Conditions: Eosinophilic Esophagitis (EoE)
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 66
Healthy volunteers: yes

Brief summary:
The principal aim of this study is to obtain safety and tolerability data when AQ280 is administered orally as single and multiple doses to healthy subjects. This information, together with the pharmacokinetic (PK) data, will help establish the doses and dosing regimen suitable for future studies in patients.

Detailed description:

Arms:
arm 1: Single dose of AQ280, 3 mg or placebo arm 2: Single dose of AQ280, dose to be determined (TBD) or placebo arm 3: Single dose of AQ280, dose TBD or placebo arm 4: Single dose of AQ280, dose TBD or placebo arm 5: Single dose of AQ280, dose TBD or placebo arm 6: AQ280 dose TBD or placebo, once daily (QD) for seven days arm 7: AQ280 dose TBD or placebo, once daily (QD) for seven days arm 8: AQ280 dose TBD or placebo, once daily (QD) for seven days

Interventions: intervention 1: AQ280 intervention 2: Placebo
Intervention descriptions: intervention 1: Dose form: capsule, hard

Strength: 3 to 100 mg

Method of administration: oral intervention 2: Active substance: none

Dose form: capsule, hard

Strength/dose: not applicable

Method of administration: oral

Protocol document:
Prot_000.pdf: 
Document Type:  
 
Final Protocol 
Document Date:  
 
30 January 2023 
Study Title: 
A Randomized, Double-blind, Placebo-controlled, Single and 
Multiple Ascending Dose, and Food Effect Evaluation Trial to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of 
AQ280 in Healthy Subjects 
Protocol Reference Number:  ARIA-1 
NCT Number:  
 
NCT05485779 
 
 






Pr ot oc ol 
C O N FI D E N TI A L  
La bc or p Dr u g De vel o p me nt St u d y: 8 4 9 3 4 0 9 
Pr ot oc ol Refere nce: A RI A - 1 
Pr ot oc ol Vers i o n 5, 3 0 Ja n uar y 2 0 2 3 
Pa ge 2 of 6 2 
S P O N S O R A P P R O V A L  
 
I ha ve rea d t he pr ot oc ol a n d a p pr o ve it: 
 
 
 
P P D


Pr ot oc ol 
C O N FI D E N TI A L  
La bc or p Dr u g De vel o p me nt St u d y: 8 4 9 3 4 0 9 
Pr ot oc ol Refere nce: A RI A - 1 
Pr ot oc ol Vers i o n 5, 3 0 Ja n uar y 2 0 2 3 
Pa ge 3 of 6 2 
I N V E S TI G A T O R A G R E E M E N T 
 
I ha ve rea d t he pr ot oc ol a n d a gree t o c o n d uct t he st u d y as descri be d herei n. 
P P D








Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 7 of 62 
The single ascending dose (SAD) portion will include: 
• 
A screening visit from 2 days up to 5 weeks before the dose of investigational medicinal 
product (IMP). 
• 
An in-clinic treatment period of 4 days which includes a 48-hour period after the dose. 
Eligible subjects will be randomized on Day 1 to AQ280 or placebo prior to administration. 
• 
A safety follow-up phone call will be conducted 1 week (±2 days) after dose administration. 
Dose administration will occur on Day 1. 
Safety assessments will include adverse event (AE) reporting, vital signs, electrocardiograms (ECGs), 
clinical laboratory tests, and physical examination. 
Blood samples to determine the PK of AQ280 and its main metabolite, AQ282, will be collected from 
predose up to 48 hours postdose. 
Part B: Multiple ascending dose 
Three sequential dose groups are planned, with subjects dosed once daily (QD). 
The multiple ascending dose (MAD) portion will include: 
• 
A screening visit from 2 days up to 5 weeks before the first dose of IMP. 
• 
An in-clinic treatment period of 9 days which includes a 48-hour period after the last dose. 
Eligible subjects will be randomized on Day 1 to AQ280 or placebo prior to administration. 
• 
A safety follow-up visit will be conducted 1 week (±3 days) after the final dose. 
For all subjects, dosing is planned to be QD on Days 1 to 7, inclusive, at approximately the same time 
each morning. The total daily dose administered will not exceed an exposure shown to be safe and 
well tolerated in Part A.  
Safety assessments will include AE reporting, vital signs, ECGs, clinical laboratory tests, and physical 
examination. 
Blood samples to determine the PK of AQ280 and its main metabolite, AQ282, will be collected from 
predose up to 24 hours postdose on Day 1; predose on Days 3 through 6; and from predose up to 
48 hours postdose on Day 7. 
Number of Subjects 
Each group will have 8 subjects, randomized 6:2 to AQ280:placebo. 
For Part A, the total will be approximately 40 subjects (8 subjects × 5 groups). 
For Part B, the total will be approximately 24 subjects (8 subjects × 3 groups). 
Additional groups may be utilized based on the need for more evaluations or groups may be removed 
based on data obtained. 
Diagnosis and Main Criteria for Inclusion 
The trial subject population are healthy subjects, male or female, 18 to 65 years, inclusive. Each group 
should contain both male and female subjects, preferably at least 2 subjects of each gender. 
Furthermore, subjects with history of any significant infectious disease are excluded to mitigate the 
potential risk of infection. Light smoking during the trial is permitted, as this is not expected to 
interfere with AQ280. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 8 of 62 
Investigational Medicinal Products, Dose, and Mode of Administration 
AQ280 capsule: 
• 
Active substance: AQ280  
• 
Dose form: capsule, hard 
• 
Strength: 3 to 100 mg (dosage strength expressed as the free base moiety of AQ280) 
• 
Start dose: 3 mg 
• 
Method of administration: oral. 
Reference Product and Mode of Administration 
Placebo capsule: 
• 
Active substance: none 
• 
Dose form: capsule, hard 
• 
Strength/dose: not applicable 
• 
Method of administration: oral. 
Duration of Subject Participation in the Study 
Part A: up to approximately 6 weeks, including screening and safety follow-up. For the food effect 
evaluation group, up to approximately 8 weeks, including screening and safety follow-up. 
Part B: up to approximately 7 weeks, including screening and safety follow-up. 
Statistical Methods 
Safety 
Adverse events will be summarized for all treated subjects (safety analysis set) and will be presented 
by Medical Dictionary for Regulatory Activities preferred term and primary system organ class, and 
by group and treatment as the number of AEs and the number (percentage) of subjects with AEs. The 
percentage of subjects with AEs will be compared between treatments by a chi-square test or Fisher’s 
exact test. 
Vital signs, ECG, and laboratory parameters will be summarized by descriptive statistics (actual 
values and changes from baseline) at each assessment timepoint by group and treatment and by shift 
tables (according to normal ranges). 
Pharmacokinetics 
Plasma concentrations and PK parameters of AQ280 and its main metabolite, AQ282, will be listed 
and summarized by descriptive statistics per dose group and (for Part B only) day. Concentration-time 
profiles will be generated per dose group. 
In Part A, where data are available, AQ280 dose proportionality will be examined across groups. The 
PK parameters AUC from time 0 extrapolated to infinity (AUC0-∞), AUC from time 0 to the time of 
the last quantifiable concentration (AUC0-tlast), and Cmax, will be analyzed for dose proportionality 
using a power model approach or analysis of variance (ANOVA) model as appropriate. Where data 
are available, the effect of food at 1 dose level in Part A will be investigated using ANOVA. 
In Part B, the PK parameters AUC over a dosing interval (AUCτ) and Cmax, on Day 7 will be analyzed 
for dose proportionality using a power model approach or ANOVA model as appropriate. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 9 of 62 
TABLE OF CONTENTS 
 TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF TABLES AND FIGURES........................................................................................11 
LIST OF ABBREVIATIONS ..................................................................................................12 
1.
INTRODUCTION ...........................................................................................................13
1.1. 
Overview ................................................................................................................13 
1.2. 
Summary of Nonclinical Pharmacology ................................................................13 
1.3. 
Summary of Safety Pharmacology ........................................................................13 
1.4. 
Summary of Toxicology ........................................................................................13 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................14 
1.6. 
Summary of Clinical Experience ...........................................................................15 
1.7. 
Study Rationale ......................................................................................................15 
1.8. 
Benefit-risk Assessment .........................................................................................16 
2.
OBJECTIVES AND ENDPOINTS .................................................................................16
3.
INVESTIGATIONAL PLAN ..........................................................................................18
3.1. 
Overall Study Design and Plan ..............................................................................18 
3.1.1. 
Part A (Single Ascending Dose) ..................................................................19 
3.1.2. 
Part B (Multiple Ascending Dose) ...............................................................21 
3.2. 
Study Start and End of Study Definitions ..............................................................22 
3.3. 
Additional Groups ..................................................................................................22 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................22 
3.4.1. 
Dose Interval ................................................................................................23 
3.5. 
Selection of Doses in the Study .............................................................................24 
3.5.1. 
Starting Dose for Single Ascending Dose ...................................................24 
3.5.2. 
Starting and Maximum Dose for Multiple Ascending Dose .......................24 
3.6. 
Dose Escalation ......................................................................................................24 
3.7. 
Dose Escalation Stopping Criteria .........................................................................25 
4.
SELECTION OF STUDY POPULATION .....................................................................26
4.1. 
Inclusion Criteria ...................................................................................................26 
4.2. 
Exclusion Criteria ..................................................................................................26 
4.3. 
Subject Number and Identification ........................................................................28 
4.4. 
Subject Withdrawal and Replacement ...................................................................28 
4.5. 
Study Termination .................................................................................................29 
5.
STUDY TREATMENTS .................................................................................................29
5.1. 
Description, Storage, Packaging, and Labeling .....................................................29 


Protocol 
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Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 10 of 62 
5.2. 
Study Treatment Administration ............................................................................29 
5.3. 
Randomization .......................................................................................................30 
5.4. 
Blinding..................................................................................................................30 
5.5. 
Treatment Compliance ...........................................................................................30 
5.6. 
Drug Accountability...............................................................................................31 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................31 
6.1. 
Concomitant Therapies ..........................................................................................31 
6.2. 
Diet .........................................................................................................................31 
6.3. 
Smoking .................................................................................................................32 
6.4. 
Exercise ..................................................................................................................33 
6.5. 
Blood Donation ......................................................................................................33 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................33 
7.1. 
Pharmacokinetic Assessments ...............................................................................33 
7.1.1. 
Sample Collection and Processing ...............................................................33 
7.1.2. 
Analytical Methodology ..............................................................................34 
7.2. 
Pharmacodynamic Assessments ............................................................................34 
7.3. 
Safety and Tolerability Assessments .....................................................................35 
7.3.1. 
Adverse Events ............................................................................................35 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................35 
7.3.3. 
Vital Signs ....................................................................................................35 
7.3.4. 
Electrocardiogram ........................................................................................36 
7.3.5. 
Physical Examination...................................................................................37 
7.3.6. 
Body Weight ................................................................................................37 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................37 
8.1. 
Determination of Sample Size ...............................................................................37 
8.2. 
Analysis Populations ..............................................................................................37 
8.2.1. 
Pharmacokinetic Population ........................................................................37 
8.2.2. 
Pharmacodynamic Population .....................................................................37 
8.2.3. 
Safety Population .........................................................................................37 
8.2.4. 
All Subjects Population................................................................................37 
8.3. 
Pharmacokinetic Analyses .....................................................................................37 
8.4. 
Pharmacodynamic Analyses ..................................................................................38 
8.5. 
Safety Analysis ......................................................................................................38 
8.6. 
Interim Analysis .....................................................................................................38 
9. 
REFERENCES ................................................................................................................39 
10. APPENDICES .................................................................................................................40 
Appendix 1: Adverse Event Reporting ..............................................................................41 
Appendix 2: Clinical Laboratory Evaluations ...................................................................44 
Appendix 3: Total Blood Volume ......................................................................................45 
Appendix 4: Contraception Guidance ................................................................................47 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 11 of 62 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................49 
Appendix 6: Schedule of Assessments ..............................................................................52 
 
LIST OF TABLES AND FIGURES 
Table 1: No Observed Adverse Effect Level Across Studies in Mice and Dogs ..............15 
Table 2: Objectives and Endpoints ....................................................................................16 
Table 3: High-fat Breakfast Content ..................................................................................32 
 
Figure 1: Planned Groups (Parts A and B) ........................................................................18 
Figure 2: Study Schematic (Part A) ...................................................................................20 
Figure 3: Study Schematic (Part A, Food Effect Evaluation) ............................................20 
Figure 4: Study Schematic (Part B) ...................................................................................22 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 12 of 62 
LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve from time 0 extrapolated to infinity 
AUC0-12 
area under the concentration-time curve over the time interval 0 to 12 hours 
postdose 
AUC0-24 
area under the concentration-time curve over the time interval 0 to 24 hours 
postdose 
AUC0-tlast 
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration 
AUCτ 
area under the concentration-time curve over a dosing interval 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRO 
contract research organization 
CYP 
cytochrome P450 
DEC 
dose escalation committee 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EoE 
eosinophilic esophagitis 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IL 
interleukin 
IMP 
investigational medicinal product 
JAK 
Janus kinase 
MAD 
multiple ascending dose 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAD 
single ascending dose 
SAE 
serious adverse event 
TMF 
trial master file 
ULN 
upper limit of normal 








Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 16 of 62 
1.8. 
Benefit-risk Assessment 
Healthy subjects in the current study will not receive any health benefit (beyond that of an 
assessment of their medical status) from participating in the study. The risks of participation 
are primarily those associated with adverse reactions to the study treatment, although there 
may also be some discomfort from collection of blood samples and other study procedures. 
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) associated with AQ280 may be found in the investigator’s brochure.1  
2. OBJECTIVES AND ENDPOINTS 
The objectives and endpoints of the study are presented in Table 2. 
Table 2: Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
 
• 
to evaluate the safety and tolerability of 
single and multiple ascending oral 
doses of AQ280, and to determine a 
safe therapeutic range of AQ280 in 
healthy subjects 
• 
number of TEAEs per subject 
• 
clinically significant abnormalities in vital signs 
(systolic and diastolic blood pressure, pulse rate, and 
oral body temperature) 
• 
abnormal ECG (QTcF interval of >450 msec for males 
and >470 msec for females, or change from baseline of 
>30 msec) measured from Day 1 (postdose) up until 48 
hours postdose in Part A and up to the follow-up visit 
in Part B 
• 
clinically significant changes in laboratory evaluations 
Secondary: 
 
• 
to determine the PK of AQ280 after 
single and multiple oral doses 
• 
to determine the PK of the AQ280 main 
metabolite, AQ282, after single and 
multiple oral doses 
• 
to determine the effect of food on the 
PK of AQ280 after single oral dose 
Part A (SAD): 
• 
primary PK parameters derived from plasma 
concentration-time profile of AQ280: AUC0-∞, Cmax 
(AUC0-tlast may be included as a primary PK parameter 
if AUC0-∞ cannot be calculated) 
• 
primary PK parameters derived from plasma 
concentration-time profile of the AQ280 main 
metabolite, AQ282: AUC0-∞, Cmax (AUC0-tlast may be 
included as a primary PK parameter if AUC0-∞ cannot 
be calculated) 
• 
comparison of the primary PK parameters of AQ280 
after single dose administration in the fasted state and 
in the fed state 
 
Part B (MAD): 
• 
primary PK parameters derived from plasma 
concentration-time profile of AQ280 on Day 1 and 
Day 7: AR, AUCτ, Cmax 
• 
primary PK parameters derived from plasma 
concentration-time profile of the AQ280 main 
metabolite, AQ282, on Day 1 and Day 7: AUCτ, Cmax 






Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 19 of 62 
3.1.1. 
Part A (Single Ascending Dose) 
Part A will comprise a single-dose, sequential group, escalating-dose design conducted in 
healthy adult male and female subjects; also incorporating a single-group, 2-period crossover 
arm investigating the effect of dosing AQ280 with food compared to dosing in the fasting 
condition. The first dose level administered is planned to be 3 mg AQ280. 
A total of approximately 40 subjects are planned to be studied in 5 groups (Groups A1 to A5; 
with one of the groups including the food effect evaluation). In each group, 6 subjects will 
receive AQ280 and 2 subjects will receive placebo. The dose will be administered in the 
fasted state in accordance with the randomization schedule on the morning of Day 1 for all 
groups, including Period 1 for the food effect evaluation group (see Section 3.1.1.1 for 
additional food-evaluation group requirements). Each group should contain both male and 
female subjects, preferably at least 2 subjects of each gender. Additional groups may be 
added based on the need for more evaluations or groups removed based on data obtained. 
The first group in Part A will be divided into 2 cohorts, with each cohort being dosed at least 
24 hours apart. The first cohort will comprise 2 subjects, with 1 subject receiving AQ280 and 
1 subject receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects 
receiving AQ280 and 1 subject receiving placebo. The 2 sentinel subjects (first cohort) will 
be dosed at least 24 hours before the second cohort of 6 subjects. Dosing of subjects in the 
second cohort will not occur if any of the dose escalation stopping criteria (Section 3.7) are 
met by the 2 sentinel subjects. Circumstances under which sentinel dosing may be introduced 
in other groups are detailed in Section 3.4.1. 
There will be a minimum of 9 days between dose escalations for each group. 
Potential subjects will be screened to assess their eligibility to enter the study from 2 days up 
to 5 weeks before the dose of AQ280 or placebo. Each subject will participate in 1 group only 
and will reside at the study site from Day -1 (the day before dosing) to Day 3 of the treatment 
period, with dose administration occurring on Day 1. A safety follow-up phone call will be 
conducted 1 week (±2 days) after dosing. 
Each eligible subject will participate in 1 treatment period only, except for the food effect 
group, where each subject will participate in 2 treatment periods. 
Based on the ongoing review of the safety, tolerability, and PK results, additional outpatient 
visits may be required. 
Safety assessments will include AE reporting, vital signs, electrocardiograms (ECGs), 
clinical laboratory tests, and physical examination. 
Blood samples to determine the PK of AQ280 and its main metabolite, AQ282, will be 
collected from predose up to 48 hours postdose. 
An overview of the study design for Part A is shown in Figure 2. 




Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 21 of 62 
3.1.2. 
Part B (Multiple Ascending Dose) 
Part B will comprise a multiple-dose, sequential group, escalating-dose design conducted in 
healthy adult male and female subjects. Part B may start prior to completion of all planned 
dose groups in Part A, at a dose equal to or less than that evaluated as safe and well tolerated 
in Part A. 
A total of approximately 24 subjects are planned to be studied in 3 groups (Groups B1 to B3). 
In each group, 6 subjects will receive AQ280 and 2 subjects will receive placebo. Each group 
should contain both male and female subjects, preferably at least 2 subjects of each gender. 
Additional groups may be added based on the need for more evaluations or groups removed 
based on data obtained. 
There will be a minimum of 9 days between dose escalations for each group. 
Potential subjects will be screened to assess their eligibility to enter the study from 2 days up 
to 5 weeks before the first dose of AQ280 or placebo. Each subject will participate in 1 group 
only and reside at the study site from Days -1 to 9. 
For all subjects, dosing is planned to be QD on Days 1 to 7, inclusive, at approximately the 
same time each morning. The dosing regimen in Part B may be changed following review of 
preliminary data from groups in Part A or previous groups in Part B. The daily dose 
administered, when given repeatedly, will be predicted to not exceed an exposure shown to 
be safe and well tolerated in Part A. Dietary state will be determined based on data obtained 
in Part A. 
A safety follow-up visit will be conducted 1 week (±3 days) after the final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional outpatient 
visits may be required. 
Safety assessments will include AE reporting, vital signs, ECGs, clinical laboratory tests, and 
physical examination. 
Blood samples to determine the PK of AQ280 and its main metabolite, AQ282, will be 
collected from predose up to 24 hours postdose on Day 1; predose on Days 3 through 6; and 
from predose up to 48 hours postdose on Day 7. 
Urine samples will be collected at intervals for the purpose of metabolite profiling. 
An overview of the study design for Part B is shown in Figure 4. 




Pr ot oc ol 
C O N FI D E N TI A L  
La bc or p Dr u g De vel o p me nt St u d y: 8 4 9 3 4 0 9 
Pr ot oc ol Refere nce: A RI A - 1 
Pr ot oc ol Vers i o n 5, 3 0 Ja n uar y 2 0 2 3 
Pa ge 2 3 of 6 2 
re gi me n f or Part  B. If t he a p pare nt ter mi nal eli mi nati o n half- life (t1/ 2) of A Q 2 8 0  is s h orter or 
l o n ger t ha n pre dicte d b y t he n o ncli nical data, f urt her d ose escalati o n ma y be re q uire d t o 
i ncl u de a re vise d d ose re gi me n. T his re vise d d ose re gi me n will be a gree d u p o n b y t he 
s p o ns or a n d D E C . 
Details of t he d osi n g re gi me n a n d d urati o n use d f or Part B  of t he st u d y will be d oc u me nte d i n 
t he T M F. 
A 4 8 - h o ur peri o d of resi de nc y after si n gle d ose i n Part A a n d fi nal d ose i n Part B is e x pecte d 
t o c orres p o n d t o   half-li ves of A Q 2 8 0. 
Base d u p o n t he n o n cli nical data, t he d urati o n of eac h treat me nt peri o d is c o nsi dere d a de q uate 
t o ac hie ve t he st u d y o bjecti ves. An i nter val of at least 7 da ys bet wee n d ose a d mi nistrati o ns i n 
t he 2 treat me nt peri o ds i n t he f o o d effect e val uati o n is c o nsi dere d a de q uate t o pre ve nt 
carr y o ver of A Q 2 8 0 . 
T his st u d y will be d o u ble bli n d a n d place b o  c o ntr olle d i n or der t o a v oi d bias i n t he c ollecti o n 
a n d e val uati o n of data d uri n g its c o n d uct. Place b o has bee n c h ose n as t he c o ntr ol treat me nt t o 
assess w het her a n y o bser ve d effects are treat me nt  relate d or si m pl y reflect t he st u d y 
c o n diti o ns. 
C o n d ucti n g t he st u d y i n healt h y s u bjects miti gates t he p ote ntial c o nf o u n di n g effects of t he 
disease state a n d c o nc o mita nt me dicati o ns.  S u bjects wit h hist or y of a n y si g nifica nt i nfecti o us 
disease are  e xcl u de d t o miti gate t he p ote ntial ris k of i nfecti o n. Li g ht s m o ki n g d uri n g t he trial 
is per mitte d, as t his is n ot e x pecte d t o i nterfere wit h A Q 2 8 0. 
3. 4. 1.  
D ose I nter v al  
F oll o wi n g t h or o u g h re vie w of all a vaila ble n o n cli nical data ( p har mac ol o gical a n d 
t o xic ol o gical), d osi n g f or t he starti n g d ose le vel i n Part A  ( Gr o u p A) will be s uc h t hat 
2 s u bjects ( 1 A Q 2 8 0  a n d 1 place b o) will be d ose d at least 2 4 h o urs bef ore t he re mai ni n g 
6 s u bjects. 
At least 3 J A K i n hi bit ors are a p pr o ve d f or cli nical use a n d se veral ot hers are i n Phase 3 
cli nical de vel o p me nt. T h us, t he ris k of o n- tar get s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns will be ne gli gi ble. T o mi ni mize t he c o nse q ue nce of a n y p ote ntial u n k n o w n 
off -tar get t o xicit y, se nti nel d osi n g will be i m ple me nte d f or t he first S A D gr o u p i n Part A . 
Base d o n k n o wle d ge of t he p har mac o d y na mic ( P D) effects of ot her J A K i n hi bit ors, i n 
partic ular t he J A K 1 -selecti ve i n hi bit or a br ociti ni b, n o effects are e x pecte d fr o m a si n gle d ose 
be y o n d 2 4 h o urs after d osi n g. T heref ore, a 2 4- h o ur i nter val bet wee n d osi n g of t he se nti nel 
s u bjects a n d t he re mai ni n g s u bjects i n t he first gr o u p is c o nsi dere d s ufficie nt, after re vie w of 
a vaila ble safet y data.  
Beca use of t he well  descri be d tar get p har mac ol o g y a n d safet y of ot her J A K i n hi bit ors, 
se nti nel d osi n g is n ot c o nsi dere d necessar y f or Part B , i n w hic h t he pre dicte d e x p os ure will 
n ot e xcee d a n e x p os ure alrea d y s h o w n t o be safe a n d well t olerate d i n Part A . 
Se nti nel d osi n g ma y  be i ntr o d uce d i n ot her gr o u ps t ha n i n t he first S A D gr o u p u n der t he 
f oll o wi n g circ u msta nces: 
C
CI




Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
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Dose escalation in both Parts A and B will only occur if data from a minimum of 6 subjects 
have been reviewed from the previous lower dose group, such that data from a minimum of 
4 subjects who have received AQ280 will be used to make the dose escalation decision. 
The justification for this is as follows: 
• The study treatment is of a known pharmacological class for which the on-target 
effects in humans are well characterized. Based upon nonclinical data, no 
clinically important off-target effects are expected within the proposed dose range. 
• A minimum of 4 subjects receiving the active drug is considered sufficient to 
characterize the safety profile and PK/PD response to AQ280. 
Prior to each dose escalation, the DEC, composed of the investigator, medical monitor, and 
sponsor medical representative as voting members and supported by additional team 
members (eg, pharmacokineticist) will review all available data in a blinded manner to ensure 
it is safe to proceed with the next planned dose level. An interim safety report, summarizing 
results from all available safety assessments, will be provided to the DEC prior to the dose 
escalation meeting. Any clinically significant results will be discussed by the DEC before 
dose escalation continues. Available interim PK data will also be reviewed to confirm that the 
study design remains appropriate. In the event of a disagreement between DEC voting 
members on the dose escalation decision, the decision of the investigator will be upheld. 
3.7. 
Dose Escalation Stopping Criteria 
The study will be halted if 1 or more subjects experience a serious adverse event (SAE) that 
is considered to be related to investigational medicinal product (IMP) or 2 or more subjects in 
the same group experience severe AEs that are considered to be related to IMP. If, following 
an internal safety review, the sponsor deems it appropriate to restart the study, this can be 
done following approval of a substantial protocol amendment. Dosing of subjects, including 
any ongoing multiple dose groups, will be stopped immediately if any of the dose escalation 
stopping criteria are met. 
In Parts A and B, following consultation with the sponsor and DEC, dose escalation will stop 
if: 
• Clinically significant abnormal signs or symptoms of similar nature occur in 2 or 
more subjects in a group that, in the opinion of the investigator, warrant stopping 
of dose escalation. 
• There is evidence of clinically significant increases in liver function tests defined 
as 3 × upper limit of normal (ULN) for aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, or gamma-glutamyl transferase or 
2 × ULN for total bilirubin in 2 or more subjects in a group (confirmed with repeat 
testing). 
• Clinically significant increases in serum creatinine, defined as 1.5 × ULN 
(confirmed with repeat testing), in 2 or more subjects in a group. 
• Hemoglobin decrease of >3.5 g/dL compared to Day -1 levels (confirmed by 
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3. History of any surgical (eg, stomach or intestinal surgery or resection) or medical 
condition that would potentially alter absorption, distribution, metabolism, and/or 
excretion of orally administered drugs. Uncomplicated appendectomy and hernia repair 
will be allowed. Cholecystectomy will not be allowed. 
4. History of any significant infectious disease, as assessed by the investigator, within 
2 weeks prior to the first dose of IMP. 
5. AST and/or ALT values >1.2 × ULN. 
6. Congenital nonhemolytic hyperbilirubinemia (including suspicion of Gilbert’s 
syndrome). 
7. Hemoglobin value, neutrophil count, and/or lymphocyte count <lower limit of normal. 
8. Clinically significant abnormal ECG at screening or check-in. 
9. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). Subjects whose results are compatible with prior immunization may be 
included at the discretion of the investigator 
10. Current active tuberculosis based on Quantiferon™ tuberculosis Gold test. 
Prior/concomitant therapy 
11. Administration of a coronavirus disease 2019 vaccine in the past 30 days prior to the 
first dose of IMP. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior to 
the first dose of IMP, unless deemed acceptable by the investigator (or designee). 
13. Use or intend to use any prescription medications/products other than hormone 
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptives within 14 days prior to the first dose of IMP, unless deemed acceptable 
by the investigator (or designee).  
14. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to check-in, unless deemed acceptable by the investigator (or 
designee). 
15. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to 
check-in, unless deemed acceptable by the investigator (or designee). 
Prior/concurrent clinical study experience 
16. Participation in a clinical study involving administration of an investigational drug (new 
chemical entity) in the past 90 days prior to dosing. 
17. Have previously completed or withdrawn from this study. 
Diet and lifestyle 
18. Alcohol consumption of >21 units per week for males and >14 units for females. One 
unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 
1/6 gill (25 mL) of spirits. 


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19. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) at 
screening or check-in. 
20. History of alcoholism or drug/chemical abuse within 2 years prior to check-in. 
21. Smoking >5 cigarettes per day, on average, or use the equivalent tobacco- or 
nicotine-containing products per day. 
22. Ingestion of poppy seed-, Seville orange-, star fruit-, or grapefruit-containing foods or 
beverages within 7 days prior to check-in. 
Other exclusions 
23. Receipt of blood products within 2 months prior to check-in. 
24. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to 
screening, or platelets from 6 weeks prior to screening.  
25. Poor peripheral venous access. 
26. Subjects who, in the opinion of the investigator (or designee), should not participate in 
this study. 
4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at screening. Subjects will be assigned 
a subject number at the time of their randomization. Assignment of subject numbers will be 
in ascending order (eg, in Part A Subjects 0101, 0102, etc, in Part B Subjects 0201, 0202, 
etc). Replacement subjects (Section 4.4) will be assigned a subject number corresponding to 
the number of the subject he/she is replacing plus 1000 (eg, Subject 1101 replaces 
Subject 0101). 
Subjects will be identified by screening identification number or subject number only on all 
study documentation. A list identifying the subjects by subject number will be kept in the Site 
Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• change in compliance with any inclusion/exclusion criterion that is clinically 
relevant and affects subject safety as determined by the investigator (or designee) 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn from dosing, the sponsor will be notified and the date and reason(s) 
for the withdrawal will be documented in the subject’s electronic case report form (eCRF). If 
a subject is withdrawn from the study, efforts will be made to perform all follow-up 
assessments, if possible (Appendix 6). Other applicable safety-related procedures may be 
performed at the investigator’s (or designee’s) and/or sponsor’s discretion. If the subject is 
in-house, these procedures should be performed before the subject is discharged from the 




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Subjects will be dosed in numerical order while seated and will not be permitted to lie supine 
for 2 hours after dosing, except as necessitated by the occurrence of an AE(s) and/or study 
procedures. 
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Labcorp Drug 
Development using a computer-generated pseudo-random permutation procedure. 
In Parts A and B, 2 subjects in each group will be randomly assigned to receive placebo. 
For the first group in Part A (Group A1), sentinel dosing will occur whereby 2 subjects 
(1 active and 1 placebo) will be dosed on 1 day and, providing no safety concerns arise, the 
remaining 6 subjects will be dosed at least 24 hours later. 
Subjects in the food effect evaluation group in Part A will receive the same treatment in 
Treatment Periods 1 and 2.  
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo capsules will be identical in appearance to the AQ280 capsules. 
• The investigator and other members of staff (with the exception of pharmacy staff 
and bioanalytical analysis staff) involved with the study will remain blinded to the 
treatment randomization code during the conduct of the study. 
• Interim bioanalytical data will be provided to Labcorp Clinical Research Unit in a 
blinded manner. 
• Where possible, PD data will be provided to Labcorp Clinical Research Unit in a 
blinded manner. 
To maintain the blind, the investigator will be provided with a sealed randomization code for 
each subject, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject 
safety or to support dose escalation decisions (in the event of possibly treatment-related SAEs 
or severe AEs), the decision to unblind resides solely with the investigator. Whenever 
possible, and providing it does not interfere with or delay any decision in the best interest of 
the subject, the investigator will discuss the intended code-break with the sponsor. If it 
becomes necessary to break the code during the study, the date, time, and reason will be 
recorded in the subject’s source data and on the individual envelope and will be witnessed by 
a second person. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of suitably qualified study 
site staff. 


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• Immediately after dose administration, visual inspection of the mouth and hands 
will be performed for each subject. 
• At each dosing occasion, a predose and postdose inventory of IMP will be 
performed on the dose containers. 
5.6. 
Drug Accountability 
The investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the sponsor or disposed 
of by the study site, per the sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or nonprescription medications/products 
during the study until the follow-up phone call or visit, unless the investigator (or designee) 
and/or sponsor have given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the investigator (or 
designee), unless its use is deemed necessary for treatment of an AE. Any medication taken 
by a subject during the course of the study and the reason for its use will be documented in 
the source data and in the eCRF.  
6.2. 
Diet 
While confined at the study site, subjects will receive a standardized diet at scheduled times 
that do not conflict with other study-related activities. Subjects will be fasted (at least 
8 hours) before collection of blood samples for clinical laboratory evaluations.  
On the days with intensive PK assessments (Day 1 for Part A and Days 1 and 7 for Part B), 
meals will be identical for each group with the exception of the high-fat breakfast for the food 
effect evaluation group. 
On Day 1 in Part A, subjects will be fasted for at least 10 hours prior to dosing until 
approximately 4.5 hours after dosing, when lunch will be provided. With the exception of 
water given with the dose, subjects will not be allowed fluids from 1 hour prior to until 


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2 hours after dosing. Meals will be provided as appropriate at other times. Other than the 
fluid restrictions on dosing days, water will be freely available at all times. 
Subjects in the food effect evaluation group in Treatment Period 2 will consume a high-fat 
breakfast (contents detailed in Table 3) before dosing. Subjects should start the meal 
30 minutes prior to administration of the IMP. Study subjects should eat this meal in 
30 minutes or less. The drug product should be administered 30 minutes after start of the 
meal. 
Table 3: High-fat Breakfast Content 
High-fat Breakfast 
120 g fried eggs (2 eggs) in vegetable oil 
50 g bacon (2 rashers) 
72 g toasted white bread (2 slices) 
13 g butter (2 pats) 
108 g hash brown (3 each) 
240 g whole milk 
Total calories: 973 kcal 
This high-fat meal contains the equivalent of approximately 150 protein calories, 
250 carbohydrate calories, and 500 to 600 fat calories. 
In Part B, the time interval between meals and dosing will be determined by the preliminary 
PK data from Part A and will be documented in the TMF. Meals will be provided as 
appropriate at other times. With the exception of water given with the dose, subjects will not 
be allowed fluids from 1 hour prior to dosing until 2 hours after dosing on the days with 
intensive PK assessments (Days 1 and 7) or until 1 hour after dosing on other days. Other 
than these fluid restrictions, water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, star fruit, or Seville oranges will not 
be allowed from 7 days prior to check-in until discharge in Part A and until the follow-up 
visit in Part B. 
Caffeine-containing foods and beverages will not be allowed from 36 hours before check-in 
until discharge in Part A and until the follow-up visit in Part B. 
Consumption of alcohol will not be permitted from 36 hours prior to check-in in Parts A 
and B until discharge in Part A. Up to 2 units/day of alcohol are permitted from discharge 
until 36 hours before the follow-up visit in Part B. 
6.3. 
Smoking 
Smoking will not be permitted from waking until after lunch on Day 1 (Part A) and on 
Days 1 and 7 (Part B), and for 1 hour before each blood pressure and pulse rate measurement 
outside these periods. Subjects will be permitted to smoke ≤5 cigarettes or equivalent 
tobacco- or nicotine-containing products per day outside of restricted times while they are 
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7.3. 
Safety and Tolerability Assessments 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to final 
discharge from the study. Subjects will be observed for any signs or symptoms and asked 
about their condition by open questioning, such as “How have you been feeling since you 
were last asked?”, at least once each day while resident at the study site and at each study 
visit. Subjects will also be encouraged to spontaneously report AEs occurring at any other 
time during the study. 
Any AEs and remedial action required will be recorded in the subject’s source data. The 
nature, time of onset, duration, and severity will be documented, together with an 
investigator’s (or designee’s) opinion of the relationship to study treatment. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the investigator (or designee) to 
have stabilized. This will be completed at the investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations at the times 
indicated in the Schedules of Assessments in Appendix 6. Clinical laboratory evaluations are 
listed in Appendix 2. The timing of clinical laboratory evaluations may be adjusted and/or 
additional clinical laboratory evaluations may be performed at other times if judged to be 
clinically appropriate or if the ongoing review of the data suggests a more detailed 
assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen, and will undergo 
an alcohol breath test at the times indicated in the Schedules of Assessments in Appendix 6. 
For all female subjects, a pregnancy test will be performed and for postmenopausal females a 
follicle-stimulating hormone test will be performed at the times indicated in the Schedules of 
Assessments in Appendix 6. 
An investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, and oral body temperature will be assessed at the 
times indicated in the Schedules of Assessments in Appendix 6. Vital signs may also be 
performed at other times if judged to be clinically appropriate or if the ongoing review of the 
data suggests a more detailed assessment of vital signs is required. 
Day 1 predose blood pressure and pulse rate will be measured in triplicate at approximately 
2-minute intervals. All subsequent measurements will be performed singly and repeated once 
if outside the relevant clinical reference ranges. Oral body temperature will be measured 
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Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
7.3.4. 
Electrocardiogram 
7.3.4.1. 
12-lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedules of Assessments in Appendix 6. Single 
12-lead ECGs will be repeated once if either of the following criteria apply:  
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
value >500 ms 
• QTcF change from the baseline (predose) is >60 ms. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. All subsequent measurements will be performed singly and repeated once if outside 
the relevant clinical reference ranges. 
7.3.4.2. 
Telemetry 
Cardiac rhythm will be monitored by telemetry at the times indicated in the Schedule of 
Assessments for Part A in Appendix 6. 
Telemetry is not planned for Part B of the study but may be implemented if any clinically 
significant findings are identified in the data from Part A. 
7.3.4.3. 
Continuous 12-lead Electrocardiogram Monitoring 
Continuous 12-lead ECG monitoring using a digital recorder will take place at the times 
indicated in the Schedule of Assessments for Part A in Appendix 6. 
All continuous 12-lead ECG data collected will be archived without extraction or analysis 
and will not be reported in the scope of this study. 
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (eg, television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording. 
When coinciding, vital sign assessments and PK sampling should always be performed after 
the ECG extraction time window. If a separate ECG machine is being used for safety 
assessments described in Section 7.3.4.1, that machine should be in place prior to the 
extraction window to permit safety ECGs to be recorded irrespective of the extraction 
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recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window. 
7.3.5. 
Physical Examination 
A full physical examination or symptom-directed physical examination will be performed at 
the timepoints specified in the Schedules of Assessments in Appendix 6. 
7.3.6. 
Body Weight 
Body weight (in light clothing) will be recorded at the times indicated in the Schedules of 
Assessments in Appendix 6. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time AQ280 is being administered to humans. However, the number of subjects in each 
part of the present study is common in early clinical pharmacology studies and is considered 
sufficient to achieve the objectives of the study. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of active study 
treatment (AQ280) and have at least 1 valid PK concentration. 
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of study treatment 
(AQ280 or placebo) and have at least 1 valid postdose PD assessment. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study treatment 
(AQ280 or placebo). 
8.2.4. 
All Subjects Population 
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol. 
8.3. 
Pharmacokinetic Analyses 
Plasma concentrations of AQ280 and its main metabolite, AQ282, and plasma PK parameters 
will be listed and summarized by descriptive statistics per dose group and (for Part B only) 
day. Concentration-time profiles will be generated per dose group. 


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Pharmacokinetic parameters will be determined from plasma concentrations of AQ280 and 
its main metabolite, AQ282, using standard noncompartmental methods. Full details of PK 
parameters will be presented in the statistical analysis plan for this study. 
In Part A, where data are available, AQ280 dose proportionality will be examined across 
groups. The PK parameters AUC from time 0 extrapolated to infinity (AUC0-∞), AUC from 
time 0 to the time of the last quantifiable concentration (AUC0-tlast), and Cmax, will be 
analyzed for dose proportionality using a power model approach or analysis of variance 
(ANOVA) model as appropriate. Where data are available, the effect of food at 1 dose level 
in Part A will be investigated using ANOVA. 
In Part B, the PK parameters AUC over a dosing interval (AUCτ) and Cmax, on Day 7 will be 
analyzed for dose proportionality using a power model approach or ANOVA model as 
appropriate. 
8.4. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized. No formal statistical analysis of 
PD data is planned. 
8.5. 
Safety Analysis 
Adverse events will be summarized for all treated subjects (safety population) and will be 
presented by Medical Dictionary for Regulatory Activities preferred term and primary system 
organ class, and by group and treatment as the number of AEs and the number (percentage) 
of subjects with AEs. The percentage of subjects with AEs will be compared between 
treatments by a chi-square test or Fisher’s exact test. 
Vital signs, ECG, and laboratory parameters will be summarized by descriptive statistics 
(actual values and changes from baseline) at each assessment timepoint by group and 
treatment and by shift tables (according to normal ranges). 
No formal statistical analysis of safety data is planned. 
8.6. 
Interim Analysis 
No formal interim analyses are planned for this study. 


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9. REFERENCES 
1. AQ280 [Investigator’s Brochure]. Place: Aqilion; Edition 1.0, Final 13 Apr 2022. 
2. Food and Drug Administration. Guidance for Industry: Estimating the Maximum Safe 
Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers 
[Internet]. Food and Drug Administration; 2005. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm078932.pdf 
 


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10. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study treatment, whether or not related to the 
study treatment. 
Assessment of Severity 
The investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
• Severe: Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The investigator (or designee) will make a determination of the relationship of the AE to the 
study treatment using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the 
study procedure/conditions. 
• Unlikely Related: The temporal association between the AE and the drug is such 
that the drug is not likely to have any reasonable association with the AE. 
• Possibly Related: The AE follows a reasonable temporal sequence from the time 
of drug administration but could have been produced by the subject’s clinical state 
or the study procedures/conditions. 
• Related: The AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears when the 
drug is reintroduced.  
Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have AEs. Any subject 
who has an ongoing AE that is possibly related or related to the investigational medicinal 
product (IMP) or study procedures at the follow-up phone call or visit will be followed up, 
where possible, until resolution or until the unresolved AE is judged by the investigator (or 


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designee) to have stabilized. This will be completed at the investigator’s (or designee’s) 
discretion. Any subject who has an ongoing AE that is not related or unlikely related to the 
IMP or study procedures at the follow-up phone call or visit can be closed out as ongoing at 
the investigator’s discretion.  
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship between an 
IMP and an AE is at least a reasonable possibility) related to any dose should be considered 
adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, investigator’s 
brochure for an unapproved IMP). 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose either: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the investigator at 
any time after cessation of the study treatment and considered by the investigator to be 
possibly related to the study treatment, will be reported to the sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 


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Definition of Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the study site. When in doubt as to whether hospitalization occurred or 
was necessary, the AE should be considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a clinical assessment form and 
added to the electronic case report form. If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘nonserious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
Serious adverse events that occur between the time of signing the informed consent form and 
until 30 days after the last dose of study treatment, regardless of relationship to the study 
treatment, must be reported within 24 hours of knowledge of the event to the sponsor or 
designee. In addition, if the investigator learns at any time of an SAE which is believed to be 
related to the study treatment then this must be reported to the sponsor, even if more than 
30 days have elapsed since the last dose of study treatment. 
Serious adverse event reporting will be conducted as described in the safety management 
plan. The SAE form will collect all relevant data concerning the AE, including: details of the 
nature of the symptoms, time of onset, duration, and severity, together with an investigator’s 
(or designee’s) opinion of the relationship to study treatment, and any action taken in relation 
to the planned administration of study treatment. In addition, the investigator should provide 
relevant medical history, concomitant medications, laboratory or diagnostic test reports, 
details of any treatment for the SAE, and all other pertinent medical information. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study treatment) does not meet the definition of 
an AE. However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus. 
 
 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 44 of 62 
Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
   Total 
   High-density lipoprotein 
   Low-density lipoprotein 
C-reactive protein 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total CO2 
Total protein 
Uric acid 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Absolute reticulocyte count 
Red blood cell count 
White blood cell (WBC) count 
WBC differential (absolute count): 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
   Large unclassified cells 
 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination  
Coagulation profile: 
Activated partial thromboplastin 
time 
International normalized ratio 
Prothrombin time 
Serology: 
Drug screen: 
Hormone panel - females only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies 
and p24 antigen 
 
Quantiferon™ tuberculosis Gold 
Including but not limited to: 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Alcoholc 
Follicle-stimulating hormonea 
Serum pregnancy test (human 
chorionic gonadotropin)b 
Urine pregnancy testb 
a Performed for all females in serum at timepoints detailed in Appendix 6. 
b Performed for all females in serum at timepoints detailed in Appendix 6. A positive urine pregnancy test will be confirmed 
with a serum pregnancy test. 
c Alcohol breath test performed at timepoints detailed in Appendix 6. 






Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 47 of 62 
Appendix 4: Contraception Guidance 
Definitions 
Female of Childbearing Potential: premenopausal female who is anatomically and 
physiologically capable of becoming pregnant following menarche. 
Female of Nonchildbearing Potential:  
1. Surgically sterile: female who is permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or 
medical records. Surgical sterilization to have occurred a minimum of 6 weeks, or at 
the investigator’s discretion, prior to screening. 
2. Postmenopausal: female at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating hormone 
(FSH) level of ≥40 mIU/mL. The amenorrhea should not be induced by a medical 
condition such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, 
or by extreme exercise. It should not be due to concomitant medications that may have 
induced the amenorrhea such as oral contraceptives, hormones, gonadotropin-releasing 
hormones, anti-estrogens, selective estrogen receptor modulators, or chemotherapy. 
Females on hormone replacement therapy with FSH levels <40 mIU/mL may be 
included at the discretion of the investigator. Females aged >60 years old whose FSH 
values are not ≥40 mIU/mL may be included at the discretion of the investigator and in 
consultation with the sponsor. 
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Subjects 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. For female subjects of childbearing potential, 2 methods (1 primary acceptable 
and 1 secondary method) of birth control are required from the time of signing the informed 
consent form (ICF) until 90 days after the follow-up phone call or visit. Primary (non-barrier) 
methods of contraception include: 
• hormonal injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the screening visit: 
o 
bilateral tubal ligation 
o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 
• hormonal implant 
• hormonal or non-hormonal intrauterine device 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 48 of 62 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
screening visit, with verbal confirmation of surgical success, and the sole partner 
for the female subject). 
A secondary (barrier) method of contraception would include: 
• condom with spermicide. 
Female subjects of childbearing potential should refrain from donation of ova from check-in 
(Day -1) until 90 days after the follow-up phone call or visit. 
Male Subjects 
Male subjects in conjunction with partners of childbearing potential use the following 
contraceptive measure: 
• condom and spermicide (even if subject has a history of vasectomy). 
In addition, use a second method of acceptable contraception from check-in until 90 days 
after discharge. Acceptable methods of contraception for female partners include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time 
of the first dose until 90 days after the follow-up phone call or visit. Male subjects are 
required to refrain from donation of sperm from check-in until 90 days after the follow-up 
phone call or visit. 
Sexual Abstinence and Same-sex Relationships 
A subject who practices total abstinence is required to identify contraceptive methods he/she 
will use in the event of sexual activity. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 49 of 62 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, informed consent form (ICF), investigator’s brochure, 
and other relevant documents must be submitted to an ethics committee (EC) by the 
investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the EC. 
• Notifying the EC of serious adverse events or other significant safety findings as 
required by EC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the EC, 
European Directive 2001/20/EC for clinical studies (if applicable), Clinical Trials 
Regulation (EU) 536/2014, and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study treatments, procedures, and potential risks of the study. 
Subjects will be instructed that they are free to obtain further information from the 
investigator (or designee) and that their participation is voluntary and they are free to 
withdraw from the study at any time. Subjects will be given an opportunity to ask questions 
about the study prior to providing consent for participation. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 50 of 62 
Following discussion of the study with study site personnel, subjects will sign the ICF in the 
presence of a suitably trained member of staff to indicate that they are freely giving their 
informed consent. A copy of the ICF will be given to the subject. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic 
case report forms (eCRFs), study-related forms, study reports, or any related publications. 
Subject and investigator personal data will be treated in compliance with all applicable laws 
and regulations. In the event the study protocol, study report, or study data are included in a 
public registry, all identifiable information from individual subjects or investigator will be 
redacted according to applicable laws and regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by sponsor or contract research organization (CRO) auditors or other 
authorized personnel appointed by the sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the sponsor or designee electronically (eg, laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the eCRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Labcorp Drug Development is responsible for the data management of this study, 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented in a 
project management plan. Additional details of quality checking to be performed on 
the data may be included in a data management plan. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 51 of 62 
• A study monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator in the study site archive for at least 5 years after 
the end of the study unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to Labcorp Drug Development electronically, will be integrated with the subject’s 
eCRF data in accordance with the data management plan. 
An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the data 
on the eCRF, data queries, and site notifications. 
Publications 
Publications will be addressed in a separate agreement.The results of this study may be 
published or presented at scientific meetings. If this is foreseen, the investigator agrees to 
submit all manuscripts or abstracts to the sponsor before submission. This allows the sponsor 
to protect proprietary information and to provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 52 of 62 
Appendix 6: Schedule of Assessments 






Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Protocol Version 5, 30 January 2023 
Page 55 of 62 
b Monitor for 12-lead ECG recording will be worn from approximately 2 hours predose to approximately 25 hours postdose on Day 1. 
c The DEC may decide to alter the sampling schedule, allowing for up to 3 additional samples to be taken and additional outpatient visits included if additional samples beyond 48 hours 
postdose are required. Such visits will not occur more than 7 days after the last dosing. 
 















SAP_001.pdf: 
Document Type:  
 
Final Statistical Analysis Plan 
Document Date:  
 
02 November 2022 
Study Title: 
A Randomized, Double-blind, Placebo-controlled, Single and 
Multiple Ascending Dose, and Food Effect Evaluation Trial to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of 
AQ280 in Healthy Subjects 
Protocol Reference Number:  ARIA-1 
NCT Number:  
 
NCT05485779 
 


 
 
 
 
St atistic al A n al ysis Pl a n  
A R a n d o mize d, D o u ble -bli n d, Pl ace b o -c o ntr olle d, Si n gle a n d M ulti ple 
Asce n di n g D ose, a n d F o o d Effect E v al u ati o n Tri al t o E v al u ate t he S afet y, 
T oler a bilit y, a n d P h ar m ac o ki netics of A Q 2 8 0 i n He alt h y S u bjects  
S A P Stat us: F i nal 
S A P Versi o n: 1. 0  
S A P Date: 2 n d N o ve m ber 2 0 2 2  
I n v esti gati o nal Me dici nal Pr o d uct: A Q 2 8 0  
Pr ot oc ol Refere n ce: A RI A -1  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 9 3 4 0 9  
 
 
S p o ns or:  
A qili o n  
Re dare gata n 4 8  
S E -2 5 2 3 6 Helsi n g b or g  
S we de n  
St u d y Site:  
La b c or p Cli nical Resea rc h U nit Lt d. 
S pri n gfiel d H o us e  
H y d e Street  
Lee ds, L S 2 9 L H  
U nite d Ki n g d o m  
 
 
Pri nci pal I n v esti gat or:  
 
 
 
I nf or mati o n descri be d herei n is c o nfi de ntial a n d m a y b e discl ose d o nl y wit h t he e x press 
writte n per mi ssi o n of t he sp o ns or.  
 
P P D


SAP 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Final Version 1.0, 2nd November 2022 
Page 2 of 30 
 
 
ST-AD-031 Version 02 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
3. STUDY DESIGN................................................................................................................... 8 
3.1. Overall Study Design and Plan ....................................................................................... 8 
3.1.1. Part A (Single Ascending Dose) .............................................................................. 9 
3.1.2. Part B (Multiple Ascending Dose) ......................................................................... 11 
4. SAMPLE SIZE JUSTIFICATION ...................................................................................... 12 
5. STUDY TREATMENTS ..................................................................................................... 13 
6. DEFINITIONS OF POPULATIONS .................................................................................. 14 
6.1. All Subjects Population ................................................................................................. 14 
6.2. Safety Population .......................................................................................................... 14 
6.3. Pharmacokinetic Population ......................................................................................... 14 
6.4. Pharmacodynamic Population ....................................................................................... 14 
7. STATISTICAL METHODOLOGY .................................................................................... 14 
7.1. General .......................................................................................................................... 14 
7.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 15 
7.1.2. Calculation of the Summary Statistics ................................................................... 16 
7.1.3. Triplicate Readings................................................................................................. 16 
7.1.4. Repeat and Unscheduled Readings ........................................................................ 16 
7.1.5. Definitions of Baseline and Change from Baseline ............................................... 17 
7.2. Subject Disposition and Population Assignment .......................................................... 17 
7.3. Screening Demographics .............................................................................................. 17 
7.4. Prior and Concomitant Medication ............................................................................... 17 
7.5. Pharmacokinetic Assessments ...................................................................................... 18 
7.5.1. Pharmacokinetic Analysis ...................................................................................... 18 
7.5.2. Presentation of Pharmacokinetic Data ................................................................... 21 
7.5.3. Pharmacokinetic Statistical Methodology .............................................................. 22 


SAP 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Final Version 1.0, 2nd November 2022 
Page 3 of 30 
 
 
ST-AD-031 Version 02 
7.6. Pharmacodynamic Assessments.................................................................................... 24 
7.6.1. Pharmacodynamic Parameters ............................................................................... 24 
7.6.2. Presentation of Pharmacodynamic Data ................................................................. 25 
7.6.3. Pharmacodynamic Statistical Methodology ........................................................... 25 
7.7. Safety and Tolerability Assessments ............................................................................ 26 
7.7.1. Adverse Events ....................................................................................................... 26 
7.7.2. Clinical Laboratory Parameters .............................................................................. 27 
7.7.3. Vital Signs Parameters ........................................................................................... 28 
7.7.4. 12-lead Electrocardiogram Parameters .................................................................. 28 
7.7.5. Other Assessments ................................................................................................. 28 
7.7.6. Safety and Tolerability Statistical Methodology .................................................... 28 
8. INTERIM ANALYSES ....................................................................................................... 28 
9. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES .......... 28 
10. REFERENCES .................................................................................................................. 28 
11. APPENDICES ................................................................................................................... 30 
Appendix 1: 
Document History ................................................................................ 30 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1:  
Objectives and Endpoints........................................................................................ 6 
Table 2: 
Presentation of Study Treatments in TFLs (Part A) ............................................. 13 
Table 3: 
Presentation of Study Treatment Sequences in TFLs (Part A; Food-effect Group 
Only) ..................................................................................................................... 13 
Table 4:  
Presentation of Study Treatments in TFLs (Part B) .............................................. 13 
 
Figure 1:  Planned Groups (Parts A and B) ............................................................................. 9 
Figure 2:  Study Schematic (Part A) ...................................................................................... 10 
Figure 3:  Study Schematic (Part A, Food Effect Evaluation) .............................................. 11 
Figure 4:  Study Schematic (Part B) ...................................................................................... 12 
 


SAP 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Final Version 1.0, 2nd November 2022 
Page 4 of 30 
 
 
ST-AD-031 Version 02 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
%AUCextrap 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
ADaM 
Analysis Data Model 
AE 
adverse event 
ANOVA 
analysis of variance 
ARAUC 
accumulation ratio based on AUC0-τ  
ARCmax 
accumulation ratio based on Cmax during the dosing interval 
AUC 
area under the concentration-time curve over the dosing interval 
AUC0-24 
area under the concentration-time curve over the time interval 0 to 24 
hours postdose 
AUC0-∞ 
area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-tlast 
area under the concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent total clearance 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
concentration at the end of the dosing interval 
CV 
coefficient of variation 
DAUC 
AUC normalized by dose administered 
DAUC0-24 
AUC0-24 normalized by dose administered 
DAUC0-∞ 
AUC0-∞ normalized by dose administered  
DAUC0-tlast 
AUC0-tlast normalized by dose administered. 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
Frel, Cmax 
relative bioavailability in the fed and fasted state based upon Cmax  
Frel,AUC0-∞ 
relative bioavailability in the fed and fasted state based upon AUC0-∞  
GLSM 
geometric least squares mean 
ICH 
International Council for/Conference on Harmonisation 


SAP 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Final Version 1.0, 2nd November 2022 
Page 5 of 30 
 
 
ST-AD-031 Version 02 
ln 
natural log 
LR 
Linearity ratio 
LSM 
least squares mean 
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio 
time period over which λz was determined as a ratio of t1/2 
λz Upper 
end of exponential fit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRAUC 
metabolite:parent ratio based on AUC0-∞ 
MRCmax 
metabolite:parent ratio based on Cmax 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QD 
once daily 
R2-adj 
adjusted coefficient for determination of exponential fit 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable concentration 
tmax 
time of the maximum observed concentration 
Vz/F 
apparent volume of distribution during the terminal phase  
WHODrug 
World Health Organization Drug Dictionary  
 


SAP 
CONFIDENTIAL 
Labcorp Drug Development Study: 8493409 
Protocol Reference: ARIA-1 
Final Version 1.0, 2nd November 2022 
Page 6 of 30 
 
 
ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 4.0 
dated 4th October 2022) and electronic case report form (eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), pharmacodynamic 
(PD), safety, and tolerability data from this study. A detailed description of the planned TFLs 
to be presented in the clinical study report (CSR) is provided in the accompanying TFL shells 
document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Aqilion. A limited amount of information about this study (eg, 
objectives, study design) is given to help the reader’s interpretation.  
This SAP must be finalized prior to any unblinding of study data for analysis purposes 
(interim or final). Additionally, the SAP and TFL shells should be finalized prior to any 
programming activities commencing.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Aqilion and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, ICH E9 guideline 
Statistical Principles for Clinical Trials.1,2,3  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
Table 1:  
Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
 
 
to evaluate the safety and 
tolerability of single and multiple 
ascending oral doses of AQ280, and 
to determine a safe therapeutic 
range of AQ280 in healthy subjects 
 
number of TEAEs per subject 
 
clinically significant abnormalities in vital signs 
(systolic and diastolic blood pressure, pulse rate, 
and oral body temperature) 
 
abnormal ECG (QTcF interval of >450 msec for 
males and >470 msec for females, or change from 
baseline of >30 msec) measured from Day 1 
(postdose) up until 48 hours postdose in Part A 
and up to the follow-up visit in Part B 
 
clinically significant changes in laboratory 
evaluations 


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 9 3 4 0 9  
Pr ot oc ol Refere n ce: A RI A -1  
Fi nal Versi o n 1. 0 , 2 n d N o ve m ber  2 0 2 2  
Pa ge 7  of 3 0  
 
 
S T -A D -0 3 1 Versi o n 0 2  
O bjecti ves  
E n d p oi nts  
Sec o n d ar y:  
 
 
t o deter mi ne t he P K of A Q 2 8 0 after 
si n gle a n d m ulti ple oral d oses 
 
t o deter mi ne t he P K of t he A Q 2 8 0 
mai n meta b olite, A Q 2 8 2, after 
si n gle a n d m ulti ple oral d oses  
 
t o deter mi ne t he effect of f o o d o n 
t he P K of A Q 2 8 0 after si n gle oral 
d ose  
Part A ( S A D):  
 
pri mar y P K para meters deri ve d fr o m plas ma 
c o nce ntrati o n -ti me pr ofile of A Q 2 8 0: A U C0 -∞, 
C ma x  ( A U C0 -tlast ma y be i ncl u de d as a pri mar y P K 
para meter if A U C 0 -∞ ca n n ot be calc ulate d)  
 
pri mar y P K para meters deri ve d fr o m plas ma 
c o nce ntrati o n -ti me pr ofile of t he A Q 2 8 0 mai n 
meta b olite, A Q 2 8 2: A U C 0 -∞, Cma x  ( A U C0 -tlast ma y 
be i ncl u de d as a pri mar y P K para meter if A U C 0 -∞ 
ca n n ot be calc ulate d)  
 
c o m paris o n of t he pri mar y P K para meters of 
A Q 2 8 0 after si n gle d ose a d mi nistrati o n i n t he 
faste d state a n d i n t he fe d state 
 
Part B ( M A D):  
 
pri mar y P K para meters deri ve d fr o m plas ma 
c o nce ntrati o n -ti me pr ofile of A Q 2 8 0 o n Da y 1 
a n d Da y 7: A R, A U C τ, Cma x  
 
pri mar y P K para meters deri ve d fr o m plas ma 
c o nce ntrati o n -ti me pr ofile of t he A Q 2 8 0 mai n 
meta b olite, A Q 2 8 2, o n Da y 1 a n d Da y  7: A U C τ, 
C ma x  
E x pl or at or y:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C
C
I
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 9 3 4 0 9  
Pr ot oc ol Refere n ce: A RI A -1  
Fi nal Versi o n 1. 0 , 2 n d N o ve m ber  2 0 2 2  
Pa ge 8  of 3 0  
 
 
S T -A D -0 3 1 Versi o n 0 2  
O bjecti ves  
E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns: A R  = acc u m ulati o n rati o; A U C 0 -∞ =  area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o 
i nfi nit y; A U C 0 -tlast = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t h e ti me of t h e last q ua ntifia ble c o nce ntrati o n; 
A U C τ = area u n der t h e c o nce ntrati o n -ti me c ur ve o ver a d osi n g i nter val; C L/ F = a p pare nt t otal cleara nce; Cma x  =  ma xi m u m 
o bser ve d c o nce ntrati o n; 
 
E C G  =  ele ctr o car di o gra m;  
 
M A D = m ulti ple asce n di n g d ose; 
P D  =  p har mac o d y na mi c; P K = p har mac o ki n etic(s); Q Tc F  = Q T i nter val c orrecte d f or heart ra te usi n g Fri d ericia’s met h o d; 
S A D = si n gle as ce n di n g d ose; t 1/ 2 = a p pare nt ter mi n al eli mi n ati o n half -life; T E A E =  treat me nt-e mer ge nt a d verse e ve nt; 
tma x  = ti me of t h e ma xi m u m o bser ve d c o nce ntrati o n; Vz/ F =  a p pare nt v ol u me of distri b uti o n.   
3.  S T U D Y D E SI G N   
3. 1.  O v er all St u d y Desi g n a n d Pl a n  
T his will be a P hase 1, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, si n gl e a n d m ulti ple 
asce n di n g d ose trial  t o e v al uate t he safet y, t olera bilit y, a n d P K of A Q 2 8 0. A n i n vesti gati o n of 
f o o d effect will be i ncl u d e d i n t he si n gle d os e a d mi nistrati o n part of t he st u d y. T he st u d y will 
be c o n d ucte d i n 2  p arts –  Part A, si n gle asce n di n g d ose ( S A D) e v al uati o ns, i ncl u di n g f o o d 
effect, a n d Part B, m ulti ple asce n di n g d ose ( M A D) e val uati o ns.  Sc he matics of t he pla n ne d 
gr o u ps f or eac h par t are prese nte d i n Fi g ure  1 . 
C
C
I
C CI
C CI








S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 9 3 4 0 9  
Pr ot oc ol Refere n ce: A RI A -1  
Fi nal Versi o n 1. 0 , 2 n d N o ve m ber  2 0 2 2  
Pa ge 1 2  of 3 0  
 
 
S T -A D -0 3 1 Versi o n 0 2  
P ote ntial s u bjects will be scree n e d t o assess t heir eli gi bilit y t o e nter t he st u d y fr o m 2 da ys u p 
t o 5 wee ks bef ore t he first d ose of A Q 2 8 0 or placeb o. Eac h s u bject will partici pate i n 1 gr o u p 
o nl y a n d resi de at t he st u d y site fr o m Da ys  -1 t o 9.  
F or all s u bjects, d osi n g is pla n ne d t o be o nce dail y ( Q D ) o n Da ys 1 t o 7, i ncl usi ve, at 
a p pr o xi matel y t he sa me ti me eac h m or ni n g. T h e d osi n g re gi me n i n Part  B ma y b e c ha n ge d 
f oll o wi n g re vie w of preli mi nar y d ata fr o m gr o u ps i n Part A or pre vi o us gr o u ps i n Part B. T he 
dail y d ose a d mi nistere d, w he n gi ve n re peate dl y, will be pre dicte d t o n ot e x cee d a n e x p os ure 
s h o w n t o be safe a n d well t olerate d i n Part A. Diet ary state will be det er mi ne d base d o n d ata 
o btai ne d i n Part A.  
A safet y f oll o w -u p visit will be c o n d ucte d 1 wee k ( ± 3 da ys) after t he fi n al d ose.  
Base d o n t h e o n g oi n g re vie w of t he safet y, t olera bilit y, a n d P K res ults, a d diti o nal o ut patie nt 
visits ma y b e re q u ire d. 
Safet y assess me nts will i ncl u de A E re p orti n g, vital si g ns, E C Gs, cli nical la b orat or y tests, a n d 
p h ysical e x a mi nati o n.  
Bl o o d sa m ples t o deter mi ne t he P K of A Q 2 8 0 a n d its mai n meta b olite, A Q 2 8 2, will be 
c ollecte d fr o m pre d ose u p t o 2 4 h o urs p ost d ose o n  Da y 1; pre d ose o n Da ys 3 t hr o u g h 6; a n d 
fr o m pre d ose u p t o 4 8 h o urs p ost d ose o n Da y 7. 
 
A n o ver vie w of t he st u d y desi g n f or Part B is s h o w n i n Fi g ure  4 . 
Fi g ure  4 :  St u d y Sc he m atic ( P a rt B)  
 
A b bre viati o ns: P K = p har mac o ki netics; Q D = o nce dail y.  
T he t otal d urati o n of st u d y partici pati o n f or eac h s u bject (fr o m scree ni n g t hr o u g h f oll o w -u p 
visit) is a ntici pate d t o be a p pr o xi matel y 7 wee ks. 
4.  S A M P L E SI Z E J U S TI FI C A TI O N   
N o f or mal statistical assess me nt, i n ter ms of sa m ple siz e, has bee n c o n d u cte d as t his is t he 
first ti me A Q 2 8 0 is bei n g a d mi nistere d t o h u ma ns. H o we ver, t he n u m ber of s u bjects i n eac h 
St u d y da y
F oll o w -u p
(± 3 da y s) 
Scree ni n g
-3 5
-2
-1
C hec k -i n
1
2
3
4
8
9
Dis c har ge
A Q 2 8 0 or Place b o D os e ( Q D)
5
6
7
1 4
P K
Tr o u gh s a m ples
P K
C CI


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part of the present study is common in early clinical pharmacology studies and is considered 
sufficient to achieve the objectives of the study. 
5. STUDY TREATMENTS  
The study treatment names and ordering to be used in the TFLs are presented for Part A 
(Table 2) and Part B (Table 4). The study treatment sequence names and ordering to be used 
in the TFLs for Part A are presented in (Table 3).  
Table 2: 
Presentation of Study Treatments in TFLs (Part A) 
Part 
Group 
Study Treatment 
Order 
in 
TFLs 
A 
A1 to A5 
Placebo 
1 
 
A1 
3 mg AQ280 (Fasted) 
2 
 
A2 
XX mg AQ280 (Fasted) 
3 
 
A3 
XX mg AQ280 (Fasted) 
4 
 
 
XX mg AQ280 (Fed) 
5 
 
A4 
XX mg AQ280 (Fasted) 
6 
 
A5 
XX mg AQ280 (Fasted) 
7 
 
Table 3: 
Presentation of Study Treatment Sequences in TFLs (Part A; Food-effect 
Group Only) 
Group 
Study Treatment Sequence 
Order 
in TFLs 
A3 
Placebo (Fasted) / Placebo (Fed) 
1 
 
XX mg AQ280 (Fasted) / XX mg AQ280 (Fed) 
2 
 
Table 4:  
Presentation of Study Treatments in TFLs (Part B) 
Group 
Study Treatment 
Order in 
TFLs 
B1 to B3 
Placebo 
1 
B1 
XX mg AQ280 QD 
2 
B2 
XX mg AQ280 QD 
3 
B3 
XX mg AQ280 QD 
4 
QD = once daily 
All TFLs will be based on actual treatments (eg, if subject was assigned to receive placebo 
but was wrongfully dosed with active treatment they would be summarized and listed under 
active treatment). 


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Protocol Reference: ARIA-1 
Final Version 1.0, 2nd November 2022 
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The TFLs will reflect the dose levels utilized in the study, and these will be displayed in 
increasing order.  
6. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 7.1.1), will be considered prior to database lock for their 
importance and taken into consideration when assigning subjects to populations. For all 
populations subjects will be analysed according to the treatment they actually received. 
6.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
6.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(AQ280 or placebo).  
6.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of active study 
treatment (AQ280) and have at least 1 valid PK concentration.  
6.4. Pharmacodynamic Population  
The PD population will include all subjects who received at least 1 dose of study treatment 
(AQ280 or placebo) and have at least 1 valid postdose PD assessment. 
7. STATISTICAL METHODOLOGY  
7.1. General  
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects assigned to the all subjects population and include 
data up to the point of study completion or discontinuation. Subjects are generally considered 
to have completed the study if they complete the scheduled follow-up phone call or visit, as 
applicable (rather than early termination visit). Any subject who discontinues the study will 
be identified accordingly in the listings. Summaries and statistical analyses will include the 
subjects assigned to the relevant population based on data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if a new version is issued during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if a new 
version is issued during the study). Pinnacle 21 Community Validator Version 4.0.1 (or 


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Final Version 1.0, 2nd November 2022 
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ST-AD-031 Version 02 
higher if a new version is issued during the study) will be utilized to ensure compliance with 
CDISC standards.  
For all statistical analyses, the hypothesis testing will be 2-sided and carried out on 0.05 
significance level, unless specifically stated otherwise.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.  
Where reference is made to ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, and changes from baseline. 
All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
7.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognized potential for: 
● Missed visits, caused by, for example: 
o Subject unable to travel to site due to restrictions, the need to quarantine, or 
COVID-19 infection 
o Subject unwilling to go to site due to fear of COVID-19 infection 
o Site postponing subject’s visit due to investigator not being available (eg, if they 
have been dispatched to hospital handling COVID-19 infections) 
● Site unable to replenish supply of investigational product 
● Incomplete data entry by sites due to limited resources to support study or no access to 
source documents or to eCRF 
● Outstanding source document verification (SDV) due to sponsor or country restrictions 
on remote SDV, or no or limited access to site(s) for on-site visits 
● Unanswered queries 
At the time of the reporting of the study results, all protocol deviations due to COVID-19 or 
related restriction will be assessed for their severity and impact on the analyses. If needed, 
appropriate statistical methods will be applied as a mitigating action (eg, data might be 
categorized into 2 analysis groups, with and without COVID-19 and related restrictions 


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impact); however, this will exclude any imputations of the missing values. Any mitigating 
actions will be agreed with Aqilion in advance and identified in the CSR.  
7.1.2. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum.  
● In general, as early termination data are not associated with any scheduled timepoint, 
they will be excluded from all calculations of summary statistics and statistical 
analyses. Exceptions may be made where justified. 
For categorical data the following rules will be applied:  
● For ordered categorical data (eg, adverse event [AE] severity), all categories between 
the possible minimum and maximum categories will be included, even if n = 0 for a 
given category.  
● For non-ordered categorical data (eg, race), only those categories for which there is at 
least 1 subject represented will be included; unless specifically stated otherwise.  
● Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This will 
ensure that the population size totals are consistent across different parameters.  
7.1.3. Triplicate Readings  
For vital signs data only, where triplicate readings are taken, the median of triplicate readings 
will replace the separate individual triplicate readings in all calculations.  
For 12-lead electrocardiogram (ECG) data only, where triplicate readings are taken, the mean 
of triplicate readings will replace the separate individual triplicate readings in all calculations.  
In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean and/or medians will be calculated, as appropriate, based on the number of readings 
available.  
7.1.4. Repeat and Unscheduled Readings  
For vital signs and 12-lead ECG data only, any predose value recorded in addition to the 
original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 


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parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations.  
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 7.1.5). 
7.1.5. Definitions of Baseline and Change from Baseline 
The baseline will be defined as the last value recorded prior to the first dose, for food-effect 
group(s) only: in each period. If the date/time of the value is incomplete or missing, it will be 
excluded from the baseline calculation, unless the incomplete date/time indicates the value 
was recorded prior to the first dose.  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint.  
The summary statistics for change from baseline will be derived from individual subjects’ 
values (eg, mean change from baseline will be the mean of the individual changes from 
baseline for all subjects, rather than difference between the mean value at the postdose 
timepoint and mean value at baseline).   
See Section 7.1.4 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 7.1.3 for more detail on handling of triplicate readings in the 
calculations.  
7.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by part and treatment will be provided, based on the safety population.  
7.3. Screening Demographics  
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed.  
A summary table by part and treatment will be provided, based on the safety population.  
7.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2022 (or later if a new version is 


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Final Version 1.0, 2nd November 2022 
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issued during the study; see the data management plan [DMP] for more details). Prior and 
concomitant medications will be listed.  
7.5. Pharmacokinetic Assessments  
7.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of AQ280 and AQ282 using noncompartmental methods in validated software 
program Phoenix WinNonlin (Certara, Version 8.1.1 or higher): 
Parameter 
Unitsa 
Definition 
AUC0-tlast 
h*ng/mL 
area under the concentration-time curve from time 0 to the time 
of the last quantifiable concentration (tlast) (Part A and Day 1 of 
Part B only) b 
AUC0-24 
h*ng/mL 
area under the concentration-time curve over the time interval 0 
to 24 hours postdose b 
AUC 
h*ng/mL 
area under the concentration-time curve over the dosing interval 
(Part B only) b 
AUC0-∞ 
h*ng/mL 
area under the concentration-time curve from time 0 
extrapolated to infinity c (Part A and Day 1 of Part B only) 
%AUCextrap 
h*ng/mL 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to 
infinity(Part A and Day 1 of Part B only) 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
Ctrough 
ng/mL 
concentration at the end of the dosing interval 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance (AQ280 only) 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
(AQ280 only) 
MRAUC 
 
metabolite:parent ratio based on AUC0-∞ 
MRCmax 
 
metabolite:parent ratio based on Cmax 
Frel, AUC0-∞ 
 
relative bioavailability in the fed and fasted state based upon 
AUC0-∞ (Food effect group (A3) only) 
Frel, Cmax 
 
relative bioavailability in the fed and fasted state based upon 
Cmax ( Food effect group (A3) only) 
ARAUC 
 
accumulation ratio based on AUC0-τ (Part B only) 
ARCmax 
 
accumulation ratio based on Cmax during the dosing interval  
(Part B only) 
LR 
 
Linearity ratio 
DAUC0-tlast 
h*ng/mL/mg AUC0-tlast normalized by dose administered. 
DAUC0-24 
h*ng/mL/mg AUC0-24 normalized by dose administered 


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 9 3 4 0 9  
Pr ot oc ol Refere n ce: A RI A -1  
Fi nal Versi o n 1. 0 , 2 n d N o ve m ber  2 0 2 2  
Pa ge 1 9  of 3 0  
 
 
S T -A D -0 3 1 Versi o n 0 2  
D A U C  
h * n g/ m L/ m g  A U C  n or malize d b y d ose a d mi nistere d  ( Part B o nl y) 
D A U C 0 -∞ 
h * n g/ m L/ m g  A U C 0 -∞ n or malize d b y d ose a d mi nistere d  
D C ma x  
n g/ m L/ m g  
C ma x  n or malize d b y d ose a d mi nistere d  
a U ni ts are base d o n c o nce ntrati o n u nits ( pr o vi d e d b y t h e bi oa nal ytical la b or preferre d u nits f or prese ntati o n of P K 
para meters) a n d d ose u nits use d i n t h e st u d y.  
b T he A U C will be calc ulate d usi n g t h e li near tra pez oi d al r ule f or i ncreasi n g c o nce ntrati o ns a n d t h e l o garit h mic r ule f or 
decreasi n g c o nce ntrati o ns (li near u p/l o g d o w n r ule).  
c Base d o n t he last o bser ve d q ua ntifia ble c o nce ntrati o n  
d Calc ulate d b y di vi di n g t he para meter b y t h e d ose ( m g)  
A d diti o nal P K para meters ma y be deter mi ne d w here a p pr o priate.  
P ha r mac o ki netic a n al ysis will be carri e d o ut w here p ossi ble usi n g act ual d ose a d mi nistere d 
( m g) a n d act ual p ost d ose bl o o d sa m pli n g ti mes. If a n act ual ti me is missi n g, t he sa m ple 
c o nce ntr ati o n res ult will be treate d as missi n g u nl ess t here is scie ntific j usti ficati o n t o i ncl u de 
t he res ult usi n g t he n o mi nal ti me.  
T he para meters C ma x , Ctr o u g h, tlast, a n d tma x  will be o btai ne d directl y fr o m t he c o nce ntr ati o n -
ti me pr ofiles. If Cma x  occ urs at m ore t ha n 1 ti me p oi nt, t ma x  will be assi g ne d t o t he first 
occ urre nce of C ma x . 
T he meta b olite: pare nt rati o(s) ( M R A U C  or M R C ma x ) will be calc ulate d as f oll o ws: 
M R
A U C  = ( A U C 0 -∞ [ A Q 2 8 2] / M W [ A Q 2 8 2]) / ( A U C0 -∞ [ A Q 2 8 0] / M W [ A Q 2 8 0]), 
w here M W is t he m olec ular wei g ht of eac h a nal yt e  
M R
C ma x  = ( C ma x  [ A Q 2 8 2]/ M W [ A Q 2 8 2]) / ( Cma x  [ A Q 2 8 0] / M W [ A Q 2 8 0]), 
w here M W is t he m olec ular wei g ht of eac h a nal yt e  
T he m olec ular wei g hts of A Q 2 8 0 a n d A Q 2 8 2 t o be use d i n t he a dj ust me nt are as f oll o ws:  
 
 
T he para meter A U C 0 -tlast or ot her c o m m o n partial area m a y b e use d t o d eter mi ne M R A U C  if 
A U C 0 -∞ ca n n ot be relia bl y calc ulate d f or t he maj orit y of s u bjects.  
T he acc u m ulati o n rati o(s) ( A R A U C  a n d A R C ma x ) will be calc ulate d as f oll o ws: 
A R A U C  = A U C 0 -τ Pr ofile Da y  7 / A U C 0 -τ Pr ofile Da y  1  
A R C ma x  = C ma x  Pr ofile Da y  7 / C ma x  Pr ofile Da y  1  
T he li nearit y r ati o ( L R) will be calc ulate d as rati o of A U C 0 -τ f oll o wi n g m ulti ple d osi n g t o 
A U C 0 -∞ f oll o wi n g a si n gl e d ose: 
L R = A U C 0 -τ Pr ofile Da y  7 / A U C 0 -∞ Pr ofile Da y  1  
C CI


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Final Version 1.0, 2nd November 2022 
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7.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-∞, t1/2, CL/F and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie, the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR. 
7.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax. An exception may be made for 
metabolites, where Cmax may be the last timepoint. 
If the extrapolated area is >20%, AUC0-∞ (and derived parameters) may be excluded from the 
summary statistics and statistical analysis at the discretion of the sponsor or 
pharmacokineticist.  
If AUC0-∞ cannot be determined reliably for all subjects and/or dose levels, an alternative 
AUC measure, such as AUC to a fixed timepoint, may be used in the statistical analysis of 
dose proportionality/food effect.   


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7.5.1.3. Criteria for Handling Concentration Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated as 
missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
● If a predose analyte concentration is missing, following a single dose (Part A) or Day 1 
dose (Part B) it will be set to 0 by default within Phoenix WinNonlin. 
● For multiple dose part of the study (Study Profile Day 7), if the analyte concentration at 
the end of the dosing interval (τ) is missing, this may be substituted with the predose 
concentration. Similarly, if the predose concentration is missing then this may be 
substituted with the concentration at τ. 
7.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value in the first treatment period will be considered 
anomalous and set to missing for the PK analysis. This will be set to 0 by default in Phoenix 
WinNonlin. 
If the predose concentration is >5% of Cmax in the second treatment period for the food effect 
group (A3), all PK concentration and parameter data will be excluded from the summary 
statistics and statistical analysis for that period. 
7.5.2. Presentation of Pharmacokinetic Data 
All PK concentrations and parameters will be listed.  
Summary tables, arithmetic mean (+ standard deviation [SD]) figures, overlaying individual 
figures, and individual figures by treatment and time postdose will be provided for plasma 
PK concentrations. All figures will be produced on both linear-linear and linear-logarithmic 
scales, with the exception of figures across all days, which will be produced on the 
linear-linear scale only. The +SD bars will only be displayed on the linear-linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters.  


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A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times the median tmax. 
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the plasma concentration will be flagged and excluded from the summary statistics.  
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For plasma concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
For PK parameters the following rule will apply: 
● Geometric mean and coefficient of variation will not be calculated for tlast or tmax. 
7.5.3. Pharmacokinetic Statistical Methodology  
7.5.3.1. Dose Proportionality 
A statistical analysis will be conducted to investigate the dose proportionality of AUC0-tlast, 
AUC0-∞, and Cmax for AQ280 and AQ282 on profile day 1 for Part A and AUC0-τ and Cmax for 
AQ280 and AQ282 on profile day 7 for Part B. 
The PK parameters will be analyzed using a power model5 that will have the following form: 
parameter = intercept × dose^slope × random error 
Using the natural log (ln) transformation,6 a power model can be expressed as a linear 
regression equation: 
ln(parameter) = intercept + slope × ln(dose) + random error 
Dose proportionality holds if the slope of the regression line is close to 1.  The estimate of the 
slope and its 95% confidence interval will be used to quantify the degree of 
non‑proportionality. For each PK parameter separately, a pooled estimate (across all doses) of 
slope, corresponding 95% confidence interval (CI), and between-subject coefficient of 
variation (CV) will be calculated. Figures (on the logarithmic-logarithmic scale) containing 
individual values, the power model line (95% CI), and the dose proportionality line (defined 
as the power model line with slope of 1) will be created for each PK parameter. Additionally, 
figures (on the logarithmic-linear scale) containing individual values and geometric means 
will be created for each corresponding PK parameter normalized by dose administered.  
The lack of fit test will be conducted for the statistical assessment of linearity assumption, 
and thus appropriateness of a power model. The lack of fit model will be the same as the 
power model fitted, but with dose included as an additional fixed effect. The statistical 


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assessment will rule the linearity assumption acceptable if the diagnostic plots appear 
reasonable and the lack of fit 2-sided p-value >0.05 (dose effect is not significant at the 0.05 
level of significance). The assessment of linearity assumption may also occur via visual 
examination of the figures by the pharmacokineticist. This assessment may override the 
statistical assessment; where this occurs, it will be detailed in the CSR.  
If the assumption of linearity is ruled acceptable and the 95% CI for the slope spans 1, it will 
be deemed that there is no statistical basis to conclude a lack of proportionality.   
If the assumption of linearity is ruled unacceptable for any PK parameter, its corresponding 
PK parameter normalized by dose administered will be ln-transformed and analyzed using an 
analysis of variance (ANOVA) model.7 The model will include dose as a factor.  
For each PK parameter separately, the geometric least squares mean (GLSM) for each dose, 
p-values for the overall, and pairwise dose comparisons will be calculated. Residual plots will 
be produced to assess the adequacy of the model(s) fitted.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because no adjustment for multiple comparisons will be performed. 
Examples of the SAS code that will be used are as follows: 
Power Model Analysis  
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output solutionf = <data out>; 
run; 
Power Model Analysis (Between-subject Variability) 
proc mixed data = <data in> covtest alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 class ldose; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output covparms = <data out>; 
run; 
(Note: Pooled Geometric CV (%) = 100*(sqrt(exp(estimate)-1))) 
Power Model Analysis (Lack of Fit Test) 
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday paramn param; 
 class dose; 
 model lpk = ldose dose / htype = 1 ddfm = kr2; 
 ods output tests1 = <data out>; 
run; 
ANOVA Model Analysis 
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 class dose; 
 model ldnpk = dose / cl residual ddfm = kr2; 
 lsmeans dose / cl pdiff;  
 ods output lsmeans = <data out>;  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 9 3 4 0 9  
Pr ot oc ol Refere n ce: A RI A -1  
Fi nal Versi o n 1. 0 , 2 n d N o ve m ber  2 0 2 2  
Pa ge 2 4  of 3 0  
 
 
S T -A D -0 3 1 Versi o n 0 2  
 o d s  o u t p u t  d i f f s  =  < d a t a  o u t > ;  
 o d s  o u t p u t  t e s t s 3  =  < d a t a  o u t > ;  
r u n ;  
7. 5. 3. 2.  F o o d Effect   
A statistical a nal ysis will be c o n d ucte d  t o i n vesti gate t he f o o d effect o n t he treat me nt b y 
c o m pari n g X X m g A Q 2 8 0  (fe d) treat me nt t o X X m g A Q 2 8 0  (faste d) treat me nt f or Part A 
o nl y .  
T he nat ural l o g (l n) -tra nsf or me d6 A U C 0 -tlast, A U Ct 1-t 2, A U C0 -∞, a n d Cma x  f or A Q 2 8 0 a n d 
A Q 2 8 2 o n pr ofile da y 1  will be a nal yze d usi n g a  mi x e d m o del .7 T he m o del will i ncl u de 
act ual treat me nt as a  fi x e d effect a n d s u bject as a ra n d o m effect . 
F or eac h P K para meter s e parat el y, t h e least s q uares mea n ( L S M) f or eac h treat me nt, 
differe n ce i n L S Ms bet w ee n t he fe d a n d faste d treat me nts, a n d c orres p o n di n g 9 0 % a n d 9 5 % 
c o nfi de nce i nter vals ( CIs) will be calc ulat e d; t hese val ues will t he n be bac k -tra nsf or me d t o 
gi ve t he ge o metric least s q uare me a n ( G L S M), rati o of G L S Ms, a n d c orres p o n di n g 9 0 % a n d 
9 5 % CIs ; 2-si de d p-val ue will als o be calc ulate d .  
A d diti o nall y, t he p o ole d esti mate (acr oss treat me nts) of t he wit hi n -s u bject c oefficie nt of 
variati o n ( C V) will be calc ulate d, a n d resi d ual pl ots will be pr o d uce d t o ass ess t he a de q u ac y 
of t he m o del(s) fitte d.  
E x a m ples of t he S A S c o de t hat will be use d are as f oll o ws:  
Mi xe d M o del A n al ysis  
p r o c  m i x e d  d a t a  =  < d a t a  i n > ;  
 b y  p a r c a t 1 n  p a r c a t 1  p k d a y  p a r a m n  p a r a m ;  
 c l a s s  t r t a n  u s u b j i d ;  
 m o d e l  l p k  =  t r t a n  /  c l  r e s i d u a l  d d f m  =  k r 2 ;  
 l s m e a n s  t r t a n  /  c l  p d i f f  =  c o n t r o l ( ' 1 ' )  a l p h a  =  0 . 1 ;  
 l s m e a n s  t r t a n  /  c l  p d i f f  =  c o n t r o l ( ' 1 ' )  a l p h a  =  0 . 0 5 ;  
 r a n d o m  i n t e r c e p t  /  s u b j e c t  =  u s u b j i d ;   
 o d s  o u t p u t  l s m e a n s  =  < d a t a  o u t > ;   
 o d s  o u t p u t  d i f f s  =  < d a t a  o u t > ;  
 o d s  o u t p u t  c o v p a r m s  =  < d a t a  o u t > ;  
r u n ;  
7. 6.  P h ar m a c o d y n a mi c Ass ess me nt s  
7. 6. 1.  P h ar m a c o d y n a mi c P ar a meters  
I n Parts A a n d B, t he relati ve c ha n ge fr o m baseli n e t o 4 8 h o urs after last d ose will be 
assesse d i n:  
 
 
 
 
 
 
 
 
C
C
I


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 9 3 4 0 9  
Pr ot oc ol Refere n ce: A RI A -1  
Fi nal Versi o n 1. 0 , 2 n d N o ve m ber  2 0 2 2  
Pa ge 2 5  of 3 0  
 
 
S T -A D -0 3 1 Versi o n 0 2  
 
 
I n Part B o nl y, t he relati v e c ha n ge fr o m bas eli ne t o 4 8 h o urs after l ast d ose will be assesse d 
i n: 
 
 
 
 
 
 
T he relati ve c ha n ge fr o m baseli ne will be cal c ulat e d as:  
𝑟𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝑐ℎ𝑎𝑛𝑔𝑒=  𝑣𝑎𝑙𝑢𝑒−𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 × 1 0 0  
w h ere b aseli ne is t he last val ue rec or de d pri or t o t he first d ose.  
I n Part B o nl y, t he a bs ol ute c ha n ge fr o m baseli ne t o 4 8 h o urs after l ast d ose will be assesse d 
i n: 
 
 
 
 
T he a bs ol ute c h a n ge fr o m baseli ne will be calc ul ate d as:  
𝑎𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑐ℎ𝑎𝑛𝑔𝑒= 𝑣𝑎𝑙𝑢𝑒−𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 
w here b aseli ne is t he last val ue rec or de d pri or t o t he first d ose.  
Assess me nts ma y b e o bt ai ne d fr o m se p arat e bl o o d c ollecti o ns or fr o m sc h e d ule d safet y 
cli nical c he mistr y or he m at ol o g y pa n els, as a p p lica ble. 
7. 6. 2.  Prese nt ati o n of P h ar m a c o d y n a mic D at a  
All P D para meters, a n d t heir relati ve a n d a bs ol ute ( Part B o nl y) c ha n ges fr o m baseli ne will 
be liste d.  
S u m mar y ta bles a n d mea n fi g ures b y treat me nt a n d ti me p oi nt will be pr o vi de d f or all P D 
para meters a n d t heir relati ve a n d a bs ol ute ( Part B o nl y) c h a n ges fr o m baseli ne.  
Val ues rec or de d as < x, ≤x, > x, or ≥x will be dis pla ye d i n t he listi n gs as rec or de d. F or t he 
deri vati o n of listi n g fla gs, all calc ulati o ns, a n d prese ntati o n i n t he fi g ures, < x a n d ≤x val ues 
will be set t o half of x , w hereas > x a n d ≥x val ues will be set t o x. 
7. 6. 3.  P h ar m a c o d y n a mi c St atistic al Met h o d ol o g y   
N o i nfere ntial statistical a nal ys es are pla n ne d.  
C
C
C
I
C
C
I


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7.7. Safety and Tolerability Assessments  
7.7.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.0 (or higher if a new version is issued during the study; see the DMP for more 
details).  
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, or starts prior to the first dose and increases in severity after the first dose. 
A treatment-related TEAE will be defined as a TEAE with a relationship of possibly related 
or related to the study treatment, as determined by the investigator.  
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last associated dose for TEAEs only. Where the last associated dose is referring to the last 
dose received prior to the start of a TEAE.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
For the AE data the following rules will apply:  
● For the derivation of treatment-emergent status (applicable to all AEs): If the start 
date/time of an AE is incomplete or missing, an AE will be assumed to not be a TEAE, 
unless the incomplete start date/time or the end date/time indicates an AE started after 
the first dose.  
● For the derivation of treatment-related status (applicable to TEAEs only): If the study 
treatment relationship for a TEAE is missing, a TEAE will be assumed to not be a 
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● For the derivation of onset time (applicable to TEAEs only): If the start date/time of a 
TEAE is missing, onset time will not be calculated. If the start date/time of a TEAE is 
incomplete, where possible, the minimum possible onset time will be calculated and 
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of the last associated dose is 
01MAY2019/08:00 and recorded start date/time of a TEAE is 03MAY2019, then the 
minimum possible onset time will be calculated by assuming a TEAE started at the first 
hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as onset 
time ≥01:16:00 in the listing). If the start date of a TEAE is the same as the date of the 
last associated dose but the start time of a TEAE is missing, an onset time will be 
presented as ‘≥00:00:01’. Any clock changes will be accounted for in the derivation.  
● For the derivation of duration (applicable to all AEs): If the end date/time of an AE is 
missing, duration will not be calculated. If the start or end date/time of an AE is 
incomplete, where possible, the maximum possible duration will be calculated and 
presented in ‘≤DD:HH:MM’ format (eg, if the start of an AE date/time is 
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the maximum 
possible duration will be calculated by assuming an AE ended at the last hour and 
minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as 
duration ≤02:15:59 in the listing). Any clock changes will be accounted for in the 
derivation.  
● For the calculation of TEAE summary statistics: If the severity of a TEAE is missing, 
that TEAE will be counted under the ‘missing’ category. 
● For the calculation of TEAE summary statistics: If a subject experienced multiple 
TEAEs with the same preferred term for the same treatment, this will be counted as 1 
TEAE for that treatment under the maximum severity recorded.  
7.7.2. Clinical Laboratory Parameters  
All clinical laboratory parameters and their changes from baseline will be listed; any value 
outside the clinical reference range will be flagged. Separate listings will be provided for any 
parameter for which there is any individual subject value outside the respective clinical 
reference range.  
Summary tables and boxplots by treatment and timepoint will be provided for clinical 
chemistry, hematology, and coagulation parameters and their changes from baseline.  
Shifts from baseline tables will be provided for clinical chemistry, hematology and 
coagulation parameters.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, and presentation in the figures, <x and ≤x values 
will be set to half of x, whereas >x and ≥x values will be set to x.  


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7.7.3. Vital Signs Parameters  
All vital signs parameters and their changes from baseline will be listed; any value outside 
the clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided for all vital signs 
parameters and their changes from baseline.  
Shifts from baseline tables will be provided for vital signs parameters.  
7.7.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters and their changes from baseline will be listed; any value outside 
the clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided for all 12-lead 
ECG parameters and their changes from baseline.  
Shifts from baseline tables will be provided for 12-lead ECG parameters.  
7.7.5. Other Assessments  
Medical history will not be listed.  
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
7.7.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  
8. INTERIM ANALYSES  
No formal interim analyses are planned for this study. 
9. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
The statistical analysis for the food effect group (A3)  was changed to use a mixed model 
which differs from the stated analysis of variance model in the protocol. 
10. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8). 
17 July 1997.  
3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  


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4. ICH. ICH Harmonised Tripartite Guideline: Addendum on estimands and sensitivity 
analysis in clinical trials to the guideline on statistical principles for clinical trials (E9 [R1]). 
20 November 2019  
5. Gough K, Hutchinson M, Keene O, et al. Assessment of dose proportionality: report from 
the statisticians in the pharmaceutical industry/Pharmacokinetics UK Joint Working 
Party. Drug Inf J. 1995;29(3):1039-1048. 
6. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
7. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 


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11. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable