Conditions: Healthy Volunteer Study Opioid-use Disorder
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 57
Healthy volunteers: yes

Brief summary:
The primary objectives of this study are to evaluate the safety and tolerability of KNX100 administered orally as a single and multiple ascending doses in healthy volunteers.

Detailed description:
This is an adaptive, Phase 1, first-in-human (FIH), single treatment, double blind, placebo controlled, randomized, single and multiple ascending dose study of KNX100 administered to healthy volunteers. Approximately 64 male and female healthy subjects will be enrolled into this study. Healthy subjects who meet all the eligibility criteria will be randomly assigned to Cohorts 1-5 for the Single Ascending Dose and Cohorts 1-3 for the Multiple Ascending Dose. Each cohort will evaluate 8 subjects; 6 subjects will receive KNX100 (study drug) and 2 subjects will receive placebo.

Each cohort will be enrolled sequentially, and dose escalation decisions will be made according to protocol by the Cohort Review Committee (CRC) consisting of the investigators and medical monitor. Subjects and clinical staff will be blinded to therapy assignment. KNX100 will be provided in capsule form as 5, 25 and 100 mg capsules for oral administration and the dose range will be 5 to 50mg.

Arms:
arm 1: KNX100 which will be provided in capsule form as 5, 25 and 100 mg capsules for oral administration. Study drug will be encapsulated in hydroxypropyl methylcellulose (HPMC) dark green opaque size 0 capsules and packaged in 100 mL high density polyethylene (HDPE) bottles with polypropylene (PP) twist-off closures. arm 2: KNX100 matching placebo will be provided in capsule form for oral administration. The placebo will be encapsulated in HPMC dark green opaque size 0 capsules and packaged in 100 mL HDPE bottles with PP twist-off closures.

Interventions: intervention 1: KNX100
Intervention descriptions: intervention 1: KNX100 will be provided in capsule form as 5, 25 and 100 mg capsules for oral administration. Study drug will be encapsulated in hydroxypropyl methylcellulose (HPMC) dark green opaque size 0 capsules and packaged in 100 mL high density polyethylene (HDPE) bottles with polypropylene (PP) twist-off closures.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol: KTX-101 
Study Title: 
A Phase 1 Study Investigating the Safety, Tolerability and 
Pharmacokinetics of KNX100 in Healthy Volunteers  
Study Number: 
KTX-101 
Study Phase: 
1 
Product Name: 
KNX100 (active ingredient: KNX100 Phosphate) 
IND Number: 
IND 155,839  
Clinical Trials.Gov Number:  
NCT04901078 
Indication: 
Mitigation of opioid withdrawal symptoms  
Investigators: 
Single center (Australia) 
 
 
Sponsor: 
Kinoxis Therapeutics Pty, Ltd (Kinoxis) 
Suite 201, 697 Burke Road 
Camberwell Victoria 3124 Australia 
 
 
Sponsor Contact: 
Dr. Tina Soulis 
Vice President, Clinical Strategy and Development 
Kinoxis Therapeutics Pty Ltd. 
tina.soulis@kinoxistherapeutics.com 
 
Amendment 
Version 
Date 
Original Protocol: 
1.0  
21 September 2021 
Amendment 1 
2.0 
05 January 2022 
Amendment 2  
2.1 
12 May 2022 
Amendment 3 
3.0 
29 September 2022 
Amendment 4 
4.0 
29 December 2022 
Amendment 5 
5.0 
20 February 2023 
Amendment 6 
6.0 
07 July 2023 
 
 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators and Kinoxis or its designees.  It is the property of Kinoxis and should 
not be copied by or distributed by persons not involved in the clinical investigation of 
Kinoxis’ proprietary product (KNX100) unless such persons are bound by a confidentiality 
agreement with Kinoxis. 


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SPONSOR SIGNATURES 
Study Title: 
A Phase 1 Study Investigating the Safety, Tolerability and Pharmacokinetics of 
KNX100 in Healthy Volunteers  
Study Number: 
KTX-101 
Final Date: 
07 July 2023 
This study clinical study protocol was subjected to critical review and the information it contains 
is consistent with the moral, ethical, and scientific principles governing clinical research as set 
out in the Declaration of Helsinki and the Principles of Good Clinical Practice (GCP) as 
described in the International Council for Harmonisation (ICH) E6 GCP guideline and Title 21 
Code of Federal Regulations parts 50, 54, 56, and 312.  
This protocol has been approved by the Sponsor for execution.  The following personnel 
contributed to writing and/or approving this protocol: 
Signed: 
Date: 
Sharon Hanegraaf 
VP, Drug Development 
Kinoxis Therapeutics Pty Ltd 
Signed: 
Date: 
Tina Soulis, Ph.D. 
VP, Clinical Strategy and Development 
Kinoxis Therapeutics Pty Ltd 
Jul 7, 2023
Jul 7, 2023


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INVESTIGATOR’S SIGNATURE 
Study Title: 
A Phase 1 Study Investigating the Safety, Tolerability and Pharmacokinetics of 
KNX100 in Healthy Volunteers  
Study Number: 
KTX-101 
Final Date: 
07 July 2023 
 
I have read the KTX-101 protocol and agree to conduct the study as outlined.   
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol.   
I agree to conduct the study in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, are consistent with the Good Clinical Practices guidelines of the 
International Council for Harmonisation, and according to applicable regulatory requirements.  
 
Principal Investigator 
Signature: 
 
Print Name: 
 
Print Title: 
 
Institution/Affiliation: 
 
Date of Signature: 
 
 
 


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SYNOPSIS 
Study Title:  A Phase 1 Study Investigating the Safety, Tolerability and Pharmacokinetics of 
KNX100 in Healthy Volunteers  
Name of Finished Product:  KNX100 
Name of Active Ingredient:  KNX100 Phosphate 
Study Number:  KTX-101  
Study Phase:  1 
Study Centers:  One site (Australia) 
Primary Objectives:  The primary objectives of this study are to evaluate the safety and 
tolerability of KNX100 administered orally as a single ascending dose and multiple ascending 
doses in healthy volunteers. 
Secondary Objectives:  The secondary objective of this study is to determine the 
pharmacokinetic (PK) profile of KNX100 and its metabolites following administration of 
KNX100 as single and multiple oral doses in healthy volunteers.  
Study Design:  This is an adaptive, Phase 1, first-in-human (FIH), single treatment, double 
blind, placebo controlled, randomized, single/multiple ascending dose study of KNX100 
administered to healthy volunteers (Part A and B).  Approximately 64 male and female healthy 
subjects will be enrolled into Part A and B in this study.  Healthy subjects who meet all the 
eligibility criteria will be randomly assigned to Cohorts 1-4 in Parts A or Cohorts 1-3 in Part B 
of the study.  Each cohort will evaluate 8 subjects; 6 subjects will receive KNX100 (study 
drug), and 2 subjects will receive placebo.  
Additional cohorts may be added as required, based on safety profile and Cohort Review 
Committee (CRC) authorization.  
Each cohort will be enrolled sequentially, and dose escalation decisions will be made 
according to protocol by the CRC consisting of the investigators and medical monitor.  
Subjects and clinical staff will be blinded to therapy assignment.   
Planned Number of Patients:  Approximately 64 healthy subjects will be randomized for 
study participation.  The total number of subjects will depend on the number of dose levels 
assessed during dose-escalation to determine the Recommended Phase 2 dose (RP2D) of 
KNX100.   
Randomization will be controlled either via a list or Interactive Web Response System. 
Diagnosis and Main Criteria for Inclusion:  This study will evaluate healthy volunteers 
(male and female) who are between 18 and 55 years of age (inclusive) with a body mass index 
(BMI) of 18-32 (inclusive).  Subjects must be willing to comply with study requirements and 
must agree to abstain from consuming alcohol or using recreational drugs.  Subjects with 
specific underlying conditions (e.g., mental illness, human immunodeficiency virus (HIV), 
hepatitis, cardiovascular disease) or any medical history that would jeopardize their safety 
cannot participate.  Additionally, subjects with clinically significant electrocardiogram (ECG), 


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electroencephalogram (EEG), physical examination, or laboratory findings will not be 
enrolled.  Female subjects of childbearing potential must be willing and able to use defined 
methods of contraception throughout the study and for 30 days after the final follow-up visit. 
Test Product; Dose; and Mode of Administration:  KNX100 will be provided in capsule 
form as 5, 25 or 100 mg capsules for oral administration.  Study drug will be encapsulated in 
hydroxypropyl methylcellulose (HPMC) dark green opaque size 0 capsules and packaged in 
100 mL high density polyethylene (HDPE) bottles with polypropylene twist-off closures. 
Dosing will be based on the assigned treatment group.  This study will evaluate doses of 
KNX100 starting with a single ascending dose (Part A, SAD) of 5 mg, increasing up to a 
maximum of 50 mg and a multiple ascending dose (Part B, MAD) starting at 10 mg and 
increasing up to 35 mg per dose, as tolerated.  Individual doses will be dispensed by unblinded 
site pharmacy staff.  Dose escalation will progress upon CRC approval.  Subjects will take the 
study drug in the morning after an overnight fast.  For subjects enrolled into MAD Cohort 3, 
subjects will take study drug in the morning after an overnight fast and again, approximately 8 
hours after the first dose following a 2-hour fast. 
Reference Therapy; Dose; and Mode of Administration:  KNX100 matching placebo will 
be provided in capsule form for oral administration.  The placebo will be encapsulated in 
HPMC dark green opaque size 0 capsules and packaged in 100 mL HDPE bottles with 
polypropylene twist-off closures. 
Dosing will be based on the assigned treatment group.  An equivalent number of capsules will 
be administered to subjects receiving placebo (e.g., the first dose of study drug will be one 
5 mg capsule; subjects receiving placebo will also receive only one capsule).  Individual doses 
will be dispensed by unblinded site pharmacy staff.  Subjects will take the study drug in the 
morning after an overnight fast. For subjects enrolled into MAD Cohort 3, subjects will take 
study drug in the morning after an overnight fast and again, approximately 8 hours after the 
first dose following a 2-hour fast. 
Duration of Treatment:  
The length of the treatment period for each subject in Part A is 1 day (1 dose administered). 
For Part B Cohorts 1 and 2, the length of the treatment period for each subject is 7 days (7 
doses administered). For Cohort 3, the length of the treatment period for each subject is 7 days 
(14 doses administered). 
During Part A, subjects will remain in the Phase 1 unit for 30 hours after study drug 
administration for PK sampling and safety evaluations.  For Part B, subjects will remain in the 
Phase 1 unit for 7 days of study drug administration, PK sampling and safety evaluations, and 
be discharged on Day 8 after PK and safety evaluations.   


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Duration of Patient Study Participation:   
Subjects in Part A (SAD) will be on study for up to 38 days:  
• Screening:  up to 28 days  
• Treatment:  1 day  
• Follow-up:  7 (± 2) days following completion of treatment  
Subjects in Part B (MAD) will be on study for up to 44 days:  
• Screening:  up to 28 days  
• Treatment:  1 dose each day for 7 days (Cohorts 1 and 2) 
 
 
 
 
 1 dose administered twice daily for 7 days (Cohort 3) 
• Follow-up:  7 (±2) days following completion of treatment 
Safety Assessments:  
The primary safety endpoints include:   
• Incidence of treatment emergent adverse events (TEAEs), treatment emergent serious 
adverse events (TESAEs), related adverse events (AEs), AEs leading to 
discontinuation, and AEs by severity. 
• Clinical laboratory testing from protocol-specified standard urine and blood tests, 
including liver function tests (LFTs) and thyroid function tests (TFTs: triiodothyronine 
[T3], thyroxine [T4], thyroid stimulating hormone [TSH]). 
• Change in clinical observations from baseline, including body temperatures, vital 
signs, ECGs, and EEGs. 
Pharmacokinetic Variables: 
The secondary PK endpoints include assessment of:   
• Maximum observed concentrations (Cmax) following dose administration.   
• Time of Cmax (Tmax) following dose administration.   
• Area under the concentration-time curve (AUC) from time zero to last quantifiable 
concentration (AUC0-last), from time zero to 24 hours postdose administration 
(AUC0-24) and, as data permit, from time zero to extrapolated to infinity (AUC0-∞). 
• As data permit, additional disposition parameters including terminal half-life (t1/2), 
volume of distribution (Vz/F), and oral clearance (CL/F) may be calculated. 
• Accumulation ratio (RAC) for Cmax and AUC0-24; Day 7 vs Day 1 (MAD phase only). 
• 
Other PK parameters will be calculated as deemed appropriate. 
Statistical Methods:  All data will be presented in the data listing.  AEs will be summarized 
for each treatment and cohort and overall, by system organ class and preferred term to include 
the number and percentage of subjects who experience at least one AE.  AEs will also be 
summarized by relatedness, severity, study drug discontinuation, and seriousness.  Clinical 
laboratory results, vital signs, body temperature, pulse oximetry measurements, EEGs and 


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single-lead ECG results will be summarized by actual values and change from baseline.  
Physical examination findings will be presented in a data listing. 
Plasma concentration data will be summarized over time by treatment using descriptive 
statistic (number of observations, arithmetic mean, standard deviation, arithmetic coefficient 
of variation [CV], geometric mean, geometric CV, median, minimum, and maximum). Mean 
and individual plasma concentration versus time profiles will be presented in figures on both 
linear and semi logarithmic scales. 
For the PK parameters, descriptive statistics will be provided for each parameter (number of 
observations, arithmetic mean, standard deviation, arithmetic CV, geometric mean, geometric 
CV, median, minimum, and maximum).  


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TABLE OF CONTENTS 
SPONSOR SIGNATURES ............................................................................................................. 2 
INVESTIGATOR’S SIGNATURE ................................................................................................ 3 
SYNOPSIS ...................................................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................ 8 
LIST OF FIGURES ...................................................................................................................... 11 
LIST OF TABLES ........................................................................................................................ 11 
LIST OF APPENDICES ............................................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS ................................................................... 12 
1. 
INTRODUCTION ................................................................................................................ 16 
1.1. 
Disease Background.................................................................................................... 16 
1.1.1. 
Opioid Use Disorder ......................................................................................... 16 
1.1.2. 
Opioid Withdrawal ........................................................................................... 17 
1.1.3. 
Currently Available Treatments for Opioid Withdrawal .................................. 17 
1.2. 
Rationale for KNX100 ................................................................................................ 18 
2. 
STUDY OBJECTIVES ......................................................................................................... 20 
2.1. 
Primary Objectives...................................................................................................... 20 
2.2. 
Secondary Objectives.................................................................................................. 20 
3. 
INVESTIGATIONAL PLAN ............................................................................................... 20 
3.1. 
Overall Study Design and Plan ................................................................................... 20 
3.2. 
Rationale for Study Design and Control Group .......................................................... 22 
3.2.1. 
Starting Dose Justification ................................................................................ 23 
3.2.2. 
Maximum Dose ................................................................................................. 25 
3.3. 
Study Duration and Dates ........................................................................................... 26 
4. 
STUDY POPULATION SELECTION ................................................................................ 26 
4.1. 
Study Population ......................................................................................................... 26 
4.2. 
Inclusion Criteria ........................................................................................................ 26 
4.3. 
Exclusion Criteria ....................................................................................................... 27 
5. 
STUDY TREATMENTS ...................................................................................................... 29 
5.1. 
Description of Treatments........................................................................................... 29 
5.1.1. 
Study Drug ........................................................................................................ 29 
5.1.2. 
Placebo .............................................................................................................. 29 
5.2. 
Treatments Administered ............................................................................................ 29 
5.3. 
Selection and Timing of Dose for Each Subject ......................................................... 30 
5.3.1. 
Sentinel Subject Review and Toxicity Management ........................................ 30 
5.3.2. 
Part A Dosing .................................................................................................... 30 


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5.3.3. 
Part B Dosing .................................................................................................... 31 
5.3.4. 
Dose Escalation ................................................................................................. 32 
5.4. 
Method of Assigning Subjects to Treatment Groups .................................................. 33 
5.5. 
Blinding....................................................................................................................... 33 
5.6. 
Unblinding .................................................................................................................. 35 
5.7. 
Missed Doses .............................................................................................................. 35 
5.8. 
Overdose ..................................................................................................................... 35 
5.9. 
Concomitant Therapy.................................................................................................. 35 
5.10. Restrictions ................................................................................................................. 36 
5.10.1. 
Smoking ............................................................................................................ 36 
5.10.2. 
Prior Therapy .................................................................................................... 36 
5.10.3. 
Fluid and Food Intake ....................................................................................... 36 
5.10.4. 
Exercise ............................................................................................................. 36 
5.11. Treatment Compliance ................................................................................................ 37 
5.12. Packaging and Labeling .............................................................................................. 37 
5.13. Storage and Accountability ......................................................................................... 37 
6. 
STUDY PROCEDURES ...................................................................................................... 38 
6.1. 
Information Statement and Consent Form .................................................................. 38 
6.2. 
Randomization ............................................................................................................ 39 
6.3. 
Demographic and Baseline Characteristics ................................................................ 39 
6.4. 
Physical and Neurological Examinations ................................................................... 40 
6.5. 
Vital Signs ................................................................................................................... 40 
6.6. 
Gastrointestinal Symptoms ......................................................................................... 41 
6.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 41 
6.8. 
Concomitant Medications ........................................................................................... 42 
6.9. 
Contraception .............................................................................................................. 42 
6.10. 12-Lead Electrocardiograms ....................................................................................... 43 
6.11. Electroencephalograms ............................................................................................... 44 
6.11.1. 
Screening and Baseline Procedures and Assessments ...................................... 44 
6.11.2. 
Dosing Phase Assessments ............................................................................... 45 
6.12. Pharmacokinetic Assessments .................................................................................... 45 
6.12.1. 
Determination of Drug Concentration in Pharmacokinetic Samples ................ 45 
6.13. Clinical Laboratory Tests ............................................................................................ 45 
6.14. Sample Collection, Storage, and Shipping ................................................................. 46 
6.14.1. 
Handling, Storage, and Destruction of Biological Samples ............................. 46 
6.14.2. 
PK Samples ....................................................................................................... 46 
6.14.2.1. 
Timing of PK samples ............................................................................ 46 


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6.14.3. 
Collection of Plasma for Exploratory Analysis of PD Biomarkers .................. 46 
6.15. End of Study Visit/Early Termination Visit ............................................................... 47 
6.16. Dispensing Study Drug ............................................................................................... 47 
6.17. Adverse Events Assessments ...................................................................................... 47 
6.17.1. 
Definition .......................................................................................................... 48 
6.17.2. 
Timing and Reporting Period ........................................................................... 48 
6.17.3. 
Severity ............................................................................................................. 49 
6.17.4. 
Relationship/Causality ...................................................................................... 49 
6.17.5. 
Expectedness ..................................................................................................... 50 
6.17.6. 
Suspected Adverse Reaction ............................................................................. 50 
6.17.7. 
Suspected Unexpected Serious Adverse Reaction ............................................ 50 
6.17.8. 
Follow-up of Adverse Events ........................................................................... 51 
6.17.9. 
Clinical Laboratory and Investigational Findings Adverse Events .................. 51 
6.17.10. Serious Adverse Events .................................................................................... 52 
6.17.11. Reporting Adverse Events ................................................................................ 52 
6.17.11.1. Reporting Serious or Unexpected Adverse Events ................................. 53 
6.17.12. Expedited Reporting Requirements .................................................................. 54 
6.17.13. Pregnancy .......................................................................................................... 54 
6.18. Safety Contact Information ......................................................................................... 54 
6.19. Definition of Clinical Significance ............................................................................. 54 
6.20. Study Stopping Rules .................................................................................................. 55 
6.20.1. 
Maximum Clinical Exposure ............................................................................ 55 
6.20.2. 
Maximum Tolerated Dose Definition ............................................................... 55 
6.21. Removal of Subjects from the Study or Study Drug .................................................. 56 
6.21.1. 
Criteria for Discontinuation or Withdrawal of a Subject .................................. 56 
6.21.2. 
Subject Withdrawal of Consent ........................................................................ 57 
6.21.3. 
Study Withdrawal - Early Termination Procedures .......................................... 57 
6.21.4. 
Lost to Follow-up .............................................................................................. 58 
6.22. Discontinuation of the Study ...................................................................................... 58 
6.23. Appropriateness of Measurements .............................................................................. 58 
7. 
QUALITY CONTROL AND ASSURANCE ...................................................................... 58 
8. 
PLANNED STATISTICAL METHODS ............................................................................. 59 
8.1. 
General Considerations ............................................................................................... 59 
8.2. 
Determination of Sample Size .................................................................................... 59 
8.3. 
Analysis Populations ................................................................................................... 59 
8.4. 
Demographics and Baseline Characteristics ............................................................... 60 
8.5. 
Study Endpoints .......................................................................................................... 60 


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8.5.1. 
Primary Safety Endpoints ................................................................................. 60 
8.5.2. 
Secondary Pharmacokinetic Endpoints ............................................................ 60 
8.6. 
Statistical Analysis of Safety Variables ...................................................................... 61 
8.7. 
Statistical Analysis of Pharmacokinetic Variables ..................................................... 61 
8.8. 
Interim Analysis .......................................................................................................... 62 
9. 
ADMINISTRATIVE CONSIDERATIONS ......................................................................... 62 
9.1. 
Investigators and Study Administrative Structure ...................................................... 62 
9.2. 
Human Research Ethics Committee Approval ........................................................... 62 
9.3. 
Ethical Conduct of the Study ...................................................................................... 63 
9.4. 
Subject Information and Consent................................................................................ 63 
9.5. 
Subject and Study Confidentiality .............................................................................. 64 
9.6. 
Case Report Forms and Study Records ...................................................................... 64 
9.6.1. 
Data Collection ................................................................................................. 65 
9.6.2. 
Source Data ....................................................................................................... 65 
9.7. 
Study Monitoring ........................................................................................................ 65 
9.8. 
Cohort Review Committee ......................................................................................... 66 
9.8.1. 
Blinded Data Review ........................................................................................ 66 
9.9. 
Protocol Violations/Deviations ................................................................................... 67 
9.10. Access to Source Documentation ............................................................................... 68 
9.11. Data Generation and Analysis .................................................................................... 68 
9.12. Retention of Data ........................................................................................................ 68 
9.13. Financial Disclosure.................................................................................................... 69 
9.14. Changes to the Clinical Study Protocol ...................................................................... 70 
9.15. Disruption Due to Coronavirus Disease 2019 (COVID-19) Pandemic ...................... 70 
9.16. Publication and Data Disclosure Policy ...................................................................... 70 
10. REFERENCE LIST .............................................................................................................. 71 
 
LIST OF FIGURES 
Figure 1 
Study Phases and Activities .............................................................................. 22 
 
LIST OF TABLES 
Table 1 
FDA Approved Medications for Opioid Use Disorder Indications .................. 17 
Table 2 
Dose Strength Per Capsule ............................................................................... 29 
Table 3 
Planned Dose-Escalation Schedule (SAD Part A) ............................................ 31 
Table 4 
Planned Dose-Escalation Schedule (MAD Part B) ........................................... 32 


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Table 5 
Example 4-Digit Subject Randomization Numbers .......................................... 33 
Table 6 
Reporting Requirements for Adverse Events ................................................... 53 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments - SAD ............................................................. 73 
Appendix 2 
Schedule of Assessments – MAD ........................................................... 76 
Appendix 3 
PK Blood Sampling, EEG and ECG Schedule During Dosing Periods . 79 
Appendix 4 
KTX-101 Normal Ranges for Vital Signs and ECG Parameters ............ 81 
Appendix 5 
List of Laboratory Tests .......................................................................... 82 
Appendix 6 
Country-Specific Safety Reporting (Australia)....................................... 84 
 
LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AUC 0-t 
area under the concentration-time curve from time zero to last quantifiable 
concentration 
AUC 0-∞ 
area under the concentration-time curve from time zero to infinity 
AUC 0-24 
area under the concentration-time curve from time zero t0 24 hours 
b.i.d 
twice daily 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CL 
clearance  
CL/F 
oral clearance 
Cmax 
maximum plasma drug concentration 
Cmin 
minimum plasma drug concentration 
CNS 
central nervous system 
CRA 
clinical research associate 
CRC 
Cohort Review Committee 


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Abbreviation 
Definition 
CRO 
contract research organization 
CSSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMP 
data management plan 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
EOS 
end of study 
ET 
early termination 
FDA 
Food and Drug Administration (US Government) 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HDPE 
high density polyethylene 
HED 
human equivalent dose  
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropyl methylcellulose 
HREC 
Human Research Ethics Committee (Australian equivalent of IRB) 
ICH 
International Conference on Harmonisation  
IED 
interictal epileptiform discharges 
IND 
Investigational New Drug  
IP 
intraperitoneal 
IUD 
intrauterine device 
KNX100 
Study drug: 1-methyl-1,4,5,10-tetrahydropyrazolo[3,4-
b][1,5]benzodiazepine phosphate 
LFT 
liver function test 
LOEL 
lowest-observed-effect-level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAD 
multiple ascending dose 


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Abbreviation 
Definition 
MAT 
medication-assisted treatment 
MRSD 
maximum recommended starting dose 
MRT 
mean residence time 
MTD 
maximum tolerated dose 
NAcSh 
nucleus accumbens shell 
NHMRC 
National Health and Medical Research Council (Australian government) 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed- effect-level 
OTC 
over-the-counter 
OUD 
opioid use disorder 
PAD 
pharmacologically effective dose range 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PI 
principal investigator 
PP 
per protocol set 
RAC 
accumulation ratio 
RP2D 
recommended phase 2 dose 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAF 
Safety Set 
SAR 
suspected adverse reaction 
SID 
Subject Identification Number 
SD 
Standard deviation 
SOA 
Schedule of Assessments 
SSI 
significant safety issue 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half life 
T3 
free triiodothyronine 
T4 
thyroxine 
TEAEs 
treatment emergent adverse events 
TESAEs 
treatment emergent serious adverse events 


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Abbreviation 
Definition 
TFT 
thyroid function test 
TGA 
Therapeutic Goods Administration 
Tmax 
time to maximum plasma concentration 
TSH 
thyroid stimulating hormone 
Vz/F 
apparent volume of distribution 
US 
United States 
USM 
urgent safety measures 
WOCBP 
women of childbearing potential  


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1. INTRODUCTION 
1.1. 
Disease Background 
1.1.1. 
Opioid Use Disorder 
Opioid use disorder (OUD) is defined in the Diagnostic and Statistical Manual of Mental 
Disorders (DSM-5) as a problematic pattern of opioid use leading to clinically significant 
impairment or distress.  The DSM-5 diagnostic criteria for OUD include presentation of at least 
2 of the following: 
• Opioids are often taken in larger amounts or over a longer period than was intended. 
• There is a persistent desire or unsuccessful efforts to cut down or control opioid use. 
• A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, 
or recover from its effects. 
• Craving, or a strong desire or urge to use opioids. 
• Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, 
or home. 
• Continued opioid use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of opioids. 
• Important social, occupational, or recreational activities are given up or reduced because 
of opioid use. 
• Recurrent opioid use in situations in which it is physically hazardous. 
• Continued opioid use despite knowledge of having a persistent or recurrent physical or 
psychological problem that is likely to have been caused or exacerbated by the substance. 
• Exhibits tolerance.  
• Exhibits withdrawal.  
Opioids, a broad class of drugs that act on opioid receptors in the brain, spinal cord, and other 
parts of the body are commonly prescribed for pain, with approximately 3%-4% of the adult US 
population prescribed long-term opioid therapy (Boudreau et al., 2009; Volkow and McLellan 
2016), however, long-term use can be associated with misuse, addiction, morbidity, and 
mortality.  The opioid (opioid analgesics/heroin/fentanyl) overdose epidemic is among the most 
pressing public health issues in the US (Volkow et al., 2014).  Opioid overdose is the number 
one cause of preventable deaths in the United States (US), killing more people than motor 
vehicle accidents.  In Australia, opioids accounted for just over 3 deaths a day in 2018 and were 
linked to more than half of the drug induced deaths across the country.  Poor management of 
opioid withdrawal is a major contributor to the development and maintenance of harmful opioid 
use.  Opioid-associated morbidity and mortality are described by the Centers for Disease Control 
(CDC) as a national epidemic which continues to escalate, with a record 68,821 opioid overdose 


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deaths recorded in 2020 (CDC WONDER).  In 2020, over 92,000 people died from drug 
overdoses, making it a leading cause of injury-related death in the US and of those deaths, 
over 70 percent involved a prescription or illicit opioid (CDC 2021).  These alarming trends led 
the US Department of Health and Human Services (HHS) to deem prescription-opioid overdose 
deaths an epidemic and prompted multiple federal, state, and local actions (CDC 2013). 
1.1.2. 
Opioid Withdrawal 
Opioid withdrawal is the rapid onset of severe physical and mental distress following a partial or 
total reduction of opioid consumption.  Portenoy (1996) observed that addiction occurred due to 
2 factors:  the inherent reinforcing properties of the opioid drugs, and the psychological/social/ 
physiological factors of the individual which predispose to addiction.  Abrupt cessation of 
opioids in physically dependent subjects results in acute withdrawal symptoms.  The time of 
onset, peak, and duration of these symptoms depends on the elimination half-life of the opioid 
that was used prior to cessation, but the symptoms are essentially the same irrespective of the 
specific opioid. 
Opioid withdrawal symptoms develop within several hours to a few days following termination 
or reduction of heavy or prolonged opioid use.  Symptoms include sweating, rapid pulse, 
increased hand tremor, insomnia, nausea, vomiting, physical agitation, anxiety, transient visual, 
tactile, or auditory hallucinations/illusions and grand mal seizures (Dijkstra et al., 2007).  Opioid 
withdrawal symptoms occur both in subjects who have been using opioids appropriately, and in 
subjects with OUD.  In subjects with OUD, the occurrence of withdrawal symptoms and the 
relief of withdrawal when opioids are used are important drivers of continuing use. 
1.1.3. 
Currently Available Treatments for Opioid Withdrawal  
Medication-assisted treatment (MAT) is the primary treatment for OUD.  However, only a 
limited number of FDA approved pharmacological treatment options are currently available for 
OUD and they are underutilized:  fewer than 20% of persons in the US with OUD receive an 
OUD-specific treatment (Wu et al., 2016).  Drugs approved to treat OUD are presented in 
Table 1, along with their specific FDA approved indication(s). 
Table 1 
FDA Approved Medications for Opioid Use Disorder Indications 
Medication 
Mechanism 
FDA Label Indication (Abbreviated) 
Naloxone 
Opioid receptor antagonist 
Opioid overdose 
Lofexidine 
Adrenergic receptor agonist 
Opioid withdrawal 
Methadone 
Opioid receptor agonist 
Detoxification, maintenance treatment 
Buprenorphine 
µ-opioid receptor partial agonist 
Detoxification, maintenance treatment 
Buprenorphine/naloxone 
See above 
Maintenance treatment 
Naltrexone 
Opioid receptor antagonist 
Relapse prevention following detoxification 


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The drug treatments presented in Table 1 suffer from a mixture of suboptimal efficacy and safety 
which contributes to poor uptake and treatment adherence.  For example, lofexidine, the first 
FDA approved drug for mitigating opioid withdrawal symptoms following abrupt opioid 
discontinuation, achieved only modest improvements in acute opioid withdrawal symptoms and 
treatment retention, while causing concerning side-effects, including hypotension, bradycardia, 
and insomnia (Gorodetzky et al., 2017; Choy, 2018).  Naltrexone and maintenance treatments 
suffer from both poor treatment initiation and compliance, with a recent large cohort study 
finding only 11%, 17%, and 6% of subjects initiated methadone, buprenorphine, or naltrexone 
treatment respectively, within 12 months of a nonfatal overdose, with median treatment retention 
periods of just 5, 4, and 1 month(s) (Larochelle et al., 2018). 
Despite the limited number of treatment options currently available and their underutilization, 
there is very little in the clinical pipeline for the treatment of OUD.  A recent pharmaceutical 
industry report identified only 29 current clinical programs for substance use disorders.  Of these, 
only 15 were ongoing clinical programs testing new molecular entities (NMEs), with no novel 
clinical programs specifically targeting OUD (Thomas and Wessel, 2018).  Clearly there is an 
urgent need to develop novel pharmacological treatments for OUD and, importantly, to progress 
novel treatments expeditiously into clinical development. 
1.2. 
Rationale for KNX100  
Kinoxis Therapeutics Pty Ltd (Kinoxis) is developing a new chemical entity, KNX100 as a small 
molecule intended for the treatment of symptoms associated with opioid withdrawal in patients 
with OUD.  KNX100 was originally developed by the University of Sydney, Australia and is 
now owned by Kinoxis.  KNX100 was selected from a number of molecules under development 
as it demonstrated potent anti-addictive and prosocial effects in several different animal models 
and activated brain regions and cell types of interest.  
The opioid crisis in the US continues to escalate, with a record 49,860 opioid overdose deaths 
recorded in 2019 (CDC WONDER).  Treating OUD, including managing opioid withdrawal 
symptoms, presents a considerable challenge for health care professionals and there are currently 
only a limited number of drugs approved for the treatment of OUD (including treatments for 
overdose and withdrawal).  These include µ-opioid receptor antagonists (naloxone and 
naltrexone), opioid maintenance treatments (µ-opioid receptor agonist and partial agonists, 
methadone and buprenorphine, respectively, and combination partial agonist/antagonist 
treatments), and the α2-adrenergic agonist, lofexidine.  Opioid maintenance therapies are 
associated with risk of overdose, diversion, abuse, and compliance issues.  Naloxone is primarily 
used to treat overdose and naltrexone suffers from uptake, compliance, and efficacy issues.  
Lofexidine demonstrates limited efficacy and has significant cardiovascular liabilities. 


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Pharmacologically, opioids bind to opioid receptors located in the brain, spinal cord, and other 
parts of the body.  Activation of opioid receptors in different parts of the central and peripheral 
nervous systems mediates the various effects of opioids.  These include analgesia, respiratory 
depression, and opioids’ addictive properties.  Opioid withdrawal occurs following a 
discontinuation or reduction of opioid use, or administration of a µ-opioid receptor partial 
agonist or antagonist.  Opioid withdrawal syndrome consists of often severe somatic 
(e.g., hyperalgesia, gastrointestinal upset, and chills) and affective (e.g., anxiety, dysphoria, and 
intense craving for opioids) symptoms.  Withdrawal typically begins within 1-2 days of the last 
dose of an opioid or commencement of dose tapering, and symptoms can last for 2-4 weeks or 
longer.  Opioid withdrawal is caused by adaptations that occur in the nervous system as a result 
of repeated activation of opioid receptors.  Poor management of opioid withdrawal is a major 
contributor to the development and maintenance of harmful opioid use as it is the first barrier to 
switching to maintenance therapy, dose tapering, or discontinuation. 
KNX100 was discovered through a comprehensive drug discovery program where it was initially 
selected for further development based on its ability to positively modulate social behavior in 
rodents and to activate key brain regions of interest, primarily the hypothalamus, as measured by 
c-fos immunohistochemistry.  Kinoxis subsequently examined in vivo efficacy of KNX100 
across a wide range of preclinical disease models including rodent and primate models of 
stimulant use disorders and rodent models of nicotine use disorder and OUD.  In a C57BL/6 
mouse model of opioid withdrawal, KNX100 was shown to dose dependently inhibit 
withdrawal-induced jumping (believe to be an escape behavior that captures the intense 
dysphoria being experienced during withdrawal) and paw tremors (a somatic symptom of opioid 
withdrawal).  
Kinoxis has further evaluated the neural mechanisms causally involved in KNX100 effects on 
opioid withdrawal in mice.  Using c-fos immunofluorescence to measure neural activation, it was 
observed that KNX100 inhibited opioid withdrawal-induced hyperactivation in 8 brain regions 
implicated in the opioid withdrawal syndrome: the lateral parabrachial nucleus, dorsal raphe, 
lateral periaqueductal gray, ventral tegmental area, medial division of the central amygdala, 
lateral habenula, nucleus accumbens shell (NAcSh), and ventral division of lateral septum.  The 
NAcSh has been heavily implicated in opioid withdrawal.  Subsequent studies using in vivo fiber 
photometry, which allows measurement of neural activation with millisecond precision in freely 
moving mice undergoing opioid withdrawal, demonstrated that KNX100 powerfully inhibited 
both the elevated baseline activity in the NAcSh and the withdrawal-jumping-related activity in 
this region.  Further, it was also demonstrated that chemogenetic inhibition of the NAcSh 
inhibited opioid withdrawal-induced jumping in mice, and infusion of KNX100 directly into the 
NAcSh, at concentrations known to reach this brain region following oral administration in our 
efficacy dose range, inhibits withdrawal jumping.  These data strongly indicate that KNX100 
binding in the NAcSh, and subsequent inhibition of withdrawal-induced activity in this brain 


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region, plays a key role in its in vivo efficacy in reducing the severity of the opioid withdrawal 
syndrome in mice. 
In nonclinical efficacy studies, KNX100 demonstrated significant activity in the mitigation of 
symptoms of opioid withdrawal in mice following naloxone induced precipitated withdrawal.  
In nonclinical studies, KNX100 also showed a favorable pharmacokinetic (PK) profile.  It was 
rapidly absorbed in both rats and dogs, and the oral bioavailability appeared to increase dose 
dependently.  Data obtained in the toxicity studies provided an acceptable safety profile and 
no-observed-adverse-effect levels (NOAELs) were clearly established and consistent across 
species.  
Based on the favorable nonclinical evaluations performed to date (refer to the KNX100 
Investigator’s Brochure), Kinoxis is conducting this first-in-human (FIH) study to determine the 
safety and tolerability of single and multiple ascending doses of KNX100 in healthy volunteers. 
2. STUDY OBJECTIVES 
2.1. 
Primary Objectives  
The primary objectives of this study are to evaluate the safety and tolerability of KNX100 
administered orally as a single and multiple ascending doses in healthy volunteers. 
2.2. 
Secondary Objectives  
The secondary objectives of this study are to determine: 
1. The PK profile of ascending doses of KNX100 and its metabolites when administered as 
a single oral dose in healthy volunteers.  
2. The PK profile of ascending doses of KNX100 and its metabolites when administered as 
multiple doses in healthy volunteers. 
3. The PK profile of KNX100 and its metabolites when administered twice daily as multiple 
doses in healthy volunteers. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 1, FIH, single site, single treatment, 2-part, double blind, placebo controlled, 
randomized, single ascending dose (SAD)/multiple ascending dose (MAD) study designed to 
evaluate the safety and tolerability of KNX100 as compared to placebo.  This study will enroll 
healthy volunteers. 


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The planned enrollment is approximately 64 male and female subjects.  The total number of 
subjects will depend on the number of dose levels assessed in dose-escalation.  Completed 
subjects will have received either KNX100 (active study drug) or placebo.  Subjects who 
discontinue will be replaced to achieve the targeted number of evaluable subjects in each cohort. 
Healthy subjects who meet all eligibility criteria will be sequentially enrolled and assigned to a 
single cohort in Cohorts 1-4 in Part A of the study or in Cohorts 1-3 in Part B of the study.  Each 
cohort selected will evaluate 8 subjects; 6 subjects will be randomly assigned to receive 
KNX100, and 2 subjects will be randomly assigned to receive placebo.  Each cohort will be 
enrolled sequentially, and the subsequent dose increase will be based on the Cohort Review 
Committee (CRC) evaluation of data known to date. 
Additional cohorts may be added as required, based on safety profile and CRC authorization.  
Part A (SAD) will initially dose 2 sentinel subjects (one with KNX100 and one with placebo) in 
Cohort 1.  The center will review safety and tolerability up to and including the 48-hour 
timepoint for the sentinel subjects before dosing the remaining subjects in the dose cohort.  The 
CRC will be informed and authorize the decision to continue with the remainder of the cohort 
dosing.  Each subject will receive 1 dose, administered orally, of study drug.  All subjects in each 
cohort will have their data, up to and including the 30 -hour postdose timepoint, evaluated for 
safety and tolerability by the CRC before opening the next dose cohort based on assessment of 
all available data.  The dosing schedule may be extended if additional observations are needed at 
a particular cohort.  In the absence of unacceptable AEs, the CRC may decide to open the next 
cohort before they have reviewed all data from all 8 evaluable subjects who have completed up 
to and including the 30-hour timepoint postdose.  
Subjects will be housed in the clinic from Day -3 prior to study drug administration and will 
remain in-house for 30 hours postdose (Day 2) for PK and safety assessments. 
Part B (MAD) will evaluate up to 3 doses based on doses established during Part A (SAD).  Each 
subject will receive 7 doses of study drug, administered either once (Cohorts 1 and 2) or twice 
daily (Cohort 3).  All subjects in each MAD cohort will have their AE, PK, and 
electroencephalography (EEG) data, acquired up to and including Day 8, evaluated for safety 
and tolerability by the CRC before opening the next higher dose cohort. Subjects will be housed 
in the clinic from Day -3 prior to study drug administration and will remain in-house for 24 
hours post morning dose (Day 8) for PK and safety assessments. 
The study will be comprised of 3 periods:  Screening (up to 28 days); Treatment (1 day for the 
SAD subjects and 7 days for MAD subjects) and Follow-up.   Subjects will have a follow-up 
visit 7 days after the last dose.  As SAD dosing is a single dose on Day 1, follow-up will occur 


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on Day 7.  MAD dosing involves either single daily dosing (Cohorts 1 and 2) or twice daily 
dosing (Cohort 3) on Days 1 to 7, with a follow-up visit occurring on Day 14. 
The overall study design is summarized in Figure 1.  Refer to Appendix 1 and Appendix 2 for a 
detailed schedule of assessments. 
Figure 1 Study Phases and Activities  
Part A – SAD single dose   
Part B- MAD 7 days 
 
 
 
 
 
 
3.2. 
Rationale for Study Design and Control Group 
Study Design:  This study is a 2-part, single site, single treatment, double-blind, randomized, 
placebo-controlled, dose escalating study to assess the safety, tolerability, and PK of single and 
multiple ascending doses and twice daily dosing of KNX100 administered orally to healthy 
males and females.  Investigators and subjects will be blinded to treatment; however, the site 
pharmacist will be unblinded.  Members of the CRC will be blinded; however, specific members 
may be unblinded to enable evaluation of PK and safety data for dose escalation decisions if 
required. 
The design of this study is typical of those used for FIH studies with a "dose leader" (sentinel) 
design to better manage the safety aspects of the study.  A sentinel design will be implemented 
during Part A, (SAD), with 2 subjects being dosed on the first dosing day of each Cohort.  Of 
these, one will receive KNX100, and one will receive placebo.  Safety and tolerability will be 
reviewed for these 2 sentinel subjects by the site, and CRC, before dosing the remaining subjects 
in the dose cohort. 
All data for subjects in each SAD cohort collected up to and including the 30-hour samples 
postdose will be evaluated for safety and tolerability before opening the next higher dose cohort.  
In each MAD cohort, data for subjects up to and including the 24-hour timepoint post morning 
dose on Day 8 will be evaluated for safety and tolerability before opening the next higher dose 
cohort.  The dosing schedule may be extended if additional observations are needed at a 
particular cohort.  In the absence of unacceptable AEs, the CRC may decide to open the next 
3 Cohorts 
24 HV 
10-35mg 
6:2 Active vs Placebo 
4 Cohorts 
40 HV 
5-50mg 
6:2 Active vs Placebo 
Follow up to at 
least 7 days after 
last dose 
Screening up 
to 28 days  


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cohort before having reviewed data from all of the evaluable subjects who have completed Day 7 
in the SAD cohorts and Day 14 in the MAD cohorts. 
Dose:  This study employs a SAD followed by a MAD design.  Part A Cohort 1 will initially 
evaluate a low dose of KNX100 (5 mg).  For the following cohorts (2-4), the KNX100 dose will 
be increased as agreed by the CRC up to a maximum of 50 mg of KNX100 (Table 3) or to the 
maximum exposure level defined in Section 6.20.1, whichever occurs first.  In Part B (MAD), 
dosing will initially evaluate a low dose of 10 mg, followed by a high dose to be selected based 
on safety, tolerability and exposure data generated in Part A.  Cohort 3 of Part B will evaluate 
twice daily (b.i.d) dosing.  The dose will be selected based on PK data from the preceding 
cohort.  KNX100 and placebo will be encapsulated in identical size 0 capsules to ensure blinding 
of study treatment.  Additionally, subjects assigned to receive placebo will have the same 
number of capsules as subjects receiving KNX100.  Predefined stopping rules are provided to 
ensure the safety of all study subjects are defined in Section 6.20. 
Control:  A matching placebo control will be administered to evaluate treatment-related effects. 
Population:  KNX100 has not been previously administered to humans; therefore, its effects in 
humans are as yet unknown.  A healthy volunteer population with carefully considered 
inclusion/exclusion criteria will avoid the potential for interaction of KNX100 with any 
underlying disease state or concomitant medication that it may be necessary for subjects to take, 
while ensuring that subjects are fit and well enough for participation in the study.  Females of 
child-bearing potential will have to undergo a pregnancy test prior to enrollment. 
3.2.1. 
Starting Dose Justification 
Animal doses (intraperitoneal [IP] and oral) assessed in primary pharmacology models were used 
to predict the human efficacious dose of oral KNX100.  The efficacious doses administered to 
mice were converted to human dose equivalents per the FDA Guidance for Industry: Estimating 
the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers (July 2005).   


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Extensive preclinical efficacy data for the target indication of opioid withdrawal has been 
obtained using IP injection in mice.  However, to date, preclinical efficacy data following oral 
administration in an opioid withdrawal mouse model is unavailable.  The data collected in 
efficacy studies evaluating the effects of KNX100 (IP) on naloxone induced opioid withdrawal 
models in C57BL/6 mice and KNX100 (PO) in nicotine withdrawal models allow for a 
reasonable estimation of an effective dose range in humans, assuming allometric scaling on a 
mg/kg basis and similar affinities of KNX100 to pharmacodynamic (PD) targets in humans and 
C57BL/6 mice.  Based on the available animal data, a pharmacologically effective dose range 
(PAD) of approximately 0.89-1.78 mg/kg of KNX100 phosphate (equivalent to 53-107 mg/day 
in a 60 kg adult) was anticipated for reducing the symptoms of opioid withdrawal in humans. 
The human PK parameter estimates for CL/F and V/F based on single dose preclinical data from 
mouse, rat, and dog studies following oral administration was predicted using multiple allometric 
scaling approaches.  Overall, the range of doses using multiple methods of prediction ranged 
from 53 to 125 mg.  However, clearance in the rodent was much lower than in human, resulting 
in higher exposure levels that would not be achieved at the 53 or 125 mg doses.  The AUC 
following a 3.7 mg/kg IP dose in the mouse was 23.3 h*ng/mL.  Using the observed human CL/F 
value of 356,000 mL/h, a dose required to achieve the target AUC can be obtained using the 
following equation:  Dose (ng) = CL (mL/h) × AUC (h×ng/mL).  Using this formula, a total 
daily dose of 8.3 mg was derived.  However, the Cmax following the 3.7 mg/kg IP dose was 
45.5 ng/mL.  Based on the clinical data already obtained, a dose of around 20 mg could be 
estimated to achieve a Cmax of 46 ng/mL.  
The NOAEL reported in the 28-day repeat dose toxicology studies in rat and dog (Beagle) was 
50 mg/kg/day in rat and 15 mg/kg/day in dog which is equivalent to a human equivalent dose 
(HED) of the free base equivalent of 8.1 mg/kg/day and 8.3 mg/kg/day, respectively.  Based on a 
maximum recommended starting dose (MRSD) of 1/10th of the NOAEL and using the most 
conservative approach, an MRSD of 0.81 mg/kg of free base which is equivalent to 1.2 mg 
KNX100 phosphate per kg per day.  Assuming an average human weight of 60 kg, this would 
equate to a clinical starting dose of ~72 mg/day.   


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However, the severity, reversibility, and monitorable nature of the toxicity defining the NOAEL 
impacts how it influences the selection of the safe starting dose.  Respiratory effects (decreased 
tidal and minute volume premonitory to decreased respiration rate in the rat) and central nervous 
system (CNS) effects (decreased body temperature and hypoactivity premonitory to convulsions 
in the rat; tremor, ataxia and hypoactivity premonitory to convulsions in the dog) both inform the 
selection of the safe starting dose.  The severity of the CNS effects and trend towards greater-
than-dose-proportional KNX100 exposure suggest a minimum of a 10-fold dose margin relative 
to the CNS effect threshold is appropriate to be protective of patient health.  CNS effects, 
therefore, serve as the primary basis for selection of the starting and escalating clinical dose 
regimens.   
The selection of the starting dose for human studies was based on the CNS NOEL determined in 
the 28-day dog toxicology study.  In the dog, the CNS NOEL dose (7.5 mg free base/kg) 
corresponded to a HED of 6 mg KNX100 phosphate/kg.  Therefore, 1/10th of this value is 
equivalent to 0.6 mg KNX100 phosphate/kg, or 36 mg KNX100 phosphate in a 60 kg subject 
which would be the maximum recommended starting dose. 
However, due to observation of convulsions and other CNS effects in the toxicology studies, 
Kinoxis commenced dosing at a dose lower than the calculated MRSD.  Kinoxis defined the FIH 
starting dose as 5 mg KNX100 phosphate in a 60 kg subject.  This starting dose is a more 
conservative dose than the toxicology program directs and predicted a Cmax of 50 ng/mL and an 
AUC0- 24 of 125 ng×hr/mL, which is approximately 30-fold lower than the exposure at the CNS 
NOEL in dogs, approximately 60- 90-fold lower than the exposure at which convulsions were 
observed in dogs.  Based on the allometric body surface area (BSA) scaling approach, this 
starting dose was ~75-fold lower than the HED of the dog NOEL for convulsions reported in the 
28-day toxicology study, 150-fold lower than the HED of the NOAEL in rats and dogs, and 250-
fold lower than the dog LOEL for convulsions reported in the 28-day toxicology study. 
Based on predictive modelling, the proposed starting dose of 5 mg was anticipated to achieve a 
maximum plasma concentration of approximately 50 ng/mL, well below the applied exposure 
cap.  Subsequent clinical doses will be established based on scaling of the exposure results from 
the 5 mg dose. 
3.2.2. 
Maximum Dose 
An upper limit of 35 mg per day is supported by the nonclinical data and human PK data, 
specifically by exposure at the 1/10th of the NOEL of 2.75 mg/kg established in the 14-day dog 
EEG study, however this will be guided by emerging safety and PK data.  Dose escalation will 
stop at any time if unacceptable safety findings are identified or if the maximum concentration 
(Cmax) or area under the curve (AUC) exceeds or is likely to exceed 1/10th of the exposure 
associated with the NOEL of 2.75 mg/kg seen in the 14-day dog EEG study (84.9 ng/mL or 82.7 


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h×ng/mL for KNX100 and 26.5 ng/mL and 45.7 hr × ng/mL for KNX100A, respectively).  In 
this case, the CRC may stop the study, or modify the dose downwards in subsequent cohorts. 
3.3. 
Study Duration and Dates 
This study is expected to run for approximately 12 months from the start of subject screening to 
the last subject finishing the study. 
4. STUDY POPULATION SELECTION 
4.1. 
Study Population 
This study will enroll approximately 64 healthy volunteers at a single site in Australia. 
This clinical study can fulfill its objectives only if appropriate subjects are enrolled.  The 
following eligibility criteria are designed to select healthy subjects for whom protocol treatment 
and procedures are considered appropriate.  All relevant medical and non-medical conditions 
should be taken into consideration when deciding whether this protocol is suitable for a 
particular subject. 
4.2. 
Inclusion Criteria 
Subjects will be eligible for participation in the study only if they meet ALL of the following 
inclusion criteria.   
None of the inclusion criteria are eligible for re-screening.  No waivers will be granted and any 
deviation from below will be recorded as a major protocol deviation.  An exception can apply for 
subjects who meet the inclusion and exclusion criteria, but then miss a cohort because it is filled.  
This would mean they are no longer eligible due to the 28-day screening window lapse.  These 
are the only subjects that may be rescreened.   
1. Ability to understand and provide written informed consent. 
2. Body mass index (BMI) within the range of 18-32 (inclusive). 
3. Healthy male and female volunteers ≥18 and ≤55 years old at Screening. 
4. Able and willing to comply with the requirements of the study and complete the full 
sequence of protocol related doses, procedures, and evaluations. 
5. Willing to agree not to use alcohol or recreational drugs and willing to have drug 
screening, prior to the first dose of KNX100 and if drug use is suspected while active in 
the study. 
6. Willing to agree not to smoke cigarettes or use tobacco-based products prior to the first 
dose of KNX100 and for the entire duration of the study. 


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7. Males who are sexually active must use a condom OR be abstinent OR have the same sex 
partner OR be surgically sterile OR have partner who is of non-childbearing potential, for 
at least 90 days after the last dose of investigational drug.  If female partner is a Woman 
of Child-Bearing Potential (WOCBP), the female partner must use highly effective 
methods of contraception, defined as below:  
• Hormonal methods of contraception including oral contraceptives containing 
combined estrogen and progesterone, a vaginal ring, injectable and implantable 
hormonal contraceptives, intrauterine hormone-releasing system (e.g., Mirena) 
and progestogen-only hormonal contraception associated with inhibition of 
ovulation. 
• Nonhormonal intrauterine device, 
• Bilateral tubal occlusion. 
Refer to Section 6.9 for further detail on contraception.  
4.3. 
Exclusion Criteria 
Subjects will not be eligible for participation in the study if they meet ANY of the following 
exclusion criteria. 
1. Clinically significant history or presence of significant cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrinological, hematological, neurological, or 
psychiatric disorder.  Any surgical or medical history which may significantly alter the 
absorption, metabolism, or elimination of drugs or constitute a risk when taking the study 
intervention; or interfering with the interpretation of data (e.g., gastric bypass, cyclical 
vomiting, etc.).  This includes a history of lymphoma, leukemia, or any malignancy 
within 5 years except for basal cell or squamous epithelial carcinomas of the skin that 
have been resected with no evidence of metastatic disease for 3 years.  
2. Subjects who have a sitting or semi-supine blood pressure at screening or Day-1, after 
resting for at least 3 minutes of systolic blood pressure >140 or <100 mmHg, or diastolic 
blood pressure >90 or <60 mmHg.  
3. Subjects who have a sitting or semi-supine pulse rate at screening or Day-1, after resting 
for at least 3 minutes, outside the range of <50 or >90 beats/minute 
4. Subjects who donated blood or who had a comparable blood loss (approximately 
500 mL) during the last 30 days prior to start of this study and while on study.  
5. Clinically significant findings on the screening, Day -1, or predose Day 1 
electrocardiogram (ECG) or physical examination, including QTcF duration >450 ms for 
males and >470 ms for females on ECG.  
6. Thyroid function tests outside the normal reference ranges and deemed clinically 
significant by the study PI (and upon repeat).  


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7. Safety laboratory tests that are outside the normal reference ranges and deemed clinically 
significant by the study PI (and upon repeat).  
8. Any history of meningitis, septicemia, or pneumonia. 
9. Any history or family history (first or second degree relative) of seizure disorder, febrile 
convulsions. 
10. Any clinically significant medical history of closed head trauma. 
11. Any history of anaphylaxis or other significant allergy.  
12. Any current diagnosis or clinically significant medical history of psychiatric illness as 
diagnosed and documented by a medical practitioner and as defined by the 
American Psychiatric Association Diagnostic and statistical manual of mental 
disorders 5th edition (DSM-5). 
13. Subjects with a history of chronic alcohol (regular daily intake of more than three 
standard drinks) or drug abuse within the last 6 months prior to first administration, or 
evidence of such abuse as indicated by the laboratory profile conducted during the 
screening examination. 
14. Subjects who have received prescription drugs or over-the-counter (OTC) medication 
including dietary supplements, COVID-19 vaccine, standard dose vitamins, or herbal 
products within 14 days prior to the first administration (with the exception of the oral 
contraceptive pill).  
15. Subjects who received any treatment agents known to alter the major organs or systems 
within 30 days prior to the first administration (e.g., diuretics, nephro- or liver toxic 
medication, barbiturates, phenothiazines, cimetidine, more than 1.0 L of caffeine-
containing beverages per day, etc.).  
16. Diagnosed infection of any kind, e.g., viral, bacterial, fungal, or mycobacterial within 
1 month prior to the first dose of KNX100 or current fever or clinical signs or symptoms 
of infection at screening or Day -1. 
17. Treatment with an unapproved investigational therapeutic agent within 30 days (or 
5-half-lives for small molecule agents) prior to the first dose of KNX100. 
18. Females who are pregnant (positive pregnancy test at screening or prior to first dose), 
lactating or unable/unwilling to use defined methods of contraception throughout the 
study. 
Laboratory assessments conducted at screening for any exclusion criterion may be repeated once 
to rule out a laboratory error.  Only the value leading to inclusion of the subject will be recorded.  
Vital signs recorded outside the exclusion criteria ranges may also be repeated once for 
confirmation.  


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5. STUDY TREATMENTS 
5.1. 
Description of Treatments 
5.1.1. 
Study Drug 
KNX100 will be provided in capsule form as either 5 mg, 25 mg, or 100 mg capsules (Table 2). 
Table 2 
Dose Strength Per Capsule 
Study Drug 
Dosage Strength/Dosage Form 
Manufacturer 
KNX100 Phosphate 
Free Base Equivalent 
KNX100 
5 mg/capsule 
3.4 mg/capsule 
Quotient Sciences 
(formerly Arcinova Ltd). 
KNX100 
25 mg/capsule 
16.8 mg/capsule 
Quotient Sciences 
(formerly Arcinova Ltd) 
KNX100 
100 mg/capsule 
67.1 mg/capsule 
Quotient Sciences 
(formerly Arcinova Ltd) 
 
5.1.2. 
Placebo  
KNX100 matching placebo will be provided in capsule form.  An equivalent number of capsules 
will be administered to subjects receiving placebo (e.g., the first dose of study drug will be one 5 
mg capsule; subjects receiving placebo will also receive only one capsule). 
5.2. 
Treatments Administered 
Both KNX100 and placebo will be administered orally based on the assigned treatment group 
(refer to Section 5.3).  For each cohort, a total of 8 subjects will be dosed (6 with KNX100 and 
2 with placebo). 
Part A will evaluate doses of KNX100 starting with 5 mg and increasing up to a maximum of 
50 mg per day (Table 3).  Doses post the 5 mg dose will be decided by the CRC upon review of 
all available data. 
Part B will evaluate a low- (10 mg), and high-dose, based on the doses evaluated in Part A and 
the safety, tolerability, and PK of doses in the previous cohorts, administered for 7 consecutive 
days (Table 4).  Part B (Cohort 3) will evaluate twice daily dosing of a single dose, selected 
based on the safety, tolerability, and PK of doses in the previous cohorts, administered for 
7 consecutive days (Table 4). 


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5.3. 
Selection and Timing of Dose for Each Subject 
Pertinent information for the SAD study is provided in Section 5.3.2, along with the proposed 
dose escalation schedule in Table 3. 
Pertinent information for Part B is provided in Section 5.3.3, along with the proposed dose 
escalation schedule in Table 4. 
Subjects in both Part A (SAD) and Part B (MAD) phases will be housed in the clinic from 
Day - 3 prior to each dose and remain in-house for 30 hours postdose (Day 2) for Part A and 8 
days post initial dose for Part B (Day 8). 
5.3.1. 
Sentinel Subject Review and Toxicity Management 
Part A Cohorts 1 through 4 will initiate dosing with 2 sentinel subjects who are randomly 
assigned so that 1 subject receives KNX100 and the other receives placebo.  Following dosing of 
study medication, site personnel will observe the sentinel subjects for 48 hours, at which time the 
investigator will review the safety and tolerability for both sentinel subjects.  This will include 
housing of the sentinel subjects in the Phase 1 unit for 30 hours postdose and then a follow up 
phone call at approximately 48 hours postdose administration. 
Data reviewed will include AEs, clinical laboratory results, vital signs, and ECGs, EEGs, and PK 
parameters for both subjects.  PK will be evaluated to ensure that exposure has not exceeded the 
maximum clinical exposure cap defined in Section 6.20.1.  Upon acceptance of reviewed data by 
the site and CRC, dosing may continue for the remaining 6 subjects.  The investigator will 
document the review and decision by email to Sponsor representatives. 
5.3.2. 
Part A Dosing  
Study drug will be administered once on Day 1.  Part A dosing will commence with 2 sentinel 
subjects prior to dosing the remainder of each cohort (refer to Section 5.3.1). 
Study drug will be administered in the morning together with a glass of tap water under a fasted 
state, i.e., after an overnight fast of at least 10 hours and no food is allowed for at least 2 hours 
after drug administration.  Please refer to Section 5.10.3 for information related to fluid and food 
restrictions both pre- and postdose. 
Table 3 provides the planned dose-escalation schedule.  Of note, dose escalations will not exceed 
dose-doubling in principle. 


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Table 3 
Planned Dose-Escalation Schedule (SAD Part A) 
Cohort 
Oral Daily Dose 
(mg/day)1 
Total Number of Capsules (Number - Strength)1 
KNX100 
Placebo 
KNX100 
Placebo2 
1 
5 
0 
1 capsule (1 × 5 mg) 
1 capsule (1 × 0 mg) 
2 
15 
0 
3 capsules (3 × 5 mg) 
3 capsules (3 × 0 mg) 
3 
25 
0 
25 mg: 1 capsule (1 × 25 mg) 
25 mg: 1 capsule (1 × 0 mg) 
4 
50  
0 
50 mg: 2 capsules (2 × 25 mg) 
50 mg: 2 capsules (2 × 0 mg) 
Abbreviations:  PK = pharmacokinetics. 
1 All dose levels beyond Cohort 1 may change based on emerging safety and PK data. 
2 An equivalent number of capsules will be administered to subjects receiving placebo. 
 
*Additional cohorts may be added as required, based on safety profile and CRC authorization.  
Dose escalation and de-escalation will follow the processes outlined in Section 5.3.4. 
5.3.3. 
Part B Dosing  
In Cohorts 1 and 2, study drug will be administered once daily for 7 days at approximately the 
same time each day ± 30 minutes.  In Cohort 3, study drug will be administered twice daily, 
approximately 8 hours (± 30 minutes) apart for 7 days.  Doses will be administered: 
• Morning (e.g., at 11:00 am) at approximately the same time (± 30 minutes) each day 
• Afternoon/ Evening (e.g., at 7:00 pm) at approximately the same time (± 30 minutes) 
each day 
The first dose of study drug will be administered together with a glass of tap water under a fasted 
state i.e., after an overnight fast of at least 10 hours.  For MAD Cohort 3, the second dose of 
study drug will be administered together with a glass of tap water under a fasted state i.e., after 
fasting for at least 2 hours prior to dose administration.  For all cohorts, no food is allowed for at 
least 2 hours after drug administration.  Please refer to Section 5.10.3 for information related to 
fluid and food restrictions both pre- and postdose.   
Table 4 provides the planned dose-escalation schedule for Part B (MAD).  Up to 2 dose strengths 
ranging from as low as 10 mg and up to the clinical exposure cap will be selected based on the 
tolerability and pharmacokinetics of the previous dose. 


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Table 4 
Planned Dose-Escalation Schedule (MAD Part B) 
Cohort 
Oral Daily Dose (mg/day)1 
Total Number of Capsules/Day (Number - Strength)1 
KNX100 
Placebo 
KNX100 
Placebo2 
1 
10 (Low) 
0 
2 capsules (2 × 5 mg) 
2 capsules (2 × 0 mg) 
2 
30 (High) 
0 
2 capsules (1 × 5 mg, 1 × 25 
mg) 
2 capsules (2 × 0 mg) 
3 
30 (bid) 3 
0 
2 capsules (1 × 5 mg, 1 × 25 
mg) (am) 
2 capsules (1 × 5 mg, 1 × 25 
mg) (pm) 
2 capsules (2 × 0 mg) (am) 
2 capsules (2 × 0 mg) (pm)  
Abbreviations:  am = morning; bid = twice daily; MAD = multiple ascending dose; pm = afternoon/evening   
1 Dose levels will be based on data from Part A and emerging PK data. 
2 An equivalent number of capsules will be administered to subjects receiving placebo. 
3 Dose to be administered twice daily, 8 hours apart (refer also to Section 5.3.3). 
 
5.3.4. 
Dose Escalation 
An evaluable subject is one that has been dosed, completed all assessments, and had their data 
reviewed by the CRC.  
Blinded data to be reviewed by the CRC for each subject will include (as a minimum): PK (up to 
30 hours postdose for Part A and 24 hours postdose for Part B), EEG, ECG, vital signs, pulse 
oximetry, neurological examination, and any adverse events. 
The CRC may approve dose escalation following review of cohort data if:  
• No drug related SAE’s occurring within 48 hours of administration of KNX100 or 
placebo is observed in any subject in the dose group under evaluation. 
• No drug related AE’s of Grade 3 or greater are observed in 2 or more subjects within a 
dose group. 
• The mean KNX100 Cmax OR AUC does not exceed 84.9 ng/mL or 82.7 ng×h/mL 
respectively and the mean KNX100A Cmax OR AUC does not exceed 26.5 ng/mL and 
45.7 hr × ng/mL, respectively, the exposure associated with 1/10th of the NOEL of 2.75 
mg/kg observed in the 14-day dog EEG study. 
• No emergence or evidence of other PI-deemed and or medical monitor-deemed clinically 
significant abnormal vital signs, neurological and physical examination, or safety 
parameters postdose have been observed. 
Dose increases will be permitted once review of data from all evaluable subjects has been 
performed. 


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5.4. 
Method of Assigning Subjects to Treatment Groups 
Subjects will be assigned to a cohort based on the order in which they are enrolled.  Subjects will 
be centrally randomized to treatment in a 6:2 ratio within each assigned cohort.  The first 2 
sentinel subjects will be assigned to treatment in a 1:1 ratio such that 1 subject receives KNX100 
and the other receives placebo.  Once eligibility is re-confirmed (Day -1), subjects will be 
randomized via a randomization list or an Interactive Web Response System.  Of note, after 
Cohort 1, the CRC will determine the dose to be administered; therefore, randomization codes 
will only indicate whether the subject will receive active or placebo within their cohort. 
Subjects will be sequentially assigned a Subject identification number upon signing the informed 
consent (i.e., site number 10, Screening number 001, 002 = Subject number 10-001, 10-002 etc.).  
Subjects will be identified by their Subject identification number throughout the study. Subjects 
will receive a 4-digit randomization number on Day 1 before dosing Replacement Subjects. 
Subjects can be replaced.  Replacement subjects will receive the same randomization number of 
the replaced subject +1000 (e.g., Subject 1111 will replace Subject 0111, Subject 1211 will 
replace Subject 0211, etc.).  If more than one replacement becomes necessary, additional 
replacements will be numbered 2XXX, 3XXX, and so on (Table 5).  The replacement subject 
will receive the treatment assigned to the withdrawn subject. 
Table 5 
Example 4-Digit Subject Randomization Numbers 
Cohort  
Original Subject 
Randomization Numbers 
Replacement Subject Randomization Numbers 
Part A 
Cohort 1 
0111-0118 
1111-1118, 2111-2118, 3111-3118, etc. 
Cohort 2 
0121-0128 
1121-1128, 2121-2128, 3121-3128, etc. 
Cohort 3 
0131-0138 
1131-1138, 2131-2138, 3131-3138, etc. 
Cohort 4 
0141-0148 
1141-1148, 2141-2148, 3141-3148, etc. 
Part B 
Cohort 1M 
0211-0218 
1211-1218, 2211-2218, 3211-3218, etc. 
Cohort 2M 
0221-0228 
1221-1228, 2221-2228, 3221-3228, etc. 
Cohort 3M 
0231-0238 
1231-1238, 2231-2238, 3231-3238, etc. 
 
5.5. 
Blinding 
The study will be performed in a double-blind fashion.  The investigator and study staff 
(including lab personnel), the subjects, the monitors and the Sponsor’s staff will remain blinded 
to the treatment until database lock. 


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The investigator will receive sealed envelopes with the individual randomization per subject to 
be opened in the case of emergency only. 
The pharmacist of the site will receive the randomization list to enable packaging. 
The randomization code will be kept strictly confidential by the pharmacist of the site.  
Double-blind conditions will be established so that the investigator, site personnel and subjects 
are blinded to the treatment assignments.  Parameters to achieve and maintain the double-blind 
status of the study include: 
• Sequential assignment of subject numbers within each cohort. 
• Labeling of study drug with the study number. 
• Packaging and delivery of study drug supplies to sites in a manner that maintains 
blinding. 
• Matched appearance of study drug and placebo, 
Subjects, investigators, and clinical staff will be blinded to therapy assignment.  Sponsor 
representatives involved in the conduct of the study will be blinded to therapy assignment.  
The site pharmacy staff will be unblinded to study treatment. 
To ensure study blinding, the active and placebo will be provided in identical capsules and an 
equivalent number of capsules will be administered to subjects receiving placebo (refer to 
Section 5.3.2 and Section 5.3.3). 
The following roles may be unblinded:   
• Unblinded biostatistics team that prepares the randomization materials and handles 
treatment-revealing data prior to database lock. 
• Selected study Sponsor personnel who are not directly involved in the conduct of the 
study. 
• Pharmacy team. 
• Drug-reconciliation clinical research associate (CRA). 
A list of unblinded individuals will be maintained in study files.  The pharmacy team will 
prepare the investigational product dispensing but will have no other role in the study and will 
not discuss any study-related observations with the blinded team members.  
Analysis of the safety data for dose escalation decisions will be performed on blinded data and in 
a masked fashion.  Analysis of PK parameters will be evaluated by members of the CRC.  Please 
refer to Section 9.8 for additional information. 


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5.6. 
Unblinding 
The investigator and site personnel will remain blinded to the randomization code throughout the 
duration of the study.  When necessary, code break envelopes will be available 24 hours a day, 
7 days a week to unblind a treatment assignment. 
Treatment assignment for an individual subject should be unblinded by the investigator only in 
an emergency, and only if knowledge of the treatment assignment is necessary for the clinical 
management or welfare of the subject.  If possible, the investigator should contact the medical 
monitor before unblinding, but priority should be given to safety of the subject.  The investigator 
must record the date and reason for unblinding. 
Subjects may be unblinded in the event that an AE of Grade 3 or greater is reported in 2 or more 
subjects to support CRC data review and decisions regarding dose escalation or stopping criteria. 
If deemed to be necessary, the CRC may be required to break the randomization code.  Since the 
investigator is a member of the CRC, this will be performed by the investigator.   
5.7. 
Missed Doses 
During Part A (SAD), study subjects will receive only 1 dose of product; therefore, missed doses 
will not be an issue. 
During Part B (MAD), missed doses will be recorded in the electronic case report form (eCRF) 
along with the reason.  During the MAD phase, missing 2 or more doses will constitute a 
protocol violation.  Such study subjects may be replaced with due consideration of circumstances 
by the study CRC (refer to Section 9.8).  
5.8. 
Overdose 
An accidental overdose is highly unlikely because a licensed, unblinded pharmacist will dispense 
KNX100.  In the event of an accidental overdose, the site shall contact the medical monitor 
immediately to discuss an appropriate course of action and follow-up. 
5.9. 
Concomitant Therapy 
All therapy ongoing at the time of enrollment and all therapy (other than study drug) received 
during the study is considered concomitant therapy for purposes of this study. 
Intake of prescription or nonprescription is prohibited within 14 days or 5 half-lives of the drug, 
whichever is longer, prior to the first dose study medication, until completion of the follow-up 
visit. 


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Investigators may prescribe any concomitant medications or treatments deemed necessary to 
provide adequate supportive care.  All concomitant medications taken during the study will be 
recorded with indication, dose information, and dates of administration.  
Subjects cannot be enrolled if they have received prescription drugs or OTC medication 
including dietary supplements, standard dose vitamins, or herbal products within 14 days prior to 
the first administration (with the exception the oral contraceptive pill).  
5.10. Restrictions 
As this study is being conducted in healthy volunteers and, to date, no drug-drug interactions 
have been identified, no prohibited concomitant therapy has been defined.  
5.10.1. 
Smoking 
Subjects must be non-smokers or willing to abstain from smoking or using tobacco products 
from Day -1 throughout the entirety of the study. 
5.10.2. 
Prior Therapy 
Restrictions for prior therapy are as noted in Section 4.3. 
5.10.3. 
Fluid and Food Intake  
While in the study clinic, subjects will not be allowed to consume any food and beverages not 
provided by the institution.  Standardized meals will be provided for all study subjects. 
During each dosing session, subjects will abstain from ingesting caffeine or xanthine-containing 
products (e.g., coffee, tea, cola drinks, and chocolate) for 10 hours before the start of morning 
dosing until after collection of the final PK and/or PD sample. 
Use of alcohol will not be allowed from screening until after the EOS/ET visit.  
Subjects should fast overnight prior to screening and for 2 hours prior to administration of a 
second dose of study drug (MAD Cohort 3).  Subjects should avoid consumption of food for up 
to 2 hours following administration of all doses of study drug. 
5.10.4. 
Exercise 
Subjects must abstain from strenuous physical activity for 48 hours prior to admission until 
discharge on Day 2 (SAD) or Day 8 (MAD).  


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5.11. Treatment Compliance 
Site personnel will administer study drug; therefore, treatment compliance is not a concern for 
this study. 
5.12. Packaging and Labeling 
All study treatments will be manufactured, packaged, and labeled under GMP conditions, and 
will be supplied to the clinical site pharmacy as unblinded study products.  A certificate of 
analysis will be provided for each strength. 
Study drug (KNX100 and placebo) will be encapsulated in hydroxypropyl methylcellulose 
(HPMC) dark green opaque size 0 capsules and packaged in 100 mL high density polyethylene 
(HDPE) Duma Twist-off bottles with polypropylene twist-off, 45 mm closures. 
Each bottle will have a label that will contain, at a minimum, the protocol number, lot number, 
name and strength of the product, quantity of dosage units, directions for use, storage conditions, 
country-specific regulatory caution statement, and name and address of the Sponsor.   
5.13. Storage and Accountability 
All study drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the Sponsor or designee for destruction.  All Sponsor-supplied drugs must be stored 
under the conditions specified on the label and remain in the original container until dispensed.  
Study drug should be stored at room temperature conditions (25°C [77°F]); with excursions 
permitted to 15°C-30°C [59°F-86°F], refer to USP Packaging and Storage Requirements). 
Upon receipt of the study drug, the investigator or designee must verify the contents of the 
shipments against the packing list.  The verifier should ensure that the quantity is correct, that the 
medication is received within the labeled storage conditions, and that the package is in good 
condition.  If quantity and conditions are acceptable, the investigator or designee should 
acknowledge the receipt of the shipment.  If there are any discrepancies between the packing list 
versus the actual product received, Kinoxis must be contacted to resolve the issue.  The packing 
list should be filed in the investigator’s essential document file. 
The site must maintain 100% accountability for all study drugs received and dispensed during 
the entire participation in the study.  Proper drug accountability includes, but is not limited to: 
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the drug lot (or ID or lot number) used to prepare 
each dose. 


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• Verifying that all containers used and unused are documented accurately on the log. 
• Verifying that required fields are accurately completed and are legible. 
The investigator should ensure that study drug is used only in accordance with the approved 
protocol.  Study drug shall be dispensed only to subjects enrolled in the study.  If any dispensing 
errors or discrepancies are discovered, the Sponsor must be notified immediately. 
The site must record the current study inventory on a Sponsor-approved drug accountability log.  
At a minimum, the following information will be recorded for each subject: 
• Protocol number and title. 
• Name of investigator. 
• Site identifier and number. 
• Description of Sponsor-supplied drugs. 
• Date and amount dispensed, including initials of the person dispensing the drug. 
• Date and amount returned as unused including the initials of the person receiving the 
Sponsor-supplied drug. 
The log should include a separate entry for each subject who receives Sponsor-supplied study 
drug. 
Prior to site closure or at appropriate intervals, a representative from the Sponsor or its designee 
will perform study material accountability and reconciliation before study materials are returned 
to the Sponsor or its designee for destruction.  The investigator will retain the original 
documentation regarding study material accountability and return of study materials; copies (as 
required) will be sent to the Sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of study material 
during the study conduct.  On expiry date notification from the Sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired study 
material for return to the Sponsor or its designee for destruction. 
6. STUDY PROCEDURES 
6.1. 
Information Statement and Consent Form  
Subjects who are identified as potentially suitable to participate in the study will be sent an 
information statement and consent form as approved by the Sponsor and by the Human Research 
Ethics Committee (HREC).  The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. 


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The screening visit will provide an additional opportunity for the subject to discuss any questions 
that they may have with study staff.  Study staff are responsible for ensuring that the subject 
receives adequate information, and all questions are answered appropriately.  Additionally, study 
staff must ensure subjects comprehend the information provided about the study, including a 
decision to participate will not impact usual medical care, and subjects retain an absolute right to 
withdraw at any time for any reason.  If, after this discussion, the subject still wishes to enroll, 
the staff member that conducts the consent discussion will ensure that the consent is documented 
appropriately. 
Documentation of consent must be obtained before any study-specific procedures are performed.  
A copy of the signed consent form will be given to the subject.  The date that consent was 
obtained will be recorded in the electronic case report form (eCRF) as well as the subject’s chart.  
Following documentation of consent, the subject will be allocated a screening number and will 
undergo screening assessments as indicated in Appendix 1 and Appendix 2 to ensure eligibility. 
6.2. 
Randomization  
On Day -1, the inclusion/exclusion criteria will be reviewed with the subject.  A urine pregnancy 
test will be performed for WOCBP and subjects will be screened for drugs of abuse via a test 
panel upon admission (Day -3).  Prior and concomitant medications will be reviewed.  Any AEs 
since the signing of the informed consent will be collected.  Please also refer to Appendix 1 and 
Appendix 2. 
If the subject still meets study criteria, they will be randomized prior to dosing. 
6.3. 
Demographic and Baseline Characteristics 
Demographic data and other baseline characteristics will be recorded, including date of birth or 
age, gender, self-reported race and/or ethnicity, and smoking status of the subject.  A standard 
medical, medication, and surgical history will be obtained with review of the selection criteria 
with the subject. 
A medical history will be collected during screening using forms designed to capture, at a 
minimum, the parameters specified by the protocol and to be recorded in the study case report 
form (CRF).  Medical history includes an assessment of past and present clinically significant 
diseases and surgeries or important medical events (any within the past year).  Additionally, an 
assessment of current reproductive status will be collected.   
Record all medications (e.g., prescription and OTC medications, hormonal birth control, herbal 
or homeopathic remedies, and nutritional supplements) used by the subject within 30 days prior 
to the screening visit.   


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Ongoing medical status will also be reviewed at each study visit to screen for and capture AEs. 
6.4. 
Physical and Neurological Examinations 
A medical assessment will be completed by the principal investigator (PI) or a study physician at 
study entry, and at any early withdrawal visits.  The primary purpose of the medical assessment 
at study entry is to confirm the subject’s suitability to enroll in the study.   
The physical examination will include height (screening only), body weight, and an evaluation of 
the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems.  Record any abnormality identified prior 
to administration of study medication as medical history.  
Any clinically significant, new, or worsened abnormalities that occur after administration of 
study medication should be recorded as AEs.  Additional parameters may be assessed as 
indicated by any subject symptoms. 
Abbreviated physical examinations performed throughout the study should be symptom-directed.  
Neurological examination shall include assessment of cranial nerves, motor, sensation, 
coordination, reflexes, and gait.  Abbreviated neurological examinations performed throughout 
the study include light touch/power in limbs and brief cranial nerve examination. 
Findings will be recorded as normal/abnormal for each parameter with additional description as 
indicated.  All abnormal, clinically significant, findings will be considered AEs. 
Please refer to the Schedule of Assessments (SOA) in Appendix 1 and Appendix 2 for details 
regarding timing for assessments.   
6.5. 
Vital Signs 
Vital signs will be recorded at screening, study entry, and at all visits before and after dosing of 
study drug, including: 
• body temperature,  
• respiratory parameters (including respiratory rate, saturated oxygen, pulse oximetry),  
• pulse rate,  
• heart rate (after 3-minute semi-supine rest), and  
• arterial blood pressure (systolic and diastolic; after 3-minute rest in either a semi-supine 
or sitting position).  
• peak flow measurement. 


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During the inpatient dosing period, vital signs also include respiratory rate, continuous pulse 
oximetry and saturated oxygen, which will be undertaken via telemetry within 2 hours predose 
and at 2 hours postdose (± 15 minutes) as per the schedule in Appendix 1 and Appendix 2.  For 
MAD Cohort 3, vital signs, including telemetry will be conducted following each dose (am and 
pm). 
Peak flow measurement will also be undertaken within 1 hour predose as well as at 1-, 2-, and 4-
hours (± 15 minutes) postdose.  For MAD Cohort 3, peak flow measurements will be conducted 
following each dose (am and pm). The highest of 3 peak flow measurements, at each timepoint 
shall be recorded. 
Protocol Exclusions 2 and 3 pertaining to vital signs should be checked at both Screening and 
Day -1 to confirm eligibility.  Following the Day-1 eligibility check, any subject with vital signs 
outside of acceptable range will have their vital signs repeated.  If the readings are again 
abnormal, but not clinically significant, it is at the PI’s discretion as to whether to continue the 
subject in the study.  Normal vital sign ranges for this study are presented in Appendix 4.   
For details regarding timing for assessments, please refer to the SOA in Appendix 1 and 
Appendix 2. 
6.6. 
Gastrointestinal Symptoms 
Changes in gastrointestinal function will be monitored during the MAD part of the study.  Bowel 
movements, such as constipation, and any change in bowel habits as reported by study subjects 
will be recorded daily during the dosing period.  
Please refer to the SOA in Appendix 2 for details regarding timing for these assessments. 
6.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire used for suicidality assessment developed by multiple 
institutions, including Columbia University.  The scale is evidence-supported and is part of a US 
national and international public health initiative involving the assessment of suicidality.  The 
scale has been successfully implemented across many settings, including schools, college 
campuses, military, fire departments, the justice system, primary care and for scientific research. 
The C-SSRS Risk Assessment version is intended to help establish a person’s immediate risk of 
suicide and is used in acute care settings.  
The C-SSRS will be administered at screening and again at Day 4 and Day 7 postdose during the 
MAD part of the study.  Please refer to the SOA in Appendix 2 for details regarding timing for 
assessments. 


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6.8. 
Concomitant Medications 
Concomitant medications will be assessed at each study visit by staff discussion with the study 
subjects.  For any concomitant medications not otherwise linked to reported AEs, staff should 
discuss with the subject to clarify the indication for medication. 
Refer to Section 5.9 for information on prior and concomitant medications, including those that 
must be halted within defined time periods prior to randomization. 
Please refer to the SOA in Appendix 1 and Appendix 2 for details regarding timing for 
assessments. 
COVID-19 vaccinations will be permitted if they occur more than 14 days before the treatment 
period or after the EOS visit. 
6.9. 
Contraception 
WOCBP must have a negative serum or urine pregnancy test within 24 hours prior to the start of 
study drug and must not be breastfeeding, lactating, or planning pregnancy during the study 
period.  WOCBP are defined as any female who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not 
postmenopausal.  Menopause is defined as 12 months of amenorrhea in the absence of other 
biological causes.  In addition, females under the age of 55 years must have a documented serum 
follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause.  Male 
participants with potentially postmenopausal partners who are under the age of 55 years must use 
condoms unless their partner’s postmenopausal status has been confirmed by FSH level.  
WOCBP who are not exclusively in same-sex relationships and males with partners of 
child-bearing potential must agree to use adequate contraception.  For WOCBP, contraception 
should be continued for 30 days after the final study visit.  For males, contraception should be 
continued for 90 days after the final dose of study drug.  In addition, males must not donate 
sperm for 90 days after the final dose.  
Males and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements.  However, WOCBP must still undergo pregnancy testing as per 
protocol.  
Investigators will counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.  
Investigators will advise on the use of an adequate methods of contraception, which is defined as 
use of a condom by the male partner combined with use of a highly effective method of 


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contraception by the female partner.  A highly effective method of contraception is one that has a 
failure rate of <1% when used consistently and correctly.  Male participants must inform their 
female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner.  
Highly effective methods of contraception are listed below:  
• Hormonal methods of contraception including oral contraceptives containing combined 
estrogen and progesterone, a vaginal ring, injectable and implantable hormonal 
contraceptives, intrauterine hormone-releasing system (e.g., Mirena) and 
progestogen-only hormonal contraception associated with inhibition of ovulation. 
• Nonhormonal intrauterine device (IUD) 
• Bilateral tubal occlusion 
• Vasectomized subject/partner with documented azoospermia 90 days after procedure if 
that partner is the sole sexual partner. 
For female participants, hormonal contraceptives should begin at least 1 month prior to screening 
to ensure contraceptive is in full effect.  
Complete abstinence, defined as the complete avoidance of heterosexual intercourse, is an 
acceptable form of contraception if used consistently throughout the duration of study and for the 
durations after dosing specified for males and females above.  It is not necessary to use any other 
method of contraception when complete abstinence is elected.  WOCBP who choose complete 
abstinence must continue to have pregnancy tests as per protocol.  The reliability of sexual 
abstinence needs to be evaluated by the investigator in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the subject. 
6.10. 12-Lead Electrocardiograms 
12-lead ECGs will be used to evaluate heart rate, atrial ventricular conduction, QRS and QT 
intervals, and possible arrhythmias.  ECGs include ventricular heart rate; QRS duration; PR, RR, 
QT, QTcB, and QTcF intervals; and P and T wave.  Evaluations will be recorded as normal, 
abnormal (not clinically significant), or abnormal (clinically significant). 
The 12-lead ECGs will be obtained after the subject has been resting semi-supine for at least 
3 minutes prior to the indicated times.  All ECGs should be recorded with the subject in the same 
physical position.  For each time point, 3 ECG recordings should be taken at approximately 
1 to 3-minute intervals. 
A standardized ECG machine should be used, and the subject should be tested using the same 
machine throughout the study, if possible.  When the timing of these measurements coincides 


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with a blood collection, obtain the ECG prior to the nominal time of the blood collection, blood 
pressure, and heart rate. 
Additional ECGs should also be collected if a subject experiences a cardiac AE. 
After ECGs have been recorded, the PI or a designated physician will review each of the ECGs.  
If available, a paper copy should be filed in the subject’s medical records.  For all ECGs, ECG 
intervals and an overall assessment will be recorded.  Evaluations will be recorded as normal, 
abnormal (not clinically significant), or abnormal (clinically significant). 
For details regarding timing for assessments, please refer to the SOA in Appendix 1 and 
Appendix 2.  
6.11. Electroencephalograms 
6.11.1. 
Screening and Baseline Procedures and Assessments 
Sleep deprived EEG’s shall be conducted during screening and shall be utilized for excluding 
patients at increased seizure risk, predicting overall seizure risk, informing dose escalation 
decisions once dosing has commenced, and contributing to the overall safety monitoring 
program.  These EEGs shall also be used as a baseline to facilitate detection of changes in future 
EEGs completed throughout the study.  Screening EEG’s should be conducted only after all 
other Screening activities have completed.  Subjects previously consented or screened for KTX-
101 who have undertaken a previous sleep-deprived EEG within the last 12 months, will not 
have to have this procedure repeated. 
Subjects will be admitted to the clinic at Day -3 to undertake a sleep deprived EEG on Day -2. 
Subjects will be requested to maintain their usual sleep routine, however, only sleep for 4 hours 
(± 1 hour) prior to undertaking the 1-hour screening EEG.  The EEG recording will be reviewed 
to identify any IEDs or electrographic seizures.  If present, the subject will be excluded and be 
discharged from the unit.  Volunteers that display this increased risk are referred to an epilepsy 
clinic for specialist follow-up. 
During the study, 24-hour continuous EEG recordings will also be reviewed as a safety 
assessment for any IED’s pre and postdose (as a marker of increased susceptibility postdose). 
EEG data will form part of the CRC data review package from each cohort (including sentinels 
and rest of cohort dosing) to mitigate seizure potential and allow safe dose escalation.   The 
presence of epileptiform discharges observed on the EEG recordings will also contribute to the 
stopping rules criteria and, if present, no further dose escalation will occur. 


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6.11.2. 
Dosing Phase Assessments 
During the SAD phase, subjects will undertake a continuous ambulatory EEG from at least 
30 minutes predose to 24 hours (±1 hour) after administration of their dose. 
Please refer to the SOA in Appendix 1, Appendix 2, and Appendix 3 for details regarding timing 
for assessments in the MAD phase.   
6.12. Pharmacokinetic Assessments 
Venous blood samples for determination of concentrations of KNX100 and its metabolites in 
plasma will be collected at the times presented in Appendix 3. 
6.12.1. 
Determination of Drug Concentration in Pharmacokinetic Samples 
Samples for determination of plasma concentrations of KNX100 and its metabolites will be 
analyzed using an appropriate bioanalytical method.  Full details of the analytical method will be 
described in a separate bioanalytical report.  All samples that are within the known stability of 
the analytes of interest (i.e., KNX100 and its metabolites) at the time of receipt by the 
bioanalytical laboratory will be analyzed.  In addition, the PK samples may be subjected to 
further analyses by the Sponsor to further investigate the presence and/or identity of additional 
drug metabolites. 
Drug concentration and exposure will be monitored in individual subjects and will form the basis 
of dose escalation decisions and study stopping criteria as defined in Section 6.20.1. 
6.13. Clinical Laboratory Tests 
Subjects will be required to fast overnight prior to collection of Clinical Laboratory Samples.  
All subjects undergo screening via a blood test to rule out human immunodeficiency virus (HIV), 
Hepatitis B and C.   
Serum human chorionic gonadotrophin will be determined in WOCBP at screening.  A urine 
pregnancy test will be conducted in WOCBP upon admission (Day -3). 
Urine will be collected for drug screening as well as urinalysis.  Urinalysis will be assessed by 
dipstick analysis.  Microscopic examination will be undertaken if there is an abnormality 
warranting further investigation. 
An alcohol breath test will be conducted at Screening to determine eligibility.  


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Blood samples will be collected for hematology and serum chemistry as well as coagulation 
parameters.   
Subjects will be in a seated or supine position during blood collection.  A list of the clinical 
laboratory tests is provided in Appendix 5.  Please refer to the SOA in Appendix 1 and 
Appendix 2 for details regarding timing for assessments. 
6.14. Sample Collection, Storage, and Shipping 
The site shall obtain, process, and freeze blood samples (at temperatures as per study manual) for 
the listed tests in preparation for shipment to a bioanalytical laboratory for analysis.  Full details 
pertaining to the collection, handling, and shipment of these samples are provided in the 
laboratory manual.  Safety laboratory assessments will be performed locally at the study site’s 
laboratory, based on its established methods.   
6.14.1. 
Handling, Storage, and Destruction of Biological Samples 
After analysis, samples will be disposed of or retained for further use as described below.  Any 
PK sample remaining after analysis for KNX100 and its metabolites, may be used for 
exploratory biomarker analyses.  These analyses are for Sponsor use only and will not be 
included in the clinical study report. 
Any biological samples collected for future research will be retained by the Sponsor or designee 
for a maximum of 15 years following the finalization of the clinical study report.  The results 
from future analysis will not be reported in the clinical study report. 
6.14.2. 
PK Samples 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples and reported in a separate bioanalytical report.  Samples for metabolite 
identification and/or analysis will be performed as an exploratory endpoint in this study.  The 
results from the investigation(s) may not be reported in the clinical study report but will be 
reported separately in a PK report. 
6.14.2.1. 
Timing of PK samples  
Refer to Appendix 3 for details on the timing of PK samples.  If more than one assessment is 
foreseen for a timepoint, assessments should be staggered in the same order throughout the study 
with the PK sampling point closest to the scheduled timepoint. 
6.14.3. 
Collection of Plasma for Exploratory Analysis of PD Biomarkers 
All subjects may also be asked to provide plasma samples which may be used to further 
investigate the relationship between PK and blood-borne biomarkers (yet to be identified).  


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Please refer to the SOA in Appendix 1 and Appendix 2 for details regarding timing for 
assessments. 
6.15. End of Study Visit/Early Termination Visit  
The End of Study (EOS)/Early Termination (ET) Visit will occur 7 days after last dose (±2 days) 
for Part 1 (SAD) and 7 days after the last dose (±2 days) for the MAD part of the study.  This 
visit can also take place if a subject withdraws early from the study.  
A serum pregnancy test will be performed for WOCBP.  Hematology and coagulation, 
biochemistry, and urinalysis will be performed.  The subject will be asked about AEs and prior 
and concomitant medications and an ECG will be conducted.  Every attempt will be made for 
collection of data from withdrawn subjects via attendance to an EOS/ET Visit. 
6.16. Dispensing Study Drug 
The site pharmacy (or equivalent) associated with the study site is responsible for dispensing the 
appropriate randomized/blinded study product to site staff for dosing onsite.  Dose escalation 
will progress upon CRC approval (refer to Section 9.8). 
6.17. Adverse Events Assessments 
Any new event or experience that was not present at Screening, or the worsening of an event 
present at Screening, is considered an AE (Section 6.17.1).  The investigator is responsible for 
following all AEs from onset to adequate resolution (event is resolved or subject is medically 
stable), where possible (Section 6.17.8). 
AEs will be documented from physical or neurological examination findings, clinically 
significant laboratory results (as per reference ranges indicated in the Study Procedures and 
Laboratory Manuals), vital signs, ECGs, EEGs, or any other assessments that are relevant to 
subject safety. 
The PI is responsible for reporting of all safety events that occur within the AE reporting period 
and will classify severity (Section 6.17.3) and relationship to study drug (Section 6.17.4) for each 
event.  Any event that meets the definition of a serious adverse event (SAE; Section 6.17.10) will 
be recorded and reported as an SAE. 
The PI or designee is responsible for recording all AEs on the appropriate study specific CRF, 
regardless of the AE’s likely relationship to study treatment.  Any changes in severity of an AE 
will be recorded and any AEs characterized as intermittent will be documented for each episode.   


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The CRF has been designed to capture the data elements recommended for reporting of drug 
safety events under current International Conference on Harmonisation (ICH) guidelines 
(ICH E2A, E6).   
6.17.1. 
Definition 
This study will follow the definition of “adverse events” as specified in ICH E2A: 
“Any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.” 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An AE does not include: 
• Pre-existing diseases or conditions present or detected at screening/baseline that do not 
worsen in severity or frequency. 
• Hospitalization for evaluation or treatment of a condition that predated the initial dose of 
blinded study product and has not worsened in severity since that initial dose.  
• Situations where an untoward medical occurrence has not occurred.  
o e.g., hospitalization for elective surgery, social and/or convenience admissions. 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
o Of note however, the condition that leads to the procedure *is* an AE, unless the 
condition pre-dated the initial dose of blinded study product and has not worsened 
in severity since that initial dose.  
• Overdose of either study drug or concomitant medication without any signs or symptoms. 
All AEs are classified as serious or non-serious.  Refer to Section 6.17.10 for definition of an 
SAE. 
6.17.2. 
Timing and Reporting Period 
Treatment-emergent adverse events (TEAEs) are defined as any AE starting during the active 
treatment period (from first dose to 24 hours after the last dose of study treatment). 
If an AE causes a subject to discontinue the study, the PI remains responsible for following the 
AE until the event is resolved or explained.  Frequency of follow-up evaluation is left to the 
discretion of the PI. 


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In addition, any known untoward event that occurs subsequent to the AE-reporting period that 
the PI assesses as related to the study drug should also be reported as an AE. 
6.17.3. 
Severity 
The terms “severe” and “severity” are often used to describe the intensity of a specific AE; the 
AE itself, however, may be of relatively minor medical significance (such as severe headache).  
“Severe” is not the same as “serious”, which is based on subject/event outcome or action criteria 
usually associated with events that pose a threat to a subject’s life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations (for 
communication of urgent safety concerns).  Severity, however, is a useful parameter for defining 
the safety profile of a product at a more-granular level of detail that will later be helpful to 
support a broader range of medical decision making. 
The investigator is required to grade the severity or toxicity of each AE and must assess the 
severity of AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) 
scale, as follows: 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL).  
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL.  
• Grade 4 Life-threatening consequences; urgent intervention indicated.  
• Grade 5 Death related to AE.  
6.17.4. 
Relationship/Causality 
The investigator must record his/her opinion concerning the relationship of the AE to study 
therapy or other study intervention on the eCRF, using the categories provided therein.  
Investigators will determine relatedness of an event to study drug based on a temporal 
relationship as well as if the event is unanticipated or unexplained given the subject’s clinical 
course, previous medical conditions, and concomitant medications.  
• Unrelated:  Not reasonably related to the investigational product.  AE could not 
medically (pharmacologically/clinically) be attributed to the investigational product/study 
treatment under study in this clinical study protocol.  A reasonable alternative 
explanation must be available. 


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• Related:  Reasonably related to the investigational product.  AE could medically 
(pharmacologically / clinically) be attributed to the investigational product/study 
treatment under study in this clinical study protocol.  
6.17.5. 
Expectedness 
Expected AEs related to KNX100 treatment are provided in the KNX100 Investigator’s 
Brochure.  Based on the observation of premonitory signs of seizure in dogs dosed at 
≥25 mg/kg/day in preclinical studies, a potential for risk of seizure in humans following 
administration of KNX100 has been identified.  This risk is mitigated by frequent monitoring of 
maximum plasma exposure and observation of EEGs both prior to and post dosing.  Further 
information is provided in the Investigator’s Brochure. 
An unexpected AE is any AE that is inconsistent with the nature, severity, or frequency of AEs 
expected as related to KNX100 treatment. 
6.17.6. 
Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE; that is, there is evidence to suggest a causal relationship between the 
drug and the AE.  This definition is taken from US FDA regulation (21 CFR 312.32(a)) but is 
also consistent with the Australian NHMRC (2016) guidance Safety Monitoring and Reporting in 
Clinical Trials Involving Therapeutic Goods.   Emergence of IED’s recorded following dose 
administration will be considered an SAR.  
6.17.7. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an AE that individually meets 
criteria for an SAE (Section 6.17.10) AND for an unexpected AE (Section 6.17.5) AND for a 
suspected adverse reaction (Section 6.17.6).  
For this study and per 21 CFR 312.32, an unexpected SAE is a SUSAR only if there is evidence 
to suggest a causal relationship between the drug and the AE, such as: 
• A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). 
• One or more occurrences of an event that is not commonly associated with drug exposure 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture). 
• An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 


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those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group.  
6.17.8. 
Follow-up of Adverse Events 
All measures required for AE management and the ultimate outcome of the AE must be recorded 
in the source document and reported to the Sponsor. 
All AEs (both serious and non-serious) should be followed until the event is resolved or 
explained, even if the AE causes the subject to withdraw from the study and necessitates 
follow-up after study withdrawal.  Frequency of follow-up evaluation, and method of follow-up 
(either directly or through an appropriate health care option) is left to the discretion of the 
investigator. 
6.17.9. 
Clinical Laboratory and Investigational Findings Adverse Events 
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation, or are considered otherwise medically important by 
the investigator.  If a laboratory abnormality fulfills these criteria, the identified medical 
condition (i.e., anemia, increased alanine aminotransferase [ALT]) must be reported as the AE 
rather than the abnormal value itself. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  The 
laboratory reports must be filed with the source documents.  Clinically significant abnormal 
laboratory findings are those which are not associated with an underlying disease, unless judged 
by the investigator to be more severe than expected for the subject's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 1 day after the last dose of study drug should be repeated until the values 
return to normal (or baseline) or are no longer considered clinically significant by the 
investigator or medical monitor.  If such values do not return to normal/baseline within a period 
of time judged reasonable by the investigator, the etiology should be identified, and the Sponsor 
notified. 
All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual and the SOA in Appendix 1 and Appendix 2.  If laboratory values from 
non-protocol specified laboratory assessments performed at the institution’s local laboratory 
require a change in subject management or are considered clinically significant by the 
investigator (e.g., SAE, AE, or dose modification), then the results must be recorded in the CRF. 


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6.17.10. 
Serious Adverse Events 
This study will follow the definition of serious adverse events as specified in ICH E2A: 
“A serious adverse event (experience) or reaction is any untoward medical occurrence 
that at any dose: 
• results in death, 
• is life-threatening, 
o NOTE: The term "life-threatening" in the definition of "serious" refers to an event 
in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect, 
• other medically important serious medical event.” 
In deciding whether an individual event meets the definition of an SAE, the following definitions 
will be used: 
• Life threatening means that the subject was at immediate risk of death from the event as it 
occurred.  It does not include events that may have caused death if they occurred in a 
more severe form. 
• Inpatient hospitalization means a medical requirement for overnight admission to 
hospital, due to the severity of the event and the medical requirement for inpatient 
treatment and/or monitoring.  
• Permanent disability means a permanent and substantial disruption of a subject's ability 
to carry out normal life functions. 
• Important medical events will be considered an SAE when, based upon appropriate 
medical judgment, the AE may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
6.17.11. 
Reporting Adverse Events 
Each AE is to be classified by the investigator as serious or non-serious (refer to 
Section 6.17.10).  This classification determines the reporting procedures to be followed Table 6. 


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Table 6 
Reporting Requirements for Adverse Events 
Gravity 
Reporting Time 
Type of Report 
Serious 
Within 24 hours 
SAE form 
Non-serious 
Per eCRF submission procedure 
AE eCRF 
Abbreviations:  AE = adverse event; eCRF = electronic case report form; SAE = serious adverse event. 
 
The investigator is responsible for reporting to the Sponsor within 24 hours of becoming aware 
of an event that is an SAE.  Local urgent safety measures (USMs) investigated by the site must 
also be reported to the Sponsor within 24 hours of becoming aware of the event. 
Local reporting requirements for events that meet the Australian definitions of significant safety 
issues (SSIs) (including USMs) are summarized in Appendix 6.  
The Sponsor is responsible for assessing and categorizing the safety reports received from the 
investigator.  Following receipt of the AE reports, the Sponsor or representative will code the 
events to standardized medical terminology using the Medical Dictionary for Regulatory 
Activities (MedDRA).  During the study, all AEs will be coded to the MedDRA version that is 
current at the initiation visit of the first subject in the study. 
The Sponsor is also responsible for communicating any important new information from 
investigators to the HREC and regulatory agencies, as applicable.  The Sponsor activities linked 
to review, oversight and reporting of AEs will be conducted in compliance with applicable ICH 
guidelines (ICH E2A-E2F, ICH E6) both for expedited reporting of important new safety 
information that may arise during the study, as well as final reporting of the overall safety profile 
of the product at the end of the study. 
6.17.11.1. 
Reporting Serious or Unexpected Adverse Events 
The investigator is responsible for promptly reporting all SAEs to the Sponsor.  The investigator 
will complete an SAE form and submit to the Sponsor within 1 working day after the site 
becomes aware of the event, irrespective of the causality or expectedness of the SAE. 
The investigator is also responsible for cooperating with any Sponsor requests for further 
information about the SAE and responding to such requests in a timely manner to facilitate the 
Sponsor’s fulfillment of regulatory reporting requirements.  For example, typically SAE reports 
may require information such as a detailed description of events and investigator assessment of 
causality, copies of hospital reports, autopsy reports, or other relevant documents. 
The Sponsor is responsible for expedited reporting of SUSARs to regulatory agencies.  
Expedited reporting of SUSARs will be performed in compliance with the local regulatory 
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6.17.12. 
Expedited Reporting Requirements 
Investigators are required to report any USMs to the Sponsor or its designee within 24 hours.  
The investigator will notify the HREC of SAEs and USMs, in accordance with HREC 
requirements and local laws and regulations.  A copy of this notification must be provided to the 
Sponsor or its designee. 
SAEs that are unexpected and considered related to the administration of the study drug will be 
reported by the Sponsor (or designee) to the appropriate regulatory authorities and other 
investigators in the form of an expedited safety report within 15 calendar days after receiving 
information on the SAE.  The investigators will notify their reviewing HREC, and other 
committee(s) as required by institutional policies. 
Fatal and life-threatening SUSARs will be submitted no later than 7-calendar days of first 
knowledge of the event and follow-up information submitted within an additional eight (8) days. 
The Sponsor will report any unexpected life threatening or fatal SAEs that are considered related 
to the investigational product to the appropriate regulatory authorities within 7 days of receiving 
the information. 
6.17.13. 
Pregnancy 
Pregnancies in subjects or partners must be reported to Sponsor or its designee within 24 hours 
of knowledge of the event up until and including the EOS visit.  A subject who becomes 
pregnant will immediately be discontinued from study drug. 
The pregnancy of a subject will be monitored for the full duration and/or followed until the 
outcome of the pregnancy is known.  
In the event of pregnancy in the partner of a subject, the investigator should make every 
reasonable effort to obtain the female partner’s consent for release of protected health 
information and notify the Sponsor or its designee within 24 hours of knowledge of the event.  
6.18. Safety Contact Information 
Contact information for AE reporting may be found in a separate Study Reference Manual and 
Study Safety Plan.  Site personnel may also contact the medical monitor for any safety concerns 
or questions. 
6.19. Definition of Clinical Significance 
A change in a subject's clinical status is regarded as important, whether or not it is due to an 
intervention in the context of a clinical study.  The assessment of whether a result is clinically 
significant or not will be made, taking into account: a) whether the result is out of expected 


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values documented by laboratory reference ranges, and this is true after the assessment has been 
repeated, b) other symptoms being exhibited by the study subject and medical history and c) the 
opinion of the treating physician. 
6.20. Study Stopping Rules 
CTCAE, version V5, 27Nov2017 criteria will be used during this study (Refer also to 
Section 6.17.3). 
The study will be discontinued for any of the following: 
• Using CTCAE criteria, the study will be stopped for review if drug-related toxicities of 
Grade 3 or greater (or a SAE) are observed in 2 or more subjects on active treatment in 
that dose group. 
• If any unacceptable safety findings are identified at any time during the study and/or if 
≥1 subject experience a related SAE or a related significant AE that, in the opinion of the 
CRC, warrants discontinuation of the study. 
• Any other safety concern based on the judgment of the PI and/or medical monitor and 
reviewed by the CRC. 
If post dosing EEG’s demonstrate evidence of epileptiform abnormalities, in any subject as 
evaluated by an epileptologist or a Level 3 ANZAN certified neurologist, all dosing will be 
suspended pending review and approval by the CRC.   
The decision to stop the study will be made by the CRC.  Refer to Section 9.8 for additional 
information on the CRC.   
6.20.1. 
Maximum Clinical Exposure 
Clinical PK will be considered as criteria for escalation of clinical doses.  Dosing will not exceed 
1/10th of the exposure associated with the NOEL of 2.75 mg/kg observed in the 14-day dog EEG 
study (KNX100 Cmax and AUC0- last of 84.9 ng/mL and 82.7 hr × ng/mL, respectively and 
KNX100A Cmax and AUC0-last of 26.5 ng/mL and 45.7 hr × ng/mL, respectively). 
6.20.2. 
Maximum Tolerated Dose Definition 
The maximum tolerated dose (MTD) is defined as the dose below a non-tolerated dose and 
therefore can only be determined by the observation of a dose level, which is no longer 
considered acceptable in healthy subjects.  
In this study, a dose will be considered non-tolerated and dose escalation will cease if 2 or more 
subjects in a cohort experience an AE of Grade 3 or higher occurring within 48 hours of 
administration of KNX100 or placebo at the dose level.  Once the non-tolerated dose is defined, 


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the MTD will be confirmed at the previous dose level below the non-tolerated dose, or a dose 
between the non-tolerated dose and the last tolerated dose may be investigated.  If the 
dose-escalation scheme is successfully completed for all escalating doses, 35 mg/day will be the 
highest dose studied (refer to Section 5.3.2 and Section 5.3.3 for the dosing schedule). 
6.21. Removal of Subjects from the Study or Study Drug 
6.21.1. 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the eCRF, using the following categories: 
• Voluntary withdrawal by subject decision 
o The subject is at any time free to withdraw his or her participation in the study, 
without prejudice and independent of any decision concerning participation in 
other aspects of this study. 
• AE 
o The subject has experienced an AE that requires early termination because 
continued participation imposes an unacceptable risk to the subject’s health, or the 
subject is unwilling to continue because of the AE. 
• Vital signs 
o Measurement of abnormal and out of range parameters on repeat analysis as 
required (postdose): 
 O2 saturation of <90% for 60 seconds or longer 
 Respiratory rate of <8 breaths/minute for 2 or more minutes 
 Heart rate of <50 bpm  
 Systolic blood pressure of ≤80 mmHg 
 Temperature of ≤32°C 
• EEG 
o Evidence of the emergence of epileptiform discharges as evaluated by an 
epileptologist or a Level 3 ANZAN certified neurologist.  
• ECG 
o QTcF duration >475 ms and increase exceeding 40 ms in males 
o QTcF duration >475 ms and increase exceeding 60 ms in females 
• Thyroid function tests outside the normal reference ranges (and upon repeat) and CTCAE 
Grade 2 or above. That is, symptomatic and requiring treatment.  
• Laboratory Parameters 
o Safety laboratory tests that are outside the normal reference ranges (and upon 
repeat) and deemed clinically significant by the study PI.  


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• Pretreatment event 
o The subject has a pretreatment event that requires early termination because 
continued participation imposes an unacceptable risk, or the subject is unwilling 
to continue due to the pretreatment event. 
• Pregnancy 
o If the subject is found to be pregnant, the subject must be withdrawn immediately. 
• Major protocol deviation as judged by the investigator and/or Kinoxis. 
o The discovery post-randomization that the subject was incorrectly initiated on 
investigational drug, failed to meet protocol entry criteria, or did not adhere to 
protocol requirements and continued participation poses an unacceptable risk to 
the subject’s health. 
• Compliance 
o The subject has poor compliance with study drug or study procedures. 
• Additional treatment 
o The subject requires treatment with another drug that will interfere with 
evaluation of the study drug. 
Subjects that are withdrawn from the study but are evaluable will not be replaced.  Any subject 
that is withdrawn and is not evaluable will be replaced to ensure a minimum number of evaluable 
subjects. 
6.21.2. 
Subject Withdrawal of Consent 
Subjects will be able to withdraw consent for study treatment, or discontinue from all study 
activities, at any time by their own volition with no impact on any future care they may require at 
the institution where the study is conducted.  
Discontinuing study treatment does not withdraw consent for study follow-up.  Subjects who 
wish to discontinue study treatment should continue to be followed unless they specifically also 
withdraw consent for continued follow-up.   
Note that initial consent to participate in the study also irrevocably grants the Sponsor access to 
any data or specimens collected from the subject during the study.  The subject may withdraw 
consent to participate at any time, but any data and research specimens collected prior to that 
withdrawal of consent remain in the study and remain the property of the Sponsor. 
6.21.3. 
Study Withdrawal - Early Termination Procedures 
Subjects who discontinue study treatment will have their EOS period planned, and safety follow 
up until that visit is completed (refer to the SOA in Appendix 1 and Appendix 2). 


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6.21.4. 
Lost to Follow-up 
Subjects who do not present for study visits may be considered lost to follow-up only after the 
site has exercised and documented appropriate due diligence to attempt contacting the subject.   
Prior to assessing a subject as lost to follow-up, the site must document at least 3 contact 
attempts on 3 separate days (using contact information and preferred mechanism as previously 
indicated by the subject), followed by a certified letter to the subject’s last known address.  
6.22. Discontinuation of the Study 
The study will be discontinued if the Sponsor judges it necessary for any reason, including 
Sponsor acceptance of a CRC recommendation to stop the study for safety. 
6.23. Appropriateness of Measurements 
All procedures and assessments used to evaluate the safety and tolerability of study drug are 
widely used and generally regarded as reliable, accurate, and relevant.  The specific safety 
monitoring, including clinical laboratory assessments, ECGs, and EEGs, are commonly used to 
assess healthy volunteers participating in a first-in-human study.   
7. QUALITY CONTROL AND ASSURANCE 
A study startup/investigator training will be held for all sites prior to first subject enrollment.  To 
ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
• Provide instructional material to the study sites, as appropriate. 
• Conduct a startup training session to instruct the investigators and study coordinators.  
This session will give instruction on the protocol, the completion of the eCRF, and study 
procedures. 
• Make periodic visits to the study site. 
• Be available for consultation and stay in contact with the study site personnel by 
appropriate communication media. 
• Review and evaluate eCRF data and use standard computer checks to detect probable 
errors in data collection. 
• Conduct a quality review of the database. 
In addition, the Sponsor or its representatives will periodically check a sample of subject data 
recorded against source documents at the study site (refer to Section 9.6).  The study may be 
audited by the Sponsor or its representatives, and/or regulatory agencies at any time.  
Investigators will be given notice before an audit occurs. 


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To ensure the safety of subjects in the study, and to ensure accurate, complete, and reliable data, 
the investigator will keep records of laboratory tests, clinical notes, and subject medical records 
in the subject files as original source documents for the study.  If requested, the investigator will 
provide the Sponsor, applicable regulatory agencies, and applicable ethical review boards with 
direct access to original source documents (refer to Section 9.10). 
8. PLANNED STATISTICAL METHODS 
8.1. 
General Considerations 
Kinoxis, or an appropriately qualified delegate, will be responsible for statistical analysis of all 
study data for the final clinical study report.  The final analysis will be performed after all 
subjects have completed the EOS visit or discontinued the study.  Other than analyses for CRC 
cohort reviews, no interim analysis is planned for this study. 
Data will be summarized descriptively by study medication (placebo and treatment cohort).  
In addition, select safety and PK summaries may include pooled summaries with all subjects 
receiving a single dose.  The descriptive summaries for the categorical variables will include 
counts and percentages.  The descriptive summaries for the continuous variables will include 
means, medians, standard deviations, 25th and 75th quartiles, and minimum and maximum values.  
Unless specified otherwise, all data will be listed for all randomized subjects.  
All confidence intervals will be 95%, unless stated otherwise.  
Further details of definitions will be provided in a statistical analysis plan. 
8.2. 
Determination of Sample Size 
This study is descriptive in nature, and no formal comparisons or hypothesis testing will be 
performed between study medications or dosing levels.  As such, no prospective calculations of 
statistical power have been made.  The sample size has been selected to provide sufficient 
information to have preliminary characterization of safety, tolerability, PK and PD of the study 
drug.   
8.3. 
Analysis Populations 
The Safety Set (SAF) will include all subjects who received at least one dose of study treatment.  
Subjects will be analyzed according to the treatment received.  The SAF will be used for all 
safety summaries. 
A Per Protocol Set (PP) will include all subjects who received at least one dose of any amount of 
KNX100 and do not have major protocol violations.  Major protocol violations are defined in 


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Section 9.9.  A final determination of inclusion in the PP will be made by a blinded team prior to 
database lock and unblinding.  The PP set may be used on select biomarker endpoints.  Analyses 
conducted with the PP will be based on the assigned study medication.  
For the PK assessment, the set of subjects will include those subjects who received at least one of 
study drug and had sufficient plasma KNX100 concentration data for calculation of PK 
parameters. 
8.4. 
Demographics and Baseline Characteristics 
Summary statistics will be provided for demographic and baseline characteristics in each 
analysis population and by cohort.  No formal statistical comparisons will be performed.  
Demographic and baseline characteristic data for each subject will be provided in data listings. 
8.5. 
Study Endpoints 
8.5.1. 
Primary Safety Endpoints 
The primary safety endpoints include: 
• Incidence of TEAEs and TESAEs, related AEs, AEs leading to discontinuation, and AEs 
by severity. 
• Clinical laboratory testing from protocol-specified standard urine and blood tests, 
including liver function tests (LFTs) and thyroid function tests (TFTs:  triiodothyronine 
[T3], thyroxine [T4], thyroid stimulating hormone [TSH]). 
• Change in clinical observations from baseline, including body temperatures, vital signs, 
ECGs, EEGs. 
8.5.2. 
Secondary Pharmacokinetic Endpoints 
The secondary PK endpoints include: 
• Maximum observed concentrations (Cmax) following dose administration. 
• Time of Cmax (Tmax) following dose administration. 
• Area under the concentration-time curve (AUC) from time zero to last quantifiable 
concentration (AUC0-last), from time zero to 24 hours postdose administration (AUC0-24), 
and, as data permit, from time zero to extrapolated to infinity (AUC0-∞). 
• As data permit, additional disposition parameters including terminal half-life (t1/2), 
volume of distribution (Vz/F), and oral clearance (CL/F) may be calculated. 
• Accumulation ratio (RAC) for Cmax and AUC0-24; Day 7 vs Day 1 (MAD phase only). 
• Other PK parameters will be calculated as deemed appropriate and as referred to in 
Section 8.7. 


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8.6. 
Statistical Analysis of Safety Variables 
Safety endpoints for this study are provided in Section 8.5.1.   
Summaries of safety data will be performed using the SAF.  AE data will be coded to system 
organ class and preferred term using MedDRA.  The MedDRA version will be specified in the 
study-specific data management plan (DMP). 
The number and percentage of subjects experiencing any TEAEs, overall and by system organ 
class and preferred term, will be tabulated.  TEAEs will also be summarized by severity and 
relationship.  Treatment-related events, and other events will be listed.  Concomitant medications 
will be summarized using frequency and percentage of subjects.  Results and changes from 
baseline in vital signs, ECG readings, EEG, and hematology and clinical chemistry parameters 
will be tabulated at each visit.  Abnormal ECG and laboratory findings will also be summarized. 
Individual subject listings of prior and concomitant medications, EEG, vital signs, ECG data, and 
laboratory measurements will be provided. 
In addition, ECG parameters will be analyzed as follows (data listings): 
• 450 ms <QTcF/ QTcB ≤ 480 ms480 ms <QTcF/ QTcB ≤500 ms 
• 500 ms <QTcF/ QTcB 
• 30 ms <QTcF/ QTcB change from baseline ≤60 ms 
• 60 ms <QTcF/ QTcB change from baseline 
8.7. 
Statistical Analysis of Pharmacokinetic Variables 
PK endpoints for this study are provided in Section 8.5.2.  PK concentrations and parameters will 
be listed and summarized by dose, treatment group, and measurement time using appropriate 
descriptive statistics.  The actual sampling times will be used in the parameter calculations, and 
PK parameters will be derived using standard non-compartmental methods.  Where possible, the 
following PK parameters of KNX100 and any measurable metabolites will be determined: 
• Following the single-dose part of the study: 
o Maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal rate constant 
(λz), terminal half-life (t½), area under the plasma concentration-time curve from 
zero to 24 hours (AUC0-24), from zero to the time of the last measurable 
concentration (AUC0-t) and from zero to infinity (AUC0-∞), apparent plasma 
clearance (CL/F), apparent volume of distribution (Vz/F), mean residence time 
(MRT). 
• Following the multiple-dose part of the study: 


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o Maximum plasma concentration (Cmax), time to maximum Cmax (Tmax), minimum 
plasma concentration (Cmin), area under the plasma concentration-time curve from 
zero to the end of the dosing interval (AUC0-24) will be assessed on both Day 1 and 
Day 7.  The apparent oral plasma clearance (CL/F), the apparent volume of 
distribution (Vz/F), the terminal t1/2, and the AUC extrapolated to infinity will be 
calculated on Day 7 (and Day 1 if data permit).  The extent of accumulation following 
multiple dosing (accumulation ratio [RAC]) will be evaluated for Cmax and AUC0-24. 
The Cmax and Tmax parameters will be determined through the concentration-time profiles.  
Where possible, the λz will be calculated by log-linear regression of the terminal portion of the 
concentration-time profiles where there are sufficient data and the t½ will be calculated as 
ln 2/λz.  The AUC0-t and the AUC0-24 will be calculated using the linear trapezoidal rule.  Where 
appropriate, the AUC0-t will be extrapolated to infinity using λz to obtain AUCINF.  The AUC will 
be calculated using the linear trapezoidal rule.  CL/F will be determined as dose/AUCINF.  Vz/F 
will be determined as Dose / (AUCINF * λz).   
Where possible, the appropriate PK parameters will also be determined for the metabolite (s) of 
KNX100. 
Concentrations below the limit of quantification (BLQ) will be treated as zero for descriptive 
statistics.  Mean BLQ concentrations will be presented as BLQ, and the standard deviation (SD) 
and coefficient of variation (CV) will be reported as not applicable.  Missing concentrations will 
be excluded from the calculations. 
8.8. 
Interim Analysis 
No interim analysis is planned for this study.   
9. ADMINISTRATIVE CONSIDERATIONS 
9.1. 
Investigators and Study Administrative Structure 
This study is sponsored by Kinoxis Therapeutics Pty Ltd. (Kinoxis).  Information related to 
participating sites and investigators, qualified physicians, clinical laboratories, members of the 
CRC, and other relevant administrative personnel will be kept in the Study Master File. 
9.2. 
Human Research Ethics Committee Approval 
The study protocol and informed consent, as well as any amendments (Section 9.14), will be 
reviewed by the responsible HREC in accordance with Good Clinical Practice (GCP) prior to 
initiation at a particular site.  Any member of the HREC who is directly affiliated with this study 
as an investigator or as site personnel must abstain from the vote on this study.   


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The HREC will be asked to document the date of the meeting at which the favorable opinion or 
approval was given along with a list of the members and voting members present.  The favorable 
opinion or approval must also clearly identify the study along with the study protocol and 
information statement and informed consent form versions reviewed.  Where possible, copies of 
the meeting minutes should be obtained. 
Documentation from the HREC will be filed in the Investigator Site File.  A copy will be filed in 
the Sponsor Study Master File at Kinoxis or with a designated organization.  
Relevant safety information will be submitted to the HREC during study execution in accordance 
with national regulations and requirements.  In the event of an SAE, the investigator, or Sponsor 
where applicable, will notify the relevant HREC of any SAEs and safety reports according to 
local regulation requirements (refer to Section 6.17.11 for more information regarding reporting 
SAEs). 
9.3. 
Ethical Conduct of the Study 
The Sponsor will conduct the study in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, are consistent with the GCP guidelines of the ICH, and 
according to applicable regulatory requirements.   
The investigator, head of the medical institution, or designee will promptly submit the protocol 
to applicable ethical review boards.  
As indicated in Section 9.5, an identification code assigned for each subject will be used in lieu 
of the subject’s name to protect the subject’s identity when reporting all study-related data. 
9.4. 
Subject Information and Consent 
A copy of the HREC approved version of the consent form will be provided to the Sponsor.  
Subjects who are identified as potentially being suitable to participate in the study will be given 
an information statement and consent form as approved by the Sponsor and by the site’s HREC.  
The consent form will describe the purpose of the study, the procedures to be followed, and the 
risks and benefits of participation. 
The original signed consent form must be maintained at the site and made available for 
inspection, as appropriate.  Additional information about the subject information and consent 
process is provided in Section 6.1. 


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9.5. 
Subject and Study Confidentiality 
Subjects will be identified by their assigned subject number in all written communications 
between the investigator and Sponsor or its designees.  Subject confidentiality is strictly held in 
trust by the participating investigators, research staff, and the Sponsoring institution and their 
agents, at a minimum complying with applicable local regulation.  This confidentiality is 
extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence.  No information concerning the study or data will be released to any 
unauthorized third party, without prior written approval of the Sponsor.   
Authorized representatives of the Sponsor, the HREC and regulatory agencies may inspect all 
documents and records required to be maintained by the site investigator (refer to Section 9.6).  
All laboratory specimens, evaluation forms, reports and other records that leave the site will be 
identified only by the Subject Identification Number (SID) to maintain subject confidentiality.  
All study-related information provided by the Sponsor or its designees to the investigator and not 
previously published (including, but not limited to, the active study agent identity, the IB, the 
study protocol, verbal and written communication, study data, assay methods and scientific data), 
will be considered confidential.  In addition, all information developed during the conduct of the 
clinical investigation of the study agent is also considered confidential.  Neither the investigator 
nor any of his/her employees or agents shall disclose or use this information for any purpose 
other than the performance of the clinical study.  Such information shall remain the confidential 
and proprietary property of the Sponsor, and disclosure to others will be limited to other 
physicians who are conducting studies with the same active study agent, the HREC, and the 
applicable regulatory authorities except by prior written permission of the Sponsor or its agents.  
At such time that information becomes widely and publicly available through no fault of the 
investigator, the obligation of nondisclosure toward that particular information will cease. 
9.6. 
Case Report Forms and Study Records 
Study data will be recorded/filed in subject medical files (source data) and transcribed into an 
electronic data capture system/CRF for reporting.  All required study data will be entered onto 
the Sponsor-provided eCRF.  All information in the eCRFs must be supported by original data in 
the subject’s medical records.  All medical records, laboratory printouts, notes made by the 
physician, and other materials, such as x-rays, will be considered source data and must be 
available for inspection by the Sponsor, the Sponsor’s delegates, or government representatives. 


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9.6.1. 
Data Collection 
Appropriate training prior to study initiation at that site will be conducted to assist with making 
entries and corrections to data entered into an eCRF.  The site investigator is responsible for 
maintaining adequate case histories of study subjects, including accurate eCRFs and source 
documentation (where the source documents are distinct from the CRFs).  The site investigator is 
responsible for the completeness, accuracy, legibility, and timeliness of the data reported; 
however, the investigator may exercise this responsibility by delegating the actual data 
collection, recording, and checking activities to appropriately qualified staff under the 
investigator’s supervision. 
Information in the database will refer to each study subject by a unique SID.  Study subjects will 
not be identified by name, although the study data will, of necessity, include other personally 
identifying information such as date of birth. 
9.6.2. 
Source Data  
The site investigator is responsible for maintaining adequate and accurate source documents of 
all observations and data generated during this study.  Source documents are the original 
documents, data, and records from which the subject’s eCRF data are obtained.  These include, 
but are not limited to, hospital records, clinical and office charts, laboratory and pharmacy 
records, radiographs, and correspondence.  eCRF entries may be considered source data if the 
eCRF is the site of the original data recording or as defined in the eCRF completion guidelines or 
study manuals. 
9.7. 
Study Monitoring 
The study will be regularly monitored by a Sponsor representative contract research organization 
(CRO) according to ICH-GCP standards to ensure quality of the data, preservation of the rights 
and safety of subjects, and to ensure that the study is being conducted according to the protocol 
and to ethical and relevant regulatory requirements.  The Sponsor or designee will assure the 
selection of qualified investigators, appropriate program centers, and review protocol procedures 
with the investigators and associated personnel prior to the program and during periodic 
monitoring visits.   
The Sponsor or a designee will review eCRFs for accuracy and completeness during on-site 
monitoring visits and after their return from the clinical site.  Data entered into eCRFs will be 
monitored by monitors that are adequately trained on the system.  To ensure accurate, complete, 
and reliable data, the investigator will keep records of laboratory tests, clinical notes, and subject 
medical records in the subject files as original source documents for the program.  The 
investigators will be required to agree to access by the Sponsor/Sponsor representatives to study 
documentation, including subject medical files and test results, for monitoring and auditing 


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purposes, and also to inspections by Regulatory Authorities or quality assurance auditors as 
requested.  Discrepancies will be resolved with the investigator as appropriate. 
The Sponsor or its designee will monitor the program using any of the following methods: 
• Telephone contacts, 
• Site visits, and 
• Review of original subject records, CRFs, drug accountability, storage, and general 
program documentation. 
The Sponsor reserves the right to terminate the program if access to source documentation of 
work performed in this program is denied to the Sponsor or regulatory representatives. 
All SAEs will be reviewed within time frames mandated by company procedures and local 
regulatory requirements.  All deaths and SAE reports will be reviewed by the clinical team 
during study execution to assure completeness and accuracy. 
9.8. 
Cohort Review Committee 
An independent CRC will oversee the progress of this study and periodically review the accruing 
safety data.  The CRC is intended to ensure that treatment does not pose undue risk to subjects.  
The CRC will include an appropriate group of professional specialties, including at a minimum, 
the following core individuals: 
• Blinded PI or delegate (delegation only when the PI is not available and must be a 
physician). 
• Blinded medical monitor or delegate (must be a physician). 
• Blinded neurologist with expertise in EEG analysis and interpretation. 
• Blinded pharmacokineticist 
The roles, responsibilities, constitution, and operations of the CRC (including its specific 
composition and schedule for its assessments) will be described in the CRC Plan, which will be 
reviewed and signed by each member before the first subject is randomized and treated. 
9.8.1. 
Blinded Data Review  
For Part A (SAD), the CRC will review all safety and PK data of the Sentinel subjects, collected 
up to the 30-hour postdose timepoint, to enable decision to enroll the rest of cohort.  The CRC 
will also conduct a blinded, cohort-escalation review after the final subject in a cohort has been 
dosed, using safety data from all subjects through at least the 30-hour-postdose visit, as well as 


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all available blinded PK and safety data from the current or previous cohorts. Upon acceptance 
of reviewed data, dosing for the 2 sentinel subjects in the next cohort may occur. 
For Part B (MAD), the CRC will review all safety and PK data from each cohort collected up to 
and including the 24-hour post morning dose timepoint on Day 8.  Additionally, the frequency 
and severity of the following events and findings will be used to determine the acceptability of 
escalation to the next cohort:  
• Serious AEs  
• Discontinuation of participation due to an AE  
• Adverse events  
• Clinically significant laboratory, EEG and ECG findings.  
• Study medication sensitivities and reactions.  
The safety observation period may be extended if additional safety data are required for any 
cohort.  Based on all available data, a recommendation for dose escalation or changes to the 
protocol will be made in collaboration with the investigator.   
Updated dispensing guidelines for each dose escalation will be provided based on all available 
data.  Sponsor representatives will document cohort-escalation decisions in central files.  
9.9. 
Protocol Violations/Deviations 
This protocol is intended as a FIH study to establish the safety, tolerability, and PK 
characteristics of KNX100.  As such, it is especially important that study sites and investigators 
conduct the study in accordance with the written protocol, to permit consistent data quality 
throughout the study. 
Every protocol deviation (i.e., any change, divergence, or departure from the study design or 
procedures defined in the protocol) must be recorded in the subject record (source document) and 
on the CRF and must be reported to the PI.  Protocol deviations will be assessed for significance 
by the PI, but also will be subject to review by the Sponsor.  
Protocol violations (also known as “important protocol deviations”) are a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the 
study data, or that may significantly affect a subject's rights, safety, or well-being.  At a 
minimum, these will include any instances of the following: 
• Enrollment of a subject who did not satisfy the entry criteria. 
• Failure to withdraw a subject from the study after the subject met withdrawal criteria. 
• Subject received the wrong treatment or incorrect dose. 


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• Subject received an excluded concomitant treatment. 
• Failing to collect data necessary to interpret primary endpoints. 
The investigator is responsible for promptly notifying the Sponsor or Sponsor representative of 
any important protocol deviations/protocol violations.  For these important deviations, the 
investigator and Sponsor will determine whether additional reporting is appropriate, considering 
any local requirements that exceed ICH recommendations. 
9.10. Access to Source Documentation 
The investigator is responsible for secure storage of completed source documentation and eCRFs 
until authorized to transfer the documentation to the Sponsor, or to dispose of the documentation.  
Please refer to Section 9.6.2 for a definition of source documentation.  
Study source documentation and CRFs are subject to inspection by the Sponsor, its 
representatives, the HREC, and Regulatory Authorities, at times of their choosing.  The study 
site must allow study-related monitoring audits and/or inspections when so requested by these 
authorized persons.  Please refer to Section 9.7 for more information on site monitoring audits 
and inspections. 
9.11. Data Generation and Analysis 
The Sponsor is responsible for designating appropriate personnel to build and maintain a clinical 
database appropriate for a pivotal study. 
All data from the CRFs will be transferred into a computer database, which will be designed in 
compliance with applicable conventions for standardized data sets, and with appropriate range 
checks.  Appropriate Sponsor personnel/designees will check the database against the CRF for 
accuracy.  Sponsor personnel/designees will also work with staff at study sites for clarification of 
data entries as needed (refer to Section 9.7). 
9.12. Retention of Data 
Both investigators and the Sponsor are responsible for secure storage of completed CRFs during 
the conduct of the study.  
The Sponsor is responsible for generating backup copies of the CRFs and database and is 
responsible for securely storing the backups separately from the primary files. 
Access to the database will be restricted by password.  Computers will be password protected 
and held in secure monitored facilities.   


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All data derived from the study will remain the property of the Sponsor.  Records must be 
retained in accordance with the current ICH Guidelines on GCP.  All essential study documents 
including records of subjects, source documents, eCRFs and study drug inventory must be kept 
in a study specific file. 
The site investigator will not dispose of any records relevant to this study without the written 
permission from the Sponsor and will provide the Sponsor the opportunity to collect such 
records.  The site investigator will notify the Sponsor in writing of their intent to destroy all such 
material.  The Sponsor will have 30 days to respond to the site investigator’s notice, and the 
Sponsor shall have a further opportunity to retain such materials at the Sponsor’s expense. 
If a site investigator moves, withdraws from an investigation, or retires, the responsibilities for 
maintaining the records may be transferred to another person who will accept responsibility.  
Notice of transfer must be made and agreed by the Sponsor. 
Per ICH GCP (R2), (ICH Guideline E6), at a minimum the Sponsor-specific essential documents 
(including subject-specific source documents) should be retained until either of the following is 
true: 
• At least 2 years after the last approval of a marketing application in an ICH region (and 
until there are no further marketing applications contemplated in ICH regions),  
or  
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. 
However, source data and other essential documents should be retained for a longer period if 
required by local regulations.   
In Australia, records must be kept for at least 15 years after the completion of a clinical study.  
9.13. Financial Disclosure 
The investigators and the Sponsor will sign a clinical study agreement prior to the start of the 
study, outlining the overall Sponsor and investigator responsibilities in relation to the study.   
All investigators and the Sponsor will declare any conflicts of interest.  If potential conflicts of 
interest are present, the Sponsor and investigator are jointly responsible for determining 
appropriate controls to mitigate risks to data integrity at the investigator’s site. 
Financial Disclosure Statements are required for all investigators on this study worldwide, as 
required by FDA regulation 21 CFR 54. 


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9.14. Changes to the Clinical Study Protocol 
Changes to the clinical study protocol will be documented in writing.  Substantive amendments 
will usually require submission to the IND and to the relevant HREC for approval or favorable 
opinion.  In such cases, the amendment will be implemented only after approval or favorable 
opinion has been obtained (refer to Section 9.2). 
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site.  They will be submitted to the relevant HREC or to regulatory bodies 
only where requested by pertinent regulations.  Any amendment that could affect the subject’s 
agreement to participate in the study requires additional informed consent prior to 
implementation, following the process as described in Section 6.1 and Section 9.4. 
9.15. Disruption Due to Coronavirus Disease 2019 (COVID-19) Pandemic  
If a clinical site or investigator experiences disruption due to COVID-19 (or other natural 
disaster), a shortened list of assessments may be implemented as an immediate safety measure to 
ensure at least safety, primary, and key secondary endpoints are captured for any dosed subject.  
Assessments may be performed by telephone if possible.   
If a subject develops COVID-19, this will be reported and followed as an AE per Section 6.17.  
The investigator will follow the standard operating procedures for the site as well as local, 
regional, and national guidelines for COVID-19.  Investigators should use clinical judgement as 
to whether a subject should continue, temporarily stop, or permanently withdraw from the study. 
9.16. Publication and Data Disclosure Policy 
By signing the study protocol, the investigator agrees with the use of the results of the study for 
the purposes of national and international registration, publication, and information for medical 
and pharmaceutical professionals.  Regulatory Authorities will be notified of the investigator’s 
name, address, qualifications, and extent of involvement. 
All data generated from this program are the property of the Sponsor and shall be held in strict 
confidence along with all information furnished by the Sponsor.  Independent analyses and/or 
publication of these data by the investigator or any member of his/her staff are not permitted 
without prior written consent of the Sponsor.  An investigator may not publish any data (poster, 
abstract, paper, etc.) without having consulted with the PI and Sponsor in advance and having 
received a written approval for such a publication.  
Further details on the publication process are provided in individual contractual agreements 
signed by the investigators and the Sponsor. 


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10. REFERENCE LIST 
Boudreau D, Von Korff M, Rutter CM, Saunders K, Ray GT, Sullivan MD et al. Trends in de-
facto long term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf. 
2009 December; 18(12):1166–1175. 
CDC 2013; https://www.cdc.gov/vitalsigns/prescriptionpainkilleroverdoses/index.html; last 
accessed 15 June 2020 
CDC 2021; https://www.cdc.gov/opioids/; last accessed 02 August 2021. 
CDC WONDER website:  http://www.drugabuse.gov/drug-topics/trends-statistics/overdose-
death-rates.  Last accessed 03 March 2021. 
Choy M. Pharmaceutical approval update. P.T. 2018 Aug;43(8):461-462.  
Dijkstra BAG, Krabbe PFM, Riezebos TGM, van der Staak CPF, De Jong CAJ. Psychometric 
Evaluation of the Dutch Version of the Subjective Opiate Withdrawal Scale (SOWS).  Eur 
Addict Res 2007; 13:81-88. 
Gorodetzky CW, Walsh SL, Martin PR, Saxon AJ, Gullo KL, Biswas K. A phase III, 
randomized, multi-center, double blind, placebo controlled study of safety and efficacy of 
lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. 
Drug Alcohol Depend. 2017 Jul 1;176:79-88. 
Larochelle MR, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, et al. Medication for opioid 
use disorder after nonfatal opioid overdose and association with mortality: A cohort study. 
Ann Intern Med. 2018 Aug 7;169(3):137-145. Epub 2018 Jun 19. 
Portenoy RK. Opioid therapy for chronic nonmalignant pain: clinicians’ perspective. J Law Med 
Ethics. Winter 1996;24(4):296-309. 
Thomas D, Wessel C. The state of innovation in highly prevalent chronic diseases: pain and 
addiction therapeutics. BIO Industry Analysis 2018. 
Wu L.-T, Zhu H, Swartz MS. Treatment utilization among persons with opioid use disorder in 
the United States. Drug Alcohol Depend. 2016 Dec 1;169:117-127. Epub 2016 Oct 19. 
Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies-tackling the opioid 
overdose epidemic. N Engl J Med. 2014 May 29;370(22):2063-2066. 


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Volkow ND, McLellan AT. Opioid abuse in chronic pain-misconceptions and mitigation 
strategies. N Engl J Med. 2016 Mar 31;374(13):1253-63. 
 


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Appendix 1 
Schedule of Assessments - SAD 
 
Screening 
Treatment 
Follow Up/ 
ET/EOS1 
Study Day 
-28 to -2 
-1 
1 
2 2 
7 (±2) 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria3 
X 
X 
 
 
 
Randomization4 
 
X 
 
 
 
Height and BMI 
X 
 
 
 
 
Medical History and Demographics 
X 
 
 
 
 
Physical and Neurological Exam5 
X 
X 
X 
X 
X 
Vital Signs6 
X 
X 
X 
X 
X 
Laboratory Tests7 
 
 
 
 
 
Serology 
X 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
Serum Chemistry 
X 
X 
X 
X 
X 
Urinalysis8 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
Pregnancy Test9 
X 
 
 
 
X 
Drug of Abuse Screening10 
X 
X 
 
 
 
Alcohol Breath Test 
X 
 
 
 
 
Study Drug Administration11 
 
 
X 
 
 
PK Assessments12 
 
 
X 
X 
 
Biomarker Sample13 
 
X 
X 
 
X 
EEG14 
X 
 
X 
X 
 
12-Lead ECG15 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 


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Screening 
Treatment 
Follow Up/ 
ET/EOS1 
Concomitant Medications 
X 
X3 
X 
X 
X 
Inpatient Component16 
X 
X 
X 
X 
 
Abbreviations:  BMI = body mass index; ECG = electrocardiogram; EEG = electroencephalography; ET = early termination; EOS = end of study; 
PK = pharmacokinetics; SAD = single ascending dose. 
1 All subjects will be required to attend an ET/EOS visit, even if they have withdrawn or been removed from the study.  For completed subjects, this will be at 
Day 7.  
2 For sentinel subjects this will include a follow up phone call at 48 hours. 
3 Confirmation of eligibility based on inclusion/exclusion criteria. 
4 Randomization to occur after confirmation of eligibility on Day -1 and prior to dosing on Day 1. 
5 An abbreviated neurological examination will be undertaken to include: light touch/power in limbs, brief cranial nerve examination and recording of any other 
abnormal movements; to occur on Day-1, Day 1 predose and at 30 minutes (± 15 minutes) postdose, and Day 2.  Physical and neurological examination on Day 2 
should be performed pre-discharge.   
6 Vital signs collection includes systolic and diastolic blood pressures, pulse rate and body temperature which will be measured with the subject to be seated or 
semi-supine after resting for at least 3 minutes.  Vital signs also include respiratory rate, continuous pulse oximetry and saturated oxygen, which will be 
undertaken via telemetry within 2 hours predose and at 30 hours (± 30 minutes) after dosing.  Measurements of all vital signs will be recorded within 1 hour 
predose, and at 30 minutes, 1-, 1.5-, 2-, 4-, 6-, 8- ,12-, 24- and 30-hours postdose (± 15 minutes).  Peak flow measurement will also be undertaken within 1 hour 
predose as well as at 1-, 2-, and 4-hours (± 15 minutes) postdose.  The highest of 3 peak flow measurements, at each timepoint, shall be recorded. 
7 Subjects should fast overnight prior to collection of laboratory tests at Screening.  The Day 1 laboratory tests will be undertaken at 1 hour postdose 
(± 15 minutes) and at 24 hours (± 15 minutes) postdose (Day 2).  
8 The Day 1 urinalysis tests will be undertaken at 1-hour postdose (± 60 minutes) and at 24 hours (Day 2) (± 60 minutes) postdose. 
9 Serum pregnancy test at Screening and End of study visit.  A urine pregnancy test will be conducted in women of child-bearing potential on admission to unit 
on Day -3. 
10 Test may be repeated if required. 
11 Each subject will receive study drug based on randomization (placebo or KNX100), after a 10 hour fast.   
12 Please refer to Appendix 3 for information related to PK assessments and sampling times. 
13 Plasma samples for biomarker analyses will be collected predose (Day -1), on Day 1 at 1-hour postdose (± 15 minutes), and at EOS/EOT. 
14 EEG:   Please refer to Appendix 3 for information related to EEG assessments.  


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15 Please refer to Appendix 3 for information related to ECG assessments which will be performed in triplicate.  The timing and number of ECGs may be altered, 
depending on the emerging PK and safety profile.  Additional ECGs should also be collected if a subject experiences a cardiac adverse event. 
16 Participants will be admitted to the Phase 1 unit on Day -3 so they can sleep for 4 hours prior to undertaking their sleep deprived EEG on Day -2, through to 30 
hour testing on Day 2. 


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Appendix 2 
Schedule of Assessments – MAD  
 
Screening 
Treatment 
ET/EOS1 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 2 
14 (± 2) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria3 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization4 
 
X 
 
 
 
 
 
 
 
 
 
Height and BMI 
X 
 
 
 
 
 
 
 
 
 
 
Physical and Neurological 
Exam5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gastrointestinal 
Symptoms6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests8 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Serum Chemistry 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy Test9 
X 
X 
 
 
 
 
 
 
 
 
X 
Drug Abuse Screening 
X 
X10 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X10 
 
 
 
 
 
 
 
 
 
Study Drug 
Administration11 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PK Assessments12 
 
 
X 
 
 
X12 
 
 
X 
 
 
Biomarker Sample13 
 
X 
X 
X 
X 
 
 
 
X 
 
X 


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Screening 
Treatment 
ET/EOS1 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 2 
14 (± 2) 
12-Lead ECG14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
EEG15 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS16 
X 
 
 
 
 
X 
 
 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inpatient component17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations:  BMI = body mass index; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EEG = electroencephalography; EOS = 
end of study; ET = end of treatment; PK = pharmacokinetics; MAD = multiple ascending dose; SAD = single ascending dose. 
1 All subjects required to attend an ET/EOS visit, even if they have withdrawn or been removed from the study.  
2 Day 8 is 24-hours (± 1 hour) after administration of the last morning dose.  This visit will be used to collect the “24-hour” assessments.   
3 Confirmation of eligibility based on inclusion/exclusion criteria. 
4 Randomization to occur after confirmation of eligibility on Day -1 and prior to the first dose on Day 1. 
5 An abbreviated neurological examination will be undertaken to include: light touch/power in limbs, brief cranial nerve examination up to 1 hour prior to the 
first dose and at 30 minutes (± 15 minutes) post morning dose.  
6 An assessment of bowel movements including any incidence of constipation or changes in bowel habits will be conducted daily.  On Day -1 and Day 1, the 
gastrointestinal screening assessments will be conducted as part of physical examinations.  On Days 2, 3, 4, 5, 6, 7, 8 and Day 14, a gastrointestinal questionnaire 
will be administered within 30 minutes prior to morning dosing. 
7 Vital signs will be measured with the subject to be seated or semi-supine after resting for at least 3 minutes.  Measurements will include systolic and diastolic 
blood pressures, pulse rate, body temperature, respiratory rate, saturated oxygen and pulse oximetry which will be recorded via telemetry within 2 hours predose 
and at 2 hours postdose (± 15 minutes).  Peak flow measurement will also be undertaken within 1 hour predose as well as at 1-, 2-, and 4-hours (± 15 minutes) 
postdose.  The highest of 3 peak flow measurements, at each timepoint, shall be recorded.  For MAD Cohort 3, vital signs, telemetry, and peak flow 
measurements will be recorded following each dose as per the schedule above. 
8 Laboratory tests will be undertaken as depicted above.  The Day 1 laboratory tests will be undertaken 1 hour post morning dose (± 15 minutes). 
9 A serum pregnancy test will be undertaken at screening and End of Study visit.  A urine pregnancy test will be conducted in women of child-bearing potential 
on admission (Day -3).  
10 Drug abuse screening and alcohol breath test will be conducted at admission (Day -3).  
11Subjects in Cohorts 1 and 2 of the MAD study phase will be dosed daily for 7 days at approximately the same time each day.  Each subject will receive study 
drug based on randomization (placebo or KNX100), after a 10 hour fast. Subjects will remain fasted until 2 hours (±15 minutes) post study drug administration.  


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Subjects in Cohort 3 of the MAD study phase will be dosed twice daily (b.i.d) with doses administered approximately 8 hours (± 30 minutes) apart. The first dose 
will be administered following a 10 hour overnight fast, and subjects will remain fasted until 2hours (±15 minutes) post study drug administration.  Subjects will 
be required to fast 2 hours (± 15 minutes) prior to administration of the second dose of study drug and will remain fasted until 2hours (±15 minutes) post study 
drug administration. 
12Please refer to Appendix 3 for information related to PK assessments and sampling times.  The timing and number of PK samples may be altered depending on 
emerging data and safety profile.  Please note, Day 4 predose sample is not required for Cohort 3. 
13 Plasma samples for biomarker analyses will be collected predose (Day -1), and 1 hour post morning dose (± 15 minutes) on Days 1, 2, 3, 7 and at the ET/EOS 
visit.   
14 Please refer to Appendix 3 for information related to ECG assessments.  ECGs will be undertaken in triplicate.  The timing and number of ECGs may be 
altered, depending on the emerging PK and safety profile.  ECGs should also be collected if a subject experiences a cardiac adverse event.   
15 EEG:  Please refer to Appendix 3 for information related to EEG assessments. 
16 C-SSRS: will be administered predose at screening and then within 4 hours post the morning dose on Days 4 and 7. 
17 Subjects will be admitted to the unit on Day -3 to undertake their sleep deprived EEG.  Subjects will remain in the unit during the entire dosing phase and be 
discharged after collection of Day 8 assessments.  
 


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Appendix 3 
PK Blood Sampling, EEG and ECG Schedule During Dosing Periods 
Time 
Relative to 
Dose 
Part A (SAD, HV) 
Part B (MAD, HV) 
Day 1 
Day 21 
Day 1-7 
 
Cohorts 1-2 
Cohort 3 
PK2 
ECG3 
EEG4 
PK2 
ECG3 
EEG4 
PK2 
ECG3 
EEG4 
PK5 
ECG3 
EEG4 
Predose 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
15 minutes 
X 
 
 
 
 
 
X 
 
 
 
 
 
30 minutes 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
1 hour 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
 
2 hours 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
4 hours 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
8 hours 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
8.5 hours 
 
 
 
 
 
 
 
 
 
X 
 
 
9 hours 
 
 
 
 
 
 
 
 
 
X 
 
 
10 hours 
 
 
 
 
 
 
 
 
 
X 
 
 
12 hours 
X 
 
 
 
 
 
X 
 
 
X 
 
 
16 hours 
X 
X 
 
 
 
 
 
 
 
X 
 
 
24 hours 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
30 hours  
 
 
 
X 
 
 
 
 
 
 
 
 
Abbreviations:  ECG = electrocardiogram; EEG = electroencephalography; HV = healthy volunteer; MAD = multiple ascending dose; PK = pharmacokinetics; 
SAD = single ascending dose.   
1 For Part A (SAD), Day 2 is the 24-hour timepoint after last study drug administration.  For Part B (MAD), Day 8 is the 24-hour timepoint after last study drug 
administration (Cohorts 1 and 2) and 24-hours post morning dose (Cohort 3).  This visit will be used to collect only the “24-hour” samples.   
2 During Part A (SAD), PK samples and time windows are predose, and 15 minutes (± 2 minutes), 30 minutes (± 2 minutes), 1 hour (± 5 minutes), 2-, 4-, 8-, 12-, and 24- 
and 30-hours (± 30 minutes) postdose.  During Part B (MAD Cohorts 1 and 2), PK samples will be taken at predose and 15 minutes (± 2 minutes), 30 minutes 
(± 2 minutes), 1-hour (± 5 minutes), 2-, 4-, 8-, and 12- hours (± 15 minutes) postdose on Days 1, , 4 and 7    The timing and number of PK samples may be altered 
depending on emerging data and safety profile.   


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3 Part A (SAD) ECGs and time windows are Screening, Day -1, predose, 1 hour (± 2 minutes), 2-, 4-, 8-, and 16-hours (± 5 minutes), and 24-hours (± 30 minutes).  For 
the MAD part of the study, ECGs will be undertaken at Screening, Day -1, predose, and 1-hour postdose (± 30 minutes) on Day 1 to Day 7.    ECGs will be measured 
with the subject to be seated or semi-supine after resting for at least 3 minutes. 
4 A 1-hour (± 15 minutes) EEG will be collected during Part A (SAD) at screening under sleep deprived conditions (after only 4 hours of sleep) and 24 hour ambulatory 
EEGs will be collected from at least 30 minutes (± 10 minutes) predose until 24 hours (± 1 hour) postdose (Day 1).  During Part B (MAD), a 1-hour (± 15 minutes) EEG 
will be collected at screening under sleep deprived conditions (after only 4 hours of sleep) and a 24-hour ambulatory EEG will be collected from at least 30 minutes 
(± 10 minutes) predose (Day 1) until at least 2 hours  post morning dose (Day 2).  This will incorporate both pre- and post-Day 2 dosing.  On Days 3, 4, 5, and 6, a 2-hour 
(± 10 minutes) postdose EEG will be collected commencing at least 30 minutes predose until at least 120 minutes post morning dose.  On Day 7, a 24-hour ambulatory 
EEG will be collected from at least 30 minutes (± 10 minutes) predose until 24 hours (± 1 hour) post morning dose (Day 8).  Additional EEGs may be performed as 
deemed necessary and as data emerges from study cohorts. 
5 During Part B (MAD Cohort3), PK samples will be taken at predose and 30 minutes (± 2 minutes), 1-hour (± 5 minutes), 2-, 4-, 8- (predose for 2nd dose), 8.5-, 9-, 10-, 12- and 
16- hours (± 15 minutes) postdose (Days 1 and 7 only).  Note that the 8.5-, 9-, 10-,12 and 16-hour timepoints represent 0.5-, 1-, 2-, 4-, and 8 hours after the 2nd dose).


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Appendix 4 
KTX-101 Normal Ranges for Vital Signs and ECG Parameters  
VITAL SIGNS 
Parameter 
Normal Range 
Units 
Pulse Rate 
50 – 100 
beats per minute (bpm) 
Systolic Blood Pressure 
90 - 140 
mm Hg 
Diastolic Blood Pressure 
40 - 90 
mm Hg 
Respiratory Rate 
10 - 22 
respirations per minute 
Oral Temperature 
35.5 – 37.5 
°C 
Pulse Oximetry 
≥ 95 
% 
 
ECG PARAMETERS 
Parameter 
Normal Range 
Units 
Heart Rate 
50 – 100  
bpm 
PR Interval 
≥ 120 to ≤ 220 
msec 
QRS Duration 
< 120  
msec 
QT Interval 
< 500 
msec 
QTcB  
≤ 450 (both genders) 
msec 
QTcF 
≤ 450 (both genders) 
msec 
 
 


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Appendix 5 
List of Laboratory Tests 
Hematology: 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count with differential  
 
Urinalysis:  
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite  
Blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
If there are any abnormalities considered clinically significant, the urine 
sample will be sent for microscopic examination. 
 
Serology: 
HBsAg, HCV, and HIV 
 
Serum Chemistry: 
Albumin (ALB) 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT; SGPT) 
Aspartate aminotransferase (AST; SGOT) 
Bicarbonate 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Chloride (Cl) 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH) 
Phosphate 
Potassium (K) 
Sodium (Na) 
Thyroid stimulating hormone (TSH) 
Free triiodothyronine (T3) 
Free thyroxine (T4) 
Total bilirubin 
Total protein 
 
Coagulation:  
Prothrombin time (PT) 
Activated partial thromboplastin time (PTT) 
 


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Serum human chorionic gonadotropin (hCG) (only for females who are not 
diagnosed as postmenopausal) 
 
Urine pregnancy test 
Urine Drug Screen for benzodiazepines, cannabinoids, methadone, opiates, 
sympathomimetic amines, and cocaine.   
Panel Drug Screen for Amphetamines (AMP) Methamphetamines (MET), 
Methadone (MTD), Barbiturates (BAR), Benzodiazepines (BZO), Cocaine 
(COC), Opiates (OPI), 3,4-Methylenedioxymethamphetamine (MDMA), 
Phencyclidine (PCP), Tetrahydrocannabinol (THC)  
 
Normal reference ranges will be included in the Study Procedures Manual and /or Laboratory Manual. 


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Appendix 6 
Country-Specific Safety Reporting (Australia) 
For clinical sites in Australia, the following local requirements apply, in addition to safety reporting requirements discussed in the 
main protocol. 
Significant Safety Issue 
In Australia, an SSI is defined as “a safety event that could adversely affect the safety of subjects or materially impact on the 
continued ethical acceptability or conduct of the trial” (Reference:  NHMRC [2016] Guidance:  Safety monitoring and reporting in 
clinical trials involving therapeutic goods). 
Kinoxis is responsible for reporting to the Australian Therapeutic Goods Administration (TGA) in a timely fashion for any SSIs that 
occur at any site on the study worldwide. 
Urgent Safety Measure  
In Australia, USMs are one type of SSI where Sponsors or trial investigators act immediately to protect participants from an 
immediate hazard to their health and safety.” (Reference:  NHMRC (2016).  Guidance: Safety monitoring and reporting in clinical 
trials involving therapeutic goods) 
Kinoxis is responsible for reporting to the Australian TGA and the HREC (Human Research Ethics Committee) within 24 hours of 
learning of any USMs that occur at any site on the study worldwide. 
 

SAP_001.pdf: 
C O N FI D E N TI A L
           Pa ge 1 of 2 8
St atistic al A n al ysis Pl a n
A P H A S E 1 S T U D Y I N V E S TI G A TI N G T H E S A F E T Y, 
T O L E R A BI LI T Y A N D P H A R M A C O KI N E TI C S O F 
K N X 1 0 0 I N H E A L T H Y V O L U N T E E R S
Pr ot oc ol N u m ber : K T X -1 0 1
S A P Versi o n a n d date: Fi nal v 3. 0 0 1 -Se p -2 0 2 3
S T U D Y D R U G:
K N X 1 0 0
P R E P A R E D F O R :
Ki n oxis T her a pe utics Pt y Lt d ( Ki n oxis)
S uite 2 0 1, 6 9 7 B urke R o a d
C a m ber well Vict ori a 3 1 2 4 A ustr ali a
P R E P A R E D B Y :
All uce nt
2 0 0 0 Ce nter gree n W a y, S uite 3 0 0
C ary, N C 2 7 5 1 3


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d
Statistical A nal ysis Pla n
Pr ot oc ol N u m ber: K T X -1 0 1
Fi na Versi o n 3. 0 , 0 1 -Se p -2 0 2 3
C O N FI D E N TI A L
           Pa ge 2 of 2 8
A p pr o v al Si g n at ure P a ge All uce nt
D oc u me nt A ut h or: A n na T o m ki ns
Bi ostatisticia n II
Date
D oc u me nt Re vie wer: Kris C h o w ni n g 
Direct or, Bi ostatistics , Bi ostatistics
Date
Ki n o xis T her a pe utics Pt y Lt d.
D oc u me nt Re vie wer :  Ti na S o ulis
V P, Cli nical Strate g y a n d D e vel o p me nt
Date
D oc u me nt Re vie wer: S har o n Ha n e graaf
V P, Dr u g De vel o p me nt
Date
Bi o p h ar m ace utics C o ns ult a nt
D oc u me nt A ut h or: A n na T o m ki ns
D oc u me nt Re vie wer: Kris C h o w ni n g 
Direct or, Bi ostatistics , Bi ostatistics
D oc u me nt Re vie wer: S har o n Ha n e graaf
V P, Dr u g De vel o p me nt
D oc u me nt Re vie wer :  Ti na S o ulis


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 3  of 2 8  
 
 
 
 
 
 
 
P K Secti o n A ut h or :  Mar garet D o hert y  
C o ns ulta nt P har mac o ki neticist  
 
Date  
 
 
 
 
 
 
 
 
 
0 7 - S e p - 2 0 2 3  |  1 4 : 4 0  A E S T


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 4  of 2 8  
 
Re visi o n Hist or y  
 
S A P Re visi o n C hr o n ol o g y:  
 
 
1. 0  
2 5 -J ul y-2 0 2 2  
I nitial Versi o n 
1. 1  
1 4 -Fe b -2 0 2 3  
U p date f or pr ot oc ol versi o n 4 . 0 
1. 2  
2 8 -A pr -2 0 2 3  
U p date f or pr ot oc ol v ersi o n 5. 0  a n d 
c o m me nts  
2. 0  
0 4 -Ma y -2 0 2 3  
Sec o n d Versi o n  
2. 1  
0 3 -A u g -2 0 2 3  
U p date f or pr ot oc ol versi o n 6. 0  
2. 2  
3 0 -A u g -2 0 2 3  
U p date d P K secti o n a d diti o ns a n d 
c o m me nts  
3. 0  
0 1 -Se p -2 0 2 3  
T hir d Versi o n  
 
 
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 5  of 2 8  
 
 
C o nt e nts  
1  
I ntr o d u cti o n ............................................................................................................................. 8  
2  
St u d y O bjecti ves a n d E n d p oi nts  ............................................................................................. 8  
3  
St u d y Desi g n  ........................................................................................................................... 9  
3. 1  
Ge neral Descri pti o n .......................................................................................................... 9  
3. 2  
Ra n d o mizati o n a n d Bli n di n g  .......................................................................................... 1 0  
3. 3  
Sa m ple Siz e  .................................................................................................................... 1 1  
3. 4  
C o h ort Re vie w C o m mittee  ............................................................................................. 1 1  
3. 5  
I nteri m A nal ysis ............................................................................................................. 1 1  
4  
A nal ysis Sets/ P o p ulati o ns  ..................................................................................................... 1 2  
4. 1  
Safet y Set ........................................................................................................................ 1 2  
4. 2  
Per Pr ot oc ol Set  .............................................................................................................. 1 2  
4. 3  
P har mac o ki netic Set  ....................................................................................................... 1 2  
5  
Ge neral C o nsi derati o ns  ......................................................................................................... 1 2  
5. 1  
Ge neral Data Ha n dli n g  ................................................................................................... 1 2  
5. 2  
Ge neral Defi niti o ns  ........................................................................................................ 1 3  
5. 3  
Data I m p utati o n R ules  .................................................................................................... 1 4  
5. 4  
Visit Wi n d o ws  ................................................................................................................ 1 4  
6  
A nal ysis Met h o ds .................................................................................................................. 1 4  
6. 1  
St u d y S u bje ct Data  ......................................................................................................... 1 4  
6. 1. 1  
S u bject Dis p ositi o n  ..................................................................................................1 4  
6. 1. 2  
Pr ot oc ol De viati o ns  ..................................................................................................1 5  
6. 1. 3  
De m o gra p hic a n d Baseli ne C haracteristics  .............................................................1 5  
6. 1. 4  
Me dical Hist or y  .......................................................................................................1 5  
6. 1. 5  
Pri or a n d C o nc o mita nt Me dicati o n  ..........................................................................1 5  
6. 1. 6  
St u d y Dr u g E x p os ure a n d C o m plia nce  ....................................................................1 6  
6. 2  
Efficac y  .......................................................................................................................... 1 6  
6. 3  
P har mac o ki netics  ........................................................................................................... 1 6  
6. 4  
Safe t y .............................................................................................................................. 2 0  
6. 4. 1  
A d verse E v e nts  ........................................................................................................2 0  
6. 4. 2  
Cli nical La b orat or y E val uati o ns  ..............................................................................2 1  
6. 4. 3  
Vital Si g ns  ................................................................................................................2 2  
6. 4. 4  
Tele metr y  .................................................................................................................2 2  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 6  of 2 8  
 
6. 4. 5  
Electr ocar di o gra m ( E C G)  ........................................................................................2 2  
6. 4. 6  
Electr oe n ce p hal o gra m ( E E G)  ..................................................................................2 3  
6. 4. 7  
Gastr oi ntesti nal S y m pt o ms  ......................................................................................2 3  
6. 4. 8  
C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S)  ................................................2 3  
6. 4. 9  
P h ysical E x a mi nati o ns  .............................................................................................2 4  
6. 4. 1 0  Ne ur ol o gical E x a mi nati o ns  ......................................................................................2 4  
7  
Refere n ces  ............................................................................................................................. 2 5  
8  
A P P E N DI C E S  ...................................................................................................................... 2 7  
8. 1  
A P P E N DI X 1: Partial D ate C o n ve nti o ns  ....................................................................... 2 7  
Al g orit h m f or Treat me nt E mer ge nce of A d v erse E ve nts:  ........................................................ 2 7  
Al g orit h m f or Pri or / C o nc o mita nt Me dicati o ns: ...................................................................... 2 8  
 
 
 
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 7  of 2 8  
 
A B B R E V I A TI O N S 
A E  
A d verse e ve nt  
A T C  
A nat o mic T hera pe utic Class  
B MI  
B o d y mass i n de x  
B P  
Bl o o d press ur e  
CI  
C o nfi de nce I nter val  
C T C A E  
C o m m o n Ter m i n ol o g y Criteria f or A d verse E vents  
C R C  
C o h ort Re vie w C o m mittee  
C R F  
Case re p ort f or m  
C S R  
Cli nical st u d y re p ort  
E C G  
Electr ocar di o gra m  
E E G  
Electr oe n ce p hal o gra m  
E O S  
E n d of st u d y  
F A S  
F ull a nal ysis set  
FI H  
First -i n-h u ma n  
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
L L N  
L o w er li mit of n or mal  
L L O Q  
L o w er li mit of q ua ntificati o n  
M A D  
M ulti ple asce n di n g d os e  
Me d D R A  
Me dical Dicti o nar y f or Me dical Affairs  
P P  
Per P r ot oc ol  
P K  
P har mac o ki netics  
P T  
Preferre d Ter m  
R A C  
Acc u m ulati o n rati o  
S A E  
Seri o us a d verse e ve nts  
S A D  
Si n gle asce n di n g d os e  
S A F  
Safet y a nal y sis set 
S A P  
Statistical A nal ysis Pla n  
S D  
Sta n dar d de viati o n  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nt  
T E S A E  
Treat me nt -e mer ge nt s eri o us a d verse e ve nt  
U L N  
U p per li mit of n or mal  
U L O Q  
U p per li mit of q ua ntificati o n  
 
 
 
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 8  of 2 8  
 
1  I N T R O D U C TI O N 
T he statistical a n al ysis pla n ( S A P) det ails t he pla n ne d statistical a nal ysis  met h o ds re q uir e d t o 
a d dress t he st u d y o bje cti ves as descri be d i n Ki n o xis T hera pe utics Pt y Lt d’s  ( Ki n o xis) pr ot oc o l 
K T X -1 0 1: A P hase 1 St u d y I n vesti gati n g t he Safet y, T olera bilit y a n d P har mac o ki netics of 
K N X 1 0 0 i n Healt h y V ol u nteers.  
T h is S A P s h o ul d be rea d i n c o nj u ncti o n wit h t he st u d y pr ot oc ol, case re p ort f or m ( C R F) , a n d a n y 
ot her a p plica bl e st u d y d oc u me nts . T h is versi o n of t h e S A P is base d o n t h e pr ot oc ol  v ersi o n 6. 0 , 
date d 0 7 J ul y  2 0 2 3 . Cha n ges t o t h e pr ot oc ol ma y res ult i n s u bse q ue nt c ha n ges t o t he S A P. T he 
fi nal, s p o ns or-a p pr o v e d versi o n of t he S A P m ust occ ur pri or t o d ata bas e l oc k .  
2  S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  
O bjecti ves  
E n d p oi nts  
Pri m ary  
 T he pri mar y o bje cti ves of t his st u d y 
are t o e v al uate t he safet y a n d 
t olera bilit y of K N X 1 0 0 a d mi nistere d 
orall y as a si n gle as ce n di n g d ose a n d 
m ulti ple asce n di n g d os es i n healt h y 
v ol u nteers.  
 I n ci de nce of treat me nt-e mer ge nt 
a d verse e ve nts ( T E A Es) a n d 
treat me nt-e mer ge nt seri o us a d verse 
e ve nts ( T E S A Es), relate d A Es, A Es 
lea di n g t o disc o nti n uati o n, a n d A Es b y 
se verit y 
 Cli nical la b orat or y testi n g fr o m 
pr ot oc ol -s pecifi e d sta n dar d uri ne a n d 
bl o o d tests, i ncl u di n g li ver f u ncti o n 
tests ( L F Ts) a n d t h yr oi d f u ncti o n tests 
( T F Ts: trii o d ot h yr o ni ne [ T 3], 
t h yr o xi ne [ T 4], t h yr oi d sti m ulati n g 
h or m o ne [ T S H])  
 C ha n ge i n cli nical o bser v ati o ns fr o m 
baseli ne, i ncl u di n g b o d y te m perat ur es, 
vital si g ns, electr o car di o gra ms 
(E C Gs ), electr oe nce p hal o gra ms 
(E E Gs ) 
Sec o n d ary  
 T o deter mi ne t he p h ar mac o ki netic 
( P K) pr ofile of K N X 1 0 0 a n d its 
meta b olites  f oll o wi n g a d mi nistrati o n 
of K N X 1 0 0 as si n gle  a n d m ulti ple  oral 
d ose s a d mi nistere d o nce a n d t wice 
dail y  i n he alt h y v ol u nteers. 
 Ma xi m u m o bser ve d c o nce ntrati o ns 
( Cma x ) f oll o wi n g d ose a d mi nistrati o n 
 Ti me of C ma x ( Tma x ) f oll o wi n g d ose 
a d mi nistrati o n  
 Area u n d er t he c o nce ntr ati o n -ti me 
c ur ve ( A U C) fr o m ti me zer o t o last 
q ua ntifia ble c o nce ntrati o n ( A U C 0 -last), 
fr o m ti me zer o t o 2 4 h o urs p ost-d ose 
a d mi nistrati o n ( A U C 0 -2 4), a n d, as data 
per mit, fr o m ti me zer o t o e xtra p olate d 
t o i nfi nit y ( A U C0 -∞) 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 9  of 2 8  
 
 As data per mit, a d diti o nal  dis p ositi o n 
para meters i ncl u di n g t er mi nal half -life 
(t1/ 2), v ol u me of distri b uti o n ( Vz/ F), 
a n d oral cleara nce ( C L/ F) ma y b e 
calc ulate d  
 Acc u m ulati o n Rati o ( R A C) f or C ma x  
a n d A U C 0 -2 4; Da y 7 vs D a y 1 ( M A D 
p hase o nl y)  
 Ot her P K para meters will be 
calc ulate d as  dee m e d a p pr o priate a n d 
as referre d t o i n Secti o n 8. 7 of t he 
pr ot oc ol  
 
3  S T U D Y D E SI G N  
3. 1  Ge neral Descri pti o n  
T his is a P hase 1, first -i n-h u ma n ( FI H), si n gle  site, si n gle treat me nt, t w o-part,  d o u ble -bli n d, 
place b o -c o ntr olle d, ra n d o mize d, si n gle asce n di n g d ose ( S A D) / m ulti ple asce n di n g d os e ( M A D) 
st u d y. T h e pla n ne d e nr oll me nt is a p pr o xi matel y 6 4 male a n d fe male s u bjects. T he t otal n u m ber of 
s u bjects will de pe n d o n t he n u m ber of d os e le vels assesse d i n d ose-escal ati o n. C o m plete d s u bjects 
will ha ve recei ve d eit her K N X 1 0 0 (acti ve st u d y dr u g) or place b o. S u bjects w h o disc o nti n ue will 
be re pla ce d t o a c hie ve t h e tar gete d n u m b er of e val ua ble s u bjects i n eac h c o h ort.  
Healt h y s u bjects w h o meet all eli gi bilit y criteria will be se q ue ntiall y e nr olle d a n d assi g ne d t o a 
si n gle c oh ort i n C o h orts 1 -4  i n Part A  ( S A D) of t h e st u d y or i n C o h orts 1 -3 i n Part B of t he st u d y . 
Eac h c o h ort select e d will e val uate 8 s u bjects w h o will be ra n d o ml y assi g ne d wit h a rati o of 6: 2  t o 
recei v e eit her K N X 1 0 0 or place b o. Eac h c o h ort will be e nr olle d se q ue ntiall y, a n d t he s u bse q ue nt 
d ose i ncrease will be bas e d o n t he C o h ort Re vi e w C o m mittee ( C R C) e val uati o n of data k n o w n t o 
date.  A d diti o nal c o h orts ma y b e a d d e d as re q uire d, base d o n saf et y pr ofile a n d C R C a ut h orizati o n.  
Part A ( S A D) will i nitiall y  d os e  t w o se nti nel s u bjects ( o ne assi g ne d t o K N X 1 0 0 a n d o ne assi g n e d 
t o place b o)i n C o h ort 1. T he ce nter will re vie w safet y a n d t olera bilit y u p t o a n d i ncl u di n g t he 4 8 -
h o ur ti me p oi nt f or t he se nt in el s u bjects bef ore d osi n g t he re m ai ni n g s u bjects i n t he d os e c o h ort.  
T he C R C will be i nf or me d a n d a ut h orize t he decisi o n t o c o nti n ue wit h t he re mai n der of t he c o h ort 
d osi n g. Eac h s u bject will recei v e o ne  d ose, a d mi nistere d orall y, of st u d y dr u g. All s u bj ects i n eac h 
c o h ort will ha v e t heir data , u p t o a n d i ncl u di n g t he 3 0 -h o ur p ost -d ose ti me p oi nt , e val uate d f or 
safet y a n d t olera bilit y b y t he C R C bef ore o pe ni n g t he ne xt d ose c o h ort base d o n assess me nt of all 
a vaila ble data. T h e d osi n g sc h e d ule ma y be e xte n d e d if a d diti o nal o bser vati o ns are nee de d at a 
partic ular c o h ort. I n t he a bse nce of u n acce pta ble A Es, t he C R C ma y d eci de t o o pe n t he ne xt c o h ort 
bef ore t he y h a ve re vie we d all dat a fr o m all 8 e v al ua ble s u bjects w h o h a v e c o m plete d u p t o a n d 
i ncl u di n g t he 3 0-h o ur p ost -d ose ti me p oi nt.  S u bjects will be h o use d i n t he cli nic fr o m  Da y -3 pri or 
t o st u d y dr u g a d mi nistrati o n a n d will re mai n i n-h o use f or 3 0 h o urs p ost -d ose ( Da y 2) f or P K a n d 
safet y assess me nts. 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 0  of 2 8  
 
Part B ( M A D) will e val u ate u p t o 3 d oses base d o n t he d ose s esta blis he d d uri n g Part A ( S A D). 
Eac h s u bject i n C o h orts 1 a n d 2 will recei v e st u d y dr u g  f or 7 da ys, a d mi nistere d o nce dail y. 
S u bjects i n C o h ort 3 will recei v e st u d y dr u g  f or 7 da ys, a d mi nistere d t wice dail y. All s u bjects i n 
eac h Part B ( M A D ) c o h ort will ha ve t heir A E, P K, a n d e lectr o e nce p hal o gra p h y ( E E G) data, 
ac q uire d u p t o a n d i n cl u di n g Da y 8, e val uat e d f or safet y a n d t olera bilit y b y t he C R C bef ore 
o pe ni n g t he n e xt hi g her d ose c o h ort. S u bjects will be h o use d i n t he cli nic fr o m Da y -3 pri or t o 
st u d y dr u g a d mi nistrati o n a n d will re mai n i n -h o use f or 2 4 h o urs p ost  m or ni n g d ose ( Da y 8) f or 
P K a n d safet y ass ess me nt s. 
T he st u d y will be c o m prise d of 3 peri o ds: Scree ni n g ( u p t o 2 8 d a ys); Treat me nt ( 1 da y f or Part A 
(S A D ) s u bjects a n d 7 d a ys f or Part B ( M A D ) s u bjects); a n d F oll o w -u p. S u bjects will ha ve a 
f oll o w-u p visit 7 da ys after t he last d ose. As S A D d osi n g is a si n gle d o se o n Da y 1, f oll o w -u p 
will occ ur o n Da y 7.  Part B ( M A D ) C o h orts 1 a n d 2 d osi n g i n v ol ves si n gl e dail y d osi n g o n Da ys 
1 t o 7, wit h a f oll o w -u p visit occ urri n g o n Da y 1 4.  Part B ( M A D) C o h ort 3 d osi n g i n v ol ves t wice 
dail y d osi n g o n Da ys 1 t o 7, wit h a f oll o w -u p visit occ urri n g o n Da y 1 4.  
Fi g ure 1 . St u d y P h ases a n d Acti vities 
 Part A  –  S A D si n gle d os e  
 Part B  –  M A D 7 d a ys  
 
 
 
 
 
3. 2  Ra n d o mizati o n a n d Bli n di n g  
S u bjects will be ce ntrall y ra n d o mize d t o treat me nt i n a 6: 2 rati o wit hi n eac h assi g n e d c o h ort. T he 
first 2 se nti nel s u bjects will be assi g ne d t o treat me nt i n a 1: 1 rati o s uc h t hat 1 s u bject recei ves 
K N X 1 0 0 a n d t he ot her recei ves pla ce b o. O nce eli gi bilit y i s re-c o nfir me d ( Da y -1), s u bjects will 
be ra n d o mize d via a ra n d o mizati o n list.  
T he st u d y will be perf or me d i n a d o u ble -bli n d fas hi o n. T he i n vesti gat or a n d st u d y staff (i ncl u di n g 
la b pers o n nel), t he s u bjects, t he m o nit ors, a n d t he S p o ns or’s staff will re main bli n de d t o treat me nt 
assi g n me nt u ntil data bas e l oc k. T he i n vesti gat or will recei ve seale d e n vel o pes wit h t he i n di vi d ual 
ra n d o mizati o n per s u bject t o be o pe ne d i n t he case of e mer ge nc y o nl y. T o e ns ure st u d y bli n di n g, 
t he acti ve a n d pla ce b o will be pr o vi ded i n i de ntical ca ps ules a n d a n e q ui val e nt n u m ber of ca ps ules 
will be a d mi nistere d t o s u bjects recei vi n g pl ace b o.  
T he site p har mac y staff will be u n bli n de d. A d diti o nall y, t he f oll o wi n g r oles ma y b e u n bli n de d: 
U n bli n de d bi ostatistics tea m t hat pre pares t he r a n d o mizati o n materials a n d ha n dles treat me nt -
re veali n g d ata pri or t o data base l oc k; selecte d st u d y S p o ns or pers o n nel w h o are n ot dir ectl y 
i n v ol ve d i n t he c o n d uct of t he st u d y; a n d t he dr u g -rec o nciliati o n cli nical res earc h ass ociate ( C R A). 
A list of u n bli n d e d i n di vi d uals will be mai ntai ne d i n st u d y files.  
3 C o h orts  
2 4 H V  
1 0 -3 5 m g  
6: 2 Acti ve vs Place b o  
 
 
 
 
 
4  C o h orts  
4 0 H V  
5 -5 0 m g  
6: 2 Acti ve vs Place b o  
F oll o w u p t o at 
least 7 da ys after 
last d ose 
Scree ni n g u p 
t o 2 8 da ys  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 1  of 2 8  
 
S u bjects ma y be u n bli n d e d i n t he e ve nt t hat a n A E of Gra de 3 or greater is re p orte d i n 2 or m ore 
s u bjects t o s u p p ort C R C data re vie w a n d d ecisi o ns re gar di n g d ose escalati o n or st o p pi n g criteria. 
If dee m e d necessar y, t he C R C ma y b e re q uir e d t o brea k t he ra n d o mizati o n c o de.  
3. 3  Sa m ple Size  
T he sa m ple siz e f or t his st u d y is pla n ne d f or a p pr o xi matel y 6 4  s u bjects. T he sa m ple siz e f or t his 
st u d y has bee n sele cte d wit h o ut perf or mi n g a f or mal sa m ple siz e calc ulati o n.  
3. 4  C o h ort Re vie w C o m mittee  
A n i n de pe n d e nt C R C will o versee t he pr o gress of t he st u d y a n d peri o dicall y re vie w t he accr ui n g 
safet y d ata. T he C R C is i nte n de d t o e ns ure t hat treat me nt d oes n ot p ose u n d ue ris k t o s u bjects. T he 
C R C will i ncl u de a n a p pr o priate gr o u p of pr ofessi o nal s pecialties, i ncl u di n g at a mi ni m u m, t he 
f oll o wi n g: bli n de d pri mar y i n v esti gat or ( PI ) or dele gate  ( m ust be a p h ysicia n), bli n de d me dical 
m o nit or or dele gate  ( m ust be a p h ysicia n), bli n de d ne ur ol o gist wit h e x pertise i n E E G a nal ysis a n d 
i nterpretati o n, a n d a bli n de d p har mac o ki neticist.  
F or Part A ( S A D), t he C R C will re vie w all safet y a n d P K data of t he se nti nel s u bjects, c ollecte d 
u p t o t he 3 0 -h o ur p ost -d ose ti me p oi nt, t o e na ble t he decisi o n t o e nr oll t he rest of t he c o h ort.  A n y 
A E i n a se nti nel s u bject assesse d as relate d t o st u d y me dicati o n ma y tri g ger t he nee d f or a safet y 
e val uati o n b y t he C R C t o deter mi ne if a d diti o nal s u bjects i n t he c o h ort m a y b e d ose d.  T h e C R C 
will als o c o n d uct a bli n de d, c o h ort -escalati o n re vie w after t he fi nal s u bject i n a c o h ort has bee n 
d ose d, usi n g safet y dat a  fr o m all s u bjects t hr o u g h at least t he 3 0-h o ur p ost -d ose ti me p oi nt, as well 
as all a vaila ble bli n de d P K a n d safet y d ata fr o m t he c urre nt a n d pre vi o us c o h orts.  
F or Part B ( M A D), t he C R C will re vie w all s a fet y a n d P K d ata fr o m eac h c o h ort c ollecte d u p t o 
a n d i ncl u di n g t he 2 4 -h o ur p ost -d ose ti me p oi nt o n Da y 8. A d diti o nall y,  th e fre q ue n c y a n d se v erit y 
of t he f oll o wi n g e ve nts a n d fi n di n gs will be use d t o deter mi ne t he acce pt a bilit y of escalati o n t o t he 
ne xt c o h ort:  
 Seri o us A Es  
 A Es lea di n g t o st u d y disc o nti n uati o n  
 A Es  
 Cli nicall y si g nifica nt la b orat or y, E E G, a n d E C G fi n di n gs  
 St u d y m e dicati o n se nsiti vities a n d reacti o ns  
3. 5  I nteri m A nal ysis 
T here is n o f or mal i nteri m a nal ysis pla n ne d f or t his st u d y. O n g oi n g c o h ort re vie ws will b e 
perf or me d f or d ose escalati o n decisi o ns as descri b e d i n secti o n 3. 4.  
T he fi nal a nal ysis will occ ur o nce all s u bjects c o m plete t heir e n d of st u d y ( E O S) visit or 
disc o nti n ue  fr o m t he st u d y. 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 2  of 2 8  
 
4  A N A L Y SI S S E T S/ P O P U L A TI O N S  
4. 1  Safet y Set  
T he Safet y Set ( S A F) will i ncl u de all s u bjects w h o recei ve d at least o ne d ose of st u d y tr eat me nt. 
S u bjects will be a nal yze d acc or di n g t o t he treat me nt recei ve d. T he S A F will be use d f or all safet y 
s u m maries. 
4. 2  Per Pr ot oc ol Set  
T he Per Pr ot oc ol Set ( P P) will i ncl u de all s u b jects w h o recei v e d at least o ne d ose of a n y a m o u nt 
of K N X 1 0 0 a n d d o n ot h a ve maj or pr ot oc ol vi olati o ns as defi ne d i n Secti o n 9. 9 of t he pr ot oc ol. A 
fi nal deter mi nati o n of i ncl usi o n i n t he P P will be ma de b y a bli n de d tea m pri or t o data base l oc k 
a n d u n bli n d i n g. T he P P ma y be use d o n select bi o mar ker e n d p oi nts. S u bjects will be a nal yze d 
acc or di n g t o t he ra n d o mi ze d treat me nt assi g n m e nt . 
4. 3  P har mac o ki netic Set  
T he P har mac o ki n etic  ( P K) Set will i ncl u de all  s u bjects w h o recei ve d at least o ne d ose of a n y 
a m o u nt of K N X 1 0 0 a n d ha d s ufficie nt plas ma K N X 1 0 0 c o nce ntrati o n dat a f or calc ulati o n of  at 
least o ne P K para meter  (a m o n g A U C0 -2 4 , Cma x  or T ma x ). 
S u bjects wit h pr ot oc ol vi olati o ns will be assesse d o n a partici pa nt -b y -partici pa nt basis f or 
i ncl usi o n i n t he P K P o p ulati o n . 
5  G E N E R A L C O N SI D E R A TI O N S  
5. 1  Ge neral Data Ha n dli n g  
All safet y a nal yses will be c o n d ucte d base d o n S A S 9. 4 or hi g her.   
Place b o s u bjects will be p o ole d acr oss c o h orts.  
Data i n t he cli nical dat a b ase as w ell as ve n d or d ata will be prese nt e d i n b y -s u bject data listi n gs.  
C o nti n u o us d ata will be s u m marize d b y  st u d y p art a n d c o h ort base d o n n, m ea n, me dia n, sta n d ar d 
de viati o n ( S D), first q uartile ( Q 1), t hir d q uartile ( Q 3) , mi ni m u m val ue, a n d ma xi m u m val ue. 
Cate g orical d ata will b e s u m marize d b y  st u d y part a n d  c o h ort usi n g fre q ue n c y c o u nts a n d 
perce nt a ges. U nless ot h er wise state d, t he de n o mi nat or of perce nta ges will be t he n u m ber of 
partici pa nts i n t he p o p ulati o n/ c o h ort or t he n u m ber wit h n o n -missi n g data.   
 I n s u m maries pertai ni n g t o s u bject de m o gra p hics a nd s u bject dis p ositi o n, t he n u m ber of 
missi n g val ues will be prese nte d as a se parate cate g or y wit h n o perce nt a ge, b ut o nl y if o ne 
or m ore s u bjects are missi n g data.  
 C o u nts of zer o will be prese nte d wit h o ut perce nta ges.  
N o i nfere ntial statistics will be pr o d uce d f or a n y safet y e n d p oi nts.  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 3  of 2 8  
 
Relati ve t o t he n u m ber of di gits after t he deci mal i n t he ra w d ata, s u m mar y statistics will ha ve t he 
f oll o wi n g n u m ber of di gits after t he deci mal:  
 Mi ni m u m a n d Ma xi m u m: sa me n u m ber of si g nifica nt di gits as t he ra w data  
 Mea n, Me dia n, Q 1, a n d Q 3: o ne a d diti o nal si g nifica nt di git  
 S D: t w o a d diti o nal si g nifica nt di gits  
 Perce nta ges < 1 0 0 % will be re p orte d t o o ne deci m al place a n d perce nta ges of 1 0 0 % will be 
re p orte d wit h n o d eci mal place. T he n u m ber a n d perce nt a ge will be prese nte d i n t he f or m 
of X X ( X X. X % ). P erce nt a ge val ues of less t ha n 0. 1 % will be prese nte d as X X ( < 0. 1 %).  
 S u m mar y statistics will n ot e x cee d f o ur di gits after t he d eci mal.  S o me la b orat or y 
para meters or ot her d ata ma y re q uire d e viati o n fr o m t his r ule.  
F or cli nical la b orat or y data, res ults re p orte d as bel o w t he l o wer li mit of q ua ntificati o n ( L L O Q) or 
a b o ve t he u p per li mit of q ua ntificati o n ( U L O Q) will be re place d b y t h e L L O Q a n d U L O Q, 
res pecti vel y, t o e ns ure i n cl usi o n i n a p plica ble ta bl es a n d fi g ures, b ut will be prese nte d i n a p plica ble 
listi n gs as ori gi n all y re p orte d. 
All data u p t o t he ti me of st u d y c o m pleti o n/ wit h dra wal fr o m t he st u d y will be i ncl u de d i n t he 
a nal ysis, re gar dless of d urati o n of treat me nt.  
N u m beri n g f or d ata dis pla ys will be base d o n I nter nati o nal C ou ncil f or Har m o nizati o n (I C H)  E 3.  
5. 2  Ge neral Defi niti o ns  
 
Varia ble  
Defi niti o n  
St u d y Da y  
 St u d y Da y = d ate of i nterest –  treat me nt start date + 1, w he n t he 
date of i nterest > = tr eat me nt start date; 
 ot her wise, St u d y Da y = d ate of i nterest –  treat me nt start date. 
N ote: if eit her dat e is missi n g, St u d y Da y  calc ulati o ns will n ot be 
perf or me d. S h o ul d i m p utati o n be perf or me d, t he n St u d y D a y ma y b e 
c o m p ute d, w here a p pr o priate . 
Baseli ne  
F or E C G dat a, baseli ne is d efi ne d as t he a vera ge of u p t o t hree 
meas ure me nts ta k e n  at t h e p re-d os e ti me p oi nt o n t he Da y 1 Visit if 
a vaila ble; ot her wis e, bas eli ne is defi ne d as t he l ast si n gle traci n g 
meas ure me nt ta ke n pri or t o t he first d ose of st u d y treat me nt.  
F or E E G d ata, bas eli ne is defi ne d as t he assess me nt c ollecte d at t he 
Scree ni n g Visit  ( Da y -2) i n w hic h t he patie nt was i n a slee p 
de pri ve d state . 
F or all ot her e n d p oi nts, baseli ne is d efi ne d as t he l ast n o n -missi n g 
val ue c ollecte d pri or t o r ecei vi n g t he first d ose of st u d y treat me nt 
( base d o n dat e a n d ti me of a d mi nistrati o n as a p plica ble ). F or 
e n d p oi nts wit h b ot h pla n ne d pre -d os e a n d p ost -d ose ti me p oi nt 
assess me nts o n Da y 1, o nl y pre -d ose ass ess me nts will be c o nsi dere d 
as a ca n di d ate f or baseli n e.  F or M A D C o h ort 3, vital si g ns 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 4  of 2 8  
 
assess me nts o n Da y 1 ass ociate d wit h t he sec o n d d ose  (i.e., e v e ni n g) 
will n ot be c o nsi dere d as a ca n di dat e f or b aseli ne.   
P ost -baseli ne  
Defi ne d as v al ues c ollecte d after recei pt of t he first d ose of st u d y 
treat me nt ( bas e d o n date a n d ti me of a d mi nistrati o n as a p plica ble) 
C ha n ge fr o m 
Baseli ne  
Defi ne d as: P ost -bas eli ne val ue  –  Baseli ne  val u e   
D urati o n o n St u d y  (i n 
da ys)  
E n d of st u d y d ate –  ra n d o mizati o n date + 1  
B MI ( k g/ m 2) 
B MI is c ollect e d i n t he cli nical data base  
A ge  ( yr) 
A ge is c ollecte d i n t he cli nical data bas e   
St u d y C o m pleti o n  
Defi ne d as atte n da n ce at t he E n d of St u d y ( E O S) Visit.  
 
5. 3  Data I m p utati o n R ules  
Ge nerall y, missi n g dat a will n ot be i m p ute d, a n d will be prese nte d as c ollecte d i n t he st u d y 
data base.  
I n cases w here a d vers e e ve nt or me dicati o n dates are missi n g, t he i m p utati o n met h o ds descri be d 
i n A p pe n di x 1 will be use d t o deter mi ne fla gs f or treat me nt -e m er ge nt e ve nts a n d c o nc o mita nt 
me dicati o ns.  
Ot her missi n g data met h o ds will be descri be d  wit hi n t he res pecti ve a nal ysis secti o n, as a p pr o pri ate . 
5. 4  Visit Wi n d o ws  
Data will be s u m marize d usi n g t he rec or de d n o mi nal visit val ues i n t he C R F; n o visit date 
wi n d o wi n g will be c o n d ucte d. U nsc he d ule d visit data ma y be i ncl u de d i n s u m maries of baseli ne, 
mi ni m u m/ ma xi m u m p ost -baseli ne, a n d i nci d e nce of s u bjects wit h p ote ntiall y cli nicall y si g nifi ca nt 
p ost -baseli ne res ults. U nsc he d ule d visits will als o be prese nt e d i n a p plica bl e data listi n gs . 
I n ge n eral, if m ulti ple n o n-missi n g val ues are a v aila ble at t he sa me visit /ti me p oi nt t he n t he later 
val ue will be use d i n t he a nal ysis. I n cases w here m ulti ple n o n -missi n g val u es are o n t h e sa m e dat e 
a n d ti me, t he val ue wit h t he lar ger St u d y Dat a Ta b ulati o n M o del ( S D T M) rec or d se q u e nce n u m b er 
will be use d i n t he a nal ysis .  
6  A N A L Y SI S  M E T H O D S  
6. 1  St u d y S u bject Data  
6. 1. 1  S u bject Dis p ositi o n  
T he n u m ber a n d perce nta ge  of s u bjects i n eac h a nal ysis p o p ulati o n a n d fi nal s u bject stat us 
(c o m plete d or wit h dra w n), i ncl u di n g st u d y disc o nti n uati o n reas o ns, will be pr o d uce d bas e d o n t he 
n u m ber of ra n d o mize d s u bjects. Data will be pres e nte d b y  st u d y p art a n d c o h ort . 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 5  of 2 8  
 
S u bjects c o ntri b uti n g t o eac h a nal ysis p o p ulati o n a n d fi nal dis p ositi o n stat us will be liste d.  Faile d 
eli gi bilit y criteria f or s cree n fail ures will als o be i ncl u de d i n a data listi n g.  Alc o h ol breat h test a n d 
dr u g s cree ni n g res ults will be i ncl u de d i n a data listi n g . 
6. 1. 2  Pr ot oc ol De viati o ns  
Pr ot oc ol de viati o ns will be i de ntifie d a n d classifi e d as mi n or or maj or o n t he C R F bef ore t he 
data base is l o c ke d.  Maj or p r ot oc ol de vi ati o ns will be s u m marize d b y  part,  c o h ort, a n d de viati o n 
cate g or y usi n g t he S A F  p o p ulati o n . 
A listi n g of all pr ot oc ol d e viati o ns will be pr o vi de d . 
6. 1. 3  De m o gra p hic a n d Baseli ne C haracteristics  
 
S u bject de m o gra p hics  a n d baseli ne c haracteristics  will be s u m marize d a n d liste d. T hese will 
i ncl u de a ge (as c ollecte d i n t he cli nical data base at t he Scree ni n g visit) , a ge cate g or y ( 1 8 -< 3 0, 3 0 -
< 4 0, 4 0 -< 5 0, 5 0 -5 5)  se x ( Male / Fe m ale), et h nicit y ( His pa nic or Lati n o / N ot His pa nic or Lati n o), 
race (A m erica n I n dia n or Alas ka Nati ve / Asia n / Blac k or Africa n A merica n /  Nati ve Ha waiia n 
or Pacific Isl a n der / W hite  / Ot her / N ot Re p orte d), baseli ne hei g ht (c m), baseli ne wei g ht ( k g), 
B MI ( k g/ m 2), a n d s m o ki n g stat us  ( Ne ver S m o ke d / C urre nt S m o ker / F or mer S m o ker). S u bjects 
re p orti n g m ulti ple race cate g ories will be s u m marize d u n der t he “ M ulti ple” cate g or y. Data will be 
prese nte d b y  st u d y part a n d c o h ort f or t he S A F p o p ulati o n . 
 
A listi n g of de m o gra p hi cs a n d baseli ne c h aracteristics will be pr o vi de d.  
 
6. 1. 4  Me dical Hist or y  
Ge neral 
me dical hist or y (i ncl u di n g  cli nicall y si g nifica nt diseases a n d s ur geries) 
will be 
s u m marize d b y M edical Dicti o nar y f or Me di cal Affairs ( Me d D R A) S yste m Or ga n Class  ( S O C) 
a n d Preferre d T er m  ( P T) b y  st u d y p art a n d c o h ort f or t he S A F p o p ulati o n.  A s u bject will be 
c o u nte d o nl y o nce at eac h le vel of re p orti n g. S O C will be or dere d i n acc or da nce wit h t he 
i nternati o nal a gree d u p o n s ort or der f or S O C f oll o we d b y d esce n di n g or der of o v erall P T 
i nci de nce. T he M e d D R A versi o n use d f or re p orti n g will be descri be d i n t he rele va nt ta ble a n d 
listi n g f o ot n otes. 
Ge neral me dical a n d s ur gic al hist or y will be prese nte d i n a b y -s u bject data listi n g f or t he S A F 
p o p ulati o n.  
6. 1. 5  Pri or a n d C o nc o mita nt Me dicati o n   
T he i nci de n ce of c o n c o mita nt me dicati o n use will be s u m marize d b y 
W H O Dr u g Dicti o nar y  
( W H O D D) a n at o mic t hera pe utic c he mical  ( A T C) Le vel 2 classificati o n (i.e. , t hera pe utic main 
gr o u p)  a n d preferre d na me . T he 
W H O D D v ersi o n use d f or re p orti n g will be pr o vi de d i n t he 
rele va nt ta ble a n d listi n g f o ot n otes. 
A s u bject will be c o u nte d o nl y o nce at eac h le vel of re p orti n g. Pri or me dicati o ns are t h ose w hic h 
ha ve bee n i de ntifie d t o ha ve b ee n disc o nti n ue d pri or t o t he treat me nt start date (e. g., ta ke n 
e x cl usi vel y d uri n g t he pre -t hera p y peri o d) . C o nc o mita nt t hera pies are defi ne d as all t hera p y 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 6  of 2 8  
 
o n g oi n g at t he ti me of e nr oll me nt a n d all t hera p y ot her t ha n st u d y dr u g recei ve d d uri n g t he st u d y .  
C o nc o mita nt me dicati o n use will be s u m marize d a n d prese nte d b y  st u d y p art a n d c o h ort f or t he 
S A F p o p ulati o n.  Partial start/e n d d ates will be i m p ute d acc or di n g t o A p pe n di x 1 f or t h e 
deter mi nati o n of c o nc o mita nce. Me dicati o ns will be s orte d b y d ecreasi n g f re q ue nc y of A T C 
classificati o n base d o n o verall s u bjects. Preferre d dr u g n a mes will be s orte d i n desce n di n g or der 
b y fre q ue n c y wit hi n eac h A T C classificati o n base d o n o verall s u bjects.  
All pri or a n d c o nc o mita nt me dicati o n data will be liste d i ncl u di n g t he ver bati m a n d preferre d dr u g 
na me a n d A T C Le v el 2.  
6. 1. 6  St u d y Dr u g E x p os ure a n d C o m plia nce  
St u d y dr u g a d mi nistrati o n i nf or mati o n rec or de d o n t he C R F will be prese nte d i n a data listi n g f or 
t he S A F p o p ulati o n. 
6. 2  Efficac y  
T his st u d y e nr olls healt h y v ol u nteers; effi cac y will n ot be e val uate d.  
6. 3  P har mac o ki netic s  
6. 3. 1  Plas ma P har mac o ki netic Para meters  
T he plas ma P K p ara m eters descri b e d i n t his secti o n will be deri v e d f or K N X 1 0 0 a n d met a b olites 
( data per mitti n g) bas e d o n t he plas ma c o nce ntrati o n-ti me pr ofiles as o bser ve d after t he st u d y dr u g 
a d mi nistrati o ns. Deri vati o ns will be base d o n t he act ual ela pse d ti me ( h o urs) si nce t he st u d y dr u g 
a d mi nistrati o n.  
T he p har mac o ki netic c o nce ntrati o ns 
will be pr ocesse d usi n g sta n d ar d n o n -c o m part me ntal 
a nal yti cal a p pr oac h t o deri ve t he re q u ir e d para met ers. T he s oft ware use d f or t he a nal ysis will be 
P h oe ni x ™ Wi n N o nli n ® v 8. 3 ( P harsi g ht C or p orati o n, U S A).  
T he P K para meters des cri be d i n Ta ble 4 will be deri ve d pr o vi de d t hat t he re q uire d c o nce ntr ati o ns 
data are a vaila ble.  C o n ce ntrati o ns bel o w t h e li mit of q ua ntificati o n ( B L Q) will be tr eate d as zer o 
f or descri pti ve statistics.  Mea n B L Q c o nce ntrati o ns will be prese nte d as B L Q, a n d t he sta n dar d 
de viati o n ( S D) a n d c o efficie nt of v ariati o n ( C V) will be re p orte d as n ot a p plica ble.  Missi n g 
c o nce ntr at i o ns will be e x cl u de d fr o m t he calc ulati o ns. 
 
Ta ble 4  
Plas ma P K Para meters  
W here p ossi ble, t he f oll o wi n g P K para meters of K N X 1 0 0 a n d a n y meas ura ble meta b olites will be 
deter mi ne d.  
 
 
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 7  of 2 8  
 
S A D  
Para meter ( U nit)  
Met h o d  
C ma x ( n g/ m L) 
Ma xi m u m plas ma c o nce ntrati o n 
o btai ne d directl y fr o m t he o bser ve d 
c o nce ntr ati o n vers us ti me data  
A U C 0 -∞ 
( h * n g/ m L) 
Area u n der t he plas ma c o nce ntr ati o n -ti me c ur ve fr o m ti me zer o ( pre-
d ose) e xtra p olate d t o i nfi nit y ( u nits) calc ulate d b y li near tra pez oi dal r ule 
a n d e xtra p olate d t o i nfi nit y b y t he a d diti o n of t he last q ua ntifia ble 
c o nce ntr ati o n di vi de d b y t h e ter mi nal rate c o nsta nt:  A U C 0 -last  
C last/z 
A U C 0 -last 
( h * n g/ m L) 
Area u n d er t he plas m a c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o t he 
ti me of t he last q ua ntifia ble c o nce ntr atio n at ti me “t” ( u nits), calc ulate d 
b y li near tra p ez oi dal r ule  
A U C 0 -8 
( h * n g/ m L) 
Area u n der t he plas ma c o nce ntr ati o n -ti me c ur ve fr o m ti me zer o t o 8 
h o urs after d osi n g, calc ul ate d b y li near tra pez oi dal r ule  
T ma x  ( h) 
Ti me t o ma xi m u m plas ma c o nce ntrati o n o bta i n e d directl y fr o m t he 
o bser ve d c o n ce ntr ati o n vers us ti me data  
C L/ F ( L/ h)  
Plas ma cleara nce esti mate d as d ose di vi de d b y A U C 0 -∞ 
V z / F ( L) 
v ol u me of distri b uti o n esti mate d b y di vi di n g t he a p pare nt cleara nce b y 
z 
z ( h-1 ) 
A p pare nt ter mi nal eli mi nati o n rate c o nsta nt esti mate d b y l o g -li near least-
s q uare d re gressi o n of t h e ter mi nal p art of t h e c o nce ntrati o n -ti me c ur ve 
pr ofile  
t½  ( h) 
Eli mi nati o n half -life, cal c ulate d as l n( 2)/z.   
Resi d ual area  
Perce nta ge of A U C 0 -∞ d ue t o e xtra p olati o n fr o m t he ti me of last n o n -
zer o c o nce ntr ati o n t o i nfi nit y.  
D N A U C  
D ose -n or malize d A U C, calc ulate d as A U C/ D ose w here A U C is A U C 0 -
8  a n d A U C 0 -last 
D N  C ma x  
D ose -n or malize d C ma x, calc ulate d as C ma x / D ose  
 
 
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 8  of 2 8  
 
M A D  
Para meter ( U nit)  
Met h o d  
C ma x ( n g/ m L) 
Ma xi m u m plas ma c o nce ntrati o n o btai ne d directl y fr o m t h e o bser ve d 
c o nce ntr ati o n vers us ti me data, Da y 1 a n d Da y 7  
A U C 0 -∞ 
( h * n g/ m L) 
Area u n der t h e plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o ( pre-
d ose) e xtra p olate d t o i nfi nit y ( u nits) cal c ulate d b y li n ear tra p ez oi dal 
r ule a n d e xtra p olate d t o i nfi nit y b y t h e a d diti o n of t he last q ua ntifia ble 
c o nce ntr ati o n di vi de d b y t he ter mi nal rate c o nsta nt:  A U C 0 -last  
C last/z. Da y 7 o nl y  
A U C 0 -last 
 ( h * n g/ m L) 
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o t he 
ti me of t he last q ua ntifia ble c o nce ntrati o n at ti me “t” ( u nits), o v er t he 
w h ole plas ma pr ofile o n Da ys 1 a n d 7,  calc ulate d b y li near  tra pez oi dal 
r ule. C o h orts 1, 2 a n d 3 
A U C 0 -8 h  
( h * n g/ m L) 
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 8 
h o urs after d osi n g, calc ul ate d b y li near tra pez oi dal r ule. Da ys 1 a n d 7, 
C o h orts 1, 2 a n d 3  
A U C 8 -1 6 h  
( h * n g/ m L) 
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 8 h o urs t o 
1 6 h after first d ose, cal c ulate d b y li near tra pez oi dal r ule. Da ys 1 a n d 
7, C o h ort 3  
T ma x  ( h) 
Ti me t o ma xi m u m plas ma c o nce ntr ati o n o btai ne d directl y fr o m t he 
o bser ve d c o n ce ntr ati o n vers us ti me data. Da y 1 a n d Da y 7  
C L/ F ss( L/ h)  
Plas ma cleara nce esti mat e d as d os e di vi de d b y A U C 0 -ta u. Da y 7 o nl y 
w here d ata per mits  
V z / F ( L) 
v ol u me of distri b uti o n esti mate d b y di vi di n g t he a p pare nt cleara nce b y 
z. Da y 7 o nl y  
z ( h-1 ) 
A p pare nt ter mi nal eli mi nati o n rate c o nsta nt esti mate d b y l o g -li near 
least-s q uare d re gressi o n of t he ter mi nal part of t he c o nce ntr ati o n-ti me 
c ur ve pr ofile. Da y 7 o nl y  
t½  ( h) 
Eli mi nati o n half -life, cal c ulate d as l n( 2)/z. Da y 7 o nl y  
Resi d ual area  
Perce nt a ge of A U C 0 -∞ d ue t o e xtra p olati o n fr o m t he ti me of last n o n -
zer o c o nce ntr ati o n t o i nfi nit y. Da y 7 o nl y  
R A A U C  
Acc u m ulati o n Rati o f or A U C, calc ul ate d as A U C Da y 7 / A U CDa y 1 , 
C o h orts 1, 2 a n d 3 ( n ote t he ti me i nter val o v er w hic h t he A U C will be 
deter mi ne d will be de p e n de nt o n t he q ua ntifia ble data).  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 1 9  of 2 8  
 
Para meter ( U nit)  
Met h o d  
R A  C ma x  
Acc u m ulati o n Rati o f or C ma x, calc ulate d as C ma x Da y 7/ C ma x Da y 
1  
M R A U C  
Meta b olite t o pare nt rati o f or A U C, calc ulate d as Rati o of [ A U C 
( meta b olite)/ A U C ( pare nt)] *[ m w ( pare nt)/ m w ( meta b olite)] w here 
A U C is A U C 0 -8                                                     
M R C ma x  
Meta b olite t o pare nt rati o f or C ma x, calc ul ate d as ra ti o of [ C ma x 
( meta b olite)/ C ma x ( pare nt)] *[ m w ( pare nt)/ m w ( meta b olite)] o n Da y 
7 o nl y  
 
F or n o n -c o m part me ntal a nal ysis, z will be t he ne gati ve of t he esti mate d sl o pe of t he li near 
re gressi o n of t he l o g tra nsf or me d c o n ce ntr ati o n ( nat ural l o garit h m) vers us ti me pr ofile i n t he 
ter mi nal eli mi nati o n p hase.  
At least t hree c o n ce ntr ati o n p oi nts will be use d i n esti mati n g z. T he ti me p oi nt w here l o g -li near 
z calc ulati o n be gi ns ( z  L o wer), a n d t he act ual sa m pli n g ti me of t he last q ua ntifia ble 
c o nce ntr ati o n use d t o esti mate t he z (z U p per) will be re p ort e d wit h t he c orrel ati o n c oefficie nt 
fr o m t he li near re gressi o n ( R 2 a dj uste d) t o calc ul ate z.  
Rs q a dj uste d, t he g o o d n ess of fit statistic f or t h e ter mi nal eli mi nati o n p hase, a dj uste d f or t he 
n u m ber of p oi nts use d  i n t he esti mati o n of z m ust be ≥ 0. 8.  
If t he z ca n n ot be meas ure d (e. g.: fe w er t ha n 3 n o n -zer o c o nce ntrati o ns i n t he ter mi nal eli mi nati o n 
p hase), t he n eli mi nati o n relate d P K para meters ( z, z L o wer, z U p per, A U C 0 -∞, Rs q a dj uste d, 
Resi d ual area, T 1/ 2, C L/ F, a n d Vz/ F) will n ot be re p orte d f or P K pr ofiles. If Rs q a dj uste d < 0. 8, 
t he n z, a n d its relate d P K para meters ( z, z L o wer, z U p per, A U C 0 -∞, Rs q a dj uste d, Resi d ual 
area, T 1/ 2, C L / F, a n d Vz/ F) will be fla g ge d i n i n di vi d ual listi n gs, a n d e x cl u de d fr o m a n al ys es.  
6. 3. 2  D ose Pr o p orti o nalit y (f or S A D o nl y)  
A n assess me nt of d ose pr o p orti o nalit y will n ot be base d strictl y o n statistical criteria, b ut rat her 
se veral fact ors will b e c o nsi dere d w h e n assessi n g d os e pr o p orti o nalit y, s uc h as res ults deri ve d 
fr o m a P o wer M o del ( G o u g h et al, 1 9 9 5) (e. g., t he sl o pe esti mate, a n d t he wi dt h of t he 9 0 % 
c o nfi de nce i nter val [ CI]) a n d descri pti ve statistics.  
Details are as f oll o ws:  
P o wer M o del: T he p o wer m o del will be use d t o e sti mate t he sl o pe para meter a n d its 9 0 % CI. T he 
ge n eral f or m of t he p o w er m o del is descri be d as:  
l n(𝑃𝐾 𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟𝑠) = 𝛽0 + 𝛽1 𝑙𝑛(𝐷𝑜𝑠𝑒) + 𝜀 
T his a p pr oac h is us uall y referre d t o as a p o wer m o del beca us e aft er e x p o ne ntiati o n:  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 0  of 2 8  
 
𝑃𝐾 𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟𝑠= 𝛽𝛽𝑙𝑛𝐷𝑜1  
 
w here α o nl y d e pe n ds o n t he β 0, ε a n d re prese nts t he i nterce pt of t he li ne a n d β 1 re prese nts t he 
sl o pe of t he li ne. 
De pe n de nt V aria bles ( P K Para meters):  
 C ma x, A U C 0 -t 
I n d e pe n de nt Varia bl es: 
 T he re gressi o n a b o ve is a u ni va ria ble re gressi o n. T he o nl y i n de pe n de nt v aria ble i n t his 
m o del is nat ural l o garit h m tra nsf or mati o n of d os e le vel (e. g., l n( d ose)). N o ot her c o v ariates 
will be c o ntr olle d f or.  
D ose pr o p orti o nalit y ca n ge n erall y b e c o ncl u de d if t he 9 0 % CIs ar o u n d t h e sl o pe e sti mate (i.e., 
β 1) i ncl u de t he val ue of 1.  
6. 4  Safet y  
All safet y a nal ysis re p orti n g will be base d o n t h e Safet y P o p ulati o n.  
6. 4. 1  A d verse E ve nts  
A n a d verse e ve nt ( A E) is rec or de d if it is a ne w e ve nt  t hat was n ot prese nt at Scree ni n g, or is t he 
w orse ni n g of a n e v e nt prese nt at Scree ni n g.  A treat me nt -e mer ge nt a d v erse e v e nt ( T E A E) is 
defi ne d as a n y A E t h at starts or w ors e ns aft er first d ose of st u d y dr u g. Partial start dates will be 
i m p ute d acc or di n g t o A p pe n di x 1 f or t he det er mi nati o n of treat me nt -e mer ge n ce. A n y A Es wit h 
missi n g start ti me t hat occ ur or w orse n o n st u d y d a y 1 will be ass u me d t o b e treat me nt -e mer ge nt.  
A Es will als o be assesse d f or o utc o me, se v erit y, relati o ns hi p t o st u d y dr u g, a n d seri o us ness. A n y 
missi n g se verit y assess me nts will be ass u me d t o be G ra de 3 (se vere) a n d missi n g relati o ns hi p 
assess me nts will be ass u me d t o be relate d. E x pecte d A Es relate d t o K N X 1 0 0 treat me nt are 
pr o vi de d i n t he K N X 1 0 0 I n vesti gat or’s Br oc h ure. A d verse e ve nts will be c o d e d base d o n t he 
Me d D R A f or re p orti n g b y S O C a n d P T. S O C s will be or dere d i n acc or da nce wit h t he i nter nati o nal 
a gree d u p o n s ort or der f or S O C f oll o we d b y  desce n di n g or der of o verall i nci de nce. T h e Me d D R A 
versi o n use d f or re p orti n g will be des cri be d i n t he r ele va nt ta ble a n d listi n g f o ot n otes.  
A n o ver vi e w of T E A Es will be pr o d u ce d, i n cl u di n g c o u nts a n d perce nta ges of s u bjects as well as 
n u m ber of e v e nts b y  st u d y part a n d c o h ort wit h a n y i n ci de nces of: T E A Es, T E A Es gra de 3 or 
hi g her, T E S A Es, T E A Es relate d t o s t u d y treat me nt, a n d T E S A Es  relate d t o st u d y treat me nt. 
S u m maries of a d vers e e ve nts b y S O C a n d P T will prese nt t he n u m ber a n d perce nt a ge of t otal 
s u bjects a n d n u m ber of e ve nts ( w here n ote d b el o w) b y st u d y part a n d c o h ort a n d will i ncl u de t he 
f oll o wi n g t y pes:  
 T E A Es (i ncl u di n g n u m b er of e v e nts)  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 1  of 2 8  
 
 T E A Es b y m a xi m u m se verit y  
 T E A Es b y hi g h est relati o ns hi p t o st u d y tr eat me nt  
 Treat me nt -e mer ge nt S A Es  
W he n calc ulati n g t he i nci de nce of A Es, eac h A E will be c o u nte d o nl y o nce f or a gi ve n s u bject 
wit hi n a 
Me d D R A cate g or y ( e. g., o verall, s yst e m or ga n class, or preferre d ter m) , b ut all 
occ urre nces of t he s a me e ve nt will be c o u nte d i n t h e n u m ber of e ve nts.  W he n A Es are s u m marize d 
wit hi n le vels of a n ot her A E assess me nt (e. g., relate d ness or se verit y), A Es will be c o u nte d o nce 
p er s u bject at t he w orst / hi g hest le vel of t he ass ess me nt (e. g., hi g hest  relati o ns hi p t o st u d y dr u g or 
greatest se v erit y). 
A c o m pre h e nsi ve listi n g of all a d vers e e v e nts will be pr o vi de d i n a b y -s u bject data listi n g. I n 
a d diti o n, a listi n g of all tr eat me nt -e mer ge nt S A Es will be pr o vi de d.  
6. 4. 2  Cli nical La b orat or y E val uati o ns  
Ser u m c he mistr y, h e mat ol o g y, c o a g ulati o n, a n d uri nal ysis para meters re p orte d as n u meric v al ues 
will be s u m mar ize d base d o n SI u nits. T he f oll o wi n g la b orat or y tests will be i ncl u de d i n data 
s u m maries: 
 Ser u m c he mistr y: Ala ni ne A mi n otra nsferase ( A L T), Al b u mi n, Al kali ne P h os p hatase 
( A L P), 
As partat e 
A mi n otra nsferase ( A S T), Bicar b o nate, Bilir u bi n, 
Urea, Calci u m, 
C hl ori de, Creati ni ne, Ga m ma -Gl uta m yl Tra nsferase, Gl uc os e, Lactate De h y dr o ge nas e, 
P h os p hate, P otassi u m, Pr otei n, S o di u m  
 He mat ol o g y: 
He mat o crit, 
He m o gl o bi n, 
Mea n 
C or p usc ular 
V ol u me, 
Platelets, 
Er yt hr o c ytes,  
Le u k o c yt es,  
Bas o p hils,  
Bas o p hils/ Le u k oc yt es,  
E osi n o p hils, 
E osi n o p hils/ Le u k oc ytes,  
L y m p h o c yt es,  
L y m p h oc ytes/ Le u k oc ytes,  
M o n oc ytes, 
M o n oc yt es/ Le u k oc ytes, Ne utr o p hils, Ne utr o p hils/ Le u k o c ytes  
 C oa g ulati o n: Acti vate d P artial T hr o m b o plasti n Ti me, Pr ot hr o m bi n Ti me  
 Uri nal ysis: Bilir u bi n, Bl o o d, Gl uc ose, Ket o nes, Le u k oc yt es, Nitrite, P H, Pr otei n, S pecific 
Gra vit y, Ur o bili n o ge n  
 T h yr oi d f u ncti o n  tests: T h yr o xi ne, Free; Trii o d ot h yr o ni ne, Free; T h yr oi d Sti m ulati n g 
H or m o ne  
O bser ve d val ues a n d c h a n ges fr o m b aseli ne f or la b orat or y e val u ati o ns will be s u m marize d  b y  
st u d y part a n d c o h ort at eac h visit /ti me p oi nt as well as mi ni m u m a n d m a xi m u m p ost -baseli ne . 
Ser u m c he mistr y a n d he mat ol o g y will als o be s u m marize d i n s hift fr o m baseli ne ta bles b y 
visit /ti me p oi nt a n d n or mal refere n ce ra n ge (l o w, n or mal, hi g h) . 
Li ver f u ncti o n tests usi n g vari o us t hr es h ol ds a b o v e t he u p p er li mit of n or mal will be s u m marize d, 
i ncl u di n g a n y s u bj ects m eeti n g t h e criteria f or p ot e ntial H y’s La w  defi n e d as ( A S T > = 3 x U L N 
or A L T > = 3 x U L N) a n d ( T otal Bilir u bi n > 2 x U L N) a n d ( A L P  < 2 x U L N)  at t he sa me visit . 
P ote ntiall y cli nicall y si g nifica nt p ost -baseli ne t h yr oi d f u ncti o n test res ults will be s u m marize d b y  
st u d y part a n d c o h ort at eac h visit.  
T h yr oi d F u ncti o n Test  
Criteri a  
Trii o d ot h yr o ni ne, Free [ T 3]  
< 3. 5 p m ol/ L  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 2  of 2 8  
 
T h yr oi d F u ncti o n Test  
Criteri a  
> 7. 2 p m ol/ L  
T h yr o xi ne, Free [ T 4]  
<  9 p m ol/ L  
>  2 5 p m ol/ L  
T h yr oi d Sti m ulati n g H or m o ne  
< 0. 4 mI U/ L  
> 4. 0 mI U/ L  
 
All la b orat or y para meters will be pr ovi de d i n b y -s u bject data listi n gs a n d val ues t hat are o utsi de 
n or mal ra n ges  ( hi g h vs. l o w; n or mal vs. a b n or mal) will be fla g ge d . Ser u m c he mistr y, he mat ol o g y, 
c oa g ulati o n, uri nal ysis, a n d viral ser ol o g y l a b orat or y p ara m eters  wit h res ults deter mi ne d b y t he 
i n vesti gat or t o be cli nicall y si g nifica nt will als o be liste d b y s u bject a n d visit. 
6. 4. 3  Vital Si g ns  
V ital si g ns a n d b o d y me as ure me nts  i ncl u de: hei g ht (c m); wei g ht ( k g); B MI ( k g/ m 2); s yst olic a n d 
diast olic bl o o d press ure ( m m H g);  h eart rate ( beats/ mi n); res pirat or y rate (breat hs/ mi n ); o x y ge n 
sat urati o n ( %); te m perat ure (oC); a n d t he hi g hest of 3 pea k fl o w m eas ure me nts ( L/ mi n) t a ke n o n 
Da y 1 will  be rec or de d  o n t he C R F . O bser ve d v al ues a n d c ha n ges fr o m bas eli ne  f or vital si g ns will 
be s u m mariz e d  b y st u d y part a n d c o h ort  at eac h visit a n d ti me p oi nt . 
P ote ntiall y cli nic all y si g nifica nt p ost -basel ine res ults will be s u m marize d b y  st u d y p art a n d c o h ort 
at eac h visit a n d ti me p oi nt.  
Vit al Si g n  
Criteri a  
S yst olic B P  
> 1 5 0 m m H g  
> 2 0 0 m m H g  
≤ 8 0  m m H g  
Diast olic B P  
> 1 0 0 m m H g  
> 1 1 0 m m H g  
Heart Rate  
< 5 0 b p m  
> 1 2 0 b p m  
≥ 3 0 b p m i ncrease fr o m baseli ne  
≥ 3 0 b p m decrease fr o m baseli ne  
Res pirat or y Rate  
< 8 breat hs/ mi n  
> 2 4 breat hs/ mi n  
O x y ge n Sat urati o n  
< 9 5 %  
T e m perat ure  
> 3 8. 3° C  
i ncrease of ≥ 1. 1° C fr o m baseli ne  
 
All vital si g ns res ults will be pr o vi de d i n b y -s u bject data listi n gs. 
6. 4. 4  Tele metr y  
Tele metr y res ults will be prese nte d i n b y -s u bject d ata listi n gs.  
6. 4. 5  Electr ocar di o gra m ( E C G)  
Electr ocar di o gra m ( E C G) par ameters i ncl u de: H R  ( beats/ mi n), P R i nter val ( msec), R R i nter val 
( msec), QR S d urati o n ( msec), Q T i nter val ( msec), Q Tc B i nter val ( msec), Q Tc F  i nter val ( msec), P 
wa ve ( ms ec), a n d T w a ve ( msec) . O bser ve d val ues a n d c ha n ges fr o m b aseli n e  f or E C G p ara meters 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 3  of 2 8  
 
will be s u m mari ze d b y st u d y p art a n d c o h ort  at eac h visit a n d ti me p o i nt. If tri plicate rea ds are 
ta ken , t he mea n of t he rea ds will ser ve as t he o bs er ve d val ue at t he s pecifi c visit a n d ti me p oi nt . 
I n v esti gat or-re p orte d E C G fi n di n gs s hifts fr o m b aseli ne  t o eac h p ost -b aseli ne visit /ti me p oi nt a n d 
ma xi m u m  p ost -baseli ne will be s u m marize d  b y st u d y part a n d c o h ort. Cate g ories of N or mal, 
A b n or mal –  N ot Cli nicall y Si g nifica nt, a n d A b n or mal –  Cli nicall y Si g nifica nt will be i ncl u de d.  
S u bjects meeti n g t he f oll o wi n g p ote ntiall y cli nicall y si g nifica nt criteri a p ost -baseli ne will als o be 
prese nte d:  
 4 5 0 msec  < Q Tc F / Q T c B ≤ 4 8 0  msec  
 4 8 0 msec  < Q Tc F / Q T c B ≤ 5 0 0 msec  
 5 0 0 msec  < Q Tc F / Q T c B  
 3 0 msec  < Q Tc F / Q T c B c ha n ge fr o m baseli ne ≤ 6 0 msec  
 6 0 msec  < Q Tc F / Q T c B c ha n ge fr o m baseli ne  
All E C G para meter  res ults will be pr o vi de d i n b y -s u bject data listi n gs. 
6. 4. 6  Electr oe nce p hal o gra m ( E E G)  
Fre q u e nc y a n d perce nt a ge of s u bjects s h o wi n g a n y s eiz ure acti vit y  a n d a n y i nterictal e pile ptif or m 
acti vit y i n E E G res ults will be s u m marize d b y st u d y part a n d c o h ort at eac h visit  a nd ti me p oi nt . 
All E E G res ults rec or de d o n t he C R F will be prese nte d i n b y -s u bject data listi n gs. 
6. 4. 7  Gastr oi ntesti nal S y m pt o ms  
Fre q u e nc y a n d perce nta ge of s u bjects i n Part B ( M A D) c o h orts e x perie n ci n g a n y gastr oi ntesti nal 
s y m pt o ms will be s u m mariz e d b y st u d y part a n d c o h ort at eac h visit  a n d a n y p ost -bas eli ne . All 
gastr oi ntesti nal s y m pt o m assess me nt res ults rec or de d o n t he C R F will be prese nte d i n b y -s u bject 
data listi n gs.  
Gastr oi ntesti nal s y m pt o m assess me nts will n ot be perf or me d f or P art A ( S A D) s u bje cts.  
6. 4. 8  C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S)  
At t he Scree ni n g Visit, t he Bas eli ne/ Scree ni n g Versi o n of t he C -S S R S will be a d mi nistere d t o 
Part B ( M A D) s u bjects t o assess lifeti me a n d rece nt hist or y. T he Si nce Last Visit Versi o n of t he 
C -S S R S will b e a d mi nistere d t o s u bjects at eac h s u bse q ue nt visit  ( Da y 4 a n d Da y 7). 
Data fr o m t he Bas eli ne/ Scree ni n g V ersi o n a n d fr o m t he Si nce Last Visit Versi o n of t he C -S S R S 
will be s u m mariz e d b y c o h ort. T he n u m ber of s u bjects wit h a n y p ost -b aseli ne occ urre n ce of 
s uici dal i deati o n ( C -S S R S ite ms 1 -5), s uici dal be ha vi or ( C -S S R S ite ms 6 -1 1), as well as 
occ urre nce of i n di vi d ual ite ms at eac h visit will be s u m marize d b y  st u d y p art a n d c o h ort.  
C -S S R S res ults will be prese nte d i n b y -s u bject data listi n gs. 
C -S S R S assess me nts  will n ot be c ollecte d f or Part A ( S A D) s u bjects.  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 4  of 2 8  
 
6. 4. 9  P h ysical E xa mi nati o n s 
P h ysical e x a mi nati o n  fi n di n gs w ill be pres e nte d i n b y -s u bject data listi n gs. 
6. 4. 1 0  Ne ur ol o gical E xa mi nati o n s 
Ne ur ol o gical e x a mi nati o n  fi n di n gs will be pres e nt ed i n b y -s u bj ect data listi n gs. 
 
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 5  of 2 8  
 
 
7  R E F E R E N C E S  
 
I nter nati o nal C o nfere n ce o n H ar m o nizati o n of Tec h nical Re q uire m e nts f or Re gistrati o n of 
P har mace uticals f or H u m a n Use.   I C H E 3 G ui deli n e: Str uct ure a n d c o nte nt of cli nical st u d y rep orts 
q uesti o ns & a ns w ers ( R 1). 2 0 1 2.             
htt p:// w w w.ic h. or g/file a d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 3/ E 3 _ Q As _
R 1 _ Ste p 4. p df .  Accesse d 1 3 J a n 2 0 1 6 . 
I nter nati o nal C onfere n ce o n H ar m o nizati o n of Tec h nical Re q uire m e nts f or Re gistrati o n of 
P har mace uticals f or H u m a n Use.   I C H Har m o nise d Tri partite G ui deli ne: Str uct ure a n d c o nte nt of 
clinical  
st u d y  
re p orts  
E 3.  
Ste p  
4. 
1 9 9 5.  
htt p:// w w w.ic h. or g/file a d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 3/ E 3 _ G ui de
li ne. p df. Accesse d 1 3 J a n 2 0 1 6. 
I nter nati o nal C o nfere n ce o n H ar m o nizati o n of Tec h nical Re q uire m e nts f or Re gistrati o n of 
P har mace uticals f or H u ma n Use.   I C H E 9: Statistical pri nci ples f or cli nical trials. 1 9 9 8. 
htt p:// w w w.ic h. or g/file a d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 9/ Ste p 4/ E 9
_ G ui deli ne. p df  . Accesse d 1 5 J u ne 2 0 1 6. 
I nter nati o nal C o nfere n ce o n H ar m o nizati o n of Tec h nical Re q uire m e nts f or Re gistrati o n of 
P har mace uticals f or H u ma n Use.   E 1 4 Cli nical E val uati o n of Q T/ Q Tc I nter val Pr ol o n gati o n a n d 
Pr oarr h yt h mic  
P ote ntial  
f or  
N o n -A ntiarr h yt h mic  
Dr u gs. 
2 0 0 5.  
htt ps: // w w w.ic h. or g/filea d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 1 4/ E 1 4 _ G
ui deli ne. p df . Accesse d 1 7  Fe br uar y 2 0 1 7 . 
Ha milt o n S, Ber nstei n A B, Bl a ke y G, Fa ga n V, Farr o w T, J or da n D, Seiler W, S ha n n o n A, Gertel 
A, B u da p est 
W or ki n g Gr o u p: De vel o pi n g t h e Clarit y a n d O pe n n ess i n Re p orti n g: E 3 -base d 
( C O R E) Refere n ce user ma n ual f or creati o n of cli nical st u d y re p orts i n t he era of cli nical trials 
tra ns pare n c y. Researc h I nte grit y a n d Peer Re vie w. (2 0 1 6 ) 1: 4. 
P h U S E C S S De vel o p me nt of Sta n dar d Scri pts f or A nal ysis a n d Pr o gra m mi n g W or ki n g Gr o u p.  
A nal ys es a n d Dis pla ys Ass ociate d wit h De m o gra p hics, Dis p ositi o n, a n d Me dicati o ns i n P hase 2 -
4  
Cli nical  
Trials  
a n d  
I nte grate d  
S u m mar y  
D oc u me nts.  
  
2 0 1 4. 
htt p:// w w w. p h use wi ki. or g/ wi ki/i ma ges/c/c 9/ C S S _ W hite Pa per _ De m o Dis p Me d _ v 1. 0. p df  
. 
Access e d 0 3 J a n 2 0 1 7.  
P h U S E C S S De vel o p me nt of Sta n dar d Scri pts f or A nal ysis a n d Pr o gra m mi n g W or ki n g Gr o u p.  
A nal ys es a n d Dis pla ys Ass ociate d t o N o n C o m part me ntal P har mac o ki n etics –  Wit h a F oc us o n 
Cli nical 
Trials. 
2 0 1 4. 
htt p:// w w w. p h use wi ki. or g/ wi ki/i ma ges/e/e d / P h U S E _ C S S _ W hite Pa per _ P K _fi nal _ 2 5 Marc h 2 0 1 4.
p df  . Accesse d 3 1 Dec 2 0 1 6.  
P h U S E C S S De vel o p me nt of Sta n dar d Scri pts f or A nal ysis a n d Pr o gra m mi n g W or ki n g Gr o u p.   
A nal ys es 
a n d 
Dis pl a ys 
Ass oci ate d 
wit h 
T h or o u g h 
Q T/ Q Tc 
St u dies. 
2 0 1 6. 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 6  of 2 8  
 
htt p:// w w w. p h use wi ki. or g/ d ocs/ C S S % 2 0 W hite % 2 0 Pa pers % 2 0 2 0 1 6/ 2 3 0 3 1 6 % 2 0 C S _ W hite Pa per
_ T Q T St u dies _ v 1. 0. p df  .  Access e d 0 3 J a n 2 0 1 7.  
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 7  of 2 8  
 
8  A P P E N DI C E S  
8. 1  A P P E N DI X 1: Partial Date C o n ve nti o ns  
A L G O RI T H M F O R T R E A T M E N T E M E R G E N C E O F A D V E R S E E V E N T S : 
I n c o m plete A d verse E v e nt Start  Date  
If ye ar a n d d ay  are prese nt  b ut m o nt h  is missi n g , ass u me t hat o nl y ye ar is prese nt  i n t he 
ste ps bel o w. 
If t he start dat e is c o m pletel y missi n g: set t he date t o t he first d ose date . 
If ye ar is pr ese nt a n d m o nt h  a n d d ay  are missi n g:  
 
If ye ar = year of first d ose: set t he date t o t he first d ose date.  
 
If ye ar < year of first d ose: set m o nt h  a n d d ay  t o D ece m ber 3 1st. 
 
If ye ar > year of first d ose: set m o nt h  a n d d ay  t o J a n uar y 1st. 
If m o nt h  a n d ye ar are prese nt a n d d ay is missi n g: 
 
If ye ar = year of first d ose, a n d:  
If m o nt h  = m o nt h of first d ose: set d ay  t o da y of first d ose. 
 
 
If m o nt h  < m o nt h of first d ose: set d ay  t o last da y of m o nt h . 
 
 
If m o nt h  > m o nt h of first d ose: set d ay  t o 1st da y of m o nt h . 
 
If ye ar < year of first d ose: set d ay  t o last da y of m o nt h. 
 
If ye ar > year of first d ose: set d ay  t o 1st da y of m o nt h.  
S h o ul d t he i m p ute d start date base d o n t he r ules a b o ve be aft er a c o m plete e n d date, use 
t he e n d date i nstea d of t h e date t hat w o ul d ot her wise be i m p ute d.  
 
 
 


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d  
 
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: K T X -1 0 1  
 
Fi na  Versi o n 3. 0 , 0 1 -Se p -2 0 2 3  
C O N FI D E N TI A L  
           Pa ge 2 8  of 2 8  
 
A L G O RI T H M F O R P RI O R / C O N C O MI T A N T M
E DI C A TI O N S : 
I n c o m plete Pri or/ C o nc o mita nt Me dicati o n Start Date  
If ye ar a n d d ay  are prese nt  b ut m o nt h  is missi n g , ass u me t hat o nl y ye ar is prese nt  i n t he 
ste ps bel o w. 
If t he start dat e is c o m pletel y missi n g : set t he d ate t o t he first d ose date. 
If ye ar is pr ese nt a n d m o nt h  a n d d ay  are missi n g:  
Set m o nt h  a n d d ay  t o J a n uar y 1st. 
If ye ar a n d m o nt h  are prese nt a n d d ay  is missi n g: 
Set d ay  t o 1st da y of  the  m o nt h.  
S h o ul d t he i m p ute d start date base d o n t he r ules a b o ve be aft er a c o m plete e n d date, use 
t he e n d date i nstea d of t h e date t hat w o ul d ot her wise be i m p ute d. 
 
I n c o m plete Pri or/ C o nc o mita nt Me dicati o n E n d Date  
If ye ar a n d d ay  are prese nt  b ut m o nt h  is missi n g , ass u me t hat o nl y ye ar is prese nt  i n t he 
ste ps bel o w. 
If t he e n d d ate is c o m plet el y missi n g  a n d o n g oi n g is c hec ke d : set t he d ate t o t he last d ose 
date . 
If t he e n d d ate is c o m plet el y missi n g a n d o n g oi n g is n ot c hec ke d: d o n ot i m p ute. 
If ye ar is pr ese nt a n d m o nt h  a n d d ay  are missi n g:  
Set m o nt h  a n d da y t o Dece m ber 3 1 st. 
If ye ar a n d m o nt h are prese nt a n d d ay  is missi n g: 
Set d ay  t o last da y of t he m o nt h.  
S h o ul d a n y of t he i m p ute d e n d dates c o me bef ore t he start date (eit her c o m plete or 
i m p ute d) t he n use t he start date i nstea d. 


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: 3 6 A D A C F C 0 8 3 A 4 3 C E A 3 2 C 3 D B D 6 8 A 9 0 F F 8
St at u s: C o m pl et e d
S u bj e ct: C o m pl et e wit h D o c u Si g n: K T X- 1 0 1 _ S A P _ v 3. 0 _ 0 1 S E P 2 0 2 3. d o c x
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 2 8
Si g n at ur e s: 5
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 6
I niti al s: 0
A n n a T o m ki n s
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C- 0 8: 0 0) P a cifi c Ti m e ( U S & C a n a d a)
4 5 0 N. S a m H o u st o n P ar k w a y E.,
S uit e 2 5 0
H o u st o n, T X  7 7 0 6 0
a n n a.t o m ki n s @ all u c e nt. c o m
I P A d dr e s s: 1 3 6. 5 4. 3 8. 7 9   
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             9/ 1/ 2 0 2 3 9: 3 4: 4 4 A M
H ol d er: A n n a T o m ki n s
             a n n a.t o m ki n s @ all u c e nt. c o m
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
A n n a T o m ki n s
a n n a.t o m ki n s @ all u c e nt. c o m
Bi o st ati sti ci a n I
All u c e nt
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
D F 9 1 2 2 C E- 9 5 F 1- 4 F 6 5- A 6 4 1- 7 4 2 B 8 C B E A 1 0 1
U si n g I P A d dr e s s: 1 3 6. 5 4. 3 8. 7 9
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 2 A M
Vi e w e d: 9/ 1/ 2 0 2 3 9: 4 0: 5 5 A M 
Si g n e d: 9/ 5/ 2 0 2 3 1 1: 1 7: 3 9 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
Kri s C h o w ni n g
kri s. c h o w ni n g @ all u c e nt. c o m
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
7 B A D 8 6 A A- A 2 5 B- 4 2 9 4- 8 E 1 9- C 9 8 7 0 3 A B E 0 A D
U si n g I P A d dr e s s: 6 7. 1 9 7. 1 0 2. 1 9 4
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 5 A M
R e s e nt: 9/ 1 1/ 2 0 2 3 6: 5 3: 3 3 A M
Vi e w e d: 9/ 1 1/ 2 0 2 3 7: 1 0: 5 9 A M 
Si g n e d: 9/ 1 1/ 2 0 2 3 7: 1 3: 0 6 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
M ar g ar et D o h ert y
m m d h ert y @ bi g p o n d. n et. a u
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
4 E 3 9 E E B E- 6 3 9 D- 4 B 2 B- A 3 9 D- 2 A D 8 E 2 B 2 D 7 4 D
U si n g I P A d dr e s s: 1 3 8. 1 3 0. 3 4. 2 4 5
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I h a v e r e vi e w e d t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 3 A M
Vi e w e d: 9/ 6/ 2 0 2 3 9: 3 9: 2 6 P M 
Si g n e d: 9/ 6/ 2 0 2 3 9: 4 0: 1 7 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 9/ 6/ 2 0 2 3 9: 3 9: 2 6 P M
      I D: 1 1 a d 8 9 ef-f 6 c 4- 4 a 7 2- b b c 1- 7 5 4 1 9 7 e 7 8 5 6 6
S h ar o n H a n e gr a af
s h a n e gr a af @ ki n o xi st h er a p e uti c s. c o m
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
E 7 0 7 0 E E D- B 3 4 3- 4 E F A- B 8 E 7- 7 B 2 6 7 D A F 7 C 5 0
U si n g I P A d dr e s s: 1 0 1. 1 8 2. 3 6. 8
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 4 A M
Vi e w e d: 9/ 1 0/ 2 0 2 3 1 0: 3 1: 4 9 P M 
Si g n e d: 9/ 1 0/ 2 0 2 3 1 0: 3 2: 4 6 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 9/ 1 0/ 2 0 2 3 1 0: 3 1: 4 9 P M
      I D: b d 0 a a 5 e a- d 9 2 7- 4 d 8 b- a c 0 9- e 1 6 5f b 1 a 2f 8 b
Ti n a S o uli s
ti n a. s o uli s @ ki n o xi st h er a p e uti c s. c o m
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Dr a w n o n D e vi c e
Si g n at ur e I D: 
3 6 C B F 7 C 9- 9 E 4 2- 4 5 5 A- 8 3 3 E- 3 2 6 D 6 D 6 A 1 F 8 A
U si n g I P A d dr e s s: 1 0 1. 1 8 1. 6 9. 5 6
Si g n e d u si n g m o bil e
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 5 A M
Vi e w e d: 9/ 1/ 2 0 2 3 3: 2 0: 1 4 P M 
Si g n e d: 9/ 1/ 2 0 2 3 3: 2 1: 4 2 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 9/ 1/ 2 0 2 3 3: 2 0: 1 4 P M
      I D: 5f 6 b 6 c 3 2- e d b 8- 4 1 a a- a 5f 6- 3 9 4 5 1 c 5 7 1 5f 7
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p


A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
9/ 1/ 2 0 2 3 9: 4 0: 1 5 A M
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
9/ 1/ 2 0 2 3 3: 2 0: 1 4 P M
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
9/ 1/ 2 0 2 3 3: 2 1: 4 2 P M
C o m pl et e d
S e c urit y C h e c k e d
9/ 1 1/ 2 0 2 3 7: 1 3: 0 6 A M
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e


E L E C T R O NI C R E C O R D A N D SI G N A T U R E DI S C L O S U R E   
Fr o m ti me t o ti me, All uce nt - Re g ulate d Acc o u nt ( we, us or C o m pa n y) m a y be re q uir e d b y la w 
t o pr o vi de t o y o u certai n writte n n otices or discl os ures. Des cri be d bel o w are t he ter ms a n d 
c o n diti o ns f or pr o vi di n g t o y o u s uc h n otices a n d discl os ures electr o ni cal l y t hr o u g h t h e D oc u Si g n 
s yste m. Please rea d t h e i nf or mati o n bel o w caref ull y a n d t h or o u g hl y, a n d if y o u ca n access t his 
i nf or mati o n electr o nicall y t o y o ur satisfacti o n a n d a gree t o t his Electr o nic Rec or d a n d Si g nat ure 
Discl os ure ( E R S D), ple ase c o nfir m y o ur a gree me nt b y selecti n g t he c hec k -b o x ne xt t o ‘I a gree t o 
use electr o ni c rec or ds a n d si g nat ur es’ bef ore clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n 
s yste m. 
 
Getti n g p a per c o pies   
At a n y ti me, y o u ma y re q uest fr o m us a pa p er c o p y of a n y rec or d pr o vi d e d or ma de a v aila ble 
electr o nicall y t o y o u b y us. Y o u will ha ve t he a bilit y t o d o w nl oa d a n d pri nt d oc u me nts we se n d 
t o y o u t hr o u g h t he D o c u Si g n s yste m d uri n g a n d i m me diatel y after t he si g ni n g sessi o n a n d, if y o u 
elect t o create a D oc u Si g n acc o u nt, y o u ma y access t he d oc u me nts f or a li mite d peri o d of ti me 
( us uall y 3 0 d a ys) after s u c h d oc u me nts are first se nt t o y o u. After s uc h ti me, if y o u wis h f or us t o 
se n d y o u p a per c o pies of a n y s u c h d oc u me nts fr o m o ur office t o y o u, y o u will be c har ge d a 
$ 0. 0 0  per -pa ge fee. Y o u ma y  re q uest deli ver y of s uc h pa per c o pies fr o m us b y f oll o wi n g t he 
pr oce d ure descri be d bel o w.  
 
Wit h dr a wi n g y o ur c o nse nt   
If y o u deci d e t o recei ve n otices a n d discl os ures fr o m us electr o nicall y, y o u ma y at a n y ti me 
c ha n ge y o ur mi n d a n d t ell us t hat t hereafter y o u wa nt t o recei v e re q uir e d n otices a n d discl os ures 
o nl y i n pa per f or mat. H o w y o u m ust i nf or m us of y o ur decisi o n t o recei ve f ut ure n otices a n d 
discl os ure i n pa per f or mat a n d wit h dra w y o ur c o ns e nt t o recei v e n otices a n d discl os ures 
electr o nicall y is des cr i be d bel o w. 
 
C o nse q ue nces of c h a n gi n g y o ur mi n d   
If y o u ele ct t o recei ve re q uire d n otices a n d discl os ures o nl y i n p a per f or mat, it will sl o w t he 
s pee d at w hic h we ca n c o m plete certai n ste ps i n tr a nsacti o ns wit h y o u a n d deli veri n g s er vices t o 
y o u beca use we  will nee d first t o se n d t he re q uir e d n otices or discl os ures t o y o u i n pa per f or mat, 
a n d t he n wait u ntil we recei ve bac k fr o m y o u y o ur ac k n o wle d g m e nt of y o ur recei pt of s uc h 
pa per n otices or discl os ures. F urt her, y o u will n o l o n ger be a bl e t o use t he D oc u S i g n s yste m t o 
recei v e re q uir e d n otices a n d c o nse nts electr o nicall y fr o m us or t o si g n electr o nicall y d o c u me nts 
fr o m us. 
 
All n otices a n d discl os ures will be se nt t o y o u electr o nic all y   
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e cr e at e d o n: 8/ 2 1/ 2 0 2 3 4: 0 3: 0 9 A M
P arti e s a gr e e d t o: M ar g ar et D o h ert y, S h ar o n H a n e gr a af, Ti n a S o uli s


U nless y o u tell us ot her wise i n acc or da nce wit h t he pr oce d ures des cri be d h erei n, we will pr o vi de 
electr o nicall y t o y o u t hr o u g h t he D o c u Si g n s yste m all re q uire d n otices, discl os ures, 
a ut h orizati o ns, ac k n o wle d ge m e nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u d uri n g t he c o urse of o ur relati o n s hi p wit h y o u. T o re d u ce t he c ha n ce of y o u 
i na d verte ntl y n ot recei vi n g a n y n otice or discl os ure, we prefer t o pr o vi de all of t he re q uire d 
n otices a n d discl os ures t o y o u b y t he s a me met h o d a n d t o t he sa me a d dress t hat y o u ha v e gi ve n 
us. T h us, y o u ca n recei v e all t he discl os ures a n d n otices electr o nicall y or i n pa per f or mat t hr o u g h 
t he pa per mail deli ver y s yste m. If y o u d o n ot a gree wit h t his pr ocess, pleas e let us k n o w as 
descri be d b el o w. Please als o see t he para gra p h i m me diatel y a b o ve t hat des cri bes t he 
c o nse q ue nces of y o ur ele cti n g n ot t o recei ve deli ver y of t he n otices a n d dis cl os ures 
electr o nicall y fr o m us.  
 
H o w t o c o nt act All uce nt - Re g ul ate d Acc o u nt:   
Y o u ma y c o ntact us t o let us k n o w of y o ur c ha n ges as t o h o w we ma y c o nt act y o u electr o nicall y, 
t o re q uest pa per c o pies of cert ai n i nf or mati o n fr o m us, a n d t o wit h dra w y o ur pri or c o nse nt t o 
recei v e n otices a n d discl os ures electr o nicall y as f oll o ws: 
T o c o ntact us b y e mail se n d messa ges t o: Li at y. P ort @all uce nt.c o m  
 
T o a d vise All uce nt - Re g ul ate d Acc o u nt of y o ur ne w e m ail a d dress   
T o let us k n o w of a c h a n ge i n y o ur e mail a d dress w here we s h o ul d se n d n otices a n d discl os ures 
electr o nicall y t o y o u, y o u m ust se n d a n e mail messa ge t o us at  Liat y. P ort @all uce nt.c o m a n d i n 
t he b o d y of s uc h re q uest y o u m ust state: y o ur pre vi o us e mail a d dress, y o ur ne w e mail 
a d dress.  We d o n ot re q uire a n y ot her i nf or mati o n fr o m y o u t o c ha n ge y o ur e mail a d dress.   
If y o u create d a D oc u Si g n acc o u nt, y o u ma y u p d ate it wit h y o ur ne w e mail a d dress t hr o u g h y o ur 
acc o u nt pr efere nces.  
 
T o re q uest  p a per c o pies fr o m All uce nt - Re g ul ate d Acc o u nt   
T o re q uest deli ver y fr o m us of pa per c o pies of t he n otices a n d discl os ures pre vi o usl y pr o vi de d 
b y us t o y o u ele ctr o nicall y, y o u m ust se n d us a n e mail t o  Liat y. P ort @all uce nt.c o m  a n d i n t he 
b o d y of s u c h re q u es t y o u m ust state y o ur e m ail a d dress, f ull na me, maili n g a d dress, a n d 
tele p h o ne n u m ber. We will bill y o u f or a n y fees at t hat ti me, if a n y.  
 
T o wit h dr a w y o ur c o nse nt wit h All uce nt - Re g ul ate d Acc o u nt   
T o i nf or m us t hat y o u n o l o n ger wis h t o recei ve f ut ure n otices a n d discl os ur es i n electr o nic 
f or mat y o u ma y: 


i. decli ne t o si g n a d o c u me nt fr o m wit hi n y o ur si g ni n g sessi o n, a n d o n t he s u bse q ue nt pa ge, 
select t he c h ec k-b o x i n dicati n g y o u wis h t o wit h dra w y o ur c o ns e nt, or y o u ma y;  
ii. se n d us a n e mail t o Li at y. P o rt @all uce nt.c o m a n d i n t he b o d y of s uc h re q uest y o u m ust state 
y o ur e mail, f ull na me, m aili n g a d dress, a n d tele p h o ne n u m ber.  We d o n ot nee d a n y ot her 
i nf or mati o n fr o m y o u t o wit h dra w c o nse nt..  T h e c o nse q ue nces of y o ur wit h dra wi n g c o nse nt f or 
o nli ne d oc u me nts will be t hat tra nsacti o ns ma y ta ke a l o n ger ti me t o pr o cess..  
 
Re q uire d h ar d w are a n d s oft w are   
T he mi ni m u m s yste m re q uire me nts f or usi n g t he D oc u Si g n s yste m ma y c h a n ge o ver ti me. T h e 
c urre nt s yste m r e q uire me nts are f o u n d h ere: htt ps://s u p p ort. d oc usi g n.c o m/ g ui des/si g ner -g ui de -
si g ni n g-s yste m-re q uire m e nts.  
 
Ac k n o wle d gi n g y o ur access a n d c o nse nt t o recei ve a n d si g n d oc u me nts electr o nic all y   
T o c o nfir m t o us t hat y o u ca n access t his i nf or mati o n electr o nicall y, w hi c h will be si milar t o 
ot her electr o nic n otices a n d discl os ures t hat we will pr o vi de t o y o u, pleas e c o nfir m t hat y o u ha ve 
rea d t his E R S D, a n d (i) t hat y o u are a ble t o pri nt o n pa per or electr o ni call y sa v e t his E R S D f or 
y o ur f ut ure refere n ce a n d access; or (ii) t hat y o u are a ble t o e mail t his E R S D t o a n e mail a d dress 
w here y o u will be a ble t o pri nt o n pa per or s a ve it f or y o ur f ut ur e refere nce a n d access. F urt her, 
if y o u c o nse nt t o recei vi n g n otices a n d discl os ures e x cl usi vel y i n electr o nic f or mat as des cri be d 
herei n, t he n sel ect t he c h ec k -b o x ne xt t o ‘I a gree t o use electr o ni c rec or ds a n d si g nat ur es’ bef ore 
clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yst e m.  
B y sele cti n g t he c hec k -b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ur es’, y o u c o nfir m 
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d  
 
Y o u ca n pri nt o n pa per t his Electr o nic Rec or d a n d Si g nat ure Discl os ure, or sa ve or se n d 
t his Electr o nic Rec or d a n d Discl os ure t o a l ocati o n w here y o u ca n pri nt it, f or f ut ure 
refere nce a n d access; a n d 
 
U ntil or u nless y o u n otif y  All uc e nt - Re g ulate d Acc o u nt  as des cri be d a b o v e, y o u c o nse nt 
t o recei ve e x cl usi vel y t hr o u g h el ectr o nic mea ns all n otices, discl os ures, a ut h orizati o ns, 
ac k n o wle d ge me nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u b y All uc e nt - Re g ulate d Acc o u nt d uri n g t he c o urse of y o ur relati o ns hi p 
wit h All uce nt - Re g ulate d Acc o u nt.  


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d
Statistical A nal ysis Pla n
Pr ot oc ol N u m ber: K T X -1 0 1
Fi na Versi o n 3. 0 , 0 1 -Se p -2 0 2 3
C O N FI D E N TI A L
           Pa ge 3 of 2 8
P K Secti o n A ut h or :  Mar garet D o hert y
C o ns ulta nt P har mac o ki neticist
Date
P K Secti o n A ut h or :  Mar garet D o hert y


S p o ns or: Ki n o xis T hera p e utics Pt y Lt d
Statistical A nal ysis Pla n
Pr ot oc ol N u m ber: K T X -1 0 1
Fi na Versi o n 3. 0 , 0 1 -Se p -2 0 2 3
C O N FI D E N TI A L
           Pa ge 1 0 of 2 8
Part B ( M A D) will e val u ate u p t o 3 d oses base d o n t he d ose s esta blis he d d uri n g Part A ( S A D). 
Eac h s u bject i n C o h orts 1 a n d 2 will recei v e st u d y dr u g f or 7 da ys, a d mi nistere d o nce dail y. 
S u bjects i n C o h ort 3 will recei v e st u d y dr u g f or 7 da ys, a d mi nistere d t wice dail y. All s u bjects i n 
eac h Part B ( M A D ) c o h ort will ha ve t heir A E, P K, a n d e lectr o e nce p hal o gra p h y ( E E G) data, 
ac q uire d u p t o a n d i n cl u di n g Da y 8, e val uat e d f or safet y a n d t olera bilit y b y t he C R C bef ore 
o pe ni n g t he n e xt hi g her d ose c o h ort. S u bjects will be h o use d i n t he cli nic fr o m Da y -3 pri or t o 
st u d y dr u g a d mi nistrati o n a n d will re mai n i n -h o use f or 2 4 h o urs p ost m or ni n g d ose ( Da y 8) f or 
P K a n d safet y ass ess me nt s.
T he st u d y will be c o m prise d of 3 peri o ds: Scree ni n g ( u p t o 2 8 d a ys); Treat me nt ( 1 da y f or Part A 
(S A D ) s u bjects a n d 7 d a ys f or Part B ( M A D ) s u bjects); a n d F oll o w -u p. S u bjects will ha ve a 
f oll o w-u p visit 7 da ys after t he last d ose. As S A D d osi n g is a si n gle d o se o n Da y 1, f oll o w -u p 
will occ ur o n Da y 7. Part B ( M A D ) C o h orts 1 a n d 2 d osi n g i n v ol ves si n gl e dail y d osi n g o n Da ys 
1 t o 7, wit h a f oll o w -u p visit occ urri n g o n Da y 1 4. Part B ( M A D) C o h ort 3 d osi n g i n v ol ves t wice 
dail y d osi n g o n Da ys 1 t o 7, wit h a f oll o w -u p visit occ urri n g o n Da y 1 4.
Fi g ure 1 . St u d y P h ases a n d Acti vities
Part A – S A D si n gle d os e
Part B – M A D 7 d a ys
3. 2
Ra n d o mizati o n a n d Bli n di n g
S u bjects will be ce ntrall y ra n d o mize d t o treat me nt i n a 6: 2 rati o wit hi n eac h assi g n e d c o h ort. T he 
first 2 se nti nel s u bjects  will be assi g ne d t o treat me nt i n a 1: 1 rati o s uc h t hat 1 s u bject recei ves 
K N X 1 0 0 a n d t he ot her recei ves pla ce b o. O nce eli gi bilit y i s re-c o nfir me d ( Da y -1), s u bjects will 
be ra n d o mize d via a ra n d o mizati o n list.
T he st u d y will be perf or me d i n a d o u ble -bli n d fas hi o n. T he i n vesti gat or a n d st u d y staff (i ncl u di n g 
la b pers o n nel), t he s u bjects, t he m o nit ors, a n d t he S p o ns or’s staff will re main bli n de d t o treat me nt 
assi g n me nt u ntil data bas e l oc k. T he i n vesti gat or will recei ve seale d e n vel o pes wit h t he i n di vi d ual 
ra n d o mizati o n per s u bject t o be o pe ne d i n t he case of e mer ge nc y o nl y. T o e ns ure st u d y bli n di n g, 
t he acti ve a n d pla ce b o will be pr o vi ded i n i de ntical ca ps ules a n d a n e q ui val e nt n u m ber of ca ps ules 
will be a d mi nistere d t o s u bjects recei vi n g pl ace b o.
T he site p har mac y staff will be u n bli n de d. A d diti o nall y, t he f oll o wi n g r oles ma y b e u n bli n de d: 
U n bli n de d  bi ostatistics  tea m  t hat  pre pares  t he  r a n d o mizati o n  materials  a n d  ha n dles  treat me nt -
re veali n g  d ata  pri or  t o  data base  l oc k;  selecte d  st u d y  S p o ns or  pers o n nel  w h o  are  n ot  dir ectl y 
i n v ol ve d i n t he c o n d uct of t he st u d y; a n d t he dr u g -rec o nciliati o n cli nical res earc h ass ociate ( C R A). 
A list of u n bli n d e d i n di vi d uals will be mai ntai ne d i n st u d y files.
3 C o h orts
2 4 H V
1 0 -3 5 m g
6: 2 Acti ve vs Place b o
4 C o h orts
4 0 H V
5 -5 0 m g
6: 2 Acti ve vs Place b o
F oll o w u p t o at 
least 7 da ys after 
last d ose
Scree ni n g u p 
t o 2 8 da ys 


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
M ar g ar et D o h ert y
m m d h ert y @ bi g p o n d. n et. a u
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
4 E 3 9 E E B E- 6 3 9 D- 4 B 2 B- A 3 9 D- 2 A D 8 E 2 B 2 D 7 4 D
U si n g I P A d dr e s s: 1 3 8. 1 3 0. 3 4. 2 4 5
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I h a v e r e vi e w e d t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 3 A M
Vi e w e d: 9/ 6/ 2 0 2 3 9: 3 9: 2 6 P M 
Si g n e d: 9/ 6/ 2 0 2 3 9: 4 0: 1 7 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 9/ 6/ 2 0 2 3 9: 3 9: 2 6 P M
      I D: 1 1 a d 8 9 ef-f 6 c 4- 4 a 7 2- b b c 1- 7 5 4 1 9 7 e 7 8 5 6 6
S h ar o n H a n e gr a af
s h a n e gr a af @ ki n o xi st h er a p e uti c s. c o m
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
E 7 0 7 0 E E D- B 3 4 3- 4 E F A- B 8 E 7- 7 B 2 6 7 D A F 7 C 5 0
U si n g I P A d dr e s s: 1 0 1. 1 8 2. 3 6. 8
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 4 A M
Vi e w e d: 9/ 1 0/ 2 0 2 3 1 0: 3 1: 4 9 P M 
Si g n e d: 9/ 1 0/ 2 0 2 3 1 0: 3 2: 4 6 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 9/ 1 0/ 2 0 2 3 1 0: 3 1: 4 9 P M
      I D: b d 0 a a 5 e a- d 9 2 7- 4 d 8 b- a c 0 9- e 1 6 5f b 1 a 2f 8 b
Ti n a S o uli s
ti n a. s o uli s @ ki n o xi st h er a p e uti c s. c o m
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Dr a w n o n D e vi c e
Si g n at ur e I D: 
3 6 C B F 7 C 9- 9 E 4 2- 4 5 5 A- 8 3 3 E- 3 2 6 D 6 D 6 A 1 F 8 A
U si n g I P A d dr e s s: 1 0 1. 1 8 1. 6 9. 5 6
Si g n e d u si n g m o bil e
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 9/ 1/ 2 0 2 3 9: 4 0: 1 5 A M
Vi e w e d: 9/ 1/ 2 0 2 3 3: 2 0: 1 4 P M 
Si g n e d: 9/ 1/ 2 0 2 3 3: 2 1: 4 2 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 9/ 1/ 2 0 2 3 3: 2 0: 1 4 P M
      I D: 5f 6 b 6 c 3 2- e d b 8- 4 1 a a- a 5f 6- 3 9 4 5 1 c 5 7 1 5f 7
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p