 
Stop Date/ 
Stop Time of 
PET scan 
Concentration 
at start of PET 
scan 
Occupancy (%) 
 
 
 
 
 
Programming notes: 
Concentration at start of PET scan will be calculated using the closest time before start of PET scan and the closest time after PET scan 
 
 
 
Template L_AE1_PG 
Listing 16.2.x.xx 
Listing of all adverse events 
 
Treatment 
Subject 
System Organ Class* / 
Preferred Term/ 
Verbatim Text 
Outcome/ 
Onset Date/Time/ 
Resolved Date/Time/ 
Duration 
Study Day Started/ 
Time Since Last 
Dose 
Severity/ 
Serious/ 
Withdrawal 
Frequency/ 
Action Taken (1)/ 
Other Action 
Taken 
Related to Study 
Drug/ 
Treatment 
Emergent? 
Treatment 1 
 
Gastrointestinal Disorders / 
Intestinal Spasm / 
Entero-spasm 
Resolved/ 
 
 
 34d 4h 5m 
Day x/ 
10d 7h 3m 
Mild/ 
No/ 
Yes 
Intermittent/ Dose 
not changed/ 
None 
Possibly/ 
Yes 
(1)  Action Taken with Study Treatment 
*Coded using MedDRA vXX.X 
Programming notes: 
For the listing of “other significant AEs” include (from ICH E3) AEs leading to withdrawal, AEs leading to dose reduction (including drug withdrawn, interrupted, 
reduced or similar) and AEs with AEOSE=Y. If AEOSE has not been collected then use “Otherwise significant” in the CRF. 


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Template L_LB1_PG 
 
Listing 16.2.x.xx 
Listing of clinical chemistry data outside the normal range 
 
Treatment 
Subject 
Laboratory test (units) 
Planned 
Relative 
Time 
Date/Time 
Study 
Day 
Value 
Reference Interval 
RI 
Clinically 
Significant? 
Treatment 1 
 
Alk Phos (U/L) 
Time 1 
 
 
-1 
64.00 
32.0 - 92.0 
Time 2 
 
 
85 
84.00 
32.0 - 92.0 
ALT (U/L) 
Time 1 
 
 
-1 
29.00 
10.0 - 40.0 
Time 2 
 
   
 
85 
70.00 
10.0- 40.0 
H 
Y 
 
RI for Reference Interval flag; 
H = Above reference interval, L = Below reference interval 
 
Programming notes: 
Lists only subjects with at least a high or low value 
 
 
 
Template L_VS1_PG 
Listing 16.2.x.xx 
Listing of vital signs outside the normal range 
 
Treatment 
Subject 
Planned Relative 
Time 
Date/Time 
Systolic 
Blood Pressure 
(mmHg) 
Diastolic 
Blood Pressure 
(mmHg) 
Etc 
(units) 
24 H 
 
63 
148* 
* Value outside the normal range 


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Template L_VS2_PG 
 
Listing 16.2.x.xx 
Listing of clinically significant vital signs 
 
Treatment 
Subject 
Planned Relative 
Time 
Date/Time 
Vital Sign Finding 
Comment on Clinical 
Significance 
 
Programming notes: 
Lists only values with abnormal CS 
 
 
 
Template L_EG1_PG 
 
Listing 16.2.x.xx 
Listing of QTcF, QTcB and PR interval values outside the normal range 
 
Treatment 
Subject 
Planned 
Relative Time 
Date/Time 
Heart 
Rate 
(bpm) 
PR Int. 
(msec) 
QRS 
Dur. 
(msec) 
QRS 
Axis 
(deg) 
QT Int. 
(msec) 
QTcF 
(msec) 
QTcB 
(msec) 
24 H 
 
63 
148 
78 
50 
390 
452* 
396 
 
* Value outside the normal range 
 
 
Template L_EG2_PG 
 
Listing 16.2.x.xx 
Listing of abnormal ECG findings 
 
 
Treatment 
Subject 
Planned Relative 
Time 
Date 
ECG Finding 
Comment on Clinical 
Significance 
 
 
Programming notes: 
Lists only values with Normal variant=’No’ or with comment on ECG result 
ECG Finding contains Physician’s Opinion from CRF and relates to whole trace (not individual parameters), e.g. Normal, Abnormal - NCS or Abnormal - CS 


HMR code: 21-001 
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Page 44 of 49 
 
 
Template L_PE1_PG 
 
Listing 16.2.x.xx 
Listing of abnormal physical examination findings 
 
 
Treatment 
Subject 
Planned Relative 
Time 
Date 
Site 
Details 
 
 
Programming Notes: 
List only findings with an ‘abnormal’ result. 
If subjects have multiple abnormal sites at a given time, create a separate row for each site. 
 
 
Template L_CSS_PG 
 
Listing 16.2.x.xx 
Listing of positive Columbia-Suicide Severity Rating Scale data 
 
 
Treatment 
Subject 
Planned Relative 
Time 
Date/Time 
Category 
Question 
Result 


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Appendix A: Pharmacokinetic analysis 
 
1 
Calculation methods 
 
1.1 
Data handling conventions 
 
1.1.1 Missing and BLQ concentrations 
No missing values will be imputed. 
 
For all PK assessments (calculation of parameters, and individual profile plots) BQL 
values will be taken as missing with the exception of the predose value, where a BLQ 
value will be taken as zero. 
BQL values will be taken as zero for calculation of plasma concentration summary 
statistics unless they fall between two quantifiable concentrations in which case they 
will be treated as missing. 
1.2 
AUC calculations 
 
The AUC will be calculated by a combination of linear and logarithmic methods. The 
linear trapezoidal method will be employed for all incremental trapezoids arising from 
increasing concentrations and the logarithmic trapezoidal method will be used for 
those arising from decreasing concentrations. 
It is acceptable to include data from profiles with >20% extrapolated as long as at least 
80% of the profiles in the study have <20% of the AUC(0-∞) as extrapolated area. In 
this instance, individual plasma concentration-time profiles for which the extrapolated 
areas are >20% of AUC(0-∞) will be identified. 
It is unacceptable to use AUC(0-∞) data if >40% of the AUC has been extrapolated, 
except in specific situations which should be carefully justified in the study report. 
1.3 
Lambda-z calculations 
 
The apparent terminal phase rate-constant (λz) will be estimated by linear regression 
of logarithmically transformed concentration versus time data. Only those data points 


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which are judged to describe the terminal log-linear decline will be used in the 
regression. 
During the analysis, repeated regressions are carried out using the last three points 
with non-zero concentrations, then the last four points, last five, etc. Points prior to 
Cmax are not used. Points with a value of zero for the concentration are excluded. For 
each regression, an adjusted R2 is computed. The λz using the regression with the 
largest adjusted R2 is selected. If the adjusted R2 does not improve, but is within 
0.0001 of the largest adjusted R2 value, the regression with the larger number of points 
is used. λz must be positive, and calculated from at least three data points. 
A minimum number of three data points will be used in calculating λz. 
 
1.4 
Observed v predicted values 
 
For parameters dependent on λz, the ‘predicted’ rather than the ‘observed’ parameters 
will be calculated. 
 
The ‘predicted’ parameters are calculated using Cˆ
t (the predicted value of the 
concentration at time tn); whilst the ‘observed’ parameters use the last observed 
concentration. 


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2 
Parameter definitions 
 
2.1 
Plasma parameters 
 
 
Text Symbol 
Definition 
Calculation 
Typical Units 
Log 
Transform 
WNL 
CDISC 
Controlled 
Terminology 
TFL 
Symbol 
Concentrations and times 
Cmax 
Maximum (peak) plasma 
concentration 
Obtained directly from the concentration-time 
data. 
ng/mL 
Y 
Cmax 
CMAX 
Cmax 
Cmax/Dose 
Dose-normalised AUC to 
infinity 
Calculated as Cmax /Dose administered 
(ng/mL)/mg 
Y 
Cmax_D 
CMAXD 
Cmax/D 
tmax 
Time to reach maximum 
(peak) plasma concentration 
Obtained directly from the concentration-time 
data. 
h 
N 
Tmax 
TMAX 
tmax 
Half-life 
λz 
Terminal rate constant 
Estimated by linear regression of 
logarithmically transformed concentration 
versus time data. 
1/h 
Y 
Lambda_z 
LAMZ 
λz 
t½ 
Terminal half-life 
Calculated from the terminal slope of the log 
concentration-time curve, as follows: 
log𝑒𝑒 2 
𝑡𝑡½ =  λ 
𝑧𝑧 
h 
Y 
HL_Lambda_z 
LAMZHL 
t1/2 
Areas under the curve 
AUClast 
Area under the plasma 
concentration-time curve 
from time zero to time of last 
measurable concentration 
The area under the concentration-time curve 
from zero time (pre-dose) to the time of last 
quantifiable concentration will be calculated 
using the (specified) trapezoidal method. 
h*ng/mL 
Y 
AUClast 
AUCLST 
AUClast 
AUClast/Dose 
Dose-normalised AUC from 
time zero to last measurable 
concentration 
The dose-normalised AUC from time zero to 
last measurable concentration will be 
calculated as AUClast/Dose 
Administered 
(h*ng/mL)/mg 
Y 
- 
AUCLSTD 
AUClast/D 
AUC∞ 
Area under the plasma 
concentration-time curve 
from time zero to infinity 
Calculated using the (specified) trapezoidal 
method for the interval 0 to tlast (time tlast is 
the time at which the last non-zero level was 
recorded), plus the area under the exponential 
curve from tlast to infinity, calculated as 
follows: 
h*ng/mL 
Y 
AUCINF_pred 
AUCIFP 
AUCinf 


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HMR 
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Text Symbol 
Definition 
Calculation 
Typical Units 
Log 
Transform 
WNL 
CDISC 
Controlled 
Terminology 
TFL 
Symbol 
AUC 
= C t  
Cˆ 
t −∞ 
λ 
where 
t is the 
z 
predicted value of the concentration at tlast. 
AUC∞/Dose 
Dose-normalised AUC to 
infinity 
Calculated as AUC∞/Dose administered 
(h*ng/mL)/mg 
Y 
AUCINF_D_pred 
AUCIFPD 
AUCinf/D 
%AUCextrap 
Percentage of AUC∞ 
extrapolated from from tlast 
to infinity 
%AUC 
= 100 × AUCt −∞ 
extrap 
AUC 
∞ 
% 
N 
AUC_%EXTRAP_pred 
AUCPEP 
%AUCextrap