Clinical trial NCT04076540
Conditions: Smoking Cessation
Keywords: Safety Tolerability Pharmacokinetics Healthy Volunteers
Sponsor: AstraZeneca
Start date: 2019-10-03; Completion date: 2022-01-02
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase I, first-in-human (FIH), single-center, randomized, double-blind, placebo controlled, single ascending dose, sequential group study in healthy vasectomized male and female subjects of non-childbearing potential, aged 18 to 65 years.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: AZD4041 intervention 2: Placebo
Intervention descriptions: intervention 1: Administration by Oral syringe intervention 2: Administration by Oral syringe

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol Amendment 2 
Drug Substance 
AZD4041 
Study Code 
D7460C00001 
Version 
3.0 
Date 
15 June 2021 
A Phase I, Randomized, Double-blind, Placebo-controlled Study to Assess 
the Safety, Tolerability, and Pharmacokinetics of AZD4041 Following Single 
Ascending Dose Administration to Healthy Volunteers 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden 
Regulatory Agency Identifying Number(s): IND 144437 


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VERSION HISTORY 
Version 1, 19 July 2019 
Initial creation 
Version 2, 29 April 2020 
Protocol Amendment 1 
Version 3, 15 June 2021 
Protocol Amendment 2 
This Clinical Study Protocol Amendment 2 has been subject to a peer review according to 
AstraZeneca Standard procedures.  The Clinical Study Protocol Amendment 2 is publicly 
registered and the results are disclosed and/or published according to the AstraZeneca Global 
Policy on Bioethics and in compliance with prevailing laws and regulations. 


Clinical Study Protocol Amendment 2 - 3.0 
AZD4041 - D7460C00001 
SPONSOR SIGNATURES 
AstraZeneca 
A Phase I, Randomized, Double-blind, Placebo-controlled Study to Assess 
the Safety, Tolerability, and Pharmacokinetics of AZD4041 Following 
Single Ascending Dose Administration to Healthy Volunteers 
This Clinical Study Protocol Amendment 2 has been subjected to an internal AstraZeneca peer 
review. 
I agree to the terms of this Clinical Study Protocol Amendment 2. 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca AB or its affiliate 
Medlmmune Ltd. Investigators are cautioned that the information in this Clinical Study 
Protocol Amendment 2 may be subject to change and revision. 
CONFIDENTIAL AND PROPRIETARY 
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SIGNATURE OF PRINCIPAL INVESTIGATOR 
 
 
A Phase I, Randomized, Double-blind, Placebo-controlled Study to Assess 
the Safety, Tolerability, and Pharmacokinetics of AZD4041 Following 
Single Ascending Dose Administration to Healthy Volunteers 
 
This Clinical Study Protocol Amendment 2 has been subjected to an internal AstraZeneca peer 
review. 
 
I agree to the terms of this Clinical Study Protocol Amendment 2. 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca AB or its affiliate 
MedImmune Ltd.  Investigators are cautioned that the information in this protocol amendment 
may be subject to change and revision.
 
 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ............................................................................................................... 2 
SPONSOR SIGNATURES ....................................................................................................... 3 
SIGNATURE OF PRINCIPAL INVESTIGATOR .................................................................. 4 
TABLE OF CONTENTS .......................................................................................................... 5 
1 
PROTOCOL SUMMARY ..................................................................................... 9 
1.1 
Schedule of Activities (SoA) .................................................................................. 9 
1.2 
Synopsis ................................................................................................................ 12 
1.3 
Schema .................................................................................................................. 17 
2 
INTRODUCTION ................................................................................................ 18 
2.1 
Study rationale ...................................................................................................... 19 
2.2 
Benefit/risk assessment ......................................................................................... 20 
 
Benefit .................................................................................................................. 20 
 
Potential risks and mitigation strategies ............................................................... 20 
 
Benefit/risk conclusion ......................................................................................... 24 
2.3 
AZD4041 - D7460C00001 single ascending dose study - results as of 
18 March 2021 ...................................................................................................... 24 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 26 
4 
STUDY DESIGN ................................................................................................. 27 
4.1 
Overall design ....................................................................................................... 27 
 
Overview .............................................................................................................. 27 
4.2 
Scientific rationale for study design ..................................................................... 27 
4.3 
Justification for dose ............................................................................................. 28 
4.4 
End of study definition ......................................................................................... 30 
5 
STUDY POPULATION ....................................................................................... 30 
5.1 
Inclusion criteria ................................................................................................... 30 
5.2 
Exclusion criteria .................................................................................................. 31 
5.3 
Lifestyle restrictions ............................................................................................. 33 
 
Meals and dietary restrictions ............................................................................... 33 
 
Caffeine, alcohol, and tobacco ............................................................................. 34 
 
Activity ................................................................................................................. 34 
5.4 
Screen failures ...................................................................................................... 34 
6 
STUDY TREATMENTS ..................................................................................... 34 
6.1 
Treatments administered ....................................................................................... 35 
 
Investigational products ........................................................................................ 35 


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6.2 
Preparation/handling/storage/accountability ........................................................ 35 
6.3 
Measures to minimize bias: randomization and blinding ..................................... 36 
 
Blinding Procedures ............................................................................................. 36 
 
Breaking the Blind ................................................................................................ 36 
6.4 
Treatment compliance .......................................................................................... 36 
6.5 
Concomitant therapy ............................................................................................. 36 
7 
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 37 
7.1 
Discontinuation of study treatment ....................................................................... 37 
7.2 
Lost to follow-up .................................................................................................. 39 
7.3 
Withdrawal from the study ................................................................................... 40 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................... 40 
8.1 
Efficacy assessments (not applicable) .................................................................. 41 
8.2 
Safety assessments ................................................................................................ 41 
 
Clinical safety laboratory assessments ................................................................. 41 
 
Testosterone, Luteinizing Hormone, Follicle Stimulating Hormone, and 
inhibin B assessments ........................................................................................... 43 
 
Physical examinations .......................................................................................... 43 
 
Vital signs ............................................................................................................. 43 
 
Electrocardiograms ............................................................................................... 43 
8.2.5.1 
Resting 12-lead ECG ............................................................................................ 44 
8.2.5.2 
Electronic capture and analysis of 12-lead digital ECGs ..................................... 44 
8.2.5.3 
Telemetry (real-time display) ............................................................................... 47 
8.3 
Collection of adverse events ................................................................................. 47 
 
Method of detecting AEs and SAEs ..................................................................... 47 
 
Time period and frequency for collecting AE and SAE information ................... 47 
 
Follow-up of AEs and SAEs ................................................................................ 48 
 
Adverse event data collection ............................................................................... 48 
 
Causality collection .............................................................................................. 49 
 
Adverse events based on signs and symptoms ..................................................... 49 
 
Adverse events based on examinations and tests ................................................. 49 
 
Hy’s Law .............................................................................................................. 50 
8.4 
Safety reporting and medical management .......................................................... 50 
 
Reporting of serious adverse events ..................................................................... 50 
 
Pregnancy ............................................................................................................. 50 
8.4.2.1 
Maternal exposure ................................................................................................ 50 
8.4.2.2 
Paternal exposure .................................................................................................. 51 
 
Overdose ............................................................................................................... 51 
 
Medication error ................................................................................................... 52 
 
Management of IP-related toxicities ..................................................................... 52 
 
Safety Review Committee .................................................................................... 53 
8.5 
Pharmacokinetics .................................................................................................. 54 
 
Determination of drug concentration .................................................................... 54 


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Metabolite identification in plasma ...................................................................... 55 
 
Storage and destruction of pharmacokinetic samples ........................................... 55 
8.6 
Pharmacodynamics ............................................................................................... 55 
9 
STATISTICAL CONSIDERATIONS ................................................................. 55 
9.1 
Statistical hypotheses ............................................................................................ 56 
9.2 
Sample size determination .................................................................................... 56 
9.3 
Populations for analyses ....................................................................................... 56 
9.4 
Statistical analyses ................................................................................................ 56 
 
Pharmacokinetic analyses ..................................................................................... 56 
 
Safety analyses ..................................................................................................... 57 
9.4.2.1 
Safety and tolerability ........................................................................................... 57 
9.4.2.2 
Pharmacokinetics .................................................................................................. 57 
10 
REFERENCES ..................................................................................................... 58 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 62 
 
LIST OF TABLES 
Table 1 
Schedule of Activities - Cohorts 1 to 3 ......................................................... 9 
Table 2 
Schedule of Activities - Cohorts 4 to 6 ....................................................... 11 
Table 3 
Unbound exposure margins to the 100 mg/kg PO dog CV study exposure 22 
Table 4 
Observed exposures and margins to male dog NOAEL ............................. 25 
Table 5 
Predicted exposures and margins to NOAEL ............................................. 26 
Table 6 
Objectives and endpoints ............................................................................ 26 
Table 7 
Bases of predicted human exposure to AZD4041 ....................................... 29 
Table 8 
Study treatments .......................................................................................... 35 
Table 9 
Restricted medications ................................................................................ 37 
Table 10 
Prohibited medications ................................................................................ 37 
Table 11 
Laboratory safety variables ......................................................................... 42 
Table 12 
SAD single dose time schedule for digital electrocardiogram assessments 
in D7460C00001 during the residential period ........................................... 45 
 
LIST OF FIGURES 
Figure 1 
Study design (Cohorts 1 to 3) ...................................................................... 17 
Figure 2 
Study design (Cohorts 4 to 6) ...................................................................... 17 


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LIST OF APPENDICES 
Appendix A 
Regulatory, ethical and study oversight considerations .............................. 62 
Appendix B 
Adverse event definitions and additional safety information ..................... 66 
Appendix C 
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law ............................................................................... 71 
Appendix D 
Abbreviations .............................................................................................. 76 


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1 PROTOCOL SUMMARY 
1.1 Schedule of Activities (SoA) 
Table 1 
Schedule of Activities - Cohorts 1 to 3 
Screening 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Follow–up 
Visita 
(14 days 
post-dose) 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
X 
X 
Demographic data 
X 
Medical history 
X 
Urinary drug screen 
X 
X 
Alcohol screen 
X 
X 
Testing for HIV, hepatitis B and C 
X 
Pregnancy testingb
X 
X 
FSH testing in women 
X 
Randomization 
X 
Admission to CRU 
X 
Discharge from CRU 
X 
Height, body weight, and BMIc
X 
X 
X 
X 
Study drug administration 
X 
Adverse event recording 
X 
X 
X 
X 
X 
X 
Blood pressure, temperature, 
respiratory rate, and pulse rate 
X 
X 
Xd 
X 
X 
X 
12-lead paper safety ECG
X 
X 
Xe 
Xe 
Xe 
12-lead digital ECG
Xe 
Xe 
Xe 
Telemetryf
X 
X 
Clinical laboratory evaluationsg 
X 
X 
X 
X 
Physical examination
X 
X 
X 
X 
Blood sampling for PKh
X 
X 
X 
a
Tests will be performed at follow-up and also in cases of discontinuation. 
b
Serum pregnancy test will be performed at screening and check-in. 
c
Height will be measured at screening only. 
d
Blood pressure, temperature, respiratory rate, and pulse rate will be measured at pre-dose, then at 1, 2, 3, 4, 
6, 8, 12, 24, and 48 hours post-dose. 
e
Paper and digital ECGs will be collected at the same time points as PK sampling.  Recording of ECGs will 
precede PK sampling and check of vital signs at each time point. 


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f 
Telemetry for 4 to 6 hours on Day -1 to establish a baseline.  Pre-dose to 24 hours post-dose. 
g 
Clinical laboratory assessments must be repeated if first collected more than 2 weeks before dosing. 
h 
Blood samples will be collected at pre-dose, then at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours. 
BMI  body mass index; CRU  Clinical Research Unit; ECG  electrocardiogram; FSH  follicle stimulating 
hormone; HIV  human immunodeficiency virus; PK  pharmacokinetic(s) 
 


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Table 2 
Schedule of Activities - Cohorts 4 to 6 
 
Screening 
Day -28 to  
Day -2 
Day -2 
Day -1 
Day 1 Day 2 Day 3 
Day 4 
Follow–up 
Visita 
(14±2 days 
post-dose) 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Urinary drug screen 
X 
 
X 
 
 
 
 
 
Alcohol screen 
X 
 
X 
 
 
 
 
 
Testing for HIV, hepatitis B 
and C 
X 
 
 
 
 
 
 
 
Pregnancy testingb 
X 
 
X 
 
 
 
 
 
FSH testing in women 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
X 
 
Height, body weight, and 
BMIc 
X 
 
X 
 
 
 
X 
X 
Study drug administration 
 
 
 
X 
 
 
 
 
Adverse event recording 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure, temperature, 
respiratory rate, and pulse rate 
X 
 
X 
Xd 
X 
X 
X 
X 
12-lead paper safety ECG 
X 
 
X 
Xe 
Xe 
Xe 
Xe 
 
12-lead digital ECG 
 
 
 
Xe 
Xe 
Xe 
Xe 
 
Telemetryf 
 
 
X 
X 
 
 
 
 
Clinical laboratory 
evaluationsg 
X 
 
X 
 
X 
 
 
X 
Physical examination 
X 
 
X 
 
 
 
X 
X 
Blood sampling for PKh 
 
 
 
X 
X 
X 
X 
 
Blood sampling for 
testosterone, LH, FSH, and 
inhibin B (male subjects only)i 
 
 
X 
X 
X 
X 
X 
 
a 
Tests will be performed at follow-up and also in cases of discontinuation. 
b 
Serum pregnancy test will be performed at screening and check-in. 
c 
Height will be measured at screening only. 


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d 
Blood pressure, temperature, respiratory rate, and pulse rate will be measured at pre-dose, then at 1, 2, 3, 4, 
6, 8, 12, 24, and 48 hours post-dose. 
e 
Paper and digital ECGs will be collected at the same time points as PK sampling.  Recording of ECGs will 
precede PK sampling and check of vital signs at each time point. 
f 
For all subjects in Cohort 4 and first 5 subjects in Cohort 5: Telemetry for 4 to 6 hours on Day -1 to 
establish a baseline.  Pre-dose to 24 hours post-dose.  For the remaining subjects in Cohort 5 and all 
subjects in Cohort 6: Telemetry for 24 hours on Day -1, and pre-dose to 48 hours post-dose. 
g 
Clinical laboratory assessments must be repeated if first collected more than 2 weeks before dosing. 
h 
Blood samples will be collected at pre-dose, then at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 
72 hours. 
i 
Male subjects only: samples for testosterone, LH, FSH, and inhibin B will be collected at 0 hour (0800 or 
1000) and at 4, 6, 8, 12, 22, and 24 hours on Day -1 and at 0 hour (0800 or 1000) and at 1, 2, 4, 6, 8, 12, 24, 
36, 48, and 72 hours on Day 1 to Day 3.  The ‘0’ hour time point should be approximately the same time 
that dosing is scheduled for on Day 1.  On Day 1, samples for testosterone, LH, FSH, and inhibin B will be 
collected at the same time as PK samples. 
BMI  body mass index; CRU  Clinical Research Unit; ECG  electrocardiogram; FSH  follicle stimulating 
hormone; HIV  human immunodeficiency virus; LH  luteinizing hormone; PK  pharmacokinetic(s) 
 
1.2 Synopsis 
Protocol title:  
A Phase I, randomized, double-blind, placebo-controlled study to assess the safety, 
tolerability, and pharmacokinetics of AZD4041 following single ascending dose 
administration to healthy volunteers 
Rationale:  
It is predicted that approximately 0.6 billion current smokers worldwide will die from 
smoking-related illnesses, such as chronic obstructive pulmonary disease, cardiovascular 
disease, and lung cancer (Ezzati and Lopez 2003, Doll et al 2004, Coe et al 2005, Mathers and 
Loncar 2006).  If current trends in tobacco use persist, by 2020, smoking will become the 
largest single health problem worldwide, causing approximately 8.4 million deaths annually 
(Murray and Lopez 1997).  Smokers who quit before the onset of tobacco-related illness can 
largely avoid the increased mortality risk (Doll et al 1994, Peto et al 2000).  Nevertheless, 
approximately 80% of smokers currently attempting to quit will relapse within the first month 
of abstinence (Benowitz 2009).  The development of more efficacious smoking cessation aids 
is perhaps the most cost-effective intervention possible within a health-care system (Knight et 
al 2009).  Although clinically efficacious, current smoking cessation agents have limited 
utility.  In smokers attempting to quit, approximately 23% treated with Chantix® (varenicline)  
and approximately 16% treated with Zyban (bupropion) remain abstinent after 1 year, 
compared with approximately 9% of those treated with placebo (Knight et al 2009).  
Pharmacotherapy is therefore an effective strategy to aid smoking cessation efforts, but there 
is considerable risk of relapse even when treated with the most efficacious medications 
currently available.  Further, medications that are effective aids to smoking cessation are 


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associated with a range of adverse effects.  For example, varenicline, the most effective 
medication in this category, is associated with a host of neuropsychiatric side effects, 
including changes in behavior, psychosis, anxiety, etc, and the use of varenicline may impair a 
person’s ability to drive or use machines (eMC 2018).  Bupropion, on the other hand, is 
associated with insomnia, dry mouth, and nausea (Cahill et al 2011).  These adverse effects 
may lead to premature discontinuation of these medications, leading to relapse (Catz et al 
2011).  This highlights the pressing need to develop safer and more effective smoking 
cessation therapeutics. 
The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, 
respectively) are hypothalamic neuropeptides that act through 2 closely related 
G protein-coupled receptors (GPCRs), the orexin 1 (OX1) and orexin 2 (OX2) receptors.  
Orexin A has high affinity for both receptors whereas orexin B has higher affinity for OX2 
over OX1 receptors.  Orexin transmission has been implicated in a diverse range of 
physiological functions, including feeding and energy homeostasis (Sakurai et al 1998), the 
sleep/wake cycle (Willie et al 2003; Gotter et al 2016), neuroendocrine homeostasis, 
cardiovascular functions (Samson et al 2007), and motivated behaviors (Kodadek and Cai 
2010).  Nicotine, which is the principal reinforcing component in tobacco smoke responsible 
for addiction (Stolerman and Jarvis 1995), activates orexin (hypocretin) neurons in the brain.  
This increase in orexinergic transmission is thought to play a crucial role in regulating the 
motivational properties of the drug that results in tobacco dependence (Kenny 2011).  Further, 
OX1 receptors regulate the reinstatement of extinguished drug-seeking responses in abstinent 
rats (Boutrel et al 2005, Harris et al 2005, Kenny 2011) and mice, considered animal models 
with heuristic value for understanding relapse in abstinent human drug addicts.  As such, OX1 
receptor antagonists are considered one of the most promising novel therapeutic strategies to 
facilitate smoking cessation.  Importantly, OX1 receptors play a similar role in regulating the 
addiction-related actions of opioids, psychomotor stimulants and alcohol, raising the 
possibility that OX1 receptor antagonists may have utility for the treatment of addiction across 
different classes of abused drugs. 
AstraZeneca, in partnership with Eolas Therapeutics, Inc, has developed an OX1 receptor 
antagonist, AZD4041, which demonstrates favorable drug-like physiochemical properties.  
The high level of selectivity of AZD4041 between the OX1 and OX2 receptors substantially 
reduces the potential for hypnotic effects of this OX1 antagonist since it is thought that the 
OX2 receptor is primarily responsible for the effects of orexin on sleep/wake transitions and 
maintenance of sleep states (Boutrel et al 2005).  Consistent with this possibility, AZD4041 
does not induce sleep-like electroencephalogram (EEG) waveforms in rodents across a broad 
range of doses.  AZD4041 does not measurably inhibit the activity of cytochrome P450 
enzymes or cardiac potassium ion channels (hERG) nor does it have significant actions at any 
non-OX1 receptor targets so far screened.  AZD4041 is highly brain penetrant in non-human 


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primates, and has relatively slow rates of clearance and high levels of oral bioavailability in 
dogs.  AZD4041 demonstrates in vivo efficacy in rodents and non-human primates at 
relatively low exposures. 
Objectives and endpoints: 
Objectives 
Endpoint/variable: 
Primary objective: 
 
To assess the safety and tolerability of AZD4041 
following oral administration of single ascending 
doses 
• 
Adverse events 
• 
Vital signs 
• 
Hematology, biochemistry, and urinalysis 
• 
ECG (12-lead and telemetry) 
• 
Testosterone, LH, FSH, and inhibin B (male 
subjects only) 
Secondary objectives: 
 
To characterize the pharmacokinetics of AZD4041 
following oral administration of single ascending 
doses of AZD4041 
• 
Cmax 
• 
Tmax 
• 
AUC0-t 
• 
AUC0-inf 
• 
t1/2λz 
• 
CL/F 
• 
Vss/F 
Exploratory objectives 
 
Characterize the pharmacodynamic relationship 
between drug exposure and QT interval 
An exposure–response (E-R) analysis may be 
conducted with data from this study alone or in 
combination with other studies as appropriate, with a 
pre-specified workflow described in a separate 
technical document, for the QT interval corrected for 
heart rate using Fridericia’s formula (QTcF) 
parameter, as part of the cardiac safety evaluation and 
with the intention to obtain a Thorough QT (TQT) 
study substitute.  The result of the E-R analysis may 
not be included in the main study report. 
AUC0-t  Area under the curve from time 0 to time t; AUC0-inf  Extrapolation of the area under the curve from time 
0 to infinity; CL/F  Apparent total clearance of the drug from plasma after oral administration; Cmax  Maximum 
(peak) plasma drug concentration; ECG  Electrocardiogram; E-R  Exposure-response; FSH  Follicle stimulating 
hormone; LH  Luteinizing hormone; QTcF  QT interval corrected for heart rate using Fridericia’s formula; 
t1/2λz  Terminal half-life; Tmax  Time to reach maximum (peak) plasma concentration following drug 
administration; Vss/F  Apparent volume of distribution at steady state after non-intravenous administration 
 
Overall design: 
This is a Phase I, first-in-human (FIH), single-center, randomized, double-blind, 
placebo-controlled, single ascending dose, sequential group study in healthy vasectomized 
male and female subjects of non-childbearing potential, aged 18 to 55 years. 


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Study period: 
Estimated date of first subject enrolled: Q3/2019 
Estimated date of last subject completed: Q4/2021 
Number of subjects: 
The study plans to enroll 48 healthy subjects across 6 cohorts.  Eight subjects will participate 
in each cohort.  Within each cohort, 6 subjects will be randomized to receive AZD4041 and 
2 subjects will be randomized to receive placebo.  Subjects that drop out before dosing will be 
replaced.  Dosing for each ascending dose cohort will proceed with 2 subjects in a sentinel 
cohort, such that 1 subject will be randomized to receive placebo and 1 subject will be 
randomized to receive AZD4041 in a blinded fashion.  
Treatments and treatment duration: 
The study comprises a screening period of up to 28 days (4 weeks), a 4-day in-patient period 
for Cohorts 1 to 3 and a 6-day in-patient period for Cohorts 4 to 6 during which a single oral 
dose of AZD4041 or placebo will be administered, and an out-patient follow-up period.  The 
overall study duration (screening, treatment, and follow-up periods) will therefore be 
approximately 6 weeks. 
Up to 6 dose levels of AZD4041 were planned to be investigated to explore the full dose range 
of AZD4041, with the highest dose that could be explored determined by the exposure cap 
based on the no-observed-adverse-effect level (NOAEL) exposure from the 28-day repeat 
dose toxicity study in dogs.  Three cohorts have been dosed 
  
Given that the exposure limits are predicted to be reached at 
, only vasectomised 
male and female subjects of non-childbearing potential will be enrolled in the remaining 
cohorts (Cohort 4 onwards).  The highest dose that could be explored in these remaining 
cohorts will be determined by the exposure cap based on the NOAEL exposure in female 
dogs, from the 28-day repeat dose toxicity study. 
The safety data from the sentinel subjects up to 24 hours post-dose will be reviewed by the 
Principal Investigator (PI), Clinical Research Organization (CRO) Medical Monitor, and 
AstraZeneca Study Physician before the remaining subjects in the cohort are dosed.  The 
remaining 6 subjects for each cohort will be dosed at least 24 hours after the sentinel cohort. 
Safety review committee 
A Safety Review Committee (SRC) will review data from each cohort before progression to 
the next cohort occurs. 


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Statistical methods 
Safety, tolerability, and pharmacokinetic (PK) data will be summarized descriptively as 
appropriate.  Descriptive summary statistics for continuous variables will include number, 
arithmetic mean, standard deviation, minimum, median, and maximum, while for continuous 
PK variables, descriptive summary statistics will also include geometric mean and arithmetic 
coefficient of variation.  Descriptive summary statistics for categorical data will include 
frequency and proportion.  Tests of significance of group difference (drug dose versus 
placebo) on change from baseline in safety variables will also be performed.  Model-based 
approaches will be used, if appropriate. 


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1.3 Schema 
The general study design is summarized in Figure 1 (Cohorts 1 to 3) and Figure 2 (Cohorts 4 
to 6). 
Figure 1 
Study design (Cohorts 1 to 3) 
Cohort timing 
 
 
 
 
 
 
Figure 2 
Study design (Cohorts 4 to 6) 
Cohort timing 
 
 
 
 
 
 
Screening/ 
enrollment visit 
Randomization 
and dosing 
Follow-up 
visit 
Admission 
to the unit 
Discharge 
from the unit 
In-patient period 
Day -28 to -2 
Day -1 
Day 1 
Day 3 
14 days post-dose 
Screening 
period 
Screening/ 
enrollment visit 
Randomization 
and dosing 
Follow-up 
visit 
Admission 
to the unit 
Discharge 
from the unit 
In-patient period 
Day -28 to -2 
Day -2 
Day 1 
Day 4 
14 days post-dose 
Screening 
period 


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2 INTRODUCTION 
Smoking is an epidemic of global proportions.  It is the leading cause of morbidity and 
mortality in virtually every country in the world (Lim et al 2010).  Smoking increases the risk 
of death by three-fold in smokers, compared with non-smokers (Jha et al 2013).  It is predicted 
that approximately 0.6 billion current smokers worldwide will die from smoking-related 
illnesses, such as chronic obstructive pulmonary disease, cardiovascular disease and lung 
cancer (Ezzati and Lopez 2003, Doll et al 2004, Coe et al 2005, Mathers and Loncar 2006).  If 
current trends in tobacco use persist, by 2020, smoking will become the largest single health 
problem worldwide, causing approximately 8.4 million deaths annually (Murray and Lopez 
1997).  Smokers who quit before the onset of tobacco-related illness can largely avoid the 
increased mortality risk (Doll et al 1994, Peto et al 2000).  Nevertheless, approximately 80% 
of smokers currently attempting to quit will relapse within the first month of abstinence 
(Benowitz 2009).   
The smoking epidemic comes with a great cost to society.  It is estimated that the total 
economic cost of smoking resulting from health-care expenditures and loss of productivity 
totalled 1.8% of the world’s annual gross domestic product, equivalent to US$1436 billion 
(Goodchild et al 2018).  
The development of more efficacious smoking cessation aids is perhaps the most 
cost-effective intervention possible within a health-care system (Knight et al 2009).  Although 
clinically efficacious, current smoking cessation agents have limited utility.  In smokers 
attempting to quit, approximately 23% treated with Chantix (varenicline) and approximately 
16% treated with Zyban (bupropion) remain abstinent after 1 year, compared with 
approximately 9% of those treated with placebo (Knight et al 2009).  Pharmacotherapy is 
therefore an effective strategy to aid smoking cessation efforts, but there is considerable risk 
of relapse even when treated with the most efficacious medications currently available.  
Further, medications that are effective aids to smoking cessation are associated with a range of 
adverse effects.  For example, varenicline, the most effective medication in this category, is 
associated with a host of neuropsychiatric side effects, including changes in behavior, 
psychosis, anxiety, etc, and the use of varenicline may impair a person’s ability to drive or use 
machines (eMC 2018).  Bupropion, on the other hand, is associated with insomnia, dry mouth, 
and nausea (Cahill et al 2011).  These adverse effects may lead to premature discontinuation 
of these medications, leading to relapse (Catz et al 2011).  This highlights the significant 
unmet need to develop safer and more effective smoking cessation therapeutics. 
The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, 
respectively) are hypothalamic neuropeptides that act through 2 closely related G protein 
coupled receptors (GPCRs), the OX1 and OX2 receptors.  Orexin A has high affinity for both 


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receptors whereas orexin B has higher affinity for OX2 over OX1 receptors.  Orexin 
transmission has been implicated in a diverse range of physiological functions, including 
feeding and energy homeostasis (Sakurai et al 1998), the sleep/wake cycle (Willie et al 2003; 
Gotter et al 2016), neuroendocrine homeostasis, cardiovascular functions (Samson et al 2007), 
and motivated behaviors (Kodadek and Cai 2010).  The OX1 receptor signals almost 
exclusively through Gq coupling.  Nicotine, which is the principal reinforcing component in 
tobacco smoke responsible for addiction (Stolerman and Jarvis 1995), activates orexin 
(hypocretin) neurons in the brain.  This increase in orexinergic transmission is thought to play 
a crucial role in regulating the motivational properties of the drug that results in tobacco 
dependence (Kenny 2011).  Further, OX1 receptors regulate the reinstatement of extinguished 
drug-seeking responses in abstinent rats (Boutrel et al 2005, Harris et al 2005, Kenny 2011) 
and mice, considered animal models with heuristic value for understanding relapse in 
abstinent human drug addicts.  As such, OX1 receptor antagonists are considered one of the 
most promising novel therapeutic strategies to facilitate smoking cessation.  Importantly, OX1 
receptors play a similar role in regulating the addiction-related actions of opioids, 
psychomotor stimulants and alcohol, raising the possibility that OX1 receptor antagonists may 
have utility for the treatment of addiction across different classes of abused drugs. 
2.1 Study rationale 
AstraZeneca, in partnership with Eolas Therapeutics, Inc, has developed an OX1 receptor 
antagonist, AZD4041, which demonstrates favorable drug-like physiochemical properties.  
 
  The high level of selectivity between the OX1 and OX2 
receptors substantially reduces the potential for hypnotic effects of this OX1 antagonist since 
it is thought that the OX2 receptor is primarily responsible for the effects of orexin on arousal 
(Boutrel et al 2005).  Consistent with this possibility, AZD4041 does not induce sleep-like 
EEG waveforms in rodents across a broad range of doses.  
 
 
 
 
 
  
Further details of these studies are provided in the Investigator’s Brochure.  
AZD4041 may therefore provide an attractive treatment option as a treatment for smoking 
cessation.  
This study is being conducted to assess the safety, tolerability and PK of single doses of 
AZD4041 in a small number of healthy subjects, prior to advancing AZD4041 into larger 
clinical trials of longer duration. 


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2.2 Benefit/risk assessment 
 Benefit 
AZD4041 has shown significant efficacy in the nicotine self-administration studies in rats and 
monkeys.  These models are well established with drugs effective in smoking cessation; eg, 
varenicline, showing efficacy in these experiments (O’Connor et al 2010).  AZD4041 was 
effective in a dose-dependent manner in blocking the withdrawal-induced nicotine-seeking 
response in the rat withdrawal model.  Extrapolation of IC50 or in vivo 90% inhibitory 
concentration (IC90) in the rat withdrawal model data with AZD4041 indicates that the 
target-free central nervous system exposure between 
, respectively, would 
be required for human efficacy.  
It therefore appears that AZD4041 could represent a novel strategy in the treatment of 
addictive disorders such as smoking cessation, where it has the potential to address a 
significant unmet need.  
The healthy volunteers who participate in this study are not expected to benefit from 
AZD4041. 
 Potential risks and mitigation strategies 
There is no prior clinical information for AZD4041, as this is the FIH study.  While a dual 
orexin receptor antagonist (suvorexant) is approved for the treatment of insomnia, no selective 
OX1 receptor antagonists have been approved for any indication so far.  Limited safety data 
are available for the single and multiple dosing studies with 2 selective OX1 receptor 
antagonists (ACT-539313 [Kaufmann et al 2019] and JNJ-61393215 [Salvadore et al 2019]).  
Both appeared to be well-tolerated in these initial studies with the most common reported 
adverse events (AEs) being somnolence and headache.  Thus, there is limited class 
information on the safety of this mechanism in humans.  Therefore, the starting dose will be 
selected such that the predicted exposures at this dose are several fold lower than the lowest 
predicted efficacious dose (see Section 4.3).  
In nonclinical studies, AZD4041 has been evaluated in repeat dose toxicity studies of 1 month 
duration in rats and dogs, in in vitro and in vivo genotoxicity studies, and in an in vitro 
phototoxicity study.  Safety pharmacology studies assessing effects on the respiratory, 
cardiovascular, central and peripheral nervous systems, and in vitro effects on hERG, have 
also been conducted.  
AZD4041 was negative in the Good Laboratory Practice (GLP) study in vitro Ames and 
chromosome aberration studies, and the GLP in vivo micronucleus study.  AZD4041 was also 
negative in an in vitro 3T3 phototoxicity assay. 


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No significant effects of AZD4041 were noted on the central nervous system, locomotor 
function or motor coordination in rats.  In the sleep/wake and EEG study in rats, AZD4041 
significantly increased wakefulness at the expense of non-rapid eye movement (NREM) sleep 
when compared with control.  
 
 
  In this study, any effects on 
sleep/wakefulness will be assessed via AE reporting.  Only healthy volunteers will be enrolled 
in this FIH study and any subject with a disease of the respiratory system will be excluded.  
Further, vital signs, including respiratory rate (RR), will be assessed at regular intervals after 
dosing (See Schedule of Activities [SoA], Table 1 and Table 2). 
In the hERG assay, the 
.  In a panel of in 
vitro electrophysiological assays of recombinant human voltage-gated cardiac ion channels 
(hKv4.3/hKChIP2.2 – ITO; hKv7.1/hKCNE1 – IKS; hNav1.5 – INa; hKV1.5; hCav3.2; 
hHCN4) - AZD4041 had no activity.  Therefore, a risk of QT prolongation is not expected 
with AZD4041.  In the dog cardiovascular study, sustained durations of premature ventricular 
contractions, beginning approximately 7 hours after dosing and continuing up to 24 hours 
after dosing, 
.  The onset of the 
changes was soon after the approximate Tmax 
 in the dog study.  Hemodynamic 
parameters were largely unaltered and were maintained in the physiological range of heart rate 
and blood pressure. In a dog 14-day investigative study, lower heart rate, with associated 
higher PR and QT intervals were recorded at 
; there were no changes in the rate-
corrected QT interval and no arrhythmias were noted.  There were no changes in ECG rhythm 
or waveform morphology attributable to AZD4041.  Furthermore, there were no effects on 
ECG parameters or morphology in a 28-day dog study in which dogs received up to 
. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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Table 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CV  Cardiovascular; PO  Oral 
 
While it is unclear what physiological mechanisms could be responsible for the observed 
arrhythmias, further risk mitigation measures are being added to the protocol in the form of 
extending the pre-dose telemetry for 24 hours on Day -1 to identify and exclude subjects at 
higher risk of arrhythmia events, extending the continuous cardiac telemetry for the first 
48 hours after dosing, in addition to the regular monitoring for heart rate (HR) and blood 
pressure (BP).  Subjects older than 55 years will be excluded in order to reduce the risk of 
observing benign background arrhythmic events, which are typically seen in older individuals.  
Stopping criteria based on corrected electrocardiogram (ECG) Q-T interval (QTc), HR and BP 
have been included in this FIH study.  
In the 28-day GLP toxicity studies, the key findings were lower thymus weights and thymic 
atrophy in female dogs, and effects on the male reproductive tract in dogs.  Other findings 
were increased liver weight, attributed to hepatocellular hypertrophy in rats and dogs; and 
increased thyroid weight, attributed to follicular cell hypertrophy and recorded in rats only.  
Due to the minimal severity and adaptive nature of the changes, the hepatic and thyroid 
changes were considered not adverse.  Lower thymus weights were noted for female dogs and 
correlated with increased severity of thymic atrophy, characterized by decreased thickness of 
the cortex relative to the medulla, at the high dose.  Taken together, the effect on thymus 
weight combined with the microscopic finding of atrophy was considered to be adverse.  


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There were no effects on organ weight or microscopic pathology noted for the thymus at the 
end of the recovery period, indicating recovery. 
In the dog, effects in the form of tubular degeneration/atrophy of the testes, reduced luminal 
sperm in the epididymides and immaturity and/or single cell necrosis of the prostate glands, 
with associated effects on organ weight, were noted.  There was some evidence of recovery at 
the end of the 4-week recovery period, in that findings were of a lesser severity compared to 
the main test and/or of a similar incidence/severity to the concurrent controls.  There is some 
evidence that OX1 receptors are expressed in dog seminiferous tubules (Ligouri et al 2018) 
and that orexin A is involved in the regulation of spermatogenesis (Barreiro et al 2005, 
Hakovirta et al 1999, Yan et al 1999, Yan et al 2000), which may demonstrate a potential link 
between the pharmacological action of AZD4041 and the findings in the dog.  The low dose in 
male dogs was identified as the NOAEL.  It should be noted that similar findings were not 
seen after 14 days in the dog dose range finding study, albeit with smaller numbers.  No 
effects on the male reproductive tract were seen in the rat 28-day GLP toxicity study. 
For the purpose of a single dose study, testicular toxicity is not considered to be relevant for 
vasectomised male or female subjects of non-childbearing potential.  Therefore, given that the 
exposure limits are predicted to be reached at doses 
 only 
vasectomised male and female subjects of non-childbearing potential will be enrolled in the 
remaining cohorts.  The highest dose that could be explored in these remaining cohorts will be 
determined by the exposure cap based on the NOAEL exposure in female dogs, from the 
28-day repeat dose toxicity study 
 
. 
In addition to the above risk mitigation strategies, a number of other measures are being taken 
in this study to minimize any potential risk to participants, given that this is an FIH 
administration of this compound.  The key measures among these include the following:  
• 
This study will employ sentinel dosing, whereby only 2 subjects (1 active + 1 placebo) 
will be dosed in a blinded manner at the start of a cohort and their safety will be 
monitored for 24 hours before dosing the rest of the cohort; 
• 
Further, this study will enroll only healthy non-smokers who will be carefully selected 
based on exhaustive inclusion and exclusion criteria to avoid placing such subjects at any 
significant risk; 
• 
In addition, subjects will be confined to an in-patient unit that specializes in and is 
equipped for the conduct of FIH studies, starting from the day prior to dosing and for 
72 hours after dosing. 
 


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 Benefit/risk conclusion 
The hepatic and thyroid effects were considered minimal, and adaptive and thymic atrophy 
fully recovered at the end of the recovery period.  Effects on respiration seen in the Safety 
Pharmacology study will be monitored closely with extensive vital sign assessments and 
continuous cardiac telemetry, and ECGs will be used to comprehensively monitor any 
potential arrhythmic effect. The addition of risk mitigation measures in the form of extended 
telemetry and exclusion of subjects with abnormal pre-dose telemetry indicating a high risk of 
arrhythmia events, extension of post-dose telemetry and reduction in the upper age limit for 
eligible subjects, is considered adequate to address a potential risk of NSVT in the study 
population.  In fertile (non-vasectomised) males, the dose-limiting toxicity was considered to 
be the testicular findings in the dog.  Therefore, dosing in this study was restricted to a dose 
that was predicted to provide an exposure that was 10-fold below the NOAEL exposures in 
the Dog 28-day study 
 
 However, for cohorts 
where exposures are predicted to exceed the 10-fold margin below the Dog 28-day study 
NOAEL and therefore only vasectomised males or females of non-childbearing potential are 
being enrolled (Cohort 4 onwards), dosing will be limited by the thymic findings in female 
dogs, in the Dog 28-day study.  Therefore, the revised exposure limits for these cohorts are 
proposed not to exceed a free 
, which 
correspond to the intermediate dose NOAEL exposures in the female dog at 
. 
Based on this information regarding the risks of AZD4041 and the precautions included in this 
first clinical study, the risks are considered acceptable in relation to the significant unmet need 
in subjects attempting to quit smoking.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of AZD4041 may be found in the Investigator’s Brochure. 
2.3 AZD4041 - D7460C00001 single ascending dose study - results as of 
18 March 2021 
The FIH SAD study in healthy volunteers with AZD4041 is currently ongoing and 4 cohorts 
have completed dosing and 15-day follow-up (Study AZD4041 - D7460C00001).  The doses 
tested in Cohorts 1, 2, 3, and 4 were 
, respectively.  The 5th cohort is 
partially completed (5 of 8 subjects) at an oral dose level of 
. 
  
 
  
 
  
 


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For cohorts 1, 2 and 3 the predicted exposure was planned not exceed a limit that is 
approximately 10-fold below the NOAEL exposures in males in the Dog 28-day study 
(Table 4).  Subsequent cohorts in females of non-childbearing potential and vasectomised 
males have revised exposure limits that is proposed not to exceed the intermediate dose 
NOAEL exposures in the female dog at 
.  Utilizing geometric mean data, 
observed exposures at 
 provide a 
margin to free Cmax and an 
 
margin to free AUC0-inf when compared to the female dog NOAEL derived from the 28 Day 
GLP toxicology study (Table 5).  For the partial Cohort 5 data at 
 geometric mean data 
indicates a 
 margin to free Cmax and an 
 margin to free AUC0-inf when the same 
comparison is made to the female dog NOAEL exposures. 
Table 4 
Observed exposures and margins to male dog NOAEL 
Clinical 
dose 
(mg) 
Human 
free Cmax 
(ng/mL) 
Human free 
Cmax/Dose 
Cmax 
margin to 
male dog 
NOAEL 
Human free 
AUC0-inf 
(ng·h/mL) 
Human free 
AUC0-inf/Dose 
AUC0-inf 
margin to 
male dog 
NOAEL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUC0-inf  Extrapolation of the area under the curve from time 0 to infinity; Cmax  Maximum (peak) plasma drug 
concentration; NOAEL  No-observed-adverse-effect level 
n/a = not applicable since male dog NOAEL was not utilized as exposure limit beyond Cohort 3 
Note: Exposures are provided as geometric means (n=6). 
 
Pharmacokinetic data within cohorts indicated that there was some variability in systemic 
exposure between individuals.  As an example in Cohort 3, the coefficient of variation for 
Cmax geometric mean was 24.7% and the coefficient of variation for AUC0-inf geometric mean 
was 43.7%.  For 3 subjects within Cohort 3, extrapolation of AUC0-inf following 
noncompartmental analysis was >20%, indicating some uncertainty in the calculation of this 
parameter.  However, with an extended sampling period and extrapolation of AUC0-inf  
following noncompartmental analysis of <20% in all subjects, variability in systemic exposure 
was still evident in Cohort 4, as exemplified by a coefficient of variation for Cmax geometric 
mean of 21.2% and a coefficient of variation for AUC0-inf geometric mean of 52.4%. 
Linear regression modelling with a linear scale has been employed to understand the 
relationship between Cmax and AUC0-inf.  Utilizing predicted exposures from the linear 
regression model, doses of 
 and higher are expected to have a 
 margin to the 


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female dog NOAEL, for Cmax and AUC0-inf (Table 5).  This modelling and the projected 
systemic exposures will be revised as additional PK data becomes available.  The SRC will 
evaluate the safety, tolerability, and PK of AZD4041 and determine the next dose.  The dose 
level for a given cohort will be referenced from the applicable safety summary meeting 
minutes. 
Table 5 
Predicted exposures and margins to NOAEL 
Clinical dose 
(mg) 
Human free 
Cmax (ng/mL) 
Human free AUC0-inf 
(ng·h/mL) 
Cmax margin to 
female dog 
NOAEL 
AUC0-inf margin to 
female dog 
NOAEL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a = observed data and margins based on observed PK parameters 
AUC0-inf  Extrapolation of the area under the curve from time 0 to infinity; Cmax  Maximum (peak) plasma drug 
concentration; NOAEL  No-observed-adverse-effect level 
 
3 OBJECTIVES AND ENDPOINTS 
Table 6 
Objectives and endpoints 
Objectives 
Endpoint/variable: 
Primary objective: 
 
To assess the safety and tolerability of AZD4041 
following oral administration of single ascending 
doses 
• 
Adverse events 
• 
Vital signs 
• 
Hematology, biochemistry, and urinalysis 
• 
ECG (12-lead and telemetry) 
• 
Testosterone, LH, FSH, and inhibin B (male 
subjects only) 
To characterize the pharmacokinetics of AZD4041 
following oral administration of single ascending 
doses of AZD4041 
• 
Cmax 
• 
Tmax 
• 
AUC0-t 
• 
AUC0-inf 
• 
t1/2λz 
• 
CL/F 
• 
Vss/F 


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Table 6 
Objectives and endpoints 
Objectives 
Endpoint/variable: 
Secondary objectives: 
 
Characterize the pharmacodynamic relationship 
between drug exposure and QT interval 
An exposure–response (E-R) analysis may be 
conducted with data from this study alone or in 
combination with other studies as appropriate, with a 
pre-specified workflow described in a separate 
technical document, for the QT interval corrected for 
heart rate using Fridericia’s formula (QTcF) 
parameter, as part of the cardiac safety evaluation and 
with the intention to obtain a Thorough QT (TQT) 
study substitute.  The result of the E-R analysis may 
not be included in the main study report. 
AUC0-t  Area under the curve from time 0 to time t; AUC0-inf  Extrapolation of the area under the curve from 
time 0 to infinity; CL/F  Apparent total clearance of the drug from plasma after oral administration; 
Cmax  Maximum (peak) plasma drug concentration; ECG  Electrocardiogram; FSH  Follicle stimulating hormone; 
E-R  Exposure-response; LH  Luteinizing hormone; QTcF  QT interval corrected for heart rate using Fridericia’s 
formula; t1/2λz  Terminal half-life; Tmax  Time to reach maximum (peak) plasma concentration following drug 
administration; Vss/F  Apparent volume of distribution at steady state after non-intravenous administration 
 
4 STUDY DESIGN 
4.1 Overall design 
 Overview 
This is a Phase I, FIH, single-center, randomized, double-blind, placebo-controlled, single 
ascending dose, sequential group study in healthy vasectomized male and female subjects of 
non-childbearing potential, aged 18 to 55 years. 
For an overview of the study design see Figure 1 and Figure 2, Section 1.3.  For details on 
treatments given during the study, see Section 6.1, Treatments administered. 
For details on what is included in the efficacy and safety endpoints, see Section 3, Objectives 
and endpoints. 
4.2 Scientific rationale for study design 
A single ascending dose design will be employed to assure that higher doses are administered 
to healthy subjects only after lower doses have demonstrated an acceptable safety profile as 
assessed by physical examination, clinical laboratory testing, and AE recording. 


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4.3 Justification for dose 
The doses selected for this FIH study were based on appropriate methods to predict PK in 
humans using PK/pharmacodynamic (PD) modelling of data from an in vivo model to identify 
potentially efficacious target concentration and predicted exposure margins.  
AZD4041 was predicted to exhibit low clearance and moderate volume of distribution in 
humans.  The human clearance of AZD4041 was determined via scaling of intrinsic clearance 
data from in vitro human hepatocyte incubations and the application of the well-stirred model 
with appropriate hepatic scaling factors.  The volume of distribution of AZD4041 was 
predicted utilizing in vitro and physicochemical properties and a physiologically-based PK 
model (PBPK) (Arundel 1997).  Free efficacious exposure (Ceff) in humans was estimated by 
extrapolation of data from the withdrawal-induced nicotine-seeking model in rodents.  
Utilizing rat PK and withdrawal model PD data, the maximal efficacious exposure, as 
described by the IC90, was determined using appropriate PK/PD modelling as 
 free.  
Human dose projections were then performed using the previously established PBPK model 
and clearance prediction, to estimate the once daily dose required to achieve this target-free 
Ceff at trough plasma concentration at steady state.  Using this approach, the predicted human 
efficacious 
. 
The starting dose for the first cohort was 
 with up to 5 planned dose escalations.  At the 
starting dose of 
, there was a predicted 471-fold exposure margin to free Cmax and 
a 338-fold exposure margin to free AUC0-inf  when compared to the corresponding 
toxicokinetic parameters for dog NOAEL dose level in male dogs (Table 7).  Dose levels for 
each subsequent cohort were selected based on the emerging safety and PK data; however, the 
predicted exposure was planned not exceed a limit that is approximately 10-fold below the 
NOAEL exposures in the Dog 28-day study 
 
 
.  Further details regarding data required for dose escalations were provided 
in the SRC Charter which was prepared prior to dosing.  For a single 
 human dose, the 
corresponding predicted free Cmax and free AUC0-inf exposure margins were expected to be 13- 
and 10-fold, respectively. 


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Table 7 
Bases of predicted human exposure to AZD4041 
Clinical dose 
(mg) 
Predicted human 
free Cmax 
(ng/mL) 
Predicted Cmax 
margin to male 
dog NOAEL 
Predicted human 
free AUC0-inf 
(ng·h/mL) 
AUC0-inf margin to 
male dog 
NOAEL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUC0-inf  Extrapolation of the area under the curve from time 0 to infinity; Cmax  Maximum (peak) plasma drug 
concentration; NOAEL  No-observed-adverse-effect level 
 
Based on the PK exposures observed in Cohorts 1, 2, and 3 (Table 4) the exposure limits, 
based on the male dog NOAEL, were expected to be reached in the 4th cohort.  
Therefore, the protocol was amended to only enroll female subjects of non-childbearing 
potential and vasectomised male subjects in the study in all subsequent cohorts. 
The initial exposure limits set in the study were based on testicular toxicity seen in the 28-day 
dog GLP toxicity study.  For the purpose of a single dose study, testicular toxicity is not 
considered to be relevant for vasectomised male or female subjects of non-childbearing 
potential.  It is therefore considered appropriate to enroll vasectomised males or female 
subjects of non-childbearing potential only in cohorts where exposures are predicted to exceed 
the 10-fold margin below the Dog 28-day study NOAEL exposures, ie, Cohort 4 onwards. 
In the 28-day GLP toxicity study, adverse effects in the form of increased incidence and 
severity of thymic atrophy characterised by decreased thickness of the cortex relative to the 
medulla, were noted at the high dose in female dogs.  A similar increase in incidence and 
severity was not noted in the male dog.  As a result, the NOAEL was set at the intermediate 
dose. Therefore, for cohorts where exposures are predicted to exceed the 10-fold margin 
below the Dog 28-day study NOAEL (Cohort 4 onwards), revised exposure limits are 
proposed not to exceed a free Cmax of
 
 which correspond 
to the intermediate dose NOAEL exposures in the female dog at 
.  Revised 
exposure margins for female and vasectomized male subjects are provided in Table 5. 
 


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4.4 End of study definition 
The end of study is defined as the last expected visit/contact of the last subject undergoing 
study treatment. 
A subject is considered to have completed the study when the subject has completed his/her 
last scheduled visit or last scheduled procedure, shown in the SoA (Table 1 and Table 2). 
See Appendix A 6 for guidelines for the dissemination of study results. 
5 STUDY POPULATION 
Prospective approval of CSP deviations to recruitment and enrollment criteria, also known as 
CSP waivers or exemptions, is not permitted. 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention.  Under no circumstances can 
there be exceptions to this rule.  Subjects who do not meet the entry requirements are screen 
failures (refer to Section 5.4). 
In this CSP, “enrolled” subjects are defined as those who sign informed consent.  
“Randomized” subjects are defined as those who undergo randomization and are assigned a 
randomization number. 
For procedures for withdrawal of incorrectly enrolled subjects, see Section 7.3. 
5.1 Inclusion criteria 
Subjects are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply: 
1 
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the Informed Consent Form (ICF) and in this CSP. 
2 
Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses.  
The ICF process is described in Appendix A 3. 
3 
Subjects must be ≥18 and ≤55 years of age at the time of signing the ICF. 
4 
Individuals who are healthy as determined by medical evaluation, including medical 
history, physical examination, laboratory tests, and cardiac monitoring. 
5 
Individuals who weigh ≥50 kg and who have a body mass index (BMI) between 18.0 and 
30.0 kg/m2, inclusive. 
6 
Either male or female. 


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7 
Female subjects must have a negative pregnancy test result at screening and check-in and, 
on admission to the unit, must not be lactating. 
8 
Female subjects must be of non-childbearing potential, as confirmed at screening by 
fulfilling one of the following criteria: 
(a) Post-menopausal women must have had ≥12 months of spontaneous amenorrhea with 
a follicle stimulating hormone (FSH) concentration consistently ≥40 mIU/mL and 
must have a negative pregnancy test result at screening and check-in. 
(b) Surgically sterile women, defined as those who have had a hysterectomy, bilateral 
ovariectomy (oophorectomy), bilateral salpingectomy, or bilateral tubal ligation.  
Women who are surgically sterile must provide documentation of the procedure by 
an operative report or relevant medical records, or by ultrasound, and must have a 
negative pregnancy test result at screening and check-in. 
9 
Male subjects must be vasectomized. 
5.2 Exclusion criteria  
1 
History of any clinically important disease or disorder which, in the opinion of the 
Investigator, may either put the subject at risk because of participation in the study, or 
influence the results or the subject’s ability to participate in the study. 
2 
History of any significant psychiatric disorder according to the criteria of the Diagnostic 
and Statistical Manual of Mental Disorders, 5th Edition (American Psychiatric Association 
2013) which, in the opinion of the Investigator, could be detrimental to subject safety or 
could compromise study data interpretation. 
3 
Male subjects with a history of oligospermia or azoospermia or any other disorder of the 
reproductive system. 
4 
Subjects who are undergoing treatment or evaluation for infertility. 
5 
History or presence of gastrointestinal, hepatic or renal disease or any other condition 
known to interfere with absorption, distribution, metabolism or excretion of drugs. 
6 
Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of 
administration of IP. 
7 
Any clinically important abnormalities noted at the screening assessments in clinical 
chemistry, hematology, or urinalysis results as judged by the Investigator. 
8 
Any positive result on screening for serum hepatitis B surface antigen, hepatitis C 
antibody and human immunodeficiency virus antibodies. 
9 
Abnormal vital signs, after 10 minutes supine rest, defined as any of the following: 
(a) Systolic BP <90 mmHg or ≥140 mmHg. 
(b) Diastolic BP <50 mmHg or ≥90 mmHg. 
(c) HR <45 or >85 beats per minute. 


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10 Any clinically important abnormalities in rhythm, conduction, or morphology of the 
resting ECG and any clinically important abnormalities in the 12-lead ECG which, in the 
Investigator’s opinion, may interfere with the interpretation of QTc interval changes, 
including abnormal ST-T-wave morphology. 
11 ECG interval measured from the onset of the QRS complex to the end of the T wave (QT) 
interval corrected for HR using Fridericia’s formula (QTcF) >450 ms or family history of 
long QT syndrome. 
12 ECG interval measured from the onset of the P wave to the onset of the QRS complex 
(PR[PQ]) interval shortening <120 ms (PR >110 ms but <120 ms is acceptable if there is 
no evidence of ventricular pre-excitation). 
13 PR(PQ) interval prolongation (>240 ms), persistent or intermittent second (Wenckebach 
block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV 
dissociation. 
14 Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch 
block (IBBB), or intraventricular conduction delay (IVCD) with ECG interval measured 
from the onset of the QRS complex to the J point (QRS) >110 ms.  Subjects with QRS 
>110 ms but <115 ms are acceptable if there is no evidence of, eg, ventricular 
hypertrophy or pre-excitation. 
15 In the pre-dose 24 hour telemetry, presence of ≥10 ventricular premature contractions 
(VPCs) during 1 hour, or ≥100 VPCs during 24 hours of Holter/telemetry or any 
occurrence of paired VPCs (ventricular couplets) or other repetitive ventricular rhythms 
including non-sustained or sustained (>30 second duration) “slow” (<100 bpm) or “fast” 
(≥100 bpm) ventricular tachycardias. 
16 Vaccination with COVID-19 vaccine less than 14 days prior to the proposed date of 
randomization.  If more than 1 dose of the vaccine is required as part of the vaccination 
regimen, a subject can only be randomized to receive study treatment 14 days after 
receiving the final dose of the COVID-19 vaccine. 
17 Known or suspected history of drug abuse as judged by the Investigator. 
18 Current smokers or those who have smoked or used nicotine products within the previous 
3 months. 
19 History of alcohol abuse or excessive intake of alcohol defined as an average weekly 
intake of >21 units or an average daily intake of >3 units for men or an average weekly 
intake of >14 units or an average daily intake of >2 units for women.  One unit is 
equivalent to a half pint (250 mL) of beer, 1 measure (25 mL) of spirits, or 1 glass 
(125 mL) of wine.  If a subject is currently diagnosed with abuse of or dependence on 
alcohol, the subject will not be allowed to enroll in the study, unless the alcohol 
abuse/dependence is in full (complete, not partial), sustained (>1 year) remission. 


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20 Positive screen for drugs of abuse at screening or admission to the unit or positive screen 
for alcohol at screening to the unit prior to administration of IP. 
21 History of severe allergy/hypersensitivity or ongoing clinically important 
allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to 
drugs with a similar chemical structure or class to AZD4041. 
22 Plasma donation within 1 month of screening or any blood donation/blood loss >500 mL 
during the 3 months prior to screening. 
23 Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as 
judged by the Investigator. 
24 Use of drugs with enzyme inducing properties, such as St John’s wort, within 3 weeks 
prior to administration of IP. 
25 Use of any prescribed or nonprescribed medication including antacids, analgesics (other 
than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 
600 times the recommended daily dose) and minerals during the 2 weeks prior to 
administration of IP or longer if the medication has a long half-life. 
26 Use of any prescribed or nonprescribed oral and topical inhibitors/inducers of CYP3A4 
(including shampoo). 
27 Use of hormone replacement therapy. 
28 Subjects who have previously received AZD4041. 
29 Has received another new chemical entity (defined as a compound that has not been 
approved for marketing) within 3 months of administration of IP in this study.  The period 
of exclusion begins 3 months after the final dose or 1 month after the last visit, whichever 
is the longest.  Note: subjects consented and screened, but not randomized in this study or 
a previous Phase I study, are not excluded. 
30 Involvement of any AstraZeneca or study site employee or their close relatives. 
31 Judgement by the Investigator that the subject should not participate in the study if they 
have any ongoing or recent (ie, during the screening period) minor medical complaints 
that may interfere with the interpretation of study data or are considered unlikely to 
comply with study procedures, restrictions, and requirements. 
32 Subjects who are vegans or have medical dietary restrictions. 
33 Subjects who cannot communicate reliably with the Investigator. 
5.3 Lifestyle restrictions 
 Meals and dietary restrictions 
No outside food or drink is permitted at the unit.  All meals and snacks will be provided.  
Subjects will receive standard meals and snacks at regimented times during each residential 
period. 


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Subjects should not consume grapefruit juice or other grapefruit products for up to 7 days 
before dosing and throughout the study. 
 Caffeine, alcohol, and tobacco 
Alcohol use is prohibited for 48 hours prior to the screening visit, for 48 hours prior to 
admission to the unit, during the residential period, and for 48 hours prior to the follow-up 
visit (14 days post-dose).  Subjects should consume only moderate levels of alcohol for the 
duration of the study, defined as less than 3 units (1 unit=25 mL spirits, 125 mL wine or 
250 mL beer or lager) in any 24-hour period for men and less than 2 units in any 24-hour 
period for women. 
 Activity 
Strenuous activity is prohibited from 48 hours prior to admission to the Clinical Research Unit 
(CRU) until discharge from the CRU. 
5.4 Screen failures 
Screen failures are defined as subjects who signed the ICF to participate in the clinical study 
but are not subsequently randomized.  A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. 
These subjects should have the reason for study withdrawal recorded in the electronic Case 
Report Form (eCRF). 
6 STUDY TREATMENTS 
Study treatment is defined as any IP (including marketed product comparator and placebo) or 
medical device(s) intended to be administered to a study participant according to the CSP. 
Study treatment is to be administered in the morning under fasted conditions.  Subjects will 
fast overnight (nothing to eat or drink except water) for at least 10 hours before receiving 
study treatment.  Subjects will remain fasted for 4 hours after dosing with study treatment. 


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6.1 Treatments administered 
 Investigational products 
Table 8 
Study treatments 
Study treatment name: 
AZD4041 
Dosage formulation: 
 
 
Strength/Concentrations: 
 
Placebo: 
 
 
Route of administration:  
Oral 
Dosing instructions: 
Oral syringe 
Packaging and labelling: 
Formulation to be prepared extemporaneously from drug substance at the 
clinical site.  Stock solutions to be prepared on a weekly basis and stored 
under refrigerated conditions (2°C to 8°C).  Dosing solutions to be prepared 
on a daily basis for use within 24 hours and may be stored under ambient 
conditions. 
Provider: 
AMRI, Albany, New York 
 
6.2 Preparation/handling/storage/accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled and monitored (manual or automated) area, in accordance with the 
labelled storage conditions, with access limited to the Investigator and authorized site staff. 
Details of study treatment preparation and administration are given in the Handling 
Instructions. 
A formal system for drug accountability will be implemented.  The Investigator, institution, or 
the head of the medical institution (where applicable) is responsible for study treatment 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records). 


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6.3 Measures to minimize bias: randomization and blinding 
PPD will generate the randomization schedule.  Eligible sentinel subjects within each cohort 
will be randomly assigned in a ratio of 1:1 to Active:Placebo after all entry criteria have been 
satisfied before dosing on Day 1.  Following review of sentinel safety data up to 24 hours 
post-dose, the remaining subjects within each cohort will be randomly assigned in a ratio of 
5:1 to Active:Placebo. 
 Blinding Procedures 
This is a double-blind study.  Neither the subjects nor the investigator will be aware of the 
treatment assignment.  Blinding will be maintained throughout the study by use of active and 
placebo dosage forms of similar appearance.  Access to the randomization code will be strictly 
controlled according to the standard operating procedures of PPD. 
 Breaking the Blind 
Blind breaking envelopes will be prepared.  A subject or subjects may be unblinded in the 
event of a dose-limiting toxicity, SAE, or other event, or if there is a medical emergency 
where the identity of the drug must be known to properly treat a subject.  A cohort may be 
unblinded to determine if dose escalation to the next dose level will terminate.  If a subject 
becomes seriously ill or pregnant during the study, the blind will be broken only if knowledge 
of the administered study drug will affect that subject’s treatment options.  In the event of a 
medical emergency requiring identification of the study drug administered to an individual 
subject, the investigator will make every attempt to contact the medical monitor to explain the 
need for opening the code within 24 hours of opening the code.  The investigator will be 
responsible for documenting the time, date, reason for the code break, and the names of the 
personnel involved. 
6.4 Treatment compliance 
Any change from the dosing schedule, dose interruptions, dose reductions, or dose 
discontinuations should be recorded in the eCRF. 
The Investigator is responsible for management of the IP from receipt by the study site until 
the destruction or return of all unused IP.  
6.5 Concomitant therapy 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• 
Reason for use 


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• 
Dates of administration, including start and end dates 
• 
Dosage information, including dose and frequency 
 
Table 9 
Restricted medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it is allowed): 
Antacids 
Analgesics other than paracetamol/acetaminophen 
Herbal remedies 
Megadose (20 to 600 times recommended daily 
dose) vitamins 
Megadose minerals 
In the 2 weeks prior to administration of IP, or longer 
if the medication has a long half-life, use of any of 
these medications constitutes a basis for exclusion 
from the study. 
Grapefruit juice 
Subjects should not consume grapefruit juice for up to 
7 days before dosing and throughout the study. 
IP  Investigational product 
 
Table 10 
Prohibited medications 
Prohibited medication/class of drug: 
Any other investigational drugs than provided in this study 
Any medication with enzyme inducing properties such as St John’s wort 
Hormone replacement therapy 
Oral and topical inhibitors/inducers of CYP3A4 
Vaccination with COVID-19 vaccine less than 14 days prior to the proposed date of randomization 
 
Medication other than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate section of the eCRF. 
7 DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL  
7.1 Discontinuation of study treatment 
As individual subjects are given only one dose of IP, there are no criteria for discontinuing 
study treatment.  This section describes the criteria for study termination and the 
discontinuation of planned dose escalations within the study. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 


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The study may be stopped if, in the judgement of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that: 
• 
Meet individual stopping criteria or are otherwise considered significant 
• 
Are assessed as causally related to IP 
• 
Are not considered to be consistent with continuation of the study 
 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. 
In terminating the study, the sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ wellbeing. 
After each cohort, an SRC will review and assess all the available safety and PK data from all 
of the cohorts to date in order to make a decision on the dose for the next cohort of subjects. 
Data from a minimum of 6 subjects dosed per cohort must be reviewed before each dose 
escalation. 
If any of the following scenarios occur within a cohort with a reasonable possibility of a 
causal relationship with AZD4041, escalation to the next, higher dosage level may not occur: 
General 
• 
One or more subjects, who receive AZD4041, report a SAE or experience AEs judged to 
be non-tolerable by the PI or the SRC, and are deemed related to AZD4041. 
 
Cardiovascular criteria 
• 
Two or more subjects, who receive AZD4041, have QTc prolongation defined as QTcF 
>500 ms, or a prolongation from baseline of >60 ms, confirmed (persistent for at least 
5 minutes) and determined post-dose either during continuous 12-lead ECG monitoring or 
on a repeat 12-lead ECG. 
• 
Two or more subjects, who receive AZD4041, have tachycardia defined as resting supine 
HR >125 beats per minute persisting for at least 10 minutes. 
• 
Two or more subjects, who receive AZD4041, have symptomatic bradycardia defined as 
resting supine HR <40 beats per minute or asymptomatic bradycardia defined as resting 
supine HR <30 beats per minute while awake and persisting for at least 10 minutes. 
• 
Two or more subjects, who receive AZD4041, develop hypertension defined as an 
increase in resting supine systolic BP >40 mmHg to above 180 mmHg and persisting for 
at least 10 minutes. 
• 
Two or more subjects, who receive AZD4041, develop hypotension defined as an 
asymptomatic fall in systolic BP of >20 mmHg to <70 mmHg persisting for at least 


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10 minutes, or a symptomatic fall in resting supine BP >20 mmHg (excluding vasovagal 
reaction). 
• 
Two or more subjects, who receive AZD4041, have tachycardia defined as resting supine 
heart rate >125 beats per minute persisting for at least 10 minutes.  
• 
Two or more subjects, who receive AZD4041, have a non-sustained ≥5 beat if “slow” 
(<100 bpm), or “fast”(≥100 bpm) ventricular tachycardia. 
• 
One or more subjects, who receive AZD4041, have a sustained ventricular tachycardia 
(ie, >30 second duration, or leading to hemodynamic consequences requiring immediate 
arrhythmia termination). 
Laboratory findings 
• 
One or more subjects, who receive AZD4041, fulfill Hy’s Law defined as “An increase in 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3x upper limit of 
normal (ULN) and total bilirubin (TBL) ≥2x ULN, where no other reason can be found to 
explain the combination of increases; eg, elevated serum alkaline phosphatase (ALP) 
indicating cholestasis, viral hepatitis, or another drug.”  The elevations do not have to be 
at the same time or within a specified time frame. 
• 
Two or more subjects, who receive AZD4041, have >3x ULN of either ALT or AST, or 
>2x ULN for TBL or ALP. 
Criteria for halting dose escalation 
PK data indicate that the predefined maximum exposure level/maximum plasma concentration 
(free Cmax of 
 
has been achieved, or is predicted to be achieved or 
exceeded should the dose be increased as planned.  The exposure limits should be applied on 
mean values within a cohort.  If this halting dose escalation criterion is met, the SRC will stop 
any further dose escalation.  The SRC will determine whether a lower or the same dose should 
be tested or whether the study should be terminated. 
7.2 Lost to follow-up 
A subject will be considered potentially lost to follow-up if the subject fails to return for 
scheduled visits and is unable to be contacted by the study site.   
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule. 
• 
Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject or next of kin by, eg, repeat telephone calls, 


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certified letter to the subject´s last known mailing address or local equivalent methods.  
These contact attempts should be documented in the subject’s medical record. 
• 
Efforts to reach the subject should continue until the end of the study.  Should the subject 
be unreachable at the end of the study, the subject should be considered to be lost to 
follow-up with unknown vital status at end of study and censored at latest follow-up 
contact. 
 
7.3 Withdrawal from the study 
A subject may withdraw from the study (eg, withdraw consent), at any time (IP and 
assessments) at the subject’s own request.  There will be no penalty or loss of benefit to the 
subject. 
A subject who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).  Circumstances of withdrawal will be 
documented in writing by the Investigator. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, the subject may request destruction of any samples 
taken, and the Investigator must document this in the site study records.   
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The Investigator will follow up with subjects as medically indicated.  
See SoA (Table 1 and Table 2), for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations that need to be completed.   
8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Table 1 and Table 2). 
The Investigator ensures the accuracy and completeness of eCRFs, including eligibility and 
timeliness of the data recorded and of the provision of answers to data queries according to the 
Data Management Plan.  The Investigator will sign the completed eCRFs.  A copy of the 
completed eCRFs will be archived at the study site. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study treatment. 


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Adherence to the study design requirements, including those specified in the SoA (Table 1 and 
Table 2), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  The Investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.   
Procedures conducted as part of the subject’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the CSP-specified criteria and were performed within the time 
frame defined in the SoA. 
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 150 mL.  Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
8.1 Efficacy assessments (not applicable) 
8.2 Safety assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1 and Table 2). 
 Clinical safety laboratory assessments 
The clinical chemistry, hematology, and urinalysis will be performed at a local laboratory at 
or near to the study site. 
See Table 11 for the list of clinical safety laboratory tests to be performed and to the SoA 
(Table 1 and Table 2) for the timing and frequency.  All CSP-required laboratory assessments, 
as defined in the table, must be conducted in accordance with the laboratory manual and the 
SoA (Table 1 and Table 2). 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed, dated, and retained at center 
as source data for laboratory variables. 
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7. 
Additional safety samples may be collected and analyzed if clinically indicated at the 
discretion of the Investigator.  The date of collection will be recorded on the appropriate CRF. 


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Table 11 
Laboratory safety variables 
Hematology (whole blood) 
Clinical Chemistry (serum or plasma) 
White blood cell (WBC) count 
Alanine aminotransferase (ALT) 
Red blood cell (RBC) count 
Aspartate aminotransferase (AST) 
Hemoglobin (Hb) 
Alkaline phosphatase (ALP) 
Hematocrit (HCT) 
Gamma glutamyl transpeptidase (GGT) 
Mean corpuscular volume (MCV) 
Total bilirubin 
Mean corpuscular hemoglobin (MCH) 
Unconjugated bilirubin 
Mean corpuscular hemoglobin concentration (MCHC) 
C-reactive protein (CRP) 
Neutrophils absolute count 
Blood Urea Nitrogen 
Monocytes absolute count 
Creatinine 
Eosinophils absolute count 
Glucose (fasting) 
Basophils absolute count 
Albumin 
Platelets 
Phosphate 
Reticulocytes absolute count 
Potassium 
 
Calcium 
Urinalysis 
Sodium 
Glucose 
Bicarbonate 
Protein 
Thyroid stimulating hormone (TSH)a 
Hemoglobin 
Thyroxine (T4)b 
Microscopy (if positive for blood or protein) 
Follicle stimulating hormone (FSH)c 
Viral serology 
Pregnancy test (females only) 
Human immunodeficiency virus (HIV I and II) 
Human beta chorionic gonadotrophin 
Hepatitis B surface antigen (HBsAg) 
 
Hepatitis C Virus antibody 
 
a 
Screening only 
b 
Reflex only (if TSH is abnormal) 
c 
Screening for post-menopausal women 
NB.  In case a subject shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN refer to Appendix C 
‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for further instructions 
 
Urine will be tested for alcohol and cotinine (screening only) and the following drugs of 
abuse: amphetamines (includes methamphetamines and 
ecstasy/3,4-methylenedioxymetamphetamine), barbiturates, benzodiazepines, cannabinoids 
(includes tetrahydrocanabinol), cocaine metabolites, methadone, tricyclic antidepressants, 
opiates (includes heroin, codeine, and oxycodone), and phencyclidine. 


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 Testosterone, Luteinizing Hormone, Follicle Stimulating Hormone, and 
inhibin B assessments 
In order to monitor for effects on testicular function in male subjects, samples for assessment 
of testosterone, luteinizing hormone (LH), FSH, and inhibin B levels will be collected at 
0 hour (0800 or 1000) and at 4, 6, 8, 12, 22, and 24 hours on Day -1 and at 0 hour (0800 or 
1000) and at 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours on Day 1, as listed in the SoA (Table 2).  
The results of these assessments will be taken into account at dose escalation meetings, prior 
to selecting the dose for the next cohort. 
 Physical examinations 
A complete physical examination will be performed and include an assessment of the 
following systems: cardiovascular, chest/lungs/respiratory, gastrointestinal, thyroid/neck, 
lymphatics, dermatological/skin, musculoskeletal/extremities, neurological, and 
head/ears/eyes/nose/throat (including mouth). 
Physical examination will be performed at timelines as specified in the SoA.  Investigators 
should pay special attention to clinical signs related to previous serious illnesses; new or 
worsening abnormalities may qualify as AEs; see Section 8.3.7 for details. 
 Vital signs 
Body temperature, pulse rate (PR), respiratory rate, and BP will be assessed. 
Vital signs will be measured in a semi-supine position after 5 minutes rest.  Supine and 
standing BP and PR will be measured using a semiautomatic recording device.  Supine BP 
and PR should be taken after at least 5 minutes supine rest.  Standing BP and PR should be 
taken approximately 3 minutes after the respective supine measurements.  Three consecutive 
BP readings will be recorded at intervals of at least 1 minute.  The average of the 3 BP 
readings will be recorded on the CRF. 
Respiratory rate will be measured in breaths per minute by observation at the times indicated 
in the SoA (Table 1 and Table 2). 
 Electrocardiograms 
For the timing of ECG assessments, see the SoA (Table 1 and Table 2) and Table 12. 
Twelve-lead paper ECG (pECG) allows the PI to review the ECG tracings at bedside and 
determine any potential risks.  Digital 12-lead ECGs are collected and electronically submitted 
to the AstraZeneca ECG Center for expert review and reporting of ECG intervals.  Telemetry 
is used for continuous monitoring of ECG activity as a safety measure. 


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8.2.5.1 
Resting 12-lead ECG 
Twelve-lead pECGs will be obtained after the subject has been resting in the supine position 
for at least 10 minutes.  All pECGs will be evaluated for HR, and for PR, RR, QRS, QT, and 
QTcF intervals, and the Investigator will judge the overall interpretation as normal or 
abnormal.  If abnormal, it will be decided whether or not the abnormality is clinically 
significant or not clinically significant, and the reason for the abnormality will be recorded.  
The date/time, physician interpretation (normal, abnormal clinically significant, abnormal not 
clinically significant), and all evaluated parameters and intervals will be recorded in the eCRF, 
and the paper printouts will be stored at the site. 
The PI or delegate will evaluate the printout of the pECG in real time, and with particular 
attention to the effects of clinical importance on the PR, QRS, and QTcF intervals. 
8.2.5.2 Electronic capture and analysis of 12-lead digital ECGs 
The AstraZeneca ECG Center will perform the digital ECG (dECG) analysis and 
interpretation in this study, using the EClysis© system, version 4.0, or higher. 
Continuous 12-lead dECG recordings will be performed using the site’s Mortara Telemetry 
Surveyor equipment.  At CSP-indicated time points in Table 12, 12-lead continuous dECG 
files will be extracted over at least 5 minutes from the Mortara Telemetry Surveyor 
continuous files and transmitted to the AstraZeneca central dECG repository, according to 
AstraZeneca ECG Center’s standard procedures, settings, recording, and transmission of 
dECGs. 


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Table 12 
SAD single dose time schedule for digital electrocardiogram assessments 
in D7460C00001 during the residential period 
Study 
Days 
ECG 
Number 
Time-
point 
Start Time 
hour:mina,b 
Dose 
Stop 
Time 
dECG cont.c,d,e 
Otherf 
1 
 
 
-01:30 
 
-01:00 
 
Apply the 
electrodesd 
1 
 
 
-00:40 
 
-00:30 
 
Rest in bed 
1 
1 
Pre-dose 
-00:30 
Predose 
-00:20 
10 minutes 
 
1 
 
 
-00:20 
 
-00:05 
 
Toilet use 
recommended 
1 
 
 
00:00 
IP Admin 
 
 
 
1 
2 
30 min 
00:25 
 
00:30 
5 minutese 
 
1 
3 
1 h 
00:55 
 
01:00 
5 minutese 
 
1 
4 
1.5 h 
01:25 
 
01:30 
5 minutese 
 
1 
5 
2 h 
01:55 
 
02:00 
5 minutese 
 
1 
6 
3 h 
02:55 
 
03:00 
5 minutese 
 
1 
7 
4 h 
03:55 
 
04:00 
5 minutese 
 
1 
8 
6 h 
05:55 
 
06:00 
5 minutese 
 
1 
9 
8 h 
07:55 
 
08:00 
5 minutese 
 
1 
10 
12 h 
11:55 
 
12:00 
5 minutese 
 
2 
11 
24 h 
23:55 
 
24:00 
5 minutese 
 
2 
12 
36 h 
35:55 
 
36:00 
5 minutese 
 
3 
13 
48 h 
47:55 
 
48:00 
5 minutese 
 
4 
14 
72 h 
71:55 
 
72:00 
5 minutese 
 
a 
Time points for dECG may be adjusted according to emerging PK data. 
b 
Times are approximate as dECG and safety ECGs need to be completed before blood sampling. 
c 
The subject must be in the same supine body position (max. 30 degrees flexion in the hip) at each time point 
and at all visits.  Subject’s feet should not contact the footboard of the bed. 
d 
Skin must be cleaned, and electrode positions marked with an indelible pen. Electrodes should be applied at 
least 30 minutes before first recording. 
e 
Subject must rest in bed for at least 10 minutes prior to each ECG time point. 
f 
On the dosing days, safety ECG will be printed at the end of each dECG extraction window. 
dECG  Digital electrocardiogram; ECG  Electrocardiogram; IP  Investigational product; PK  Pharmacokinetics; 
SAD  Single ascending dose 
 
The same recording device will be used for each subject at all time points, when possible.  
Date and time settings must be checked on the Mortara Telemetry Surveyor at the start of each 
study day and aligned with an official timekeeper. 
Skin preparation must be thorough and electrode positions must be according to standard 
12-lead ECG placement. 


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Electrode positions will be marked with an indelible pen at the start of each study day to 
ensure exact reposition.  Permanent electrodes will be applied at least 30 minutes before first 
study recording and left in place for the duration of each relevant study day. 
Subjects will rest in a supine position for at least 10 minutes (can be reduced to 5 minutes at 
collection time points within the first hour after dosing) before the start of each recording.  
The subject should be in the same supine body position (maximum 30 degrees flexion of the 
hip and feet not in contact with the footboard) at each recording time point during the study. 
The metadata for all dECG files will be checked by the responsible personnel at the study site 
to ensure that the files transferred to the AstraZeneca central dECG files repository can be 
approved by the AZ ECG Center to be made accessible to the ECG Scientific Advisors for 
analysis.  As a standard, 10-second ECGs will be extracted by the EClysis© system twice per 
minute from the continuous recording and initially automatically analyzed by the software. 
Lead V2 will be analyzed and reported as primary.  Lead V5 will be analyzed, for all visits, as 
backup for the individual where analysis in lead V2 is not deemed possible for pre-dose, for 
significant parts of visits or for whole visits. 
The ECG Scientific Advisor will perform all required manual corrections to the ECG 
annotations provided automatically by EClysis©. 
To provide a decision basis for dose escalation, the ECG Scientific Advisor(s) will perform a 
preliminary analysis of the first 24 hours of dECG recordings in lead V2, with the main focus 
on QT changes, wave morphology changes, and dysrhythmia. 
The AZ ECG Center Cardiologist will review the data, perform an evaluation and 
interpretation of the findings, and will provide a safety report for the SRC meeting. 
The AZ ECG Center Cardiologist will review the totality of the data and perform all necessary 
adjustments before locking the EClysis© data into a read-only state, before the data will be 
exported. 
The numerical values for ECG intervals and amplitudes will be exported and made accessible 
on the AstraZeneca dECG Central repository to accredited data management specialists for 
conversion into SAS® files. 
The following dECG variables will be reported by the AstraZeneca ECG Center: RR, PR, 
QRS and QT intervals from the lead defined as the primary analyses lead.  Derived parameters 
(QTcF, HR, and others, as applicable) are calculated by the study statistician or delegate. 


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8.2.5.3 
Telemetry (real-time display) 
To allow a real-time assessment of cardiac safety at the study site, subjects will be monitored 
by telemetry (for real-time assessment of cardiac rate and rhythm) for 24 hours on Day -1, and 
pre-dose to 48 hours post-dose. Subjects with NSVT and excessive VPCs will be excluded 
from pre-dose telemetry. Any clinically significant change noted on telemetry will be 
followed up with a 12-lead ECG.  Further evaluation and treatment will be performed as 
deemed appropriate by the Investigator.  Any finding of short, self-limiting, asymptomatic 
arrhythmia (eg, non-significant tachycardia, atrial fibrillation or flutter) that does not require 
any medical intervention, should be documented and further evaluated in the context of the 
individual subject’s history and clinical status.  Irrespective of the intervention, cardiac 
monitoring will be continued until the event resolves or the subject is deemed clinically stable 
by the Investigator. 
8.3 Collection of adverse events 
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
An AE will be reported by the subject.   
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE.  For information on how to follow-up AEs, 
see Section 8.3.3. 
 Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.   
 Time period and frequency for collecting AE and SAE information  
Serious AEs will be collected from the time of signature of ICF, throughout the treatment 
period, and including the follow-up period and last contact.  Adverse events will be collected 
from the time of administration of IP.  Non-SAEs occurring between the time of signature of 
the ICF and the administration of IP will be reported as medical history. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Section 8.4.1.  The Investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 


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Investigators are not obligated to actively seek AE or SAE in former study subjects.  
However, if the Investigator learns of any SAE, including a death, at any time after a subject’s 
last visit and the Investigator considers the event to be reasonably related to the study 
treatment or study participation, the Investigator may notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 8.4.1 and 
Appendix B. 
 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All AEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the subject is lost to follow-up  
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
CRF.  AstraZeneca retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
 Adverse event data collection 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
Intensity of the AE 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP (yes or no) 
• 
Action taken with regard to IP 
• 
Whether the AE caused the subject’s withdrawal from study (yes or no) 
• 
Outcome of the AE 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 


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• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
• 
Description of the SAE 
 
 Causality collection 
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’ 
For SAEs, causal relationship will also be assessed for other concomitant medication and 
study procedures.  Note that for SAEs that could be associated with any study procedure, the 
causal relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question can be found in Appendix B. 
 Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since you were last asked?’ or 
revealed by observation, will be collected and recorded in the CRF.  When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms.  
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
 Adverse events based on examinations and tests 
The results from the CSP-mandated laboratory tests and vital signs will be summarized in the 
Clinical Study Report (CSR).  Deterioration as compared to baseline in CSP-mandated 
laboratory values or vital signs should therefore only be reported as AEs if they fulfill any of 
the SAE criteria, are the reason for discontinuation of treatment with the IP, or qualify as AEs 
of interest. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 


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 Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3x ULN together with TBL ≥2x ULN may need to be 
reported as SAEs.  Refer to Appendix C for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law (HL). 
8.4 Safety reporting and medical management 
 Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP or to the 
study procedure(s).  All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, Investigators or other site personnel will inform 
the Medical Monitor; the AstraZeneca study physician or physician designate; and MMS 
Holdings, Inc immediately, or no later than 24 hours after they become aware of the SAE 
(initial report) using the SAE Report Form provided by MMS Holdings.  Telephone and email 
reports must be confirmed promptly either by facsimile or by overnight courier or mail. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  The Investigator or other site personnel will inform the 
Medical Monitor; the AstraZeneca study physician or physician designate; and MMS 
Holdings, Inc of any follow-up information on a previously reported SAE immediately, or no 
later than 24 hours from when the Investigator becomes aware of it. 
Contact information for the AstraZeneca study physician, the Medical Monitor, and MMS 
Holdings, Inc are included in the Study Manual. 
For guidance on the definition of an SAE, see Appendix B. 
 Pregnancy 
All pregnancies and their subsequent outcome (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth, or congenital abnormality) should be reported to: 
 
 
 
 
The reports should be made using the 
 Pregnancy Notification and Outcome Form. 
8.4.2.1 Maternal exposure 
Women of childbearing potential are not allowed to be included in this study.   


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Should a pregnancy still occur, the IP should be discontinued immediately and the pregnancy 
reported to 
 using the Pregnancy 
Notification and Outcome Form. 
If a subject becomes pregnant during the course of the study, all study drugs should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs (Section 8.4.1, Reporting of serious adverse events).  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study. 
8.4.2.2 
Paternal exposure  
Male subjects should refrain from fathering a child or donating sperm for the duration of the 
treatment period and for 4 months after the last administration of IP. 
Pregnancy of the subject’s partners is not considered to be an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) must be followed up, documented, and reported to 
 
 using the Pregnancy Notification and 
Outcome Form.  Congenital abnormalities/birth defects and spontaneous miscarriages should 
be reported and handled as SAEs (Section 8.4.1, Reporting of serious adverse events). 
The outcome of any conception occurring from the date of administration of IP until 
5 half-lives of AZD4041 or 12 weeks (whichever is longer) after the last administration of IP 
must be followed up, documented, and reported to 
 
 
 Overdose 
If a subject receives study medication in excess of that prescribed by the CSP, this will be 
considered an overdose.  There are no data on overdosing with AZD4041, as this is the first 
clinical study of AZD4041.  There is no known specific antidote.  In case of known or 
suspected overdose, symptomatic treatment as well as monitoring of vital functions should be 
performed as per the judgement of the Investigator.   
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose eCRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose CRF module 


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• 
In the event of an overdose, the Medical Monitor or physician designate should be 
contacted immediately to discuss the management plan for the subject.  A description of 
the treatment administered for the overdose as well as the subject’s clinical course will be 
recorded.  In the event of an overdose, 
 
 
• 
For overdoses associated with an SAE, the standard reporting procedures and timelines 
apply; see Section 8.3.2 and Section 8.4.1.   
 
 Medication error 
Medication errors with AstraZeneca IP are collected in all studies where medication error is 
possible.  Refer to the Pre-Startup Safety Review (PSSR) or other appropriate project 
document for specific considerations for collection of medication errors. 
For guidance, refer to the AstraZeneca Standard Operating Procedure (SOP) ‘Reporting of 
Individual Safety Events in Clinical Studies’. 
If a medication error occurs in the course of the study, the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day; ie, immediately but no later 
than 24 hours of when the Investigator becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is a 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors. 
The definition of a medication error can be found in Appendix B. 
 Management of IP-related toxicities 
The Investigator is responsible for ensuring that expertise and facilities are available for the 
management of all suspected IP-related toxicities in accordance with local procedures and 
accepted standards of medical practice.  There is no specific antidote to AZD4041.  In case of 
suspected IP-related toxicity, an appropriate level of vital sign monitoring should be instituted; 
symptomatic and supportive treatment should be provided according to the judgement of the 
Investigator.  Treatment of suspected IP-related toxicity may be guided by further 
investigations, and referral to a specialist center may be warranted. 
Any case of suspected IP-related toxicity should be reported as an AE (Section 8.3) or SAE 
(Section 8.4.1). 


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 Safety Review Committee 
After each cohort, an SRC will evaluate the safety, tolerability and PK of AZD4041 and 
determine the next dose. 
The data from at least 6 subjects in the previous cohort must be reviewed before a decision to 
escalate can be taken. 
The SRC will consist of the following core members: 
• 
Principal Investigator (Chair, voting member) 
• 
AstraZeneca Lead Physician or delegate (must be a physician) (voting member) 
• 
CRO Medical Monitor (voting member) 
• 
CRO Project Manager (nonvoting member) 
• 
Pharmacokineticist (nonvoting member) 
 
The SRC may also request to have attendance of, or offline support and input from the 
following functions, as required: 
• 
AstraZeneca and/or CRO Pharmacokinetic Scientists 
• 
AstraZeneca Team Pharmacometrician 
• 
CRO and AstraZeneca Statisticians 
• 
AstraZeneca and/or CRO Medical Specialists (eg, neurologist, AZ ECG Center 
cardiologists, etc.) 
• 
AstraZeneca and/or CRO Patient Safety Physician. 
 
The SRC voting members will make the decision for the next dose level or whether to stop the 
study after reviewing all the pertinent safety and PK data.  Other internal or external experts 
may be invited to participate in the review or may be consulted. 
If consensus among the voting SRC members cannot be reached then the PI, who has the 
ultimate responsibility for the safety of the subjects, will make the final decision on the next 
dose level or whether to stop the study.  In any event, dose escalation can only occur if agreed 
by the PI. 
The decisions of the SRC on the next dose level will be documented and provided to all the 
appropriate parties involved with the study, including the Pharmacist, to enable IP preparation 
for the next scheduled dosing day. 
Initially the data will be reviewed blinded, but if the PI or the SRC consider it necessary due 
to a safety concern, data from individual subjects or the entire cohort may be unblinded to 


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enable decision-making.  Before breaking the code, the potential decisions and actions should 
be determined.  The code will be broken according to local SOPs.  The SRC may stop dose 
escalation at any time if the SRC determines that dose escalation would pose undue risk to 
subjects.  If dose escalation is not stopped, the SRC may recommend ascending to the planned 
next higher dosage level cohort, ascending to a dosage level lower than the planned next 
higher dosage level cohort, repeat dosing at the current dosage level, or continuing with a 
lower dose than the current dosage level.   
Following review of data from a cohort of subjects, the timing of assessments and/or blood 
samples may be adjusted for subsequent cohorts. 
Additional assessment or sampling times may be added if indicated by the data. 
The following accumulated blinded safety data up to and including Day 15 post-dose 
follow-up data for a given cohort, as available, will be reviewed by the SRC: 
• 
AE profile, including description, frequency, intensity, onset, duration, and Investigator 
assessment of the relationship to IP 
• 
SAE listings and case narratives 
• 
Vital sign parameters, including BP, orthostatic BP, and pulse rate 
• 
12-lead (paper) ECG assessments and interval data 
• 
Safety report containing an analysis and review of dECG data, to be provided by the 
AstraZeneca ECG Center 
• 
Clinical laboratory test results 
• 
PK data 
• 
Testosterone, LH, FSH, and inhibin B assessment results for male subjects 
 
Full SRC details are described in the SRC Charter. 
8.5 Pharmacokinetics 
 Determination of drug concentration 
Samples for determination of drug concentration will be analyzed by analytical test sites on 
behalf of AstraZeneca, using an appropriate bioanalytical method.  Full details of the 
analytical method used will be described in a separate Bioanalytical Report. 
Incurred sample reproducibility analysis will be performed alongside the bioanalysis of the 
test samples.  The results from the evaluation will not be reported in the CSR, but separately 
in a Bioanalytical Report. 


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 Metabolite identification in plasma 
Following determination of drug concentration and appropriate assessment of incurred sample 
reproducibility, residual or back-up plasma PK samples may be utilized for investigative 
metabolite identification studies.  Utilizing appropriate analytical methods, this exploratory 
approach will aim to identify major circulating metabolites of AZD4041 in plasma.  The 
results from the evaluation will not be reported in the CSR, but reported separately in a 
Metabolite Identification Report. 
 Storage and destruction of pharmacokinetic samples 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses.  Left-over PK samples may be used for analysis of safety, 
efficacy, or biomarker laboratory parameters if samples drawn for that purpose at the same 
time point were insufficient for the analyses needed. 
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling.  
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the CSR. 
8.6 Pharmacodynamics 
To characterize the PD relationship between drug exposure and QT interval, an 
exposure-response (E-R) analysis may be conducted with data from this study alone or in 
combination with other studies as appropriate, with a pre-specified workflow described in a 
separate technical document for the QTcF parameter, as part of the cardiac safety evaluation 
and with the intention to obtain a Thorough QT study substitute.  The result of the E-R 
analysis may not be included in the main study report. 
9 STATISTICAL CONSIDERATIONS  
Safety, tolerability, and PK data will be summarized descriptively as appropriate.  Descriptive 
summary statistics for continuous variables will include number, arithmetic mean, standard 
deviation, minimum, median, and maximum, while for continuous PK variables, descriptive 
summary statistics will also include geometric mean and arithmetic coefficient of variation.  
Descriptive summary statistics for categorical data will include frequency and proportion.  
Tests of significance of group difference (drug dose versus placebo) on change from baseline 
in safety variables will also be performed.  Model-based approaches will be used, if 
appropriate. 


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9.1 Statistical hypotheses 
Based on the predicted human exposure following a 
 of AZD4041, a 
 
exposure margin to free Cmax and a 
 exposure margin to free AUC0-inf when compared 
to the corresponding toxicokinetic parameters for dog NOAEL dose level in male dogs is 
predicted.  For a 
, the corresponding free Cmax and free AUC0-inf 
exposure margins would be 
, respectively. 
9.2 Sample size determination 
Due to the exploratory nature of the study, sample size is not based on formal statistical 
considerations but is based primarily on a desire to obtain sufficient safety and tolerability 
information while exposing as few subjects as possible to the investigational treatment. 
9.3 Populations for analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
PK analysis set 
All subjects who received IP and for whom PK data are available 
Safety analysis set 
All subjects who received at least 1 dose of IP and for whom any post-dose 
data are available   
 
9.4 Statistical analyses 
A comprehensive statistical analysis plan (SAP) will be developed and finalized before 
database lock and will describe the subject populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data.  This section is a summary 
of the planned statistical analyses of the primary and secondary endpoints.  Any deviations 
from this plan will be reported in the CSR. 
 Pharmacokinetic analyses 
Standard PK variables for a single ascending dose study will be derived. 
• 
Cmax 
• 
Tmax 
• 
AUC0-t 
• 
AUC0-inf 
• 
t1/2λz 
• 
CL/F (apparent total clearance of the drug from plasma after oral administration) 
• 
Vss/F (apparent volume of distribution at steady state after non-intravenous 
administration) 


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 Safety analyses 
All safety analyses will be performed on the Safety analysis set.  Specific methods will be 
described in the SAP. 
9.4.2.1 Safety and tolerability 
Adverse events will be listed and summarized by Medical Dictionary for Regulatory 
Activities system organ class and preferred term, and by treatment regimen.  The presentation 
period of AEs will be the time from first dose to follow-up.  
Vital signs, body temperature, body weight and BMI, clinical laboratory measures, and dECG 
interval data will be summarized using descriptive statistics by treatment regimen and CSP 
time (eg, visit number, date, and time). 
Individual data for vital signs, body weight and BMI, clinical laboratory measures, dECG 
intervals, overall pECG assessments (made by the Investigator), and physical examination 
results will be flagged and listed for any potentially clinically important (PCI) values for each 
subject according to predetermined PCI criteria.  
Project-specific reference limits will be used in the statistical analysis.  When project-specific 
reference limits are not available, the reference limits of the local laboratory will be used. 
9.4.2.2 Pharmacokinetics 
AZD4041 serum concentration data will be summarized using descriptive statistics by 
treatment regimen and scheduled sampling time.  Individual and mean AZD4041 serum 
concentration versus time data will be plotted by treatment regimen. 
PK parameters of AZD4041 will be summarized using descriptive statistics by treatment 
regimen.  Dose proportionality and linearity of PK exposure parameters (AUC and Cmax) will 
be evaluated using a regression (power) model relating log transformed Cmax and AUC 
parameters to the log transformed dose.  


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alpha4beta2 nicotinic receptor partial agonist for smoking cessation.  J Med Chem 
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observations on male British doctors.  BMJ 1994;309(6959):901-11. 
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observations on male British doctors.  BMJ 2004;328(7455):1519. 
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Electronic Medicines Compendium (eMC).  Summary of Product Characteristics for Champix 
(varenicline).  Available at: https://www.medicines.org.uk/emc/product/266/smpc/print. 
Ezzati and Lopez 2003 
Ezzati M, Lopez AD.  Estimates of global mortality attributable to smoking in 2000.  Lancet 
2003;362(9387):847-52. 
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Goodchild M, Nargis N, Tursan d’Espaignet E.  Global economic cost of smoking-attributable 
diseases.  Tob Control 2018 Jan;27(1):58-64. 
Gotter et al 2016 
Gotter AL, Forman MS, Harrell CM, Stevens J, Svetnik V, Yee KL, et, al.  Orexin-2 receptor 
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11 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Appendix A Regulatory, ethical and study oversight considerations 
A 1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• 
Applicable International Conference of Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
• 
Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an Institutional Review Board/Instutional Ethics 
Committee (IRB/IEC) by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
 
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
A 2 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 


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certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
A 3 
Informed consent process 
The investigator or his/her representative will explain the nature of the study to the subject and 
answer all questions regarding the study.   
Subjects must be informed that their participation is voluntary.  Subjects will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the subject. 
If a subject declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the subject and he/she will not be 
excluded from other aspects of the study. 
Subjects who are re-prescreened are required to sign a new brief ICF.  The brief ICF is used to 
obtain subject consent for sUA, eGFR, and UACR assessments.  Subjects who are rescreened 
are required to sign a new full ICF.  The full ICF is the master ICF for the study. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each subject the objectives of the exploratory research.  Subjects will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period.  The subject will give a separate agreement to allow any 
remaining specimens to be used for exploratory research.  Subjects who decline to participate 
in this optional research will indicate this in the ICF.  If a subject withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented.  If samples already have been analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research. 


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A 4 
Data protection 
Each subject will be assigned a unique identifier by the sponsor.  Any subject records or data 
sets transferred to the sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the subject. 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
A 5 
Committees structure 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Subject Safety.  Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators. 
Safety review committee (SRC)  
An SRC will review data from each cohort before progression to the next cohort occurs. 
A 6 
Dissemination of clinical study data 
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available.  The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted. 
A 7 
Data quality assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.   
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.   


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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. 
A 8 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available. 
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study are defined as source documents.  Source data are contained in source 
documents (original records or certified copies). 


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Appendix B Adverse event definitions and additional safety information 
B 1 
Definition of adverse events 
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered. 
B 2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above. 
 
B 3 
Life-threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
B 4 
Hospitalization 
Out-subject treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 


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B 5 
Important medical event or medical treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life- threatening or result 
in death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
 
B 6 
Intensity rating scale: 
1 
mild (awareness of sign or symptom, but easily tolerated).  Usually transient and may 
require only minimal treatment or therapeutic intervention.  The event does not generally 
interfere with usual activities of daily living. 
2 
moderate (discomfort sufficient to cause interference with normal activities).  Usually 
alleviated with additional specific therapeutic intervention.  The event interferes with 
usual activities of daily living, causing discomfort, but poses no significant or permanent 
risk of harm to the subject. 
3 
severe (incapacitating, with inability to perform normal activities).  Interrupts usual 
activities of daily living, or significantly affects clinical status, or may require intensive 
therapeutic intervention. 
 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2. 


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B 7 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course.  Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 


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B 8 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.   
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error: 
• 
occurred 
• 
was identified and intercepted before the participant received the drug 
• 
did not occur, but circumstances were recognized that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error eg,  medication prepared incorrectly, even if it was not actually given to 
the participant 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated eg,  tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed eg,  kept in the fridge when it should be at room temperature  
• 
Wrong participant received the medication 
• 
Wrong drug administered to participant 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Participant accidentally missed drug dose(s) eg,  forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 


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B 9 
Labelling and shipment of biohazard samples – International 
Airline Transportation Association 6.2 Guidance Document 
The International Airline Transportation Association (IATA) classifies biohazardous agents 
into 3 categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm).  For 
transport purposes, the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005).  Infectious 
substances are now classified either as Category A, Category B, or Exempt.  There is no direct 
relationship between Risk Groups and Categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are, eg, Ebola, Lassa fever 
virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2.  They are assigned the following UN number 
and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
Exempt – all other materials with minimal risk of containing pathogens 
• 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
• 
Clinical trial samples will routinely be packed and transported at ambient 
• 
Temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm) 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used. 


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Appendix C Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law 
C 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets PHL 
criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review Adverse Event data  (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug-induced liver injury (DILI) caused by the investigational product 
(IP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
C 2 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2×ULN at any point during the study 
following the start of study medication  irrespective of an increase in alkaline phosphatase 
(ALP). 


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Hy’s Law (HL) 
AST or ALT ≥3 × ULN  together with TBL ≥2 ×ULN, where no other reason, other than the 
IP, can be found to explain the combination of increases; eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur. 
C 3 
Identification of potential Hy’s Law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥3 × ULN 
• 
AST ≥3 × ULN 
• 
TBL ≥2 × ULN 
 
Central laboratories being used: 
When a subject meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the 
AstraZeneca representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will: 
• 
Notify the AstraZeneca representative 
• 
Request a repeat of the test (new blood draw) by the central laboratory without delay 
• 
Complete the appropriate unscheduled CRF module(s) with the original local laboratory 
test result 
 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
• 
Determine whether the subject meets PHL criteria (see Appendix C 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results) 
 


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Local laboratories being used: 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the AstraZeneca representative 
• 
Determine whether the subject meets PHL criteria (see Appendix C 2 for definition) by 
reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF 
 
C 4 
Follow-up 
C 4.1 
Potential Hy’s Law criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the subject has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
 
C 4.2 
Potential Hy’s Law criteria met 
If the subject does meet PHL criteria the Investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team  
• 
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting. 
• 
For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the subject’s condition 
• 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. 
• 
Subsequent to this contact the Investigator will: 
− 
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated.  Complete the follow-up SAE Form as required. 
− 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  This includes deciding which the tests available 
in the Hy’s law lab kit should be used.  
− 
Complete the 3 Liver CRF Modules as information becomes available  
 


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C 5 
Review and assessment of potential Hy’s Law cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP, 
to ensure timely analysis and reporting to health authorities within 15 calendar days from the 
date PHL criteria were met.  The AstraZeneca Global Clinical Lead or equivalent and Global 
Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE: update the previously-submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
• 
Send an updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.   
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IP and 
seriousness criteria is medically important, according to CSP process for SAE reporting. 


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• 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously-submitted PHL SAE report 
following the CSP process for SAE reporting, according to the outcome of the review 
amending, the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 
References 
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al.  Case 
definition and phenotype standardization in drug-induced liver injury.  Clin Pharmocol Ther 
2011; 89(6):806-815. 
FDA Guidance for Industry  Drug-induced liver injury: Premarketing clinical evaluation.  
2009 July. 


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Appendix D Abbreviations  
Abbreviation or special 
term 
Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-inf 
extrapolation of the area under the curve from time 0 to infinity 
AV 
atrioventricular 
BBB 
bundle branch block 
BMI 
body mass index 
BP 
blood pressure 
CL/F 
apparent total clearance of the drug from plasma after oral administration 
Ceff 
free efficacious exposure 
Cmax 
maximum (peak) plasma drug concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case Report Form (electronic/paper) 
CRO 
clinical research organization 
CRU 
clinical research unit 
CSP 
clinical study protocol 
CSR 
clinical study report 
CV 
cardiovascular 
dECG 
digital electrocardiogram 
E-R 
exposure-response 
ECG 
electrocardiogram 
EClysis© 
user-interactive, modular computer-based system for dECG data processing, 
analysis and measurement of ECG intervals and wave amplitudes, exports and 
reports, used by the AstraZeneca ECG Center 
eCRF 
electronic Case Report Form 
EEG 
electroencephalogram 
FIH 
first in human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPCR 
G protein-coupled receptor 
hERG 
cardiac potassium ion channel 


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Abbreviation or special 
term 
Explanation 
HIV 
human immunodeficiency virus 
HL 
Hy’s Law 
HR 
heart rate 
IBBB 
incomplete bundle branch block 
IC50 
half maximal inhibitory concentration 
IC90 
in vivo 90% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IP 
investigational product 
IRB 
Institutional Review Board 
IVCD 
intraventricular conduction delay 
LH 
luteinizing hormone 
NOAEL 
no-observed-adverse-effect level 
NREM 
non-rapid eye movement 
NSVT 
non-sustained ventricular tachycardia 
OX1 
orexin 1 receptor 
OX2 
orexin 2 receptor 
PBPK 
physiologically-based pharmacokinetic model 
PCI 
potentially clinically important 
PD 
pharmacodynamic 
pECG 
paper electrocardiogram 
PK 
pharmacokinetic 
PopPK 
population pharmacokinetic 
PR 
pulse rate 
PR(PQ) 
ECG interval measured from the onset of the P wave to the onset of the QRS 
complex 
QRS 
ECG interval measured from the onset of the QRS complex to the J point 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T 
wave 
QTc 
corrected ECG Q-T interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RR 
time elapsed between 2 consecutive R waves as measured by ECG 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 


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Abbreviation or special 
term 
Explanation 
SRC 
Safety Review Committee 
TBL 
total bilirubin 
t1/2λz 
terminal half-life 
Tmax 
time to reach maximum (peak) plasma concentration following drug 
administration  
ULN 
upper limit of normal 
VPC 
ventricular premature contraction 
Vss/F 
apparent volume of distribution at steady state after non-intravenous 
administration 
 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
 
 
 
 
 
AstraZeneca 
 
AZD4041 – D7460C00001 
 
A Phase I, Randomized, Double-blind, Placebo-controlled Study to Assess 
the Safety, Tolerability, and Pharmacokinetics of AZD4041 Following Single 
Ascending Dose Administration to Healthy Volunteers 
 
07AUG2020 
 
Final Statistical Analysis Plan 
 
Version 1.0 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 2 
2.1. PRIMARY OBJECTIVES ........................................................................................................ 2 
2.2. SECONDARY OBJECTIVE ..................................................................................................... 2 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.2. STUDY ENDPOINTS ............................................................................................................. 4 
3.2.1. 
Primary Endpoints ...................................................................................................... 4 
3.2.2. 
Secondary Endpoints .................................................................................................. 4 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 4 
4.1. RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 5 
4.2. SAMPLE SIZE ...................................................................................................................... 6 
4.3. ANALYSIS POPULATION ...................................................................................................... 6 
5. 
SUBJECT DISPOSITION ............................................................................................... 6 
5.1. DISPOSITION ....................................................................................................................... 6 
5.2. PROTOCOL DEVIATIONS ..................................................................................................... 6 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 6 
6.1. DEMOGRAPHICS .................................................................................................................. 6 
6.2. MEDICAL HISTORY ............................................................................................................. 7 
7. 
TREATMENTS AND MEDICATIONS ......................................................................... 7 
7.1. PRIOR AND CONCOMITANT MEDICATIONS .......................................................................... 7 
7.2. MEDICAL OR SURGICAL TREATMENT PROCEDURES ........................................................... 7 
7.3. STUDY TREATMENTS .......................................................................................................... 7 
8. 
SAFETY ANALYSIS ....................................................................................................... 7 
8.1. ADVERSE EVENTS ............................................................................................................... 7 
8.1.1. 
Incidence of Adverse Events ....................................................................................... 8 
8.1.2. 
Relationship of Adverse Events to Study Drug ........................................................... 8 
8.1.3. 
Severity of Adverse Event............................................................................................ 8 
8.1.4. 
Serious Adverse Events ............................................................................................... 8 
8.1.5. 
Treatment-Emergent Adverse Events Leading to Study Discontinuation ................... 9 
8.2. LIVER EVENTS .................................................................................................................... 9 
8.3. CLINICAL LABORATORY EVALUATIONS ............................................................................. 9 
8.4. TESTOSTERONE, LUTEINIZING HORMONE, FOLLICLE STIMULATING HORMONE, AND 
INHIBIN B ASSESSMENTS ............................................................................................................ 11 
8.5. VITAL SIGN MEASUREMENTS ........................................................................................... 11 
8.6. ELECTROCARDIOGRAMS ................................................................................................... 11 
8.6.1. 
Twelve-Lead Paper ECG .......................................................................................... 12 
8.6.2. 
Digital ECG .............................................................................................................. 12 
8.6.3. 
Telemetry................................................................................................................... 13 


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8.7. PHYSICAL EXAMINATION ................................................................................................. 13 
9. 
PHARMACOKINETICS ............................................................................................... 13 
9.1. DATA HANDLING .............................................................................................................. 13 
9.2. PLASMA CONCENTRATION ................................................................................................ 14 
9.3. PHARMACOKINETIC PARAMETERS .................................................................................... 14 
9.4. PHARMACOKINETIC STATISTICAL ANALYSIS .................................................................... 15 
10. 
PHARMACODYNAMICS ............................................................................................ 16 
11. 
INTERIM ANALYSIS ................................................................................................... 16 
12. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 16 
13. 
REFERENCES ................................................................................................................ 16 
14. 
APPENDICES ................................................................................................................. 18 
14.1. 
SCHEDULE OF ACTIVITIES (SOA) .................................................................................. 18 
14.2. 
POTENTIAL CLINICALLY SIGNIFICANT (PCS) LABORATORY VALUES ........................... 22 
14.3. 
POTENTIAL CLINICALLY SIGNIFICANT (PCS) VITAL SIGN VALUES .............................. 26 


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LIST OF ABBREVIATIONS 
 
λz
apparent terminal phase elimination rate constant
%AUCextrap
percentage of the area extrapolated for calculation of AUC0-inf.
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-t 
area under the plasma concentration versus time curve from time zero to the 
last quantifiable concentration in plasma
AUC0-inf
extrapolation of the area under the curve from time 0 to infinity
BLQ
below the limit of quantification
BMI
body mass index
BP
blood pressure
CI
confidence interval
CL/F
apparent total body clearance
Cmax
observed maximum plasma concentration 
CRU
clinical research unit
CSR
clinical study report
CV
coefficient of variation
dECG
digital electrocardiogram
ECG
electrocardiogram
E-R
exposure-response
EClysis© 
user-interactive, modular computer-based system for dECG data processing, 
analysis and measurement of ECG intervals and wave amplitudes, exports 
and reports, used by the AstraZeneca ECG Center
eCRF
electronic case report form
GLP
Good Laboratory Practice
HL
Hy’s Law
HR
heart rate
MedDRA
Medical Dictionary for Regulatory Activities
OX1
orexin 1 receptor
OX2
orexin 2 receptor
PD
pharmacodynamics
pECG
paper electrocardiogram
PK
pharmacokinetic
PR
pulse rate
PR(PQ) 
electrocardiogram interval measured from the onset of the P wave to the onset 
of the QRS complex
QRS 
electrocardiogram interval measured from the onset of the QRS complex to 
the J point
QT 
electrocardiogram interval measured from the onset of the QRS complex to 
the end of the T wave
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula


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RR 
time elapsed between 2 consecutive R waves as measured by 
electrocardiogram
Rsq 
r2, the coefficient of determination (goodness of fit statistic); visual inspection 
of the terminal slope will be performed. In general, λz may only be retained if 
r2 ≥ 0.80
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis software
SD
standard deviation
SoA
schedule of activities
SOC
system organ class
SRC
safety review committee
t1/2 λz
terminal elimination half-life
TBL
total bilirubin
TEAE
treatment-emergent adverse event
Tmax 
time to reach maximum (peak) plasma concentration following 
drug administration
ULN
upper limit of normal
Vss/F
apparent volume of distribution at steady state
WHO
World Health Organization
 


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1. Introduction 
 
Smoking is an epidemic of global proportions. It is the leading cause of morbidity and mortality 
in virtually every country in the world (Lim et al 2010). Smoking increases the risk of death by 
three-fold in smokers, compared with non-smokers (Jha et al 2013). It is predicted that 
approximately 0.6 billion current smokers worldwide will die from smoking-related illnesses, 
such as chronic obstructive pulmonary disease, cardiovascular disease and lung cancer (Ezzati 
and Lopez 2003, Doll et al 2004, Coe et al 2005, Mathers and Loncar 2006).  
 
Pharmacotherapy is an effective strategy to aid smoking cessation efforts, but there is 
considerable risk of relapse even when treated with the most efficacious medications currently 
available. Further, medications that are effective aids to smoking cessation are associated with a 
range of adverse effects. This highlights the pressing need to develop safer and more effective 
smoking cessation therapeutics. 
 
The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2 
respectively) are hypothalamic neuropeptides that act through two closely related G protein 
coupled receptors (GPCRs), the OX1 and OX2 receptors. Orexin A has high affinity for both 
receptors whereas orexin B has higher affinity for OX2 over OX1 receptors. Orexin transmission 
has been implicated in a diverse range of physiological functions, including feeding and energy 
homeostasis (Sakurai et al 1998), the sleep/wake cycle (Willie et al 2003; Gotter et al 2016), 
neuroendocrine homeostasis, cardiovascular functions (Samson et al 2007), and motivated 
behaviors (Kodadek and Cai 2010). The OX1 receptor signals almost exclusively through Gq 
coupling. Nicotine, which is the principal reinforcing component in tobacco smoke responsible 
for addiction (Stolerman and Jarvis 1995), activates orexin (hypocretin) neurons in the brain. 
This increase in orexinergic transmission is thought to play a crucial role in regulating the 
motivational properties of the drug that results in tobacco dependence (Kenny 2011). Further, 
OX1 receptors regulate the reinstatement of extinguished drug-seeking responses in abstinent 
rats (Boutrel et al 2005, Harris et al 2005, Kenny 2011) and mice, considered animal models 
with heuristic value for understanding relapse in abstinent human drug addicts. As such, OX1 
receptor antagonists are considered one of the most promising novel therapeutic strategies to 
facilitate smoking cessation. Importantly, OX1 receptors play a similar role in regulating the 
addiction-related actions of opioids, psychomotor stimulants and alcohol, raising the possibility 
that OX1 receptor antagonists may have utility for the treatment of addiction across different 
classes of abused drugs. 
  
 
 
 
 
 
 
This study is conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single 
doses of AZD4041 in a small number of healthy subjects, prior to advancing AZD4041 into 
larger clinical trials of longer duration. 


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2. Objectives 
 
2.1. Primary Objectives 
 
The primary objectives of this study were as follows: 
 To assess the safety and tolerability of AZD4041 following oral administration of single 
ascending doses 
 To characterize the PK of AZD4041 following oral administration of single ascending 
doses of AZD4041 
 
2.2. Secondary Objective 
 
The secondary objective of this study was to characterize the pharmacodynamic (PD) 
relationship between drug exposure and QT interval. 
 
3. Investigational Plan 
 
3.1. Overall Study Design and Plan 
 
This is a Phase I, first-in-human, single-center, randomized, double-blind, placebo-controlled, 
single ascending dose, sequential group study in healthy male and female subjects of 
non-childbearing potential (Cohorts 1, 2, and 3), or healthy vasectomized male and female 
subjects of non-childbearing potential (Cohorts 4, 5, and 6), aged 18 to 65 years.  
 
The study plans to enroll 48 healthy subjects across 6 cohorts as shown in Table 3-1. 
 
Table 3-1: Dose-Level Cohorts 
Cohort 
Dose Level of AZD4041 
 
Eight subjects will participate in each cohort. Within each cohort, 6 subjects will be randomized 
to receive AZD4041 and 2 subjects will be randomized to receive placebo. Subjects that drop out 
before dosing will be replaced. Dosing for each ascending dose cohort will proceed with 2 
subjects in a sentinel cohort, such that 1 subject will be randomized to receive placebo and 1 
subject will be randomized to receive AZD4041 in a blinded fashion.  
 
The safety data from the sentinel subjects up to 24 hours post-dose will be reviewed by the 
principal investigator (PI), clinical research organization (CRO) medical monitor, and 
AstraZeneca study physician before the remaining subjects in the cohort are dosed. The 
remaining 6 subjects for each cohort will be dosed at least 24 hours after the sentinel cohort.  
 


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The study comprises a screening period of up to 28 days (4 weeks), a 4-day in-patient period 
for Cohorts 1 to 3 and a 6-day in-patient period for Cohorts 4 to 6 during which a single oral 
dose of AZD4041 or placebo will be administered, and an out-patient follow-up period. The 
overall study duration (screening, treatment, and follow-up periods) will therefore be 
approximately 6 weeks. The general study design is summarized in Figure 3-1. 
 
Figure 3-1: Study design (Cohorts 1 to 3) 
 
 
Cohort timing 
 
 
 
 
 
 
Figure 3-2: Study design (Cohorts 4 to 6) 
Cohort timing 
 
 
 
 
 
The end of study is defined as the last expected visit/contact of the last subject undergoing 
study treatment. A subject is considered to have completed the study when the subject has 
completed his/her last scheduled visit or last scheduled procedure, presented in Appendix 14.1 
Schedule of Activities (SoA). 
Screening/ 
enrollment visit 
Randomization 
and dosing 
Follow-up 
visit 
Admission 
to the unit 
Discharge 
from the unit 
In-patient period
Day -28 to -2 
Day -1 
Day 1 
Day 3 
14 days post-dose 
Screening 
period 
Screening/ 
enrollment visit 
Randomization 
and dosing 
Follow-up 
visit 
Admission 
to the unit 
Discharge 
from the unit 
In-patient period 
Day -28 to -2 
Day -2 
Day 1 
Day 4 
14 days post-dose 
Screening 
period 


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3.2. Study Endpoints 
3.2.1. Primary Endpoints 
Safety endpoints include the following: 
 The frequency and severity of adverse events (AEs)  
 Clinical laboratory test results (hematology, biochemistry, and urinalysis) 
 Vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and body temperature) 
 12-Lead ECG (paper ECG and digital ECG) and telemetry results 
 Testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and inhibin 
B (male subjects in Cohorts 4, 5, and 6 only) 
 
PK endpoints include the following:  
 Maximum (peak) plasma drug concentration (Cmax) 
 Time to reach maximum (peak) plasma concentration following drug administration 
(Tmax) 
 Area under the plasma concentration versus time curve from time zero to the last 
quantifiable concentration in plasma (AUC0-t) 
 Extrapolation of the area under the curve from time 0 to infinity (AUC0-inf) 
 Terminal half-life (t1/ 2λz) 
 Apparent total clearance of the drug from plasma after oral administration (CL/F) 
 Apparent volume of distribution at steady state after oral administration (Vss/F) 
3.2.2. Secondary Endpoints 
An exposure-response (E-R) analysis may be conducted with data from this study alone or in 
combination with other studies as appropriate, with a pre-specified workflow described in a 
separate technical document, for the QT interval corrected for heart rate using Fridericia’s 
formula (QTcF) parameter, as part of the cardiac safety evaluation and with the intention to 
obtain a Thorough QT (TQT) study substitute. The results of the E-R analysis may not be 
included in the main study report. 
 
4. General Statistical Considerations 
 
All statistical analyses will be performed using Statistical Analysis System (SAS®) software 
(SAS Institute Inc., Cary, North Carolina) Version 9.4 or higher. 
 
For categorical variables, number and percentage of subjects will be presented. Percentage will 
be rounded to 1 decimal place and will be suppressed when the corresponding number of 
subjects is zero.  
 
Continuous variables will be summarized using descriptive statistics and will include number of 
subjects, mean, median, standard deviation (SD), minimum, and maximum, unless otherwise 
specified. Geometric mean and coefficient of variation (CV) will also be presented for PK 
parameters. Minimum and maximum will be presented to the same precision as the original data, 
mean, median, and geometric mean will be presented to 1 more decimal place than the original 
data, and SD and CV will be presented to 2 more decimal places than the original data. 


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Study day will be calculated as follows: 
 
 If assessment date is on or after the date of study drug administration, then Study Day = 
Assessment Date – Dose Date + 1 
 Otherwise, Study Day = Assessment Date – Dose Date 
 
All data collected on the electronic case report form (eCRF) will be presented in data listings by 
cohorts and subject where applicable.  
 
Baseline will be defined as the last non-missing assessment prior to the study drug 
administration, including assessments from unscheduled visits. Unscheduled visits will not be 
included in summaries except for determining baseline. If there are repeated assessments at a 
post-dose time point, the first non-missing assessment will be included in the summary tables. 
 
For blood pressures summaries, the average of triplicate measurements obtained at predose on 
Day 1 will be used as the baseline, and the average of triplicate measurements at post dose 
timepoints will be used.  
 
Missing or partial date values will not be imputed unless otherwise stated. 
 
Subjects who received placebo will be pooled across cohorts for summary purpose.  
4.1. Randomization, Stratification, and Blinding 
 
Approximately 48 subjects will be randomized in this study (8 subjects in each cohort). Within 
each cohort, 2 sentinel subjects will be randomized in 1:1 ratio to receive AZD4041 or placebo, 
and the remaining 6 subjects will be randomized to receive AZD4041 or placebo in 5:1 ratio, 
following review of sentinel safety data up to 24 hours post-dose. Subjects that drop out before 
dosing will be replaced. 
 
This is a double-blind study. Neither the subjects nor the investigator will be aware of the 
treatment assignment. Blinding will be maintained throughout the study by use of active and 
placebo dosage forms of similar appearance. Access to the randomization code will be strictly 
controlled according to the standard operating procedures of PPD. 
 
Blind breaking envelopes will be prepared. A subject or subjects may be unblinded in the event 
of a dose-limiting toxicity, serious adverse event (SAE), or other event, or if there is a medical 
emergency where the identity of the drug must be known to properly treat a subject. Data will be 
reviewed blinded by the safety review committee (SRC), but if the PI or the SRC consider it 
necessary due to a safety concern, data from individual subjects or the entire cohort may be 
unblinded to enable decision-making. If a subject becomes seriously ill or pregnant during the 
study, the blind will be broken only if knowledge of the administered study drug will affect that 
subject’s treatment options. In the event of a medical emergency requiring identification of the 
study drug administered to an individual subject, the investigator will make every attempt to 
contact the medical monitor to explain the need for opening the code within 24 hours of opening 


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the code. The investigator will be responsible for documenting the time, date, reason for the code 
break, and the names of the personnel involved. 
4.2. Sample Size 
 
Due to the exploratory nature of the study, sample size is not based on formal statistical 
considerations but is based primarily on a desire to obtain sufficient safety and tolerability 
information while exposing as few subjects as possible to the investigational treatment. 
4.3. Analysis Population 
 
The safety analysis set will include all subjects who receive AZD4041 or placebo and have any 
post-dose safety data. 
 
The PK analysis set will include all subjects who receive AZD4041 and have any PK data. 
 
5. Subject Disposition 
5.1. Disposition 
 
Number and percentage of subjects who were screen failures, who were randomized, who 
completed the study, and who did not complete the study, along with the reason for not 
completing the study, and the number and percentage of subjects included in each analysis 
population, will be summarized by treatment and overall for all screened subjects.  
 
Subject disposition will be presented in a data listing. Subjects excluded from the analysis 
populations and the reasons for exclusion will be presented in a data listing. 
5.2. Protocol Deviations 
 
Protocol deviations will be summarized by treatment and overall for the safety analysis set and 
presented in a data listing.  
6. Demographics and Baseline Characteristics 
6.1. Demographics 
 
The demographics information, including age, sex, ethnicity, race, screening weight, screening 
height, and screening body mass index (BMI) will be summarized by treatment and overall for 
the safety analysis set. 
 
Subject demographics and baseline characteristics will be presented in a data listing. 


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6.2. Medical History 
 
Medical history will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version to be delineated in the clinical study 
report (CSR).  
 
Medical history data will be presented in a data listing.  
 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
 
A prior medication is defined as any medication that ends prior to the study drug administration. 
A concomitant medication is defined as any medication that starts on or after the time of study 
drug administration. Medications that started prior to the study drug administration but ends after 
the study drug administration or are ongoing will be considered both prior and concomitant. 
 
All prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary, version to be delineated in the CSR, and will be presented in a data listing. 
7.2. Medical or Surgical Treatment Procedures 
 
Medical or surgical treatment procedures which occur during the study will be presented in a 
data listing. 
7.3. Study Treatments 
 
Study drug administration data will be presented in data listings. Overdose information will be 
presented in a data listing as well. 
 
8. Safety Analysis 
 
All safety analyses will be based on the safety analysis set unless otherwise specified. 
8.1. Adverse Events 
 
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study 
drug or any event already present that worsens in intensity or frequency after exposure. 


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All AEs will be coded by SOC and preferred term using MedDRA, version to be delineated in 
the CSR. 
8.1.1. Incidence of Adverse Events 
 
Number and percentage of subjects with AEs will be presented in summary tables. A subject 
with 2 or more AEs within the same SOC and preferred term will be counted once in 
summarization level. 
 
An overview of AEs, including number of subjects with at least one AE, with at least one TEAE, 
with at least one treatment-related TEAE, with at least one moderate TEAE, with at least one 
treatment-related moderate TEAE, with at least one severe TEAE, with at least one 
treatment-related severe TEAE, with at least one SAE, with at least one treatment-related SAE, 
with at least one TEAE leading to early discontinuation, and death will be presented by treatment 
and overall.  
 
Summary tables will also be provided for all TEAEs by SOC, preferred term, treatment and 
overall. 
 
All AEs will be presented in a data listing. 
8.1.2. Relationship of Adverse Events to Study Drug 
 
The relationship of AEs to study treatment will be assessed by the investigator as not related or 
related. 
 
All TEAEs will be summarized by SOC, preferred term, relationship to study treatment, 
treatment, and overall. A subject with 2 or more events at each level of summarization will be 
counted once using the most related event. Events with missing relationship will be considered 
as related in the summaries but will be presented as missing in the data listings. 
8.1.3. Severity of Adverse Event 
 
The severity of an AE will be evaluated by the investigator as mild, moderate, or severe. 
 
All TEAEs will be summarized by SOC, preferred term, severity, treatment, and overall. A 
subject with 2 or more events at each level of summarization will be counted once using the most 
severe event. Events with missing severity will be considered as severe in the summaries but will 
be presented as missing in the data listings.  
8.1.4. Serious Adverse Events 
 
An SAE is an AE occurring during any study phase (screening [from the time of signature of 
informed consent form], treatment, follow-up), that fulfils one or more of the following criteria: 
 Results in death 


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 Is immediately life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the subject or may require medical 
treatment to prevent one of the outcomes listed above. 
 
All SAEs including death will be presented in a data listing. 
8.1.5. Treatment-Emergent Adverse Events Leading to Study Discontinuation 
 
All TEAEs leading to study discontinuation will be presented in a data listing. 
8.2. Liver Events 
 
The liver diagnostic investigations, liver risk factors/lift style events, and liver signs and 
symptoms data as collected in eCRF will be presented in data listings. 
8.3. Clinical Laboratory Evaluations 
 
The clinical chemistry, hematology, and urinalysis will be performed at visits specified in 
Appendix 14.1 SoA. 
 
Other laboratory tests include testing for immunodeficiency virus (HIV), hepatitis B and C at 
screening, urine drug screen and alcohol screen at screening and on Day -1, pregnancy test at 
screening and on Day -1, and follicle stimulating hormone (FSH) testing in women at screening. 
 
The details of clinical laboratory assessments to be performed are listed in Table 8-1. 


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Table 8-1 Laboratory Safety Variables 
 
Hematology (whole blood) 
White blood cell (WBC) count, red blood cell 
(RBC) count, hemoglobin (Hb), hematocrit 
(HCT), mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration 
(MCHC), neutrophils absolute count, 
monocytes absolute count, eosinophils absolute 
count, basophils absolute count, platelets, and 
reticulocytes absolute count
Clinical chemistry (serum or plasma) 
Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase 
(ALP), gamma glutamyl transpeptidase (GGT), 
total bilirubin, unconjugated bilirubin, 
C-reactive protein (CRP), blood urea nitrogen, 
creatinine, glucose (fasting), albumin, 
phosphate, potassium, calcium, sodium, 
bicarbonate, thyroid stimulating hormone 
(TSH)a, thyroxine (T4)b, and follicle stimulating 
hormone (FSH)c
Urinalysis 
Glucose, protein, hemoglobin, microscopy (if 
positive for blood or protein) 
Viral serology 
Human immunodeficiency virus (HIV I and II), 
hepatitis B surface antigen (HBsAg) and 
hepatitis C Virus antibody
Pregnancy test (females only) 
Human beta chorionic gonadotrophin 
Urine drug screen 
 
Alcohol and cotinine, amphetamines (includes 
methamphetamines and ecstasy/3,4 
methylenedioxymetamphetamine), barbiturates, 
benzodiazepines, cannabinoids (includes 
tetrahydrocanabinol), cocaine metabolites, 
methadone, tricyclic antidepressants, opiates 
(includes heroin, codeine, and oxycodone), and 
phencyclidine.
a Screening only 
b Reflex only (if TSH is abnormal) 
c Screening for post-menopausal women 
 
The clinical laboratory that will perform the tests will provide the reference ranges for all clinical 
laboratory parameters. Abnormal clinical laboratory values will be flagged as either high or low 
(or normal or abnormal) based on the reference ranges for each laboratory parameter and 
evaluated as clinically significant or not clinically significant by the investigator. All laboratory 
results along with the abnormal flag and clinical significance will be presented in data listings. 
The potentially clinically significant (PCS) values will also be flagged. The PCS criteria are 
defined in Appendix 14.2. 


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Actual results and changes from baseline will be summarized for hematology, chemistry, 
quantitative urinalysis laboratory tests by treatment and visit. Shift tables with categories of low, 
normal, and high for quantitative results, and normal and abnormal for qualitative results will be 
provided by treatment and visit. 
8.4. Testosterone, Luteinizing Hormone, Follicle Stimulating Hormone, and Inhibin B 
Assessments 
 
For Cohorts 4 to 6, in order to monitor for effects on testicular function in male subjects, samples 
for assessment of testosterone, LH, FSH, and inhibin B levels will be collected at 0 hour (0800 or 
1000) and at 4, 6, 8, 12, and 22 hours on Day -1 and at 0 hour (0800 or 1000) and at 1, 2, 4, 6, 8, 
12, 24, 36, 48, and 72 hours on Day 1, as listed in the SoA (Appendix 14.1).  
 
The results of these assessments will be presented in a data listing for safety population. 
8.5. Vital Sign Measurements 
 
Vital signs will be measured at specified timepoints in Appendix 14.1. Height will be measured 
at screening, and weight and BMI will be measured/calculated at specified timepoints in 
Appendix 14.1 SoA. 
 
Vital signs will include systolic and diastolic blood pressure (BP), pulse rate (PR), respiratory 
rate (RR), and body temperature. Vital signs will be measured in a semi-supine position after 5 
minutes rest. Supine and standing BP and PR will be measured using a semiautomatic recording 
device. Supine BP and PR will be taken after at least 5 minutes supine rest. Standing BP and PR 
will be taken approximately 3 minutes after the respective supine measurements. Three 
consecutive BP readings will be recorded at intervals of at least 1 minute. The average of the 3 
BP readings will be recorded on the eCRF, and these records will be used in statistical 
summaries.  
 
Orthostatic BP will be calculated as:  
BP in supine position – BP in standing position 
 
Orthostatic PR will be calculated as:  
PR in standing position – PR in supine position 
 
Actual results and changes from baseline in vital sign, weight, and BMI measurements will be 
summarized by treatment and timepoint. Vital sign measurements including the orthostatic BP 
and orthostatic PR, weight, and BMI results., along with PCS flags will be presented in a data 
listing. The PCS criteria are defined in Appendix 14.3. 
8.6. Electrocardiograms 
 
Twelve-lead paper ECGs (pECG) allow the investigator to review the ECG tracings at bedside 
and determine any potential risks. Digital 12-lead ECGs (dECG) are collected and electronically 


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submitted to the AstraZeneca ECG Center for expert review and reporting of ECG intervals. 
Telemetry is used for continuous monitoring of ECG activity as a safety measure.  
8.6.1. Twelve-Lead Paper ECG 
 
Twelve-lead pECGs will be obtained after the subject has been resting in the supine position 
for at least 10 minutes at specified timepoints in Appendix 14.1 SoA. All pECGs will be 
evaluated for heart rate, PR, RR, QRS, QT, and QTcF intervals. The Investigator will judge the 
overall interpretation as normal or abnormal. If abnormal, it will be decided whether or not the 
abnormality is clinically significant or not clinically significant, and the reason for the 
abnormality will be recorded in the eCRF. 
 
All pECG data including investigator findings will be presented in a listing.  
8.6.2. Digital ECG 
 
The AstraZeneca ECG Center will perform the digital ECG (dECG) analysis and interpretation 
in this study, using the EClysis© system, version 4.0, or higher. The following dECG variables 
will be reported by the AstraZeneca ECG Center: RR, PR, QRS and QT intervals from the lead 
defined as the primary analyses lead. Heart rate will be derived as 60/(RR in seconds) and QTcF 
will be derived as QT (msec)/(RR in seconds)1/3.  
 
The dECG data will be smoothed on an individual subject basis before performing the 
derivations above and before calculation of any changes from baseline or descriptive statistics. 
For each subject it will be done as follows: the mean value of all the measurements will be taken 
for nominal time-point recordings. At least 4 measurements with the time between the first and 
last record greater than 2.75 minutes for a nominal time-point should be present or else, the 
smoothed value at the corresponding nominal time-point will be set to missing. 
 
Digital ECG results will be listed by treatment (pooled placebo, dose level of AZD4041) for each 
subject and time-point and will include all individual and smoothed values of PR, RR, QRS, QT 
interval and the derived values of QTcF and HR. The changes from baseline for smoothed and 
derived parameters will be listed as well. 
 
Descriptive statistics of smoothed PR, RR, QRS, QT values and derived QTcF and HR values as 
well as change from baseline will be summarized by treatment group (pooled placebo, dose level 
of AZD4041, and pooled AZD4041) and nominal time-point. The baseline for the dECG 
measurements will be the smoothed pre-dose assessment on Day 1. 
 
The number and percent of subjects whose worst (i.e. highest) post-baseline smoothed QTcF 
value, according to the following categories, will be tabulated by visit, timepoint, and treatment 
group (pooled placebo, dose level of AZD4041, and pooled AZD4041): 
- Absolute value >450 msec and ≤480 msec 
- Absolute value >480 msec and ≤500 msec 
- Absolute value >500 msec 
- Increase from baseline >30 msec and ≤60 msec 


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- Increase from baseline >60 msec 
 
The above tabulations will be presented separately for the subgroups who have an elevated QTcF 
(>450 msec) at baseline and those who do not.  
 
All dECG data will be presented in a listing. 
8.6.3. Telemetry 
 
To allow a real-time assessment of cardiac safety at the study site, subjects will be monitored by 
telemetry (for real-time assessment of cardiac rate and rhythm) for 4 to 6 hours at specified 
timepoints in Appendix 14.1 SoA. Any clinically significant change noted on telemetry will be 
followed up with a 12-lead ECG. Further evaluation and treatment will be performed as deemed 
appropriate by the Investigator. The telemetry monitoring data as collected in eCRF will be 
presented in a data listing. 
8.7. Physical Examination 
 
Physical examination will be conducted at specified timepoints in Appendix 14.1 SoA. 
 
A complete physical examination will be performed and includes an assessment of the following 
systems: cardiovascular, chest/lungs/respiratory, gastrointestinal, thyroid/neck, lymphatics, 
dermatological/skin, musculoskeletal/extremities, neurological, and head/ears/eyes/nose/throat 
(including mouth). 
 
Physical examination results will be presented in a data listing. 
 
9. Pharmacokinetics 
9.1. Data Handling  
 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero for 
calculation of descriptive statistics. When all concentrations are BLQ for a timepoint, mean BLQ 
concentrations will be presented as BLQ, and the SD and CV will be reported as not applicable, 
otherwise the calculated mean will be presented. 
 
For PK parameter calculations, BLQ values will be treated as zero with the exception that a BLQ 
value between 2 quantifiable concentrations will be set as missing. If consecutive BLQ 
concentrations are followed by quantifiable concentrations in the terminal phase, those 
concentrations after BLQ concentrations will be treated as missing. 
 
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9.2. Plasma Concentration  
 
Blood samples for the determination of plasma concentrations of AZD4041 will be collected on 
Day 1 at the following time points: predose (0), and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 
and 48 hours postdose. For Cohorts 4 to 6, an additional blood sample will be collected at 72 
hours postdose. 
 
Pharmacokinetic collections that have an actual sampling time that deviates from the nominal 
collection time more than 10% will be flagged in the data listing, but the nominal sampling time 
will be used for summarization. 
 
AZD4041 plasma concentration data will be summarized using descriptive statistics (number of 
subjects, number of nonmissing values, arithmetic mean, SD, CV, median, minimum, and 
maximum) by treatment and nominal sampling time. Individual and mean AZD4041 plasma 
concentration versus time data will be plotted by treatment. For ease of presentation, mean 
plasma concentrations of AZD4041 will be plotted by nominal time by treatment on both linear 
and semi-logarithmic scales.  
 
Plasma PK concentrations of AZD4041 will be reported to the precision of the raw data in listing 
presentations; summary statistics for arithmetic mean, median, minimum, maximum, and SD 
will be reported to 3 significant figures; and CV will be reported to 1 decimal place. 
9.3. Pharmacokinetic Parameters 
 
The plasma concentration-time data for AZD4041 will be analyzed by non-compartmental 
analysis using Phoenix® WinNonlin® (Certara USA, Inc., Princeton, NJ) Version 8.0 or higher. 
Actual sampling times will be used for the estimation of all plasma PK parameters. 
 
If data allow, the following PK parameters will be calculated: 
 
Pharmacokinetic parameters: 
PK Parameter 
Definition 
Cmax  
Maximum (peak) plasma drug concentration 
Tmax 
Time to reach maximum (peak) plasma concentration following drug 
administration
AUC0-t 
Area under the curve from time 0 to time t
AUC0-inf
Extrapolation of the area under the curve from time 0 to infinity, calculated 
as AUC0- inf = AUC0-t + Clast/λz, where Clast is the last quantifiable plasma 
drug concentration
t1/2 λz
Terminal half-life, calculated as: t1/2= ln(2)/ λz
CL/F
Apparent total clearance of the drug from plasma after oral administration, 
calculated as: CL/F = Dose/AUC0- inf
Vss/F
Apparent volume of distribution at steady state
 


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In addition to the above PK parameters, which will be listed and summarized, the following 
parameters will also be listed to document the selection of data points used to estimate t1/2 using 
non-compartmental procedures: 
 
%AUCextrap 
Percentage of the area extrapolated for calculation of AUC0-∞. 
λz 
Apparent terminal elimination rate constant, where λz is the magnitude of 
the slope of the linear regression of the log concentration versus time profile 
during the terminal phase.
Number of 
points 
Number of data points used to estimate λz; a minimum of 3 data points must 
be used, and Cmax must not be included. 
λz lower 
Lower bound used for the estimation of λz. 
λz upper 
Upper bound used for the estimation of λz. 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); visual 
inspection of the terminal slope will be performed. In general, λz may only 
be retained if r2 ≥ 0.80
 
Plasma PK parameters for AZD4041 will be presented in data listings and summarized by 
treatment using descriptive statistics (number of subjects, arithmetic mean, SD, CV%, median, 
geometric mean, geometric CV%, minimum, and maximum) by treatment regimen. Tmax will be 
summarized using the descriptive statistics median, minimum, and maximum only. 
 
Plasma PK parameters of AZD4041 will be displayed to 3 significant figures in all data listings 
and summary tables, with exception of time variables (Tmax, λz lower, and λz upper) which will 
be displayed to 2 decimal places. 
9.4. Pharmacokinetic Statistical Analysis 
 
Dose-proportionality for AZD4041 will be evaluated for Cmax, AUC0-t and AUC0-inf. A power 
model will be fitted to describe the relationship between Y (Cmax, AUC0-t and AUC0-inf) and X 
(dose) using the least-squares linear regression model, ln(Y) = ln(α) + β ln(X), which is the 
logarithmic form of Y = X.  
 
The intercept of regression line, ln(), and the slope of the regression line, β, will be presented 
along with the 90% confidence interval (CI) of the slope. Dose-proportionality will be concluded 
if the 90% CI of the slope β lies entirely within [1+ln(0.8)/ln(r), 1+ln(1.25)/ln(r)], where r is a 
ratio that describes the dose range and is defined as the ratio of highest dose/lowest dose (Smith 
et al 2000). If the proportionality is not demonstrated over the entire dose range, the lowest or 
highest dose will be removed, and the analysis will be repeated until a range of proportionality is 
determined. Dose proportionality will be assessed with at least 3 dose levels. 
 
The statistical analyses will be based on the PK population. 
 


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10. Pharmacodynamics 
 
To characterize the PD relationship between drug exposure and QT interval, an 
exposure-response (E-R) analysis may be conducted with data from this study alone or in 
combination with other studies as appropriate, with a pre-specified workflow described in a 
separate technical document for the QTcF parameter, as part of the cardiac safety evaluation and 
with the intention to obtain a Thorough QT study substitute. The results of the E-R analysis will 
be presented in an E-R Analysis Report and may not be included in the main study report. The 
specification of the E-R analysis (the E-R analysis plan) is not included in this statistical analysis 
plan (SAP). 
11. Interim Analysis 
 
No formal interim analysis is planned for this study.  
The SRC will review data from each cohort before progression to the next cohort can occur. The 
blinded safety, PK concentration, and PK parameter data will be reviewed by the investigators, 
medical monitor, and sponsor’s representative as described in the SRC plan to ensure that it is 
safe to proceed with the planned dose escalation. 
12. Changes in the Planned Analysis 
There are no changes in this statistical analysis plan compared to the protocol. 
13. References 
 
Boutrel et al 2005 
Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, et al. Role for 
hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl 
Acad Sci USA 2005;102(52):19168-73. 
 
Coe et al 2005 
Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, et al. Varenicline: an 
alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 
2005;48(10):3474-7. 
 
Doll et al 2004 
Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations 
on male British doctors. BMJ 2004;328(7455):1519. 
 
Gotter et al 2016 
Gotter AL, Forman MS, Harrell CM, Stevens J, Svetnik V, Yee KL, et, al. Orexin-2 receptor 
antagonism is sufficient to promote NREM and REM sleep from mouse to man. Sci Rep 2016 
Jun3;6:27147. 
 
Harris et al 2005 
Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in 


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reward seeking. Nature 2005;437(7058):556-9. 
 
Jha et al 2013 
Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, et al. 
21st-century hazards of smoking and benefits of cessation in the United States. N Engl J Med 
2013;368(4):341-50. 
 
Kenny 2011 
Kenny PJ. Tobacco dependence, the insular cortex and the hypocretin connection. Pharmacol 
Biochem Behav 2011;97(4):700-7. 
Kodadek and Cai 2010 
Kodadek T, Cai D. Chemistry and biology of orexin signaling. Mol Biosyst 
2010;6(8):1366-75. 
 
Lim et al 2010 
Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative 
risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor 
clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease 
Study 2010. Lancet 2012;380(9859):2224-60. 
 
Mathers and Loncar 2006 
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 200s to 
2030. PLoS Med 2006;3(11):e442. 
 
Sakurai et al 1998 
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al. Orexins and 
orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that 
regulate feeding behavior. Cell 1998;92(4):573-85. 
 
Samson et al 2007 
Samson WK, Bagley SL, Ferguson AV, White MM. Hypocretin/orexin type 1 receptor in 
brain: role in cardiovascular control and the neuroendocrine response to immobilization stress. 
Am J Physiol Regul Integr Comp Physiol 2007 Jan;292(1):R382-7. 
 
Smith et al 2000 
Smith BP, Vandenhende FR, deSante KA, et al (2000)., Confidence Interval Criteria for 
Assessment of Dose proportionality.  Pharmaceutical Research, 17:1278-1283. 
 
Stolerman and Jarvis 1995 
Stolerman IP, Jarvis MJ, The scientific case that nicotine is addictive. Psychopharmacology 
(Berl) 1995;117(1):2-10. 
 
Willie et al 2003 
Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, et al. Distinct 
narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic 
dissection of Non-REM and REM sleep regulatory processes. Neuron 2003;38(5):715-30. 
 


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14. Appendices 
14.1. 
Schedule of Activities (SoA) 
 
Cohorts 1 to 3 
 
Screening
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 Day 3 Follow–up
Visita 
(14 days 
post-dose)
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Demographic data
X
Medical history
X
Urinary drug screen
X
X
Alcohol screen
X
X
Testing for HIV, hepatitis B 
and C
X 
 
 
 
 
 
Pregnancy testingb
X
X
FSH testing in women
X
Randomization
X
Admission to CRU
X
Discharge from CRU
X
Height, body weight, and 
BMIc
X 
X 
 
 
X 
X 
Study drug administration
X
Adverse event recording
X
X
X
X
X
X
Blood pressure, temperature, 
respiratory rate, and pulse 
rate
X 
X 
Xd 
X 
X 
X 
12-lead paper safety ECG
X
X
Xe
Xe
Xe
12-lead digital ECG
Xe
Xe
Xe
Telemetryf
X
X
Clinical laboratory 
evaluationsg
X 
X 
 
X 
 
X 
Physical examination
X
X
X
X
Blood sampling for PKh
X
X
X
a 
Tests will be performed at follow-up and also in cases of discontinuation. 
b 
Serum pregnancy test will be performed at screening and check-in. 
c 
Height will be measured at screening only. 
d 
Blood pressure, temperature, respiratory rate, and pulse rate will be measured at pre-dose, then at 1, 2, 3, 
4, 6, 8, 12, 24, and 48 hours post-dose. 
e 
Paper and digital ECGs will be collected at the same time points as PK sampling.  Recording of ECGs 
will precede PK sampling and check of vital signs at each time point. 


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f 
Telemetry for 4 to 6 hours on Day -1 to establish a baseline.  Pre-dose to 24 hours post-dose. 
g 
Clinical laboratory assessments must be repeated if first collected more than 2 weeks before dosing. 
h 
Blood samples will be collected at pre-dose, then at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 
hours. 
BMI  body mass index; CRU  Clinical Research Unit; ECG  electrocardiogram; FSH  follicle stimulating 
hormone; HIV  human immunodeficiency virus; PK  pharmacokinetic(s) 
 
 


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Cohorts 4 to 6 
 
Screening
Day -28 
to  
Day -2 
Day -2 Day -1 Day 1 Day 2 Day 3 Day 4 Follow–
up 
Visita 
(14 days
post-dose)
Informed consent
X
Inclusion/exclusion 
criteria
X 
 
X 
X 
 
 
 
 
Demographic data
X
Medical history
X
Urinary drug screen
X
X
Alcohol screen
X
X
Testing for HIV, 
hepatitis B 
and C
X 
 
 
 
 
 
 
 
Pregnancy testingb
X
X
FSH testing in women
X
Randomization
X
Admission to CRU
X
Discharge from CRU
X
Height, body weight, 
and BMIc
X 
 
X 
 
 
 
X 
X 
Study drug 
administration
 
 
 
X 
 
 
 
 
Adverse event recording
X
X
X
X
X
X
X
X
Blood pressure, 
temperature, respiratory 
rate, and pulse rate
X 
 
X 
Xd 
X 
X 
X 
X 
12-lead paper safety 
ECG
X 
 
X 
Xe 
Xe 
Xe 
Xe 
 
12-lead digital ECG
Xe
Xe
Xe
Xe
Telemetryf
X
X
Clinical laboratory 
evaluationsg
X 
 
X 
 
X 
 
 
X 
Physical examination
X
X
X
X
Blood sampling for PKh
X
X
X
X
Blood sampling for 
testosterone, LH, FSH, 
and inhibin B (male 
subjects only)i
 
 
X 
X 
X 
X 
X 
 
a 
Tests will be performed at follow-up and also in cases of discontinuation. 
b 
Serum pregnancy test will be performed at screening and check-in. 


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c 
Height will be measured at screening only. 
d 
Blood pressure, temperature, respiratory rate, and pulse rate will be measured at pre-dose, then at 1, 2, 3, 
4, 6, 8, 12, 24, and 48 hours post-dose. 
e 
Paper and digital ECGs will be collected at the same time points as PK sampling.  Recording of ECGs 
will precede PK sampling and check of vital signs at each time point. 
f 
Telemetry for 4 to 6 hours on Day -1 to establish a baseline.  Pre-dose to 24 hours post-dose. 
g 
Clinical laboratory assessments must be repeated if first collected more than 2 weeks before dosing. 
h 
Blood samples will be collected at pre-dose, then at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 
72 hours. 
i 
Male subjects only: samples for testosterone, LH, FSH, and inhibin B will be collected at 0 hour (0800 
or 1000) and at 4, 6, 8, 12, 22, and 24 hours on Day -1 and at 0 hour (0800 or 1000) and at 1, 2, 4, 6, 8, 
12, 24, 36, 48, and 72 hours on Day 1 to Day 3.  The ‘0’ hour time point should be approximately the 
same time that dosing is scheduled for on Day 1.  On Day 1, samples for testosterone, LH, FSH, and 
inhibin B will be collected at the same time as PK samples. 
BMI  body mass index; CRU  Clinical Research Unit; ECG  electrocardiogram; FSH  follicle stimulating 
hormone; HIV  human immunodeficiency virus; LH  luteinizing hormone; PK  pharmacokinetic(s) 
 
 


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Final Statistical Analysis Plan, Version 1.0 
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Date Issued: 29JUL2020 
 
 
 
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14.2. 
Potential Clinically Significant (PCS) Laboratory Values 
a). Hematology: 
Parameter 
Conventional 
Unit 
Low 
PCS 
Criteria
High PCS 
Criteria 
SI Unit 
Low 
PCS 
Criteria
High PCS 
Criteria 
Hematocrit 
% 
< 30 
> 50 (F) 
> 55 (M)
L/L 
< 0.3 
> 0.5 (F) 
> 0.55 (M)
Hemoglobin 
(male)
g/dL 
< 11 
> 18 
g/L 
110 
180 
Hemoglobin 
(female)
g/dL 
< 10 
> 17 
g/L 
100 
170 
Leukocyte 
(White Blood 
Cell Count)
103/µL 
≤ 2.8 
≥ 15 
109/L 
≤ 2.8 
≥ 15 
Neutrophils 
cells/mm3 
1500 
No upper limit
Proportion 
of 1.0
≤ 0.15 
No upper limit
Platelet 
Count
103/µL 
≤ 75 
≥ 700 
109/L 
≤ 75 
≥ 700 
PCS = potentially clinically significant; SI = Le Système International d'Unités (International 
System of Units).
 
 
 


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Date Issued: 29JUL2020 
 
 
 
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b). Chemistry: 
Parameter 
Conventional 
Unit
Low PCS 
Criteria
High PCS 
Criteria
SI Unit 
PCS Low 
Limit
PCS High 
Limit
Alanine 
aminotransfer
ase 
U/L 
No lower 
limit 
≥ 3 × ULN
U/L 
No lower 
limit 
≥ 3 × ULN 
Aspartate 
aminotransfer
ase 
U/L 
No lower 
limit 
≥ 3 × ULN
U/L 
No lower 
limit 
≥ 3 × ULN 
Albumin 
g/dL 
≤ 2.6 
≥ 6.0 
g/L 
≤ 26 
≥ 60 
Alkaline 
phosphatase
U/L 
No lower 
limit
≥ 3 × ULN
U/L 
No lower 
limit
≥ 3 × ULN 
Bilirubin, 
total 
mg/dL 
No lower 
limit 
≥ 1.5 × 
ULN 
µmol/L 
No lower 
limit 
≥ 1.5 × 
ULN 
Blood urea 
nitrogen 
mg/dL 
No lower 
limit 
≥ 30.0 
mmol/L 
No lower 
limit 
≥ 10.71 
Creatinine 
Kinase (CK)  
U/L 
No lower 
limit 
≥ 3 × ULN
U/L 
No lower 
limit 
≥ 3 × ULN 
Calcium, total
mg/dL 
< 8.0 
> 11.0 
mmol/L 
< 2.0 
> 2.75 
Chloride
mEq/L
≤ 85
≥ 120
mmol/L
≤ 85
≥ 120
Glucose 
mg/dL 
≤ 45.1 
≥ 200.0 
mmol/L 
≤ 2.48 
≥ 11 
Gamma 
Glutamyl 
Transferase 
(GGT) 
U/L 
NA 
≥ 3 x ULN
U/L 
No lower 
limit 
≥ 3 x ULN 
Lactate 
Dehydrogena
se (LDH) 
U/L 
No lower 
limit 
≥ 3 x ULN
U/L 
No lower 
limit 
≥ 3 x ULN 
Potassium
mEq/L
≤ 3.0
≥ 5.5
mmol/L
≤ 3.0
≥ 5.5
Protein, total 
g/dL 
≤ 5.0 
≥ 10.0 
g/L 
≤ 50 
≥ 100 
Sodium 
mEq/L 
≤ 125 
≥ 155 
mmol/L 
≤ 125 
≥ 155 
Serum 
Creatinine  
mg/dL 
No lower 
limit 
> 1.5 × 
ULN 
µmol/L 
No lower 
limit 
> 1.5 × 
ULN 
Triglycerides  
mg/dL 
No lower 
limit
> 300 
mmol/L 
No lower 
limit
> 3.39 
TSH  
µU/L 
below 
normal 
range
above 
normal 
range
mIU/L 
below 
normal 
range
above 
normal 
range
T4, free  
ng/dL 
below 
normal 
range
above 
normal 
range
pmol/L 
below 
normal 
range
above 
normal 
range


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Final Statistical Analysis Plan, Version 1.0 
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Date Issued: 29JUL2020 
 
 
 
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Parameter 
Conventional 
Unit
Low PCS 
Criteria
High PCS 
Criteria
SI Unit 
PCS Low 
Limit
PCS High 
Limit
Uric acid 
(Male) 
mg/dL 
No lower 
limit
≥  10.5  
µmol/L 
No lower 
limit
≥  624.75  
Uric acid 
(Female) 
mg/dL 
No lower 
limit
≥  8.5  
µmol/L 
No lower 
limit
≥  505.75  
PCS = potentially clinically significant; SI = Le Système International d'Unités (International 
System of Units); ULN = upper limit of normal (value provided by the laboratory). 


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Final Statistical Analysis Plan, Version 1.0 
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Date Issued: 29JUL2020 
 
 
 
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c). Urinalysis: 
Parameter 
PCS Low Limit 
PCS High Limit 
Hb/RBCs/Blood 
NA
≥ +2 
Protein/Albumin 
NA
≥ +2 
Glucose 
NA
≥ +2
NA = Not Available.
 
 


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Final Statistical Analysis Plan, Version 1.0 
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Date Issued: 29JUL2020 
 
 
 
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14.3. 
Potential Clinically Significant (PCS) Vital Sign Values 
Parameter 
Unit 
Observed 
Value 
And/ 
Or 
Change from Baseline 
Change 
from 
Supine 
to 
Standing 
Flag 
Systolic Blood 
Pressure 
(supine or 
sitting) 
mmHg 
 180 
And 
Increase of  20 mmHg 
-- 
PCS 
High 
≤ 90 
And 
Decrease of  20 mmHg 
-- 
PCS 
Low 
Diastolic 
Blood 
Pressure 
(supine or 
sitting) 
mmHg 
 105 
And 
Increase of  15 mmHg 
-- 
PCS 
High 
≤ 50 
And 
Decrease of  15 mmHg 
-- 
PCS 
Low 
Pulse (supine 
or sitting) 
bpm 
 120 
And 
Increase of  15 bpm 
-- 
PCS 
High 
≤ 50 
And 
Decrease of  15 bpm 
-- 
PCS 
Low 
Systolic Blood 
Pressure 
(supine to 
standing) 
mmHg 
≤ 80 
And 
-- 
Decrease 
of  20 
PCS 
Low 
Diastolic 
Blood 
Pressure 
(supine to 
standing) 
mmHg 
-- 
-- 
-- 
Decrease 
of  20 
PCS 
Low 
Weight 
Not Applicable 
Increase of   7% 
-- 
PCS 
High 
Decrease of   7% 
-- 
PCS 
Low 
PCS = potentially clinically significant.