Clinical trial NCT05587998
Conditions: Opioid Use Disorder
Sponsor: AstraZeneca
Start date: 2022-08-31; Completion date: 2023-05-25
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, 2 fixed sequences, multiple dose study in healthy male and/or female recreational opioid users.

This study is being primarily conducted to assess the effect on respiratory drive of morphine administered after multiple doses of AZD4041 compared to morphine administered alone in healthy recreational opioid users.

The study will include up to 44 participants who will be randomized to either AZD4041 and morphine (28 participants) or placebo and morphine (16 participants). This is to ensure completion of at least 36 participants (24 AZD4041 + morphine, and 12 Placebo + morphine on Day 15).

The total study duration will be up to 54 days (including screening) per participant.

Detailed description:

Arms: arm 1: Participants will receive a single intravenous (IV) dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1. arm 2: Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Interventions: intervention 1: Morphine intervention 2: AZD4041 intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive IV dose of Morphine as stated in arm description. intervention 2: Participants will receive oral doses of AZD4041 as stated in arm description. intervention 3: Participants will receive oral doses of placebo as stated in arm description.

Protocol documents:
Prot_000.pdf: 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, FIXED SEQUENCE 
STUDY TO ASSESS THE EFFECT ON RESPIRATORY DRIVE OF MULTIPLE 
DOSES OF AZD4041 WHEN CO-ADMINISTERED WITH A SINGLE DOSE OF 
MORPHINE IN HEALTHY RECREATIONAL OPIOID USERS 
Protocol Number: 
D7460C00003 
Altasciences Project Number: 
AZN-P1-265 
Investigational Product: 
AZD4041 
Phase of Development: 
Phase 1 
Sponsor: 
AstraZeneca AB 
151 85 Södertälje 
Sweden 
COMPLIANCE 
The study will be conducted in accordance with standards of Good Clinical Practice, as defined by the 
International Council for Harmonisation and all applicable federal and local regulations. 
Protocol Version 
Date 
1.0 
(Original) 
August 09, 2022 
2.0 
(Amendment 01) 
September 16, 2022 
 
 
 CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to investigator(s) 
and to the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It may not be 
used, divulged, published or otherwise disclosed without the written authorization from Altasciences or the 
sponsor. 


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PROTOCOL AMENDMENT 01 – SUMMARY OF CHANGES 
Description of Change Made Section/Location 
Rationale 
Changed manufacturer, 
concentration and volume of 
administration of opioid 
treatment (morphine). 
• Study Synopsis (Opioid, Dose, 
and Mode of Administration) 
• Section 3.2 (Study Treatments) 
• Section 5.1.2 (Morphine) 
Lack of supply by 
original manufacturer. 
Clarified a discrepancy in 
exclusion criterion #23.  
Changed: 
‘Positive test result for 
alcohol and/or drugs of abuse 
upon admission on Day -1.’ 
To: 
‘Positive test result for 
alcohol and/or drugs of abuse 
upon admission on Day -2.’ 
Section 4.2 (Exclusion Criteria) 
To be consistent with the 
accurate information 
presented in Table 6-1 
(Schedule of Activities) 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT 01 – SUMMARY OF CHANGES ........................................................................... 2 
TABLE OF CONTENTS ............................................................................................................................................ 3 
LIST OF IN-TEXT TABLES ..................................................................................................................................... 7 
LIST OF IN-TEXT FIGURES ................................................................................................................................... 8 
STUDY SYNOPSIS ..................................................................................................................................................... 9 
STUDY ADMINISTRATIVE STRUCTURE ......................................................................................................... 14 
1. 
INTRODUCTION .............................................................................................................................................. 15 
1.1. Background ................................................................................................................................................... 15 
1.2. Study Rationale ............................................................................................................................................. 16 
1.3. Risk/Benefit Assessment ............................................................................................................................... 16 
1.3.1. Known Potential Benefits....................................................................................................................... 16 
1.3.2. Important Potential Risks ....................................................................................................................... 17 
1.3.3. Risk/Benefit Conclusion ........................................................................................................................ 23 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................................... 25 
3. 
STUDY DESIGN ................................................................................................................................................ 26 
3.1. Overall Study Design .................................................................................................................................... 26 
3.2. Study Treatments ........................................................................................................................................... 28 
4. 
SUBJECT POPULATION ................................................................................................................................ 28 
4.1. Inclusion Criteria ........................................................................................................................................... 28 
4.2. Exclusion Criteria .......................................................................................................................................... 29 
4.3. Rescreening Criteria ...................................................................................................................................... 32 
4.4. Withdrawal Criteria ....................................................................................................................................... 32 
4.4.1. Before First Treatment Administration .................................................................................................. 32 
4.4.2. After First Treatment Administration ..................................................................................................... 32 
4.5. Lifestyle and/or Dietary Requirements.......................................................................................................... 34 
4.6. Concomitant Treatment ................................................................................................................................. 35 
5. 
STUDY TREATMENTS .................................................................................................................................... 35 
5.1. Investigational Products ................................................................................................................................ 35 
5.1.1. AZD4041 
 and Placebo oral solution ................................................................................... 35 
5.1.2. Morphine ................................................................................................................................................ 36 
5.2. Investigational Product Management ............................................................................................................ 36 
5.2.1. Packaging, Labeling and Dispensing ..................................................................................................... 36 
5.2.2. Storage and Handling ............................................................................................................................. 36 
5.2.3. Method of Assigning Subjects to Treatment Groups ............................................................................. 36 
5.2.4. Blinding .................................................................................................................................................. 37 
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5.2.5. Study Drug Accountability ..................................................................................................................... 37 
5.3. Administration of Study Drug ....................................................................................................................... 37 
5.4. Meals ............................................................................................................................................................. 38 
5.5. Fluids ............................................................................................................................................................. 38 
5.6. Other Protocol Restrictions ........................................................................................................................... 38 
6. 
STUDY PROCEDURES .................................................................................................................................... 38 
6.1. Safety Assessments ....................................................................................................................................... 44 
6.1.1. Medical History ...................................................................................................................................... 44 
6.1.2. Recreational Alcohol/Drug Use ............................................................................................................. 44 
6.1.3. Physical Examination ............................................................................................................................. 44 
6.1.4. Neurological Examination ...................................................................................................................... 44 
6.1.5. Vital Signs .............................................................................................................................................. 44 
6.1.6. 12-Lead Electrocardiogram .................................................................................................................... 45 
6.1.7. ECG Telemetry ...................................................................................................................................... 52 
6.1.8. Continuous and Spot Oxygen Saturation ............................................................................................... 53 
6.1.9. Continuous and Spot End-Tidal Carbon Dioxide ................................................................................... 53 
6.1.10. Continuous and Spot Respiratory Rate .................................................................................................. 54 
6.1.11. Laboratory Evaluations .......................................................................................................................... 55 
6.1.12. Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................................... 55 
6.1.13. Clinical Opioid Withdrawal Scale (COWS) ........................................................................................... 56 
6.1.14. Assessment of Respiratory Depression .................................................................................................. 56 
6.1.15. Medical Interventions for Signs of Respiratory Depression................................................................... 56 
6.1.16. Rescue Therapy ...................................................................................................................................... 57 
6.2. Pharmacokinetic Assessments ....................................................................................................................... 57 
6.2.1. Pharmacokinetic Blood Sampling .......................................................................................................... 57 
6.2.2. Pharmacokinetic Urine Sampling ........................................................................................................... 59 
6.2.3. Pharmacokinetic Sample Processing, Storage and Shipping .................................................................. 59 
7. 
ADVERSE EVENTS DOCUMENTATION .................................................................................................... 59 
7.1. Definitions ..................................................................................................................................................... 59 
7.2. Severity Assessment ...................................................................................................................................... 60 
7.3. Causality Assessment .................................................................................................................................... 61 
7.4. Adverse Event Monitoring ............................................................................................................................ 61 
7.5. Reporting of Pregnancy ................................................................................................................................. 62 
7.6. Serious Adverse Event Reporting ................................................................................................................. 62 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................................................... 63 
8.1. Analysis Populations ..................................................................................................................................... 63 


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8.1.1. Randomized Population ......................................................................................................................... 63 
8.1.2. Safety Population ................................................................................................................................... 63 
8.1.3. Completer Population ............................................................................................................................. 64 
8.1.4. Pharmacokinetic Population ................................................................................................................... 64 
8.2. Demographic Data and Other Baseline Characteristics ................................................................................. 64 
8.3. Safety............................................................................................................................................................. 64 
8.3.1. Safety Endpoints .................................................................................................................................... 64 
8.3.2. Safety Analysis ...................................................................................................................................... 65 
8.4. Pharmacokinetics .......................................................................................................................................... 68 
8.4.1. Pharmacokinetic Parameters .................................................................................................................. 68 
8.4.2. Summary and Presentation of PK data ................................................................................................... 70 
8.4.3. Pharmacokinetic Statistical Methodology .............................................................................................. 70 
8.5. Determination of Sample Size ....................................................................................................................... 70 
9. 
REFERENCES ................................................................................................................................................... 71 
10. APPENDIX 1: ETHICS ..................................................................................................................................... 77 
10.1. Institutional Review Board ............................................................................................................................ 77 
10.2. Ethical Conduct of the Study ......................................................................................................................... 77 
10.3. Subject Information and Consent .................................................................................................................. 77 
10.4. Subject Confidentiality .................................................................................................................................. 77 
11. APPENDIX 2: DATA COLLECTION, RETENTION, AND MONITORING ............................................ 78 
11.1. Case Report Forms ........................................................................................................................................ 78 
11.2. Data Management and Processing ................................................................................................................. 78 
11.3. Quality Control and Quality Assurance ........................................................................................................ 78 
11.4. Record Retention ........................................................................................................................................... 78 
11.5. Monitoring of the Study ................................................................................................................................ 78 
12. APPENDIX 3: ADMINISTRATIVE PROCEDURES .................................................................................... 80 
12.1. Liabilities ....................................................................................................................................................... 80 
12.2. Adherence to Protocol ................................................................................................................................... 80 
12.3. COVID-19 Response Plan ............................................................................................................................. 80 
12.4. Statement of Investigator ............................................................................................................................... 80 
12.5. Delegation of Investigator Duties .................................................................................................................. 81 
12.6. Premature Termination or Suspension of a Study ......................................................................................... 81 
13. APPENDIX 4: PROTOCOL REVIEW AND APPROVALS ......................................................................... 82 
14. APPENDIX 5: LIST OF ABBREVIATIONS .................................................................................................. 85 
15. APPENDIX 6: CLINICAL LABORATORY EVALUATIONS ..................................................................... 88 
16. APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION ..................................................................................................................... 89 


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17. APPENDIX 8: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – SINCE LAST VISIT 
VERSION ................................................................................................................................................................... 90 
18. APPENDIX 9: CLINICAL OPIOID WITHDRAWAL SCALE (COWS) .................................................... 91 
19. APPENDIX 10: CONTRACEPTION GUIDANCE ........................................................................................ 93 
20. APPENDIX 11: PHYSICAL EXAMINATION FORM .................................................................................. 94 
21. APPENDIX 12: NEUROLOGICAL EXAMINATION FORM ..................................................................... 95 
 


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LIST OF IN-TEXT TABLES 
Table 1-1 
Observed MAD study Exposures and Calculated Margins to Dog NOAEL (3-
month GLP study) ................................................................................................. 22 
Table 1-2 
Observed MAD study Exposures and Calculated Margins to Rat NOAEL (1-
month GLP study) ................................................................................................. 22 
Table 3-1 
Treatment Sequences ............................................................................................ 28 
Table 5-1 
Study Treatments .................................................................................................. 36 
Table 6-1 
Schedule of Activities ........................................................................................... 40 
Table 6-2 
 Vital Sign Recording Schedule ............................................................................ 45 
Table 6-3 
Acceptable Windows for Vital Sign Assessments Procedures ............................. 45 
Table 6-4 
Safety ECG Recording Schedule .......................................................................... 46 
Table 6-5 
Acceptable Windows for 12-Lead Safety Electrocardiogram Assessments 
Procedures ............................................................................................................. 46 
Table 6-6 
Digital Electrocardiogram Schedule ..................................................................... 47 
Table 6-7 
Window Allowance for dECG time points ........................................................... 51 
Table 6-8 
Spot Oxygen Saturation Recording Schedule ....................................................... 53 
Table 6-9 
Acceptable Windows for SpO2 Assessments Procedures .................................... 53 
Table 6-10 
Spot End-Tidal CO2 Recording Schedule ............................................................. 54 
Table 6-11 
Acceptable Windows for EtCO2 Assessments Procedures .................................. 54 
Table 6-12 
Spot Respiratory Rate Recording Schedule .......................................................... 55 
Table 6-13 
Acceptable Windows for Respiratory Rate Assessments Procedures .................. 55 
Table 6-14 
Pharmacokinetic Blood Sampling Schedule for Morphine and its Metabolites ... 58 
Table 6-15 
Pharmacokinetic Blood Sampling Schedule for AZD4041 .................................. 58 
Table 6-16 
Acceptable Windows for Timed PK Blood Specimen Collection Procedures ..... 58 
Table 6-17 
Pharmacokinetic Urine Sampling Schedule for AZD4041 ................................... 59 
Table 7-1 
Adverse Event Relationship to Study Drug .......................................................... 61 
Table 8-1 
Pharmacokinetic Parameters in Plasma ................................................................ 68 


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LIST OF IN-TEXT FIGURES  
Figure 3-1 
Study Design ......................................................................................................... 27 


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STUDY SYNOPSIS 
Name of 
Sponsor/Company: 
AstraZeneca AB 
Name of Product: 
AZD4041 
Title of Study: 
A Randomized, Double-blind, Placebo-controlled, Fixed Sequence Study to 
Assess the Effect on Respiratory Drive of Multiple Doses of AZD4041 When 
Co-administered With a Single Dose of Morphine in Healthy Recreational Opioid 
Users 
Study Development 
Phase: 
Phase 1 
Objectives: 
Primary objective: 
• 
To assess the effect on respiratory drive of morphine administered after 
multiple doses of AZD4041 compared to morphine administered alone in 
healthy recreational opioid users  
Secondary objectives: 
• 
To assess the safety and tolerability of multiple doses of AZD4041 when 
co-administered with a single dose of morphine in healthy recreational 
opioid users 
• 
To assess the pharmacokinetics (PK) of AZD4041 and morphine in 
healthy recreational opioid users 
• 
To assess the impact of multiple dose administrations of AZD4041 on the 
PK of morphine and its metabolites  
• 
To assess the impact of morphine on steady-state PK of AZD4041 
• 
To assess the renal clearance of AZD4041 
Endpoints: 
Safety: 
Primary 
Incidence of clinically significant changes in respiratory parameters, defined as: 
• 
Incidence of increased end tidal carbon dioxide (EtCO2) of at least 
10 mmHg compared to baseline or >50 mmHg (sustained for at least 
30 seconds) 
• 
Incidence of reduction in SpO2 to <92% (sustained for at least 
30 seconds) 
Secondary 
• 
SpO2 (%) 
 Mean time to reduction in SpO2 to <92% (sustained for at least 
30 seconds) 
 Mean duration of reduction in SpO2 to <92% (sustained for at least 
30 seconds) 


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 Maximum postdose reduction of SpO2 adjusted for baseline  
 Mean postdose SpO2 
• 
EtCO2 (mmHg) 
 Mean time to each increased EtCO2 episode of at least 10 mmHg 
compared to baseline or >50 mmHg (sustained for at least 30 seconds) 
 Mean duration of each increased EtCO2 episode of at least 10 mmHg 
compared to baseline or >50 mmHg (sustained for at least 30 seconds) 
 Maximum postdose increase in EtCO2 adjusted for baseline 
 Mean postdose EtCO2 
• 
Respiratory rate (breaths/min) 
 Incidence of reduced respiratory rate to <6 breaths/min (sustained for 
at least 30 seconds) 
 Mean time to each reduced respiratory rate episode of <6 breaths/min 
(sustained for at least 30 seconds) 
 Mean duration of each reduced respiratory rate episode of 
<6 breaths/min (sustained for at least 30 seconds) 
 Maximum postdose decrease in respiratory rate adjusted for baseline 
 Mean postdose respiratory rate 
• 
Incidence, frequency, severity and relationship of AEs 
• 
Vital signs (blood pressure, heart rate, and oral temperature) 
• 
ECGs (12-lead safety ECGs, 12-lead digital ECGs, ECG telemetry) 
• 
Clinical laboratory test results (clinical chemistry, hematology, 
coagulation, urinalysis) 
• 
Physical examination findings 
• 
Neurological examination findings 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) findings 
• 
Type of medical intervention used, summarized for each event of 
significantly increased EtCO2, reduced SpO2, or respiratory rate 
Pharmacokinetic: 
Plasma samples will be analyzed to determine concentrations of AZD4041, 
morphine, morphine-6-glucuronide and morphine-3-glucuronide. 
Pharmacokinetic parameters for morphine, morphine-6-glucuronide and 
morphine-3-glucuronide include, but are not limited to, the following: 
Day 1 and Day 15 : 
• 
Cmax: Maximum observed plasma concentration 
• 
tmax: Time to maximum observed plasma concentration 
• 
AUC0-t: Area under the plasma concentration vs time curve from time 0 to 
the time of the last measurable concentration  


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• 
AUC0-∞: Area under the concentration time curve extrapolated to infinity, 
calculated as AUC0-T + Clast/λZ, where Clast is the last quantifiable 
concentration at time Tlast 
• 
t1/2,z: Terminal elimination half-life, calculated as ln(2)/λ  
• 
Tlast: Time of last measurable observed concentration 
• 
CL: Total body clearance, calculated as Dose/AUC0-∞ (parent drug only) 
• 
Vz: Volume of distribution based on terminal phase (parent drug only) 
Pharmacokinetic parameters for AZD4041 include, but are not limited to, the 
following: 
Days 2 to 7 and 9 to 14: 
• 
Ctrough: Predose concentration observed immediately prior to the next 
successive dose 
Days 8 and 15: 
• 
Cmax,ss: Maximum observed plasma concentration 
• 
tmax,ss: Time to maximum observed plasma concentration 
• 
Ctrough: Predose concentration observed immediately prior to the next 
successive dose  
• 
AUCτ: Area under the concentration time curve over the dosing interval at 
steady-state, calculated from 0 to 24 hours (dosing interval) 
• 
Cav: Average concentration during a dosing interval, after the last dose of 
a multiple dose regimen, calculated as AUCτ/τ 
• 
t1/2, z: Terminal elimination half-life, calculated as ln(2)/λ (Day 15 only)  
• 
CLss/F: Apparent clearance at steady-state, calculated as Dose/AUCτ  
• 
Vzss/F: Apparent volume of distribution at steady-state (based on 
terminal phase) 
Urine samples will be analyzed to determine concentrations of AZD4041.  
Pharmacokinetic parameters for AZD4041 include, but are not limited to, the 
following: 
Day 15:  
• 
Aeτ: Amount of drug excreted in urine  
• 
fe/F: Cumulative fraction of unchanged drug excreted in urine over the 
dosing interval 
• 
CLR: Apparent renal clearance 
• 
t1/2: Elimination half-life 


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Investigational 
Product, Dose, and 
Mode of 
Administration 
(proposed): 
AZD4041 oral solution 
 (active drug dissolved in vehicle) 
Manufacturer of Drug Substance: AstraZeneca  
Dose: 
 
Mode of administration: Oral 
Placebo, Mode of 
Administration: 
Vehicle (
) without active drug 
(AZD4041) 
Manufacturer: MEDISCA 
Mode of administration: Oral 
Opioid, Dose, and 
Mode of 
Administration 
Morphine for intravenous (IV) use (Duramorph PF®), 
 
Manufacturer of Drug Substance: Hikma Pharmaceuticals USA Inc. 
Dose: 
 
Mode of administration: IV 
Study Design: 
This is a Phase 1, randomized, double-blind, placebo-controlled, 2 fixed sequence 
multiple dose study in healthy male and female recreational opioid users. 
This study will consist of 3 phases: Screening and Qualification phase, Treatment 
phase, and Follow-up/Early Termination (ET). 
After a Screening period of up to 27 days (Day -30 to Day -3), eligible subjects 
will be admitted to the clinical research unit (CRU) on Day -2. Subjects will be 
randomized to 1 of 2 fixed treatment sequences (28 subjects in Sequence 1, and 
16 subjects in Sequence 2) on Day -1. 
Subjects will be required to present a negative urine drug and alcohol screen upon 
admission on Day-2, except for tetrahydrocannabinol (THC). If THC is positive at 
admission, a cannabis intoxication evaluation will be done by an Investigator, and 
subjects may be permitted to continue in the study at the discretion of an 
Investigator. Subjects will then undergo a naloxone challenge where an initial 
0.2 mg IV dose of naloxone hydrochloride (HCl) will be administered. The 
subject will be observed for signs or symptoms of opioid withdrawal. If there is 
no evidence of withdrawal within 1 minute (as assessed by a Clinical Opioid 
Withdrawal Scale [COWS] score of <5), an additional 0.6 mg IV dose of 
naloxone HCl will be given, and the subject will be observed for signs and 
symptoms of withdrawal for 5 minutes (as assessed by COWS). Subjects who 
present symptoms of withdrawal during the qualification process will be excluded 
from the study and will not be eligible to enter the Treatment phase. 
In total, subjects will be confined to the CRU for approximately 20 days from 
Day -2 to Day 18 (until approximately 72 hours following the last study drug 
administration). 
On Day 1, subjects will receive a single 
 IV dose of morphine. From Day 2 
to Day 15, subjects will receive a 
 oral dose of AZD4041 or placebo once 
daily for 14 consecutive administrations. On the morning of Day 15, the 
 
oral dose of AZD4041 or placebo will be combined with a single 
 IV dose 
of morphine. 
In order to limit the number of subjects being treated with investigational product 
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on any single day, eligible subjects will be assigned to different subgroups. 
Subgroup sizes should be limited to no more than 8 subjects. Dosing of subgroups 
should be staggered to occur on different days, with at least 2 days between the 
start of dosing for sequential subgroups. 
A Follow-up visit will occur approximately 7 days after the last drug 
administration. 
Duration of 
Treatment and 
Subject 
Confinement: 
Duration of clinical trial (per subject): 
Screening: Day -30 to Day -3 (up to 27 days) 
Qualification: Day -2 to Day -1 (2 days) 
Treatment: Subjects will be confined to the clinical site for approximately 
20 days, from Day -2 until Day 18 (ie, until 72 hours following the last study drug 
administration)  
Follow-up visit: Subjects will be followed-up approximately 7 days after the last 
drug administration. 
Total study duration: up to 54 days (including Screening) 
Study Population: 
Healthy, male and/or female recreational opioid users 
Planned Number 
of Subjects: 
Approximately 44 subjects will be randomized (28 AZD4041 + morphine and 16 
Placebo + morphine) to ensure completion of at least 36 subjects (24 AZD4041 + 
morphine, and 12 Placebo + morphine on Day 15). 
Bioanalysis: 
Plasma concentrations of AZD4041, morphine, morphine-6-glucuronide and 
morphine-3-glucuronide will be measured by validated bioanalytical methods. 
Urine concentrations of AZD4041 will also be measured by a validated 
bioanalytical method. 
Safety Analysis: 
The safety analysis will be fully detailed in a statistical analysis plan (SAP). 
Pharmacokinetic 
Analysis: 
The PK parameters will be determined by non-compartmental analysis using 
appropriate software. The PK analysis will be fully detailed in a SAP. 
Statistical 
Analysis: 
The statistical analyses will be fully detailed in a SAP. 
 
 




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1. 
INTRODUCTION 
1.1. Background 
Opioid use disorder (OUD) is a public health crisis responsible for significant morbidity, 
mortality, and productivity loss. In 2019, approximately 70% of deaths from drug overdose 
involved opioids (CDC, 2020), and seven out of 1000 babies (~90 babies each day) were born 
with neonatal abstinence syndrome because their mothers had OUD (Healthcare Cost and 
Utilization Project, 2016). OUD presents an enormous economic burden in the US estimated to 
be $170-215 billion per year (Society of Actuaries, 2019), with the total annual costs to the 
healthcare system in 2018 alone estimated at over $89 billion (Murphy, 2020). These economic 
burdens and costs to health, quality of life, and public assistance programs are all directly or 
indirectly related to OUD. There are only 3 Food and Drug Administration (FDA) approved 
treatments for OUD, all of which target μ opioid receptors, which are the major targets for opioid 
actions in the brain. Methadone, buprenorphine, and naltrexone act as an agonist, partial agonist, 
and antagonist, respectively, at μ opioid receptors. While each is effective with supervised use 
and accessory support services, such as counselling, they have limited clinical efficacy and 
utility (Leslie et al, 2019, Mancher et al, 2019). Limitations include intrinsic rewarding 
properties that lead to misuse/diversion (Hall et al, 2008, Leslie et al, 2019, Mancher et al, 2019), 
unpleasant side effects (Chen and Ashburn, 2015) that reduce compliance, such as withdrawal 
symptoms (Mancher et al, 2019), and high residual rates of relapse to drug use 
(Leslie et al, 2019, Wakeman et al, 2020). Since OUD and its deleterious consequences are a dire 
national health crisis, the US National Institute on Drug Abuse (NIDA) has identified several 
high priority drug targets for rapid therapeutic development (Rasmussen et al, 2019). OX1 
receptor antagonists are high on this list and are considered one of the most promising targets for 
the development of novel OUD treatments (Rasmussen et al, 2019). 
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, 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 (Gotter et al, 2016), neuroendocrine 
homeostasis, cardiovascular functions (Samson et al, 2007), and motivated behaviours 
(Kodadek and Cai, 2010). A considerable body of preclinical studies suggests that orexin 
transmission at OX1 receptors plays a major role in the motivation to seek and consume opioids 
and other drugs of abuse (Quarta et al, 2009; Porter-Stransky et al, 2017; Fragale et al, 2019). 
Indeed, pharmacological blockade of OX1 receptors or genetic deletion of the gene encoding this 
receptor markedly decreases the consumption of opioids and other addictive drugs such as 
nicotine and cocaine in laboratory animals without altering their willingness to engage in and 
seek natural reinforces such as food or sex (Kohlmeier et al, 2013). 
Based on these findings, it has been proposed that excessive orexin transmission at OX1 
receptors may play a fundamental role in the development and maintenance of OUD. Recent 
human brain studies provide compelling support for this hypothesis. Post-mortem human brain 
studies have revealed that the numbers of orexin neurons detected in the lateral hypothalamus of 
those suffering from OUD are markedly upregulated compared with non-OUD patients 


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(Pantazis et al, 2020). Rodents treated with opioids also show increased numbers of orexin 
neurons in the brain (Thannickal et al, 2018). This response is thought to reflect the de novo 
production of orexin peptides by neurons in the hypothalamus in response to opioid use, which 
contributes to the excessive orexin transmission hypothesized to drive the pathologically 
elevated motivation to seek and consume opioids (Thannickal et al, 2018). Based on compelling 
preclinical studies and clinical literature, OX1 receptor antagonists are considered one of the 
most promising novel therapeutic strategies to treat OUD (Rasmussen et al, 2019). Importantly, 
OX1 receptors play a similar role in regulating the addiction-related actions of nicotine, 
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.  
1.2. Study Rationale 
AstraZeneca (AZ), in partnership with Eolas Therapeutics, Inc, is developing an OX1 receptor 
antagonist, AZD4041, which demonstrates favourable drug-like physiochemical properties. The 
half maximal inhibitory concentration (IC50) for AZD4041 at OX1 and OX2 receptors is 5 nM 
and > 5000 nM, respectively. 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 
electroencephalogram (EEG) waveforms in rodents across a broad range of doses. AZD4041 
does not measurably inhibit the activity of cytochrome P450 enzymes or human ether-a-go-go-
related gene (hERG) channels nor does it have significant actions at any non-OX1 receptor 
targets so far screened. AZD4041 is highly brain penetrant in nonhuman primates and has 
relatively slow rates of clearance and high levels of oral bioavailability in dogs. AZD4041 
demonstrates in vivo efficacy, as measured by reduced oxycontin-seeking behaviours, in 
rodents - at relatively low exposures. Further details of these studies are provided in the 
Investigator’s Brochure (AZD4041 Investigator’s Brochure).  
AZD4041 may therefore provide an attractive treatment option for OUD. 
This study is being primarily conducted to assess the effect on respiratory drive of morphine 
administered after multiple doses of AZD4041 compared to morphine administered alone in 
healthy recreational opioid users. This study will also assess the safety, tolerability, and 
pharmacokinetics (PK) of multiple doses of AZD4041when co-administered with single dose of 
morphine in healthy recreational opioid users. The PK of AZD4041 and morphine in healthy 
recreational opioid users will be assessed. Moreover, the impact of multiple dose administrations 
of AZD4041 on the PK of morphine and metabolites will also be assessed, including the impact 
of morphine on steady-state PK of AZD4041. 
1.3. Risk/Benefit Assessment 
1.3.1. Known Potential Benefits 
AZD4041 has shown significant efficacy in oxycodone self-administration studies in rats. In 
addition, AZD4041 reduces cue-induced reinstatement of oxycodone seeking behaviours and 
blocks craving-like behaviours in a rat model of oxycodone withdrawal. Supporting the 
feasibility of developing a safe and potent OX1 receptor antagonist for OUD is the fact that two 
dual OX1/OX2 receptor antagonists (suvorexant and lemborexant, so-called DORAs) have 


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already received FDA approval as sleep-promoting agents. The sleep-promoting actions of 
DORAs primarily reflect their ability to block the OX2 receptors. Neither of these DORAs show 
any evidence of concerning side-effects in the general population despite their wide-spread use. 
This suggests that novel OX1 receptor selective antagonists, devoid of the sleep-promoting 
effects that limit the utility of DORAs for non-sleep-related disorders such as OUD, are unlikely 
to be associated with mechanism related toxicity in humans (O’Connor et al, 2010). It therefore 
appears that AZD4041 could represent a novel strategy in the treatment of addictive disorders 
such as OUD, where it has the potential to address a significant unmet need. It is thought 
unlikely that the recreational opioid users participating in the current study will benefit from 
taking the AZD4041 study treatment. However, it is anticipated that the study will provide 
important safety and PK data that will inform the scientific rationale for further development of 
AZD4041 as a potential treatment of OUD. 
1.3.2. Important Potential Risks 
Potential risks of AZD4041 based on data observed in animal studies include thymus effects 
(including atrophy), male reproductive tract effects, and arrhythmias.  
In nonclinical studies, AZD4041 has been evaluated in repeat dose toxicity studies of 1 month 
duration in rats, and in studies of 1- and 3-months duration in 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) in vitro Ames and chromosome 
aberration studies and in the GLP in vivo micronucleus study. AZD4041 was also negative in an 
in vitro 3T3 phototoxicity assay. 
No significant effects of AZD4041 were noted on the central nervous system (CNS), 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 sleep when 
compared with control. In a respiratory study conducted in rats, no significant effects were seen 
except at the highest dose of 100 mg/kg where lower tidal volume (11% below) was noted when 
compared with vehicle control at baseline. A similar effect was noted with AZD4041 alone in a 
study with a morphine challenge; increased respiratory depression was also noted following 
morphine administration after AZD4041. For the current clinical study, effects on 
sleep/wakefulness will be assessed via AE reporting. Only healthy subjects will be enrolled in 
the current study and subjects with respiratory co-morbidities will be excluded. In addition, vital 
signs will be assessed at regular intervals after dosing (See Schedule of Activities, Table 6-1). 
In the hERG assay, the IC50 for AZD4041 was calculated to be 219.3 µM. 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, were noted in 1 dog only at the highest dose of 100 mg/kg. The onset of the changes was 
soon after the approximate Tmax (average of 4.6 hours) in the dog study. Hemodynamic 


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parameters were largely unaltered and were maintained in the physiological range of heart rate 
(HR) and blood pressure (BP). In a dog 14-day investigative study, lower HR, with associated 
longer PR and QT intervals, were recorded at 60 mg/kg/day; 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 the 1-month dog study in which dogs received up to 60 mg/kg/day. 
In the 1-month 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. There were no effects on organ 
weight or microscopic pathology noted for the thymus at the end of the recovery period, 
indicating recovery. Effects on the thymus were not recorded in the dog 3-month study. 
In the dog 1-month study, 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. In the 
3-month dog study, there were changes in the prostate (atrophy and lower weight) and testes 
(vacuolation of Leydig cells) and epididymides (epithelial vacuolation). In comparison to the 
1-month study, these changes were generally not as marked, considered to be non-adverse and 
followed longer term administration at generally higher exposures. Following 1 month of 
administration, the no-observed-adverse-effect-level (NOAEL) was established as 
100 mg/kg/day in the rat and 10 mg/kg/day in the dog. The NOAEL in the dog 3-month study 
was 60 mg/kg/day. There is evidence that OX1 receptors are expressed in dog seminiferous 
tubules (Ligouri, 2018) and are 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. 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 1-month GLP toxicity study. 
The AZD4041 single ascending dose (SAD) study (Protocol D7460C00001) was completed for 
6 cohorts of healthy volunteer with N= 8 subjects per cohort randomly assigned to receive either 
AZD4041 or placebo (N= 6 AZD4041 and N=2 placebo). Single oral doses explored in the SAD 
study were 
. There were no severe treatment 
emergent adverse events (TEAEs), severe adverse events (SAEs) or TEAEs leading to study 
discontinuation over the course of the study. There were no apparent dose-related trends with 
respect to the reporting of AEs. The most common TEAEs to be reported in subjects treated with 
AZD4041 include ventricular tachycardia (5.6%), back pain (5.6%), nausea (2.8%), vomiting 
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(2.8%) and dyspnea (2.8%). No clinically significant changes have been reported for laboratory 
safety, vital sign, or 12-lead ECG parameters. 
Two short episodes of non-sustained ventricular tachycardia (NSVT) were observed in the SAD 
study in subjects who had received AZD4041, 1 each in Cohort 4 (
) and Cohort 5 (
), 
observed at 8 hours and 6.5 hours postdose, respectively. The NSVT events were asymptomatic 
and resolved spontaneously. Across the full dose range of the study, no trends for changes or 
prolongations in ECG parameters including QTcF, QRS, and PR interval; or changes in the QRS 
and T-wave morphology that would indicate, for example, hERG-related potassium or sodium 
channel effects. There was no evidence for systematic changes in HR. In 12-lead ECG telemetry 
files of the 2 subjects with NSVT, no notable QTcF prolongation or QRS interval prolongation, 
or changes in QRS or T wave morphologies were found. No subject in the study has had a QTcF 
> 450 msec. Only 1 subject in the study had an increase in QTcF > 30 msec (32 msec), which 
occurred at 6 hours postdose. Neither subject appears to be different from the rest of the subjects 
in their cohort based on exposure parameters (Area under the curve, Cmax, Tmax, concentration at 
6 and 8 hours).  
The multiple ascending dose (MAD) study of AZD4041 (Protocol D7460C00002) has recently 
completed in Canada and interim data [blinded to treatment assignment] are available pending 
database lock. Three dose levels of AZD4041 were explored (
) in 
healthy volunteers, who received repeat once-daily doses for 14 days (N=12 subjects per cohort 
with N=9 receiving AZD4041 and N=3 receiving placebo). Cardiac monitoring included 
extended periods of ECG telemetry and Holter ECG recording. Dose escalation proceeded 
uneventfully across the cohorts. Exposures for AZD4041 (Cmax and AUC) increased in an 
approximate dose proportionate manner from 
 and remained within the range 
predicted. Maximum exposures (Tmax) were observed between 0.5 to 3.0 hours postdose. The 
effective half-life for AZD4041 ranged from 18.6 to 21.3 hours, comparable to that observed in 
the SAD study. Accumulation ratios over the dosing period ranged from 1.27 to 1.59 for Cmax 
and from 1.66 to 1.81 for AUC. Steady state exposures (Ctrough) were achieved at Day 6 for the 
 dose and Day 8 for the 
 dose levels. With respect to the pre-defined 
limits of human exposure and exposure predictions for potential doses higher than 
, further 
dose escalation was not undertaken. No medically important tolerability or safety issues were 
raised by the dose escalation committee with respect to any of the safety endpoints (including 
vital signs, 12-lead ECGs, safety blood tests and urinalysis) during the course of the study. There 
were no observed SAEs or dose-limiting toxicities. Adverse events were mild in nature and were 
mostly resolved by checkout. The most common TEAEs, reported in two or more subjects, were 
NSVT (observed for two subjects in Cohort 1 [
placebo] and one subject in Cohort 3 
[
placebo]), post lumbar puncture syndrome, medical device site reaction, headache, and 
nausea. The NSVT events were detected on Holter ECG monitoring; they were non-sustained 
and resolved spontaneously. One of the subjects with NSVT in Cohort 1 reported palpitations on 
Day 2 and was withdrawn by the Investigator before dosing on (Day 3) for safety reasons due to 
these adverse events. In Cohort 3 
placebo), one episode of NSVT was observed on 
Day 2, ~7.5 hours after dosing. The event was asymptomatic and resolved without intervention 
or recurrence. No clinically significant changes or trends for changes were observed for 
laboratory safety assessments, vital sign parameters, or ECG intervals in the MAD study. 
Overall, AZD4041 was considered to have a good safety and tolerability profile when 
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administered to healthy volunteers in repeat oral doses (once daily for 14 days) up to 
 in 
the MAD study. A detailed summary of the available human safety and PK data is provided in 
the Investigator’s Brochure (AZD4041 Investigator’s Brochure). 
There is limited class information on the safety profile of selective OX1 receptor antagonists in 
humans. While two DORA (suvorexant and lemborexant) are 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, Kaufmann et al, 2021] and 
JNJ-61393215 [Salvadore et al, 2019]). Both appeared to be well tolerated in these initial studies 
with the most common reported AEs being somnolence and headache.  
The following safety measures will be monitored continuously for signs of respiratory depression 
from up to 1 hour prior to dosing up to approximately 6 hours following dosing in the Treatment 
phase: 
x End-tidal carbon dioxide (EtCO2) monitoring 
x Blood oxygen saturation (SpO2) monitoring 
x Respiratory rate monitoring 
Safety measurements of EtCO2 and SpO2 are accepted endpoints for the evaluation and 
monitoring of respiratory function, change in oxygenation, and change in ventilation (Linko and 
Paloheimoi, 1989, Jabre et al, 2009, Manifold et al, 2013, and Waugh et al, 2011). Monitoring 
EtCO2 has been shown to be more sensitive in the detection of respiratory depression than 
monitoring respiratory rate and pulse oximetry alone (Goli et al, 2012). In the clinical setting, 
respiratory depression is usually described in terms of decreased respiratory rates, decreased 
SpO2 levels, (Cashman et al, 2004) or elevated EtCO2 levels and, therefore, these measures are 
appropriate to monitor for respiratory depression in the context of this study. 
Serious, life-threatening, or fatal respiratory depression may occur with use of morphine 
(Infumorph Label 2019). Subjects will be monitored for respiratory depression in a fully 
equipped and staffed environment. Details of mitigating signs of respiratory depression and 
medical interventions are provided in Sections 6.1.15 and 6.1.16.  
Additional safety measures implemented at predose and specified timepoints postdose will 
include the collection and documentation of AEs and vital signs (ie, systolic and diastolic BP, 
HR, and oral temperature), respiratory rate, and SpO2. Cardiovascular risk mitigations include 
appropriate eligibility criteria, individual and study-level stopping criteria; and a sufficiently 
stringent level of cardiac monitoring will be retained for the current clinical study protocol, 
similar to MAD study protocol; 12-lead safety ECGs, alongside extended periods of ECG 
telemetry and Holter monitoring have been implemented to monitor for any arrhythmias. 
Subjects will be determined as eligible for inclusion into the study based on measures of clinical 
laboratory testing, vital signs, medical history, Columbia-Suicide Severity Rating Scale 
(C-SSRS), physical examination, and ECG. 
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Justification for Dose selection
The rationale for the planned AZD4041 dose level (
) for the current study is based on an 
understanding of data accumulated across non-clinical studies and clinical experience to-date and
summarised as follows:
x
AZD4041 was found to have a good safety profile and to be well tolerated by healthy 
volunteer subjects administered single oral doses up to 
 in the completed single -
dose study (D7460C00001) and up to 
 administered once daily for 14 days in the 
repeat-dose study (D7460C00002). The observed PK data in the studies indicate 
dose-related and approximately dose-proportional exposures. Steady state exposures were 
achieved after 6 to 8 days of repeat dosing. The observed steady-state exposures are 
aligned with those previously predicted from simulations and modelling. Exposures 
observed at the 
 repeat dose level in the MAD study do not exceed those previously 
achieved at the highest (
) single dose level explored in the SAD study (see 
Investigator’s Brochure for details of human safety and PK). 
x
Safety margins for AZD4041 have been based on PK data observed in the MAD study at 
the 
 dose level and calculated with respect to exposure data achieved at the 
NOAEL exposures observed in the 3-month dog GLP study (60 mg/kg) and the 1-month 
rat GLP study (100mg/kg). The 3-month study is considered to provide the most robust 
and comprehensive assessment of the effects of AZD4041 in the dog. The lowest 
NOAEL exposures from the repeat dose toxicology studies are from the rat 1-month 
study (see Table 1-1 and Table 1-2). The relevant safety margins at the proposed 
 
dose level are therefore considered to be 22-fold and 13.2-fold for maximum observed 
concentration (free Cmax, ss) and total exposure at steady-state (free AUCtau.ss), 
respectively. 
x
Concentrations of AZD4041 that are predicted to be therapeutically efficacious and 
relevant to humans with opioid-use disorder have been estimated by extrapolation of 
exposures at a dose level which is effective in a rat oxycodone withdrawal model. In the 
rodent model, a total plasma exposure of 523 nM and a free plasma exposure of 147 nM 
were estimated at an efficacious AZD4041 dose of 
 (PO). Analysis of PK data 
from the human MAD study indicates that it is possible to achieve comparable systemic 
exposures that are predicted to achieve efficacy. In humans, once daily repeat 
 
doses of AZD4041 for 14 days provided a mean total Cmax of 1828 nM (941 ng/mL) and 
free Cmax of 327 nM (168.4 ng/mL). Likewise, human study provided a mean total Ctrough
concentration of 697 nM (359 ng/mL) and free Ctrough concentration of 125 nM 
(64ng/mL) for 
 dose at steady-state. Preliminary evaluation of AZD4041 steady 
CNS penetration at the 
 dose level in the MAD study indicate a total brain-to-
unbound plasma drug partition coefficient (Kp,uu) of 0.295. Corresponding estimates for 
the brain free concentrations (mean Cmax.ss = 97 nM and Ctrough.ss = 39 nM) are 
comparable to the estimated free brain exposure of AZD4041 (25 nM) predicted to confer 
efficacy in the rodent oxycodone withdrawal model. Furthermore, measured free brain 
concentrations in humans following dosing of 
 to steady state exceed the in vitro 
inhibitory constant for AZD4041 at the human orexin 1 receptor (Ki = 1.5 to 7.9 nM) and 
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are in line with exposures where OXR1 target engagement would be expected (see 
Investigator’s Brochure for details). 
x The proposed 
 dose level for AZD4041 is considered appropriate for the current 
study, because (1) the expected steady-state exposures at 
 provide coverage over a 
range of exposures that are predicted to be therapeutically efficacious for the treatment of 
opioid use disorder in humans, and (2), therefore provides for a robust evaluation of the 
potential for AZD4041 to interact with single doses of morphine at a dose level that is 
considered to be at the higher limit of plausible efficacious and therapeutically-relevant 
doses. 
Table 1-1 
Observed MAD study Exposures and Calculated Margins to Dog NOAEL 
(3-month GLP study) 
Clinical dose 
(mg) 
Total Cmax.ss 
(ng/mL)  
Human Free 
Cmax.ss 
(ng/mL) 
Total 
AUCtau.ss 
(ng·h/mL) 
Human Free 
AUCtau.ss 
(ng·h/mL) 
Free Cmax.ss 
margin to dog 
NOAEL 
Free AUCtau.ss 
margin to dog 
NOAEL 
232 
41.5 
3030 
540 
91 
105 
478 
85.6 
6290 
1125.9 
44 
50 
941 
168.4 
12609 
2257.1 
22 
25 
A human plasma protein binding value of 17.9% has been applied to calculate human free Cmax and AUCtau. 
For the NOAEL values, combined sex (male and female) toxicokinetic data have been utilized. 
Dog NOAEL (60 mg/kg) exposures for free Cmax (3,764 ng/mL) and free AUClast (56,883 ng.h/mL) were used to 
calculate safety margins. 
Human exposures for the planned 
 dose level should not exceed 1/10th of the NOAEL in the 3-month dog 
study. Based on observed human exposures, free Cmax.ss is not expected to exceed 376 ng/mL and free AUCtau.ss is not 
expected to exceed 5688 ng.h/mL. 
Table 1-2 
Observed MAD study Exposures and Calculated Margins to Rat NOAEL 
(1-month GLP study) 
Clinical dose 
(mg) 
Total 
Cmax.ss  
(ng/mL)  
Human 
Free 
Cmax.ss 
(ng/mL) 
Total 
AUCtau.ss 
(ng·h/mL) 
Human 
free 
AUCtau.ss 
(ng·h/mL) 
Free Cmax.ss 
margin to dog 
NOAEL 
Free AUCtau.ss 
margin to dog 
NOAEL 
232 
41.5 
3030 
540 
90 
55 
478 
85.6 
6290 
1125.9 
44 
26 
941 
168.4 
12609 
2257.1 
22 
13.2 
A human plasma protein binding value of 17.9% has been applied to calculate human free Cmax and AUCtau. 
For the NOAEL values, combined sex (male and female) toxicokinetic data have been utilized. 
Rat NOAEL (100 mg/kg) exposures for free Cmax (3,751 ng/mL) and free AUClast (29,793 ng.h/mL) were used to 
calculate safety margins. 
Human exposures for the planned 
 dose level should not exceed 1/10th of the NOAEL in the 1-month rat 
study. Based on observed human exposures, free Cmax.ss is not expected to exceed 375 ng/mL and free AUCtau.ss is 
not expected to exceed 2979 ng.h/mL. 
x The dose of morphine administered in this study is not expected to present any significant 
risk to the subjects (Duramorph Label 2010). In adults, the recommended initial IV 
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morphine dose is between 2 mg to 10 mg/70 kg of body weight. Doses of morphine of up 
to 
 have been safely administered intravenously in non-dependent, recreational 
opioid users (Stoops et al, 2010, Webster et al, 2011). A supratherapeutic dose of 
morphine was selected for this study to increase the likelihood of evaluating effects on 
respiratory parameters. The dose of 
 IV was selected for this study as it has been 
safely administered in prior studies of opioid experienced, non-dependent recreational 
users (Osterlund et al, 2001, Osterlund et al, 1999, Thompson et al. 1999, Skarke et al, 
2003, Bailey et al, 1991).  
x The potential for AZD4041 (
 administered once daily for 14 days) to interact with 
single doses of morphine at a metabolic level is considered to be low in this study. In 
vitro studies indicate that AZD4041 shows minimal or no inhibition across a panel of 
cytochrome P450 (CYP) enzymes with IC50 values all determined to be > 30 PM. 
AZD4041 is considered to pose a low risk as a perpetrator of drug-drug interactions via 
inhibition of transporters such as OATP1B1 (IC50 = 38 PM), BCRP (IC50 = 48 PM) or 
P-glycoprotein (IC50 = 282 PM) and poses a low risk as a perpetrator via induction of 
CYP enzymes (4-fold and 100 fold induction of CYP1A2 and CYP34 at 30 PM, 
respectively). While CYP3A4 contributes to >90% of AZD4041 metabolism in vitro, it is 
not expected that single doses of morphine (
) will appreciably affect the 
metabolism or clearance of AZD4041. 
1.3.3. Risk/Benefit Conclusion 
The hepatic and thyroid effects observed in the preclinical studies were considered minimal and 
adaptive; and thymic atrophy was noted to have fully recovered at the end of the recovery period. 
On the basis of data observed in the safety pharmacology study, the effects of AZD4041 co-
administered with single doses of morphine, on respiratory drive will be evaluated and monitored 
in the clinical study by measuring EtCO2, O2 saturation, and respiratory rate.  
Cardiac arrhythmia remains a potential risk during the ongoing exploratory clinical development 
of AZD4041 and appropriate risk mitigation measures have been implemented into the protocol.  
Women of non-childbearing potential may be enrolled into the study. Inclusion of fertile (non-
vasectomised) males in the study is justified on the basis that the 3-month dog GLP study 
provides the most robust and comprehensive evaluation of AZD4041 on the male reproductive 
tract in this species. A NOAEL has been identified in the dog study with respect to toxicologic 
effects seen in the prostate, testes and epididymides. Human exposures to AZD4041 at 
steady-state for the planned dose level (
, once daily for 14 days) are not expected to exceed 
1/10th of the NOAEL in the 3-month dog study. These exposures are also significantly lower 
than those identified at the NOAEL in the rat 1-month study. No reproductive effects have been 
seen in the rat 1-month GLP study. In addition, the planned dose of AZD4041 has been 
evaluated previously in a 14-day MAD clinical study; the dosing regimen was generally well 
tolerated and no significant medical or safety concerns were raised by the dose escalation 
committee. 
Based on the considerations regarding the potential risks of AZD4041, exposure of healthy 
volunteer subjects with a history of recreational opioid use to repeat doses of AZD4041 is 
considered justifiable in relation to the significant unmet need to develop improved efficacious 
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treatments for opioid-use disorder. It is expected that the safety, tolerability and PK data acquired 
in the current study in healthy volunteer who are opioid users, will provide a scientific basis and 
rationale for the subsequent evaluation of AZD4041 in patients with OUD. 
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 (AZD4041 
Investigator’s Brochure). 




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OBJECTIVES 
ENDPOINTS 
 Mean postdose respiratory rate 
• 
Incidence, frequency, severity, and 
relationship of AEs 
• 
Vital signs (blood pressure, heart rate, and 
oral temperature) 
• 
ECGs (12-lead safety ECGs, 12-lead digital 
ECGs, and ECG telemetry) 
• 
Clinical laboratory test results (clinical 
chemistry, hematology, coagulation, 
urinalysis) 
• 
Physical examination findings 
• 
Neurological examination findings 
• 
C-SSRS findings 
• 
Type of medical intervention used, 
summarized for each event of significantly 
increased EtCO2,  reduced SpO2, or respiratory 
rate 
To assess the PK of AZD4041 and morphine in 
healthy recreational opioid users 
Plasma concentrations as well as PK parameters for 
AZD4041 and morphine and its metabolites as 
described in Section 8.4 
To assess the impact of multiple dose 
administrations of AZD4041 on the PK of 
morphine and its metabolites 
Plasma concentrations as well as PK parameters for 
AZD4041 and morphine and its metabolites as 
described in Section 8.4 
To assess the impact of morphine on 
steady-state PK of AZD4041 
Plasma concentrations as well as PK parameters for 
AZD4041 and morphine and its metabolites as 
described in Section 8.4 
To assess the renal clearance of AZD4041 
Urine concentrations as well as PK parameters for 
AZD4041 as described in Section 8.4 
Abbreviations: AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram 
EtCO2 = end tidal carbon dioxide; PK = pharmacokinetic; SpO2 = oxygen saturation. 
3. 
STUDY DESIGN 
3.1. Overall Study Design 
This is a Phase 1, randomized, double-blind, placebo-controlled, 2 fixed sequences, multiple 
dose study in healthy male and/or female recreational opioid users. 
This study will consist of 3 phases: Screening and Qualification, Treatment phase, and 
Follow-up (see Figure 3-1).  


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Figure 3-1 
Study Design
After a Screening period of up to 27 days (Day -30 to Day -3), eligible subjects will be admitted 
to the clinical research unit (CRU) on Day -2. Subjects will be randomized to 1 of 2 fixed 
treatment sequences (28 subjects in Sequence 1, and 16 subjects in Sequence 2) on Day -1. 
Subjects will be required to present a negative urine drug and alcohol screen upon admission on 
Day-2, except for tetrahydrocannabinol (THC). If THC is positive at admission, a cannabis 
intoxication evaluation will be done by an Investigator, and subjects may be permitted to 
continue in the study at the discretion of an Investigator. Subjects will then undergo a naloxone 
challenge where an initial 0.2 mg intravenous (IV) dose of naloxone hydrochloride (HCl) will be 
administered. The subject will be observed for signs or symptoms of opioid withdrawal. If there 
is no evidence of withdrawal within 1 minute (as assessed by a Clinical Opioid Withdrawal Scale 
[COWS] score of <5), an additional 0.6 mg IV dose of naloxone HCl will be given, and the 
subject will be observed for signs and symptoms of withdrawal for 5 minutes (as assessed by 
COWS). Subjects who present symptoms of withdrawal during the qualification process will be 
excluded from the study and will not be eligible to enter the Treatment phase. 
In total, subjects will be confined to the CRU for approximately 20 days from Day -2 to Day 18 
(until approximately 72 hours following the last study drug administration).  
On Day 1, subjects will receive a single 
IV dose of morphine. From Day 2 to Day 15, 
subjects will receive a 
 oral dose of AZD4041 or placebo once daily for 14 consecutive 
days. On the morning of Day 15, the 
 oral dose of AZD4041 or placebo will be combined 
with a single 
 IV dose of morphine.
In order to limit the number of subjects being treated with investigational product (IP) on any 
single day, eligible subjects should be assigned to different subgroups. Subgroup sizes should be 
limited to no more than 8 subjects. Dosing of subgroups should be staggered to occur on 
different days, with at least 2 days between the start of dosing for sequential subgroups.  
A Follow-up visit will occur approximately 7±2 days after the last study drug administration. 
The schedule of activities of the study is described in Table 6-1.
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3.2. Study Treatments 
The following treatments will be administered according to Table 3-1. 
x Test: A single 
 of AZD4041 oral solution will be 
administered once daily from Day 2 to Day 15 according to the randomization schedule. 
x Placebo: Vehicle without active drug (AZD4041) will be orally administered once daily 
from Day 2 to Day 15 according to the randomization schedule. 
x Morphine: A 
 of morphine will be intravenously 
administered on Days 1 and Day 15 only. 
Table 3-1 
Treatment Sequences 
 
Day 1 
Days 2 to 14 
Day 15a 
Sequence 1 
(n=28) 
 Morphine  
 AZD4041 
once daily 
 AZD4041 + 
 
Morphine  
Sequence 2 
(n=16) 
 Morphine  
Placebo 
once daily 
Placebo + 
 Morphine 
a. 
The assigned treatment (AZD4041 or Placebo) will be administered orally immediately (within 1 minute) after 
the end of morphine infusion. 
4. 
SUBJECT POPULATION 
Subjects meeting all the inclusion criteria and none of the exclusion criteria at Screening may be 
eligible for participation in this study. Continued eligibility will be assessed upon admission to 
the clinical site, prior to the first study drug administration. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or enrolled in the study. 
4.1. Inclusion Criteria 
1. Recreational opioid user, not currently considered to have moderate or severe substance 
use disorder for opioids (based on the Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition [DSM-5] criteria) and has experience with opioid use for non-
therapeutic purposes (ie, for psychoactive effects) on at least 10 occasions in their 
lifetime and at least 1 occasion in the last 12 weeks prior to Screening 
2. Provision of signed and dated informed consent form (ICF) prior to the initiation of any 
protocol-specific procedures 
3. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
4. Healthy adult male or female, 18 to 55 years of age, inclusive, prior to the first study drug 
administration 
5. Body mass index (BMI) within 18.0 kg/m2 to 35.0 kg/m2, inclusive, and body weight at 
least 50 kg at Screening 
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6. A female study subject of non-childbearing potential must meet 1 of the following 
criteria: 
(1) Physiological postmenopausal status, defined as the following: 
a) absence of menses for at least 1 year prior to the first study drug administration 
(without an alternative medical condition); and 
b) Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at Screening 
AND/OR 
(2) Surgical sterile, defined as those who have had hysterectomy, bilateral oophorectomy 
and/or bilateral salpingectomy, or bilateral tubal ligation. Women who are surgically 
sterile must provide documentation of the procedure by an operative report, ultrasound, 
or other verifiable documentation. 
7. If male, must agree to use a highly effective method of contraception (see APPENDIX10 
for contraception guidance) when engaging in sexual activity and must not donate sperm 
during the study and for at least 4 months (120 days) after the last dose of study 
medication 
8. Healthy in the opinion of an Investigator, as determined by no clinically significant 
findings from medical history, physical examination, 12-lead ECG, vital signs, oxygen 
saturation (SpO2), respiratory rate, or clinical laboratory (including hematology, 
coagulation, clinical chemistry, urinalysis, and serology [Screening visit only]) at 
Screening visit and/or prior to the first study drug administration 
4.2. Exclusion Criteria 
1. Female who is pregnant according to the pregnancy test at Screening or prior to the first 
study drug administration 
2. Male subjects with a history of oligospermia or azoospermia or any other disorder of the 
reproductive system 
3. Male subjects who are undergoing treatment or investigation for infertility 
4. History of moderate or severe substance or alcohol use disorder (excluding nicotine and 
caffeine) within the past 2 years, as defined by the DSM-5 
5. History of any significant psychiatric disorder according to the criteria of the DSM-5 
which, in the opinion of the Investigator, could be detrimental to subject safety or could 
compromise study data interpretation.  
6. History of significant hypersensitivity to AZD4041, morphine and/or other opioids, 
naloxone, or any related products (including excipients of the study formulations) as well 
as severe hypersensitivity reactions (like angioedema) to any drugs 
7. History of any significant disease, including [but not necessarily limited to] significant 
hepatic, renal, cardiovascular, pulmonary, hematologic, neurological, psychiatric, 
gastrointestinal, endocrine, immunologic, ophthalmologic, or dermatologic disease of any 
etiology (including infections) identified at Screening 


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8. Presence or history of significant gastrointestinal, liver or kidney disease, or any other 
condition [including those that may result from surgery] that is known to interfere with 
drug absorption, distribution, metabolism, or excretion, or known to potentiate or 
predispose to undesired effects.  
9. Oxygen saturation (SpO2) below 95% at Screening or prior to first study drug 
administration 
10. Any abnormal vital signs, after no less than 5 minutes rest (supine position), as defined in 
the list below, at Screening and/or prior to the first study drug administration. Out of 
range test may be repeated once for each visit at the discretion of the Investigator.  
• Systolic BP < 90 mmHg or > 140 mmHg  
• Diastolic BP < 50 mmHg or > 90 mmHg  
• HR < 45 or > 90 beats per minute (bpm) 
11. 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, particularly in the protocol-defined primary 
lead, or left ventricular hypertrophy at Screening or prior to the first study drug 
administration (out of range test may be repeated once for each visit at the discretion of 
the Investigator) 
12. Prolonged QT interval corrected for HR using Fridericia’s formula (QTcF) > 450 ms at 
Screening or prior to first study drug administration 
13. Shortened QTcF < 340 ms at Screening or prior to first study drug administration 
14. Family history of long QT syndrome  
15. 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 preexcitation) at Screening or prior to first study drug 
administration.  
16. PR (PQ) interval prolongation (>220 ms), persistent or intermittent second (Wenckebach 
block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV 
dissociation at Screening or prior to first study drug administration.  
17. Persistent or intermittent complete bundle branch block, incomplete bundle branch block, 
or intraventricular conduction delay 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 ventricular hypertrophy or preexcitation at 
Screening or prior to first study drug administration. 
18. In the predose 24-hour telemetry, presence of ≥10 ventricular premature contractions 
(VPCs) during 1 hour, or ≥ 100 VPCs during 24 hours of 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. 


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19. Any clinically significant illness in the 28 days prior to the first study drug administration 
20. Heavy smoker (>20 cigarettes per day) and/or is unable to abstain from smoking or 
unable to abstain from the use of prohibited nicotine containing products for at least 
1 hour before and at least 6 hours after study drug administration (including e-cigarettes, 
pipes, cigars, chewing tobacco, nicotine topical patches, nicotine gum, or nicotine 
lozenges) 
21. Regularly consumes excessive amounts of caffeine or xanthines within 30 days prior to 
Screening, defined as greater than 6 servings (1 serving is approximately equivalent to 
120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day 
22. History of suicidal ideation within 1 year of Screening (score of 4 or 5 as per the 
C-SSRS) or any suicidal behavior (as per C-SSRS) within 2 years of Screening, or is 
currently at risk of suicide in the opinion of an Investigator 
23. Positive test result for alcohol and/or drugs of abuse upon admission on Day -2. Subjects 
with positive marijuana results at admission may be rescheduled at the discretion of an 
Investigator. If THC is positive at admission, a cannabis intoxication evaluation will be 
done by an Investigator and subjects may be permitted to continue in the study at the 
discretion of an Investigator. Other positive test results should be reviewed to determine 
if the subject may be rescheduled, in the opinion of an Investigator 
24. Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) 
or Hepatitis C Virus Antibody (HCVAb) 
25. Any other clinically significant abnormalities in laboratory test results at Screening that 
would, in the opinion of an Investigator, increase the subject's risk of participation, 
jeopardize complete participation in the study, or compromise interpretation of study data 
26. Treatment with an investigational drug within 30 days or 5 times the half-life (whichever 
is longer) prior to Screening 
27. Use of any prescription drugs (with the exception of hormone replacement therapy) in the 
14 days prior to the first study drug administration, that in the opinion of an Investigator 
would put into question the status of the participant as healthy 
28. Use of St. John’s wort in the 28 days prior to the first study drug administration 
29. Use of over-the-counter (OTC) products (including herbal preparations and supplements) 
within 7 days prior to the first study drug administration, with the exception of ibuprofen 
or acetaminophen 
30. Donation of plasma in the 7 days prior to the first study drug administration 
31. Donation of 1 unit of blood to American Red Cross or equivalent organization or 
donation of over 500 mL of blood in the 56 days prior to the first study drug 
administration 
32. Is, in the opinion of an Investigator or designee, considered unsuitable or unlikely to 
comply with the Study Protocol for any reason 


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33. Poor venous access at Screening, as judged by an Investigator 
34. Use of any prescribed or nonprescribed oral and topical inhibitors/inducers of CYP3A4 
(including shampoo) 
35. Is an AZ or study site employee or their close relatives 
4.3. Rescreening Criteria 
Subjects may be required to be rescreened as part of this study. Subject who are screen failures, 
due to transient exclusion criteria (ie, blood donations, consumption of products within last 
28 days, etc), may be rescreened at the discretion of the Investigator, in consultation with the 
Sponsor.  
A subject within the original screening window must meet all eligibility criteria with the 
following conditions: 
• All Day -2 and/or Day -1 procedures (Table 6-1) must be repeated, if already done 
• The subject will retain his/her original subject identification number  
A subject outside of the original screening window must repeat all screening procedures, meet all 
eligibility criteria, and have a new subject identification number issued. 
4.4. Withdrawal Criteria 
4.4.1. Before First Treatment Administration 
Before the first treatment administration, inclusion/exclusion criteria will govern the subjects to 
be dosed. If either the urine drug (except for THC) and alcohol screen or the naloxone challenge 
is positive, the subject will be excluded from the study. Subjects withdrawn before first treatment 
administration will not be followed up and will not undergo End-of-Study/Early Termination 
assessments. Other safety assessments may be performed if required. 
Subjects are free to withdraw their consent to participate in the study at any time, without 
prejudice. The reason for their withdrawal or for deciding to end their participation will be 
documented. 
4.4.2. After First Treatment Administration 
Subjects may, at any time, voluntarily withdraw from the study or be removed from the study at 
the discretion of an Investigator or Sponsor. An Investigator may withdraw a subject at any time 
for any (but not limited to) of the following reasons: if it is determined that continuing the study 
would result in a significant safety risk to the subject or if their behavior is deleterious to the 
study environment. If such withdrawal occurs, or if the subject fails to return for visits, an 
Investigator should determine the primary reason for a subject’s premature withdrawal from the 
study and record the reason in the subject’s study documents.  
In the case of a clinically significant illness detected during the trial (including COVID-19 
diagnosis), the Principal Investigator (or delegate) will, in consultation with the Medical Monitor 
and Sponsor Physician, determine the most appropriate course of action on an individual basis. 
Evaluations will include but are not limited to: 


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• The safety of the subject and other study participants 
• The possible effect the illness would have on the results gathered during the trial, and 
their ability to be appropriately analyzed or interpreted 
• The possibility of suspending participation then re-initiating it after recovery 
• The implication of any inclusion or exclusion criteria that would contradict possible 
actions 
• The implication of any adherence to regulatory guidelines that may be affected by actions 
decided; for example group effect analysis 
• The sample size calculation, current number of subjects, and possibility of replacement 
subjects 
Evaluations and decision-making for subject removal will be documented in the study file, 
reported to the Sponsor, and discussed where appropriate in the Clinical Study Report. 
Attempts should be made to have such subjects complete the End of Study/Early Termination 
assessments. End-of-Study/ET assessments should be performed as soon as possible after the last 
study treatment administration. 
For subjects lost to follow-up (ie, those subjects whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw), an Investigator should show 
"due diligence" by documenting in the source documents steps taken to contact the subject, 
eg, dates of telephone calls (at least 3), registered letters (at least 1), etc. 
 Stopping Rules 
4.4.2.1.1. Individual Subject Stopping Rules 
Participation in the clinical study may be discontinued by an Investigator (or delegate) in charge 
of the study or by the Sponsor for any of the following reasons, but not limited to: 
• AEs (including if a subject develops any significant illness or needs to undergo any major 
surgery during course of the study) 
• Subject non-compliance (including any violation of protocol requirements which may 
affect the study outcome) 
Subjects will be discontinued from the clinical study for any of the following reasons, but not 
limited to: 
• Total serum bilirubin > 2x upper limit of normal (ULN) 
• Aspartate aminotransferase (AST) > 3x ULN 
• Alanine aminotransferase (ALT) > 3x ULN 
• Creatinine > 1.5x ULN 
4.4.2.1.2. Trial Stopping Rules 
Clinical trial stopping rules: 


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• If 2 AZD4041-related (based on Investigator or Sponsor assessment) SAEs occur 
(Grade 3, 4, or 5) 
• Occurrence of 1 death attributable to the study treatment\ 
• At least 2 subjects who received 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 postdose either on 12-lead digital ECG (dECG) obtained 
during continuous 12-lead ECG monitoring or on a repeat 12-lead safety ECG  
• At least 2 subjects who received AZD4041 have tachycardia defined as resting supine 
HR > 125 beats per minute persisting for at least 10 minutes 
• At least 2 subjects who received 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 persisting for at least 10 minutes 
• At least 2 subjects who received AZD4041 develop hypertension defined as an increase 
in resting supine systolic BP > 40 mmHg and above 180 mmHg and persisting for at least 
10 minutes 
• At least 2 subjects who received AZD4041 develop hypotension defined as an 
asymptomatic fall in systolic BP > 20 mmHg and below 70 mmHg persisting for at least 
10 minutes, or a symptomatic fall in resting supine systolic BP > 20 mmHg (excluding 
vasovagal reaction or where the Investigator considers this to be most likely related to 
morphine administration) 
4.5. Lifestyle and/or Dietary Requirements 
• Subjects will be prohibited from consuming food or beverages containing grapefruit 
and/or pomelo for 7 days prior to the first dosing and during the study. 
• Subjects will be prohibited from consuming alcohol for 48 hours prior the first dosing 
and during the study. They will also be prohibited from recreational drug use from 
screening until the follow-up visit. In case of any doubt, a test for alcohol and/or a drug 
screen may be performed if requested by an Investigator. If a subject presents with a 
positive alcohol test or drug screen at any time after the screening visit, the subject may 
be rescheduled at the discretion of an Investigator. If THC is positive at check-in, a 
cannabis intoxication evaluation will be done by an Investigator, and inclusion will be at 
his or her discretion. 
• Subjects will be prohibited from consuming food or beverages containing xanthines 
(ie, tea, coffee, cola drinks, energy drinks or chocolate) for 48 hours prior to the first 
dosing and during the study. 
• Subjects will eat only the food provided by the study site during confinement at the CRU. 
• During the study, subjects who are smokers should not smoke more than 20 cigarettes per 
day. Subjects will abstain from smoking for 1 hour prior and until 6 hours after each drug 
administration. 


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x Subjects will be asked to refrain from driving, operating machinery, or engaging in 
hazardous activities until they and an investigator are convinced the study drug is not 
impairing their judgment and/or ability to perform skilled tasks. 
4.6. Concomitant Treatment 
The naloxone challenge will consist of an initial IV dose of 0.2 mg naloxone HCl. Subjects will 
be observed for signs or symptoms of opioid withdrawal. If there is no evidence of withdrawal 
within 1 minute (as assessed by a COWS score of <5), an additional intravenous dose of 0.6 mg 
naloxone HCl will be given, and subjects will be observed for signs and symptoms of withdrawal 
for 5 minutes (as assessed by COWS). Subjects who present symptoms of withdrawal during the 
qualification process will be excluded from the study and will not be eligible to enter the 
Treatment phase.  
Except for medication which may be required to treat AEs (eg, paracetamol/acetaminophen), no 
other treatment or medication other than the study drugs will be allowed from the first dosing 
until all study activities and evaluations have been completed.  
Subjects will be instructed to notify the study site about any new medications (eg, those required 
to treat AEs) taken after the start of the study treatment. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the subject has 
received the study treatment must be listed in the subject CRF. The drug name and dose taken 
will be noted. An investigator or delegate and/or the Sponsor will decide whether the subject will 
be permitted to remain in the study, depending on the drug used, the time of drug intake, etc. 
5. 
STUDY TREATMENTS 
5.1. Investigational Products 
The active IP will be provided by the Sponsor. The placebo will be provided by the CRU. 
5.1.1. AZD4041 
 and Placebo oral solution 
The AZD4041 active formulation and placebo are presented in Table 5-1. 
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Subjects who sign the ICF and are randomized but do not receive the study treatment may be 
replaced. Subjects who sign the ICF are randomized and receive the study treatment, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will generally not be 
replaced. However, consideration may be given to the replacement of such subjects in order to 
enable the completion of at least 36 subjects (n=24 randomized to Sequence 1 and n=12 
randomized to Sequence 2) to ensure that the scientific integrity of the study is maintained. 
Replacement of subjects will be at the discretion of the Principal Investigator in consultation and 
agreement with the Medical Monitor and Sponsor Physician. Any decision to replace subjects 
should not conflict with the pre-defined individual subject or study stopping rules, or otherwise 
jeopardise the safe conduct of the study. 
5.2.4. Blinding 
The randomization code will not be available to the personnel of the bioanalytical facility until 
the bioanalytical phase of the study has been completed. The treatment assignment will not be 
known by the study participants. 
Furthermore, the randomization code will not be available to the physician and clinical staff 
involved in the collection, monitoring, revision, or evaluation of AEs, as well as clinical staff 
who could have an impact on the outcome of the study, and including the pharmacokineticist (or 
delegate, until all the case report forms (CRFs) have been approved and signed and the 
bioanalytical phase of the study has been completed. 
The preparation and/or administration of the products will be done by designated personnel that 
are not directly involved in the clinical aspects of the trial. 
The randomization code must not be broken except in emergency situations where the 
identification of a subject’s study treatment is required by an Investigator for further treatment to 
the subject or to complete a SAE report. Randomization information will be held by designated 
individual(s). The date and reason for breaking the blind must be recorded. 
5.2.5. Study Drug Accountability 
Complete and accurate inventory records of all study drugs will be maintained. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. 
The labeling, storage conditions, quantity of reserve samples for the IP, and retention period of 
the reserve samples shall comply with the current Food and Drug Administration (FDA) rules 
and regulations. Drug accountability will be performed at the completion of the trial. 
5.3. Administration of Study Drug 
Study treatments as described in Section 3.2 will be administered in the morning. The date and 
time of each dose will be recorded. For each subject, Day 1 to Day 14 scheduled postdose 
activities and assessments will be performed relative to the time of AZD4041/placebo 
administration or end of morphine infusion. From Day 15, all scheduled postdose activities will 
be performed relative to the end of morphine infusion, with the exception of PK sampling for 
AZD4041. 


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On Day 1, a single intravenous infusion of morphine will be administered to the subjects over a 
10-minute interval (± 30 seconds) in the morning. 
On Days 2 to 15, an oral dose of the assigned treatment (either AZD4041 or Placebo) once daily 
will be administered to subjects using a syringe for 14 consecutive days. The dose will be 
administered directly into the subject’s mouth. 
On the morning of Day 15, the oral dose of the assigned treatment (either AZD4041 or Placebo) 
will be combined with a single intravenous infusion of morphine. A single intravenous infusion 
of morphine will be administered to the subjects over a 10-minute interval (± 30 seconds). The 
assigned treatment (AZD4041 or Placebo) will then be administered orally immediately (within 
1 minute) after the end of morphine infusion. 
The study drugs will be dispensed only to eligible subjects and administered under the 
supervision of study personnel. Treatment compliance will be verified according to the site’s 
standard operating procedures (SOPs). 
5.4. Meals 
Food intake will be controlled for the confinement period and for all subjects. 
Subjects will be required to fast at least 10 hours prior to start of morphine infusion on 
Days 1 to 15. 
On Days 1, 8, and 15, subjects will also be required to fast (abstain from food) for at least 
4 hours after dosing (after end of morphine infusion on Day 15). 
5.5. Fluids 
Fluid intake other than water will be controlled for each confinement period and for all subjects. 
On Days 1, 8, and 15, water will be permitted as needed except from at least 1 hour predose 
(prior to start of morphine infusion on Days 1 and 15) until 1 hour after dosing (after end of 
morphine infusion on Days 1 and 15). 
No water restriction will be implemented for the study drug administrations on Days 2 to 7, and 
Days 9 to 14. 
5.6. Other Protocol Restrictions 
On Days 1, 8 and 15, subjects will remain seated or kept in minimal ambulatory movement for 
the first 4 hours following study drug administration (after end of morphine infusion on Days 1 
and 15), avoiding both vigorous exertion and complete rest. On Days 2 to 7, and Days 9 to 14, 
subjects will remain seated or kept in minimal ambulatory movement for the first hour following 
study drug administration, avoiding both vigorous exertion and complete rest. However, should 
AEs occur at any time, subjects may be placed in an appropriate position. During these intervals, 
subjects will be permitted, under supervision, to get up (eg, to use the washroom facilities). 
Subjects will not engage in strenuous activity at any time during the confinement period. 
6. 
STUDY PROCEDURES 
An overview of the study activities for each participant is detailed in Table 6-1. 


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Version 2.0 (Amendment 01), 16-SEP-2022 
 
Page 39 of 95 
Unless otherwise stated in the protocol, the SOPs of the study facilities, which are available for 
all activities relevant to the quality of the study, will be followed during this study. When the 
nominal time for multiple events occurs simultaneously, the events will be staggered using their 
acceptable windows (acceptable windows for each assessment are specified in the following 
sections of this protocol), with priority given to those events related to primary study endpoints. 
Safety procedures will be carried out in the following order if scheduled at the same time: ECG 
recording> vital sign assessments, respiratory rate, SpO2, EtCO2> dECG extraction> PK 
sampling. 
Any deviation from protocol procedures should be noted in the source documentation and 
compiled for reporting in the Clinical Study Report. 
 










Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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6.1. Safety Assessments 
Safety assessments will include physical examination, neurological examination, vital signs 
(systolic and diastolic BP, HR, and oral temperature), 12-lead safety ECGs, 12-lead dECGs, 
ECG telemetry, C-SSRS questionnaires, clinical laboratory tests, EtCO2, SpO2, respiratory rate, 
and AE monitoring. At the discretion of an Investigator, additional safety assessments may be 
performed as needed to ensure subject safety. 
6.1.1. Medical History 
The medical history at Screening will include all queries by the medical and clinical staff related 
to the subject’s well-being and history of relevant past medical events/experiences. Medical 
history will include all demographic data (age, sex, race, body weight, height, and BMI) and 
baseline characteristics. Alcohol and smoking habits will also be recorded. 
6.1.2. Recreational Alcohol/Drug Use 
A lifetime history of all drug use, including alcohol, will be collected as scheduled in Table 6-1. 
For drug use (except alcohol), history, including drug preference (ie, drug of choice), frequency 
of use, and date of last use will be collected using reported drug names and drug class (eg, 
cannabinoids, depressants, dissociative anesthetics, hallucinogens, opioids and morphine 
derivatives, and stimulants). DSM-5 modules will be included as a part of the recreational 
drug/alcohol use history and used to screen for alcohol and substance use disorder. 
6.1.3. Physical Examination 
A physical examination will be performed by a medically qualified and licensed individual as 
outlined in Table 6-1. 
The physical examination will include a general review of the following body systems (at 
minimum): head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological (if a 
full neurological examination is not scheduled), and general appearance, unless a symptom-
oriented physical exam is indicated. 
A Sponsor-provided form will be used to facilitate a standardized approach to the physical 
examination (APPENDIX 11). 
6.1.4. Neurological Examination 
Neurological examination (assessments of basic mental status, cranial nerves, motor function, 
reflexes, sensation, proprioception, coordination, and gait) will be performed as scheduled in 
Table 6-1. 
A Sponsor-provided form will be used to facilitate a standardized approach to the physical 
examination (APPENDIX 12). 
6.1.5. Vital Signs 
Vital signs will be measured as outlined in Table 6-1 and specifically in Table 6-2.  


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
Page 45 of 95 
Table 6-2  Vital Sign Recording Schedule 
Vital Sign Recording - Scheduled Timepoints 
Screening 
Day -2 
Days 1: predose and 1, 2, 3, 4, 6, 8, and 12 hours postdose 
Days 2 to 14: predose, and 1 hour postdose 
Day 15: predose and 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours postdose 
Follow-up visit/ET 
Abbreviations: ET = Early Termination 
Vital signs will include BP, HR, and oral temperature (at Screening, Day -2, discharge, and 
Follow-up visit/Early Termination only).  
Vital signs will be taken while subjects are rested and supine for at least 5 minutes. 
The acceptable windows for vital sign assessments are presented in Table 6-3. 
Table 6-3 
Acceptable Windows for Vital Sign Assessments Procedures 
Elapsed Time  
Accepted Window 
Predose 
within 60 minutes 
> 0 hour and ≤ 24 hours 
± 30 minutes 
> 24 hours and ≤ 72 hours 
± 60 minutes 
 
6.1.6. 12-Lead Electrocardiogram 
 12-Lead Safety Electrocardiogram 
The 12-lead safety ECGs will be performed as outlined in Table 6-1 and specifically in 
Table 6-4. Additional safety ECGs may be performed at the Investigator’s discretion. The 
12-lead ECGs will be obtained after the subject has been resting in the supine position for at least 
10 minutes. All 12-lead ECGs will be evaluated for HR, and for PR, time elapsed between two 
successive R-waves of the QRS signal on the ECG (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 electronic CRF (eCRF), and the paper printouts will be 
stored at the site. The Investigator (or designee) will evaluate the printout of the 12-lead ECG in 
real time, and with particular attention to the effects of clinical importance on the PR, QRS, and 
QTcF intervals.  


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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Table 6-4 
Safety ECG Recording Schedule 
Safety ECG Recording - Scheduled Timepointsa  
Screening 
Day -2 
Days 1b: predose and 1, 2, 4, 6, and 12 hours postdose 
Days 2 to 14b: predose and 1 hour postdose 
Day 15b: predose and 1, 2, 4, 6, 12, 24, 48, and 72 hours postdose 
Follow-up visit/ET 
Abbreviations: ET = Early Termination 
a. Safety procedures will be carried out in the following order: ECG recording>Vital sign assessments>PK sampling 
b. Predose safety ECGs should be recorded within 60 minutes of the scheduled dosing time and BEFORE vital sign 
assessments and PK sampling. 
 
The acceptable windows for 12-lead safety ECG assessments are presented in Table 6-5. 
Table 6-5 
Acceptable Windows for 12-Lead Safety Electrocardiogram Assessments 
Procedures 
Elapsed Time  
Accepted Window 
Predose 
within 60 minutes 
> 0 hour and ≤ 24 hours 
± 30 minutes 
> 24 hours and ≤ 72 hours 
± 60 minutes 
 Electronic Capture of 12-lead Continuous Digital Electrocardiogram 
The AZ ECG Center will perform the dECG analysis, using the EClysis© system, version 4.0, or 
higher. Lead V2 will be used as the primary analysis lead, with lead V5 as the primary backup 
lead and lead II as the secondary back-up lead, for all time points when lead V2 is found to be 
unsuitable for analysis. 
At clinical study protocol-indicated time points in Table 6-6, 12-lead continuous dECG files will 
be recorded using the 12-lead Mortara Holter equipment (H12+) according to AZ ECG Center’s 
standard procedures for settings/configuration, recording and transfer of dECGs. The 12-lead 
Holter memory cards will be sent to the AZ ECG Center with an agreed courier. 
It is to be noted that the 12-lead Holter recordings will serve multiple purposes. It will be the source 
for 12-lead dECG extractions. In addition to providing 12-lead dECG extractions, the recordings will 
be used for prolonged arrhythmia monitoring as part of the safety data collection (these data will be 
analyzed at a later stage and will not be available for the bedside safety monitoring at site). The 
first ECG recording with Holter device starts on Day -1 (approximately 24 hours before dosing) 
and continues to 72 hours postdose (Day 4). On Day 8, recording will start at least 1 hour before 
dosing and continue to 24 hours postdose. On Day 15, recording will start at least 1 hour before 
dosing and continue to 72 hours postdose (Day 18). Specific extraction times for dECG are 
presented in Table 6-6. 
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 Holter equipment, at the start of each study 


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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day and aligned with an official timekeeper. The metadata of each file will be checked by the 
responsible personnel at the study site to ensure that the cards sent to the AZ central dECG files 
repository have correct metadata. 
Skin preparation must be thorough and electrode positions must be according to standard 12-lead 
ECG placement. 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. Electrode positions 
for dECG take precedence over those for telemetry. Subjects will rest in a supine position for at 
least 5 to 10 minutes before the start of each recording. A shorter resting period (at least 
5 minutes) may be done in certain cases, depending on competing procedures in the study.  
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. 
From the continuous dECG files received at the AZ ECG Centre, the EClysis© system will 
extract continuous files of at least 5 minutes length at clinical study protocol-indicated time 
points in Table 6-6. The extraction window can be adjusted by the responsible ECG Scientific 
Advisor during the Metadata approval procedure, based on the ‘Clinical Logs’ received from the 
site. As standard, from each dECG extracted window, 10-second ECGs will then be extracted by 
the EClysis© system twice per minute and automatically analyzed by the software. The ECG 
Scientific Advisor will perform all necessary manual corrections of the ECG annotations 
provided automatically by EClysis©. All dECGs from 1 subject will be analyzed by a single 
reader in a blinded manner. 
The AZ ECG Centre Cardiologist will finally review all data and perform all necessary 
adjustments before locking the data into a read-only state. From the locked data, the numerical 
values for the ECG intervals and amplitudes will then be made accessible on a secure file share 
of the AZ dECG central repository to accredited Data Management specialists for conversion 
into SAS® files. 
The following dECG variables will be reported by the AZ ECG Centre: RR, PR, QRS, and QT 
intervals from the lead, defined as the primary analysis lead, as well as potential T-wave 
morphology changes. 
Derived parameters (QTcF, HR, and others, as applicable) are calculated by the study statistician 
or delegate. 
Table 6-6 
Digital Electrocardiogram Schedule  
Study 
Day 
Visit 
Number 
ECG 
Number 
Time:  
Start of the 
Extraction 
Window,  
Hour:Mina,b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Min 
dECG 
Continuous c, d, e 
Otherf 
1 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
1 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
1 
2 
1 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
 
1 
2 
 
00:00 
IP 
administration 
 
 
 


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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Study 
Day 
Visit 
Number 
ECG 
Number 
Time:  
Start of the 
Extraction 
Window,  
Hour:Mina,b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Min 
dECG 
Continuous c, d, e 
Otherf 
1 
2 
2 
00:25 
 
00:30 
5 min 
 
1 
2 
3 
00:55 
 
01:00 
5 min 
 
1 
2 
4 
01:55 
 
02:00 
5 min 
 
1 
2 
5 
03:55 
 
04:00 
5 min 
 
1 
2 
6 
05:55 
 
06:00 
5 min 
 
1 
2 
7 
07:55 
 
08:00 
5 min 
 
1 
2 
8 
11:55 
 
12:00 
5 min 
 
2 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
2 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
2 
2 
9 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 2 
2 
2 
 
00:00 
IP 
administration 
 
 
 
2 
2 
10 
00:25 
 
00:30 
5 min 
 
2 
2 
11 
00:55 
 
01:00 
5 min 
 
2 
2 
12 
01:55 
 
02:00 
5 min 
 
2 
2 
13 
03:55 
 
04:00 
5 min 
 
2 
2 
14 
05:55 
 
06:00 
5 min 
 
2 
2 
15 
07:55 
 
08:00 
5 min 
 
2 
2 
16 
11:55 
 
12:00 
5 min 
 
3 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
3 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
3 
2 
17 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 3 
3 
2 
 
00:00 
IP 
administration 
 
 
 
3 
2 
18 
03:55 
 
04:00 
5 min 
 
3 
2 
19 
11:55 
 
12:00 
5 min 
 
4 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
4 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
4 
2 
20 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 4 
4 
2 
 
00:00 
IP 
administration 
 
 
 
4 
2 
21 
03:55 
 
04:00 
5 min 
 
5 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
5 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
5 
2 
22 
-01:00 (within 60 
min prior to 
Predose 
-00:50 
10 min 
Predose Day 5 


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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Study 
Day 
Visit 
Number 
ECG 
Number 
Time:  
Start of the 
Extraction 
Window,  
Hour:Mina,b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Min 
dECG 
Continuous c, d, e 
Otherf 
dosing) 
5 
2 
 
00:00 
IP 
administration 
 
 
 
5 
2 
23 
3:55 
 
04:00 
5 min 
 
6 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
6 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
6 
2 
24 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 6 
6 
2 
 
00:00 
IP 
administration 
 
 
 
7 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
7 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
7 
2 
25 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 7 
7 
2 
 
00:00 
IP 
administration 
 
 
 
8 
2 
 
-02:00 
 
 
-01:30 
 
 
Apply electrodes 
8 
2 
 
-01:10 
 
 
-01:00 
 
 
Rest in bed d 
8 
2 
26 
-01:00 (within 
60 min prior to 
dosing) 
 
Predose 
 
-00:50 
 
10 min 
 
Predose Day 8 
8 
2 
 
00:00 
IP 
administration 
 
 
 
8 
2 
27 
00:55 
 
01:00 
5 min 
 
8 
2 
28 
03:55 
 
04:00 
5 min 
 
 
8 
2 
29 
05:55 
 
06:00 
5 min 
 
8 
2 
30 
07:55 
 
08:00 
5 min 
 
8 
2 
31 
11:55 
 
12:00 
5 min 
 
9 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
9 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
9 
2 
32 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 9 
9 
2 
 
00:00 
IP 
administration 
 
 
 
10 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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Study 
Day 
Visit 
Number 
ECG 
Number 
Time:  
Start of the 
Extraction 
Window,  
Hour:Mina,b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Min 
dECG 
Continuous c, d, e 
Otherf 
10 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
10 
2 
33 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 10 
10 
2 
 
00:00 
IP 
administration 
 
 
 
11 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
11 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
11 
2 
34 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 11 
11 
2 
 
00:00 
IP 
administration 
 
 
 
11 
2 
35 
03:55 
 
04:00 
5 min 
 
12 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
12 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
12 
2 
36 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 12 
12 
2 
 
00:00 
IP 
administration 
 
 
 
13 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
13 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
13 
2 
37 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 13 
13 
2 
 
00:00 
IP 
administration 
 
 
 
13 
2 
38 
03:55 
 
04:00 
5 min 
 
14 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
14 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
14 
2 
39 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 14 
14 
2 
 
00:00 
IP 
administration 
 
 
 
15 
2 
 
-02:00 
 
-01:30 
 
Apply electrodes 
15 
2 
 
-01:10 
 
-01:00 
 
Rest in bed d 
15 
2 
40 
-01:00 (within 
60 min prior to 
dosing) 
Predose 
-00:50 
10 min 
Predose Day 15 
15 
2 
 
00:00 
IP 
 
 
 


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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Study 
Day 
Visit 
Number 
ECG 
Number 
Time:  
Start of the 
Extraction 
Window,  
Hour:Mina,b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Min 
dECG 
Continuous c, d, e 
Otherf 
administration 
15 
2 
41 
00:25 
 
00:30 
5 min 
 
15 
2 
42 
00:55 
 
01:00 
5 min 
 
15 
2 
43 
01:55 
 
02:00 
5 min 
 
15 
2 
44 
03:55 
 
04:00 
5 min 
 
15 
2 
45 
05:55 
 
06:00 
5 min 
 
15 
2 
46 
07:55 
 
08:00 
5 min 
 
15 
2 
47 
11:55 
 
12:00 
5 min 
 
16 
2 
48 
23:55 
 
24:00 
5 min 
 
16 
2 
49 
35:55 
 
36:00 
5 min 
 
17 
2 
50 
47:55 
 
48:00 
5 min 
 
18 
2 
51 
71:55 
 
72:00 
5 min 
 
a. 
Time points for dECG may be adjusted according to emerging PK data. 
b. Subjects must be in the same supine body position (maximum 30 degrees flexion in the hip) at each time point 
and at all visits with feet out of contact with footboard. 
c. 
Skin must be cleaned and electrode positions marked with an indelible pen. Electrodes should be applied at least 
30 minutes before the first recording. 
d. The subjects must rest in bed (supine position) for at least 10 minutes prior to each dECG time point. A shorter 
resting period (at least 5 minutes) may be done in certain cases, depending on competing procedures in the 
study. 
e. 
The subject must remain awake. 
f. 
In some cases (when continuous monitoring is being performed), re-application of electrodes would not always 
be necessary. Electrodes are checked for contact and replaced if needed. 
Abbreviations: dECG = digital electrocardiogram, ECG = electrocardiogram; IP = investigational product; 
min = minute; PK: pharmacokinetic. 
Note: On Day 1 and Day 15, predose time points are relative to start of morphine infusion and postdose time points 
are relative to end of morphine infusion. 
Table 6-7 
Window Allowance for dECG time points 
Procedure 
Time Point 
Tolerance 
Window 
Notes 
Days 1 
Predose 
- 60 min to 0 h 
Within max 1h predose. Start of dECG Extraction 
time window should occur at 5-7 min prior to 
nominal PK sampling timepoint. Subject should 
have been awake for at least 1h prior to dECG 
baseline in studies where ECG/QT are important 
Days 2-15 
Predose 
- 60 min to 0 h 
Within max 1h predose. Start of dECG Extraction 
time window should occur at 5-7 min prior to 
nominal PK sampling timepoint. N.B. dECG 
should always be sampled immediately before 
supine vital PK draw. 


Protocol No: D7460C00003  
 
Altasciences Project No: AZN-P1-265 
 
Version 2.0 (Amendment 01), 16-SEP-2022 
 
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Procedure 
Time Point 
Tolerance 
Window 
Notes 
Days 1-15 
Up to 12 h postdose 
- 15 to + 15 min 
Start of dECG Extraction time window should 
occur at 5-7 min prior to nominal PK sampling 
timepoint ±15 min. N.B. dECG should always be 
sampled immediately before supine vital PK draw 
Day 2 
24 h postdose 
- 60 to + 60 min 
Start of dECG Extraction time window should 
occur at 5-7 min prior to nominal PK sampling 
timepoint ±60 min. N.B. dECG should always be 
sampled immediately before supine vital PK draw 
Day 16 
24 and 36h postdose 
- 60 to + 60 min 
Start of dECG Extraction time window should 
occur at 5-7 min prior to nominal PK sampling 
timepoint ±60 min. N.B. dECG should always be 
sampled immediately before supine vital PK draw 
Days 17 and 18 
48 and 72h postdose 
 
- 2h to + 2h 
 
Start of dECG Extraction time window should 
occur at 5-7 min prior to nominal PK sampling 
timepoint ±2h. N.B. dECG should always be 
sampled immediately before supine vital PK draw 
Notes: 
Start of dECG Extraction time window should occur at 5-7 min prior to nominal PK sampling time point. ECG 
needs to be closely coordinated with PK in ECG critical studies to maintain precision for analysis, or modelling, so 
the deviation from nominal time tolerance window for PK sets the frame also for dECG  
N.B. dECG should always be sampled immediately before supine vitals, followed by PK blood draw. Other, less 
rest dependent pharmacodynamic measurements follow immediately after the PK draw  
The tolerances for dECG reporting in this document represent those used in the clinic when ensuring the subject is 
prepared for the start of dECG Extraction time window.  
Time window deviations for actual dECG results will be calculated and provided by the AstraZeneca ECG center 
during analysis as these will relate to the time of extraction of each ECG. This information will not be available in 
the study database. 
6.1.7. ECG Telemetry  
Subjects will be monitored by telemetry as outlined in Table 6-1. To allow a real-time 
assessment of cardiac safety (HR, rhythm, and ECG morphology) at the CRU, subjects will be 
monitored at least by 2-lead telemetry. Telemetry monitoring will be performed on Day -1 
(starting approximately 24 hours before the start of morphine IV infusion) until 72 hours after 
the end of morphine IV infusion (Day 4), on Day 7 at least 30 minutes prior to AZD4041 or 
placebo dosing until 48 hours post Day 7 dose (Day 9), and on Day 15 at least 30 minutes before 
the start of morphine IV infusion and until 72 hours after the end of morphine IV infusion 
(Day 18). Any clinically significant change noted on telemetry will be followed up with a 
12‑lead safety ECG. Further evaluation including any treatment will be performed as deemed 
appropriate by the Investigator. Any finding of short, self-limiting, asymptomatic arrhythmia (eg, 
non‑significant supraventricular tachycardia, atrial fibrillation or flutter, ventricular 
extrasystoles, ventricular tachycardia), should be documented and further evaluated in the 
context of the individual subject’s history and clinical status. Irrespective of the intervention, 


Protocol No: D7460C00003  
 
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Version 2.0 (Amendment 01), 16-SEP-2022 
 
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cardiac monitoring will be continued until an observed event resolves or the subject is deemed 
clinically stable by the Investigator. 
6.1.8. Continuous and Spot Oxygen Saturation 
Assessments will include continuous and spot SpO2 monitoring, as scheduled in Table 6-1. 
Continuous and spot SpO2 will be monitored using a capnography monitor except for the spot 
SpO2 at Screening, Day -2, and Follow-up visit/ET which will use a portable pulse oximeter 
placed on the subjects’ fingertip. SpO2 will be continuously monitored for alarms from at least 
1 hour prior to each study drug administration (prior to start of morphine IV infusion on Day 1 
and Day 15) and will continue for up to 6 hours following each study drug administration (after 
the end of morphine IV infusion on Day 1 and Day 15), or longer if deemed medically necessary. 
Spot SpO2 will be documented as scheduled in Table 6-8. Baseline SpO2 will be determined at 
6 timepoints predose on Day 1. The baseline value will be determined by averaging the 
6 readings.  
Table 6-8 
Spot Oxygen Saturation Recording Schedule 
Spot Oxygen Saturation Recording - Scheduled Timepoints 
Screening 
Day -2 
Day 1: predose (at -60, -50, -40, -30, -20, and -10 minutes) and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 
and 12 postdose 
Days 2 to 7: predose  
Day 8: predose and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose 
Days 9 to 14: predose  
Day 15: predose and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
Follow-up visit/ET 
Abbreviation: ET = Early Termination 
Note: On Day 1 and Day 15, predose time points are relative to start of morphine infusion and postdose time points 
are relative to end of morphine infusion.  
The acceptable windows for spot SpO2 recording are presented in Table 6-9. 
Table 6-9 
Acceptable Windows for SpO2 Assessments Procedures 
Elapsed Time  
Accepted Window 
≥ -1 hour and < 1 hour 
± 10 minutes 
≥ 1 hour and ≤ 24 hours 
± 30 minutes 
6.1.9. Continuous and Spot End-Tidal Carbon Dioxide 
End-tidal carbon dioxide (EtCO2) will be monitored and measured using a standardized 
methodology and configuration using MICROSREAMTM consumables to sample gas via nasal 
cannulae and the CAPNOSTREAMTM20P bedside monitor according to Altasciences SOP on 
Capnography (CLS-5105-00, September 1st 2020). Using this configuration, for the 
spontaneously breathing healthy volunteer subject, baseline EtCO2 measurements can be 


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expected to fall within the range 34-48 mmHg. Measurement of EtCO2 has been applied 
successfully in the setting of clinical pharmacology studies for the evaluation of respiratory 
function (Viscusi et al, 2021). Historical data sets generated at the Altasciences clinical unit have 
recorded EtCO2 values with acceptable variability in relatively small cohorts of healthy volunteer 
subjects. For example, in a cohort of N=8 subjects, mean baseline EtCO2 was found to be 36.6 
mmHg with SD 2.2 mmHg. In another cohort of N=15 subjects, mean baseline EtCO2 was found 
to be 36.1 mmHg with SD 3.88 mmHg. 
Assessments will include continuous and spot EtCO2 through a capnography monitor, as 
scheduled in Table 6-1. EtCO2 will be monitored continuously for alarms at least 1 hour prior to 
each study drug administration (prior to start of morphine IV infusion on Day 1 and Day 15) and 
will continue for up to 6 hours following each study drug administration (after the end of 
morphine IV infusion on Day 1 and Day 15), or longer if deemed medically necessary. Spot 
EtCO2 will be recorded as scheduled in Table 6-10. Baseline EtCO2 will be determined at 6 time 
points predose on Day 1. The baseline value will be determined by averaging the 6 readings.  
Table 6-10 
Spot End-Tidal CO2 Recording Schedule 
Spot End-Tidal CO2 Recording - Scheduled Timepoints 
Day 1: predose (at -60, -50, -40, -30, -20, and -10 minutes) and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8 
and 12 postdose 
Days 2 to 7: predose  
Day 8: predose and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8 and 12  hours postdose 
Days 9 to 14: predose 
Day 15: predose and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours postdose 
Note: On Day 1 and Day 15, predose time points are relative to start of morphine infusion and postdose time points 
are relative to end of morphine infusion.  
The acceptable windows for EtCO2 assessments are presented in Table 6-11. 
Table 6-11 
Acceptable Windows for EtCO2 Assessments Procedures 
Elapsed Time  
Accepted Window 
≥ -1 hour and < 1 hour 
± 10 minutes 
≥ 1 hour and ≤ 24 hours 
± 30 minutes 
 
6.1.10. 
Continuous and Spot Respiratory Rate 
Assessments will include continuous and spot respiratory rate as scheduled in Table 6-1. 
Continuous and spot respiratory rate will be monitored/measured using a capnography monitor 
except at Screening, Day -2, and Follow-up visit/ET where it will be measured by counting the 
number of breaths per minute. Respiratory rate will be continuously monitored for alarms from 
at least 1 hour prior to each study drug administration (prior to start of morphine IV infusion on 
Day 1 and Day 15) and will continue for up to 6 hours following each study drug administration 
(after the end of morphine IV infusion on Day 1 and Day 15), or longer if deemed medically 
necessary. Spot respiratory rate will be measured as scheduled in Table 6-12. Baseline 


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respiratory rate will be determined at 6 timepoints predose on Day 1. The baseline value will be 
determined by averaging the 6 readings.  
Table 6-12 
Spot Respiratory Rate Recording Schedule 
Spot Respiratory rate Recording - Scheduled Timepoints 
Screening 
Day -2 
Day 1: predose (at -60, -50, -40, -30, -20, and -10 minutes) and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8 
and 12 postdose 
Days 2 to 7: predose  
Day 8: predose (within 60 minutes) and 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8 and 12  hours postdose 
Days 9 to 14: predose 
Day 15: predose (within 60 minutes) and15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours 
postdose 
Follow-up visit/ET 
Abbreviation: ET = Early Termination 
Note: On Day 1 and Day 15, predose time points are relative to start of morphine infusion and postdose time points 
are relative to end of morphine infusion.  
The acceptable windows for respiratory rate assessments are presented in Table 6-11. 
Table 6-13 
Acceptable Windows for Respiratory Rate Assessments Procedures 
Elapsed Time  
Accepted Window 
≥ -1 hour and < 1 hour 
± 10 minutes 
≥ 1 hour and ≤ 24 hours 
± 30 minutes 
 
6.1.11. 
Laboratory Evaluations 
Laboratory evaluations will be performed as outlined in Table 6-1. 
The laboratory evaluations to be conducted for this study are presented in APPENDIX 6. 
Additional clinical laboratory tests may be performed by the medical laboratory as part of larger 
standard test panels (not required for subject safety). 
The Investigator or delegate will assess each abnormal value to determine if it is clinically 
significant. Postdose clinically significant laboratory values will be reported as AEs, if 
applicable, as judged by the Investigator or delegate. 
Only test results required by the Protocol and/or abnormal results will be entered in the clinical 
database and reported in the Clinical Study Report, based on report requirement. 
6.1.12. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire designed for the assessment of suicidal ideation and behaviour in 
adolescents and adults. 


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The C-SSRS will assess suicidality over the month preceding Screening as well as over the 
subject’s lifetime. At Screening, the “Baseline/Screening” version of the scale will be used, and 
at subsequent visits the “Since Last Visit” version of the scale will be used. Versions of the 
instrument relevant to the subject’s native language (ie, English) should be used. C-SSRS 
evaluations will be undertaken at the timepoints indicated in Table 6-1. 
The questionnaire must be administered by an Investigator or other individual that is suitably 
qualified by education or training. See APPENDIX 7 for a sample C-SSRS –Baseline/Screening 
version assessment and APPENDIX 8 for a sample C-SSRS-Since Last Visit version assessment. 
If there is a positive result for suicidality on the C-SSRS after Screening (defined by a subject 
answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the C-SSRS), the subject 
will be evaluated by an Investigator or medically qualified Sub-investigator for continuation in 
the study. 
If a subject becomes suicidal during the study, an Investigator should provide the appropriate 
treatment to the subject. 
6.1.13. 
Clinical Opioid Withdrawal Scale (COWS) 
The naloxone HCl challenge will be conducted as indicated in Table 6-1 for eligible subjects. 
Clinical Opioid Withdrawal Scale is a clinician-administered, pen and paper instrument that rates 
11 common opiate withdrawal signs or symptoms. The summed score of the eleven items can be 
used to assess a subject’s level of opiate withdrawal and to make inferences about their level of 
physical dependence on opioids (Wesson and Ling, 2003). The scale must be administered by an 
Investigator or other individual that is suitably qualified by education or training. See 
APPENDIX 9 for a sample of COWS. 
6.1.14. 
Assessment of Respiratory Depression 
Capnography alarms will be set to evaluate for respiratory depression and will include: 
• An increase in EtCO2 of at least 10 mmHg compared to baseline or >50 mmHg, 
whichever value is the lowest 
• A reduction in O2 saturation to <92% 
• A reduction in respiratory rate to <6 breaths per minute 
All alarms will be assessed for clinical significance and reported as AEs, as applicable. 
Supplemental oxygen will be given as medically necessary. Events will be timed using a 
stopwatch or equivalent to confirm clinical relevance. Interventions used to treat respiratory 
depression will be documented. 
6.1.15. 
Medical Interventions for Signs of Respiratory Depression 
In the event that subjects show signs and symptoms of respiratory depression, the Investigator or 
study staff will begin intervention procedures that may escalate in the degree of intervention as 
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• Verbal stimuli: Call the subject’s name loudly. If no response and/or no improvement in 
respiratory depression, proceed to physical stimuli. 
• Physical stimuli: Apply sternal rub to subject and/or apply nail bed pressure. If subject is 
unable to be aroused and/or there is no improvement in signs of respiratory depression, 
proceed to O2 administration and prepare for possible naloxone administration (if there is 
no improvement with verbal or physical stimuli, there is a high likelihood of requiring 
naloxone administration). 
• O2 administration: Administer oxygen with a target SpO2 of 95-100%. Prepare naloxone 
for administration if no improvement in respiratory depression clinical parameters or as 
per Investigator discretion. 
• Naloxone administration: Administer naloxone (eg, 4 mg/spray IN every 2-3 minutes; 0.4 
mg IV every 2-3 minutes to a maximum of 10 mg) and titrate until adequate 
oxygenation/ventilation is achieved. 
The Investigator or designee will choose the appropriate level of intervention as deemed 
medically necessary. Subjects who receive intervention will be evaluated to determine if further 
intervention (eg, hospitalization) is warranted. Subjects who show significant signs of respiratory 
depression that requires naloxone administration or poses significant safety concerns may be 
withdrawn from the study at the discretion of the Investigator or designee. 
6.1.16. 
Rescue Therapy 
The clinical study site is equipped with emergency equipment and supplies that correspond with 
the level of risk associated with this study. In case of a medical emergency or an SAE requiring 
medical intervention, emergency equipment and supplies will be available and will include, but 
may not be limited to, stocked crash carts, oxygen source, suction pump, and defibrillator. 
Emergency medication (eg, naloxone) or rescue medication required for advanced cardiac life 
support may be administered if deemed necessary by an Investigator or designee. If required, 
subjects will be transported to a hospital. 
During the Qualification and Treatment periods, the PI or designee will be on-site at the time of 
study drug administration until at least 6 hours postdose. Advanced cardiac life support-certified 
staff will be present on site and an Investigator will be readily available by telephone. 
When not available on-site, the PI or designee will be on-call until the end of the study. While 
confined in the CRU, subjects will be supervised by staff nurses and/or paramedics. Dedicated 
nurses and/or paramedics will be available to monitor AEs and perform safety measures. The 
date and time of rescue medication administration as well as the name and dosage regimen of the 
rescue medication will be recorded. 
6.2. Pharmacokinetic Assessments 
6.2.1. Pharmacokinetic Blood Sampling  
The complete blood sampling schedule for morphine and its metabolites is presented in 
Table 6-14. The complete blood sampling schedule for AZD4041 is presented in Table 6-15. 


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Table 6-14 
Pharmacokinetic Blood Sampling Schedule for Morphine and its 
Metabolites 
Pharmacokinetic Blood Sampling - Scheduled Timepointsa 
Day 1: predose, 5, 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose 
Day 15: predose, 5, 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose 
a 
Predose is relative to the start of morphine intravenous infusion. Nominal times listed are relative to the end of 
morphine intravenous infusion. 
Table 6-15 
Pharmacokinetic Blood Sampling Schedule for AZD4041 
Pharmacokinetic Blood Sampling - Scheduled Timepointsa 
Days 2 to 7: predose 
Day 8: predose, 5, 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose 
Days 9 to 14: predose 
Day 15: predose, 5, 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose 
a. 
Nominal times listed are relative to the time of AZD4041 administration. 
Blood samples will be collected by direct venipuncture into a labeled tube containing the 
appropriate anticoagulant as specified by the bioanalytical facility. As an option to the subject or 
if judged necessary by the clinical staff, blood samples may be collected from an indwelling 
cannula which will be placed in the vein of the subject. 
The actual time of all PK blood draws will be recorded and reported for all subjects. 
Windows for timed PK blood sample collections are presented in Table 6-16. PK samples 
collected outside of the pre-specified windows will be documented as protocol deviations. Since 
actual times are to be used for the PK analysis, deviations will be reflected in the analysis unless 
indicated otherwise upon review of the data. 
Table 6-16 
Acceptable Windows for Timed PK Blood Specimen Collection 
Procedures 
Elapsed Time  
Accepted Window 
Predose 
within 5 minutesa 
> 0 hour to ≤ 30 minutes 
± 1 minute 
> 30 minutes to ≤ 4 hours 
± 2 minutes 
> 4 hours to ≤ 12 hours 
± 5 minutes 
> 12 hours to ≤ 24 hours 
± 10 minutes 
> 24 hours to 72 hours 
± 2 hours 
a. On Day 1 and Day 2, the accepted window can be increased to within 60 minutes. 
AZD4041, morphine, morphine-6-glucuronide, and morphine-3-glucuronide concentrations for 
PK assessments will be obtained through bioanalysis of the plasma derived from the blood 
samples drawn during this study, using validated bioanalytical methods. 


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6.2.2. Pharmacokinetic Urine Sampling 
The complete urine sampling schedules are presented in Table 6-17 for AZD4041. 
Table 6-17 
Pharmacokinetic Urine Sampling Schedule for AZD4041 
Pharmacokinetic Urine Sampling - Scheduled Timepointsa 
Day 15 
Predose spot collection, 0-6 hours, 6-12 hours, 12-24 hours, 24-48 hours, and 
48-72 hours postdose 
a. 
Urine will be collected at the specified intervals (-60 minutes for predose spot collection and ±20 minutes for 
postdose spot collections) 
AZD4041 concentrations for PK assessments will be obtained through bioanalysis of the urine 
collected during this study, using a validated bioanalytical method.  
6.2.3. Pharmacokinetic Sample Processing, Storage and Shipping 
Blood and urine samples for PK determination will be processed, stored, and shipped according 
to the sample processing instructions supplied by the bioanalytical facility.  
7. 
ADVERSE EVENTS DOCUMENTATION 
7.1. Definitions 
An AE is defined as any untoward medical occurrence in a subject administered an IP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal clinical laboratory 
finding, for example), symptom, or disease temporally associated with the use of an IP, whether 
or not related to the IP. 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility the 
drug caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the AE. A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any AE caused by a drug. 
An AE may be: 
• A new illness, 
• Worsening of a concomitant illness, 
• An effect of the study drug including comparator; it could be an abnormal clinical 
laboratory value as well as a significant shift from baseline within normal range which an 
Investigator considers to be clinically important. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 
A SAE or reaction is any untoward medical occurrence that at any dose: 


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• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions), 
• Is a congenital anomaly or birth defect, 
• Is an important medical event (including development of drug dependence or drug abuse) 
that may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above (according to medical judgment of an Investigator) 
An AE of special interest (AESI: serious or non-serious) is one of scientific and medical concern 
specific to the Sponsor’s drug product, for which ongoing monitoring and rapid communication 
by the Investigator to the Sponsor may be appropriate. An AESI is a noteworthy event for the 
particular product or class of products that a Sponsor may want to monitor carefully. It could be 
serious or non-serious (eg, hair loss, loss of taste, impotence), and could include events that 
might be potential precursors or prodromes for more serious medical conditions in susceptible 
individuals. Such events may require further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the Sponsor to 
other parties (eg, regulatory authorities) might also be warranted. 
The following AESI(s) has been specified for the study intervention(s) in this protocol: 
• Cardiac arrhythmia (including NSVT) 
Non-serious AESIs are to be recorded in electronic data capture (EDC) within 72 hours, and 
serious AESIs are to be reported to the sponsor within 24 hours. 
7.2. Severity Assessment 
All AEs will be graded per the current National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI-CTCAE). 
Every effort will be made to obtain an adequate evaluation of the severity. 


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7.3. Causality Assessment 
An Investigator will determine the relationship of any AE to the study drug using the guidelines 
presented in Table 7-1. 
Table 7-1 
Adverse Event Relationship to Study Drug 
Relationship to Drug 
Comment 
Reasonable Possibility 
A temporal relationship exists between the AE onset and 
administration of the IP that cannot be readily explained by the 
subject’s clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be 
related, based on the known therapeutic and pharmacologic actions or 
AE profile of the IP. 
In case of cessation or reduction of the dose the AE may abate or 
resolve and it may reappear upon rechallenge. 
No Reasonable Possibility 
Evidence exists that the AE has an etiology other than the IP. 
For SAEs, an alternative causality must be provided (eg, preexisting 
condition, underlying disease, intercurrent illness, or concomitant 
medication). 
AE = adverse event; IP = investigational product; SAE = serious adverse event 
7.4. Adverse Event Monitoring 
For the purposes of this study, the monitoring period for AEs extends from the pre-trial 
evaluation until the follow-up visit. Registration of new AEs will start from the moment of ICF 
signature and will stop 7 days after the last study drug administration (ie, stop registration on 
new AEs on follow-up visit in case last AZD4041 dose was administered on Day 15).  
Subjects will be questioned on their health status from the beginning of the study, before 
departure from the clinical site, and at the follow-up visit. Open-ended questions will be asked. 
During the study, all AEs reported by the subject, observed by the clinical staff, or elicited by 
general questioning will be recorded for all subjects and reported in the CRF.  
From the signing of the ICF until the first study drug administration, AEs will be recorded as 
screening events or as part of on the medical history eCRF page, as applicable. AEs occurring 
after study drug administration will be recorded on AE eCRF page and indicated as TEAEs in 
the Clinical Study Report, as well as non-serious AESI (defined in Section 7.1). 
Any AE which remains unresolved as of the last study visit will require an evaluation and 
follow-up until the AE has been resolved, stabilized or a reasonable explanation for its 
persistence found, or is deemed mild and safely resolving. 
In the case of AEs deemed related to the IP, every effort will be made to determine the final 
outcome. 
If necessary, every effort will be made to obtain an adequate follow-up of the subjects. Should 
any subject choose to withdraw from the study, they will be advised of the safety precautions to 
be taken. For those subjects whose status is unclear because they fail to appear for study visits 






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8.1.3. Completer Population 
The Completer Population will include all subjects in the Safety Population who complete the 
entire Treatment phase and the follow-up period (up to at least Day 22). This population will be 
used for inferential analysis of maximum postdose increase in EtCO2 (Emax (postdose – predose)), 
maximum postdose reduction in SpO2 (Emax (predose – postdose)), and maximum postdose decrease in 
respiratory rate (Emax (predose – postdose)). 
8.1.4. Pharmacokinetic Population 
All subjects in the Safety Population who receive at least 1 dose of morphine or AZD4041 and 
have at least 1 PK concentration after dosing will be included in the PK Population. 
The PK population will be further described in a SAP. 
8.2. Demographic Data and Other Baseline Characteristics 
Listings and descriptive summary statistics of demographic (age, height, weight and BMI) and 
baseline data will be presented. 
Statistics for demographic and baseline data will be detailed in a Statistical Analysis Plan (SAP). 
8.3. Safety 
Statistics for summary of AEs and safety results will be detailed in a SAP. 
8.3.1. Safety Endpoints 
The primary safety endpoints are: 
• Incidence of increased EtCO2 of at least 10 mmHg compared to baseline or >50 mmHg 
(sustained for at least 30 seconds) 
• Incidence of reduction in SpO2 to <92% (sustained for at least 30 seconds) 
The secondary safety endpoints are: 
• Mean time to reduction in SpO2 to <92% (sustained for at least 30 seconds) 
• Mean duration of reduction in SpO2 to <92% (sustained for at least 30 seconds) 
• Maximum postdose reduction of SpO2 adjusted for baseline  
• Mean postdose SpO2 
• Mean time to each increased EtCO2 episode of at least 10 mmHg compared to baseline or 
>50 mmHg (sustained for at least 30 seconds) 
• Mean duration of each increased EtCO2 episode of at least 10 mmHg compared to 
baseline or >50 mmHg (sustained for at least 30 seconds) 
• Maximum postdose increase in EtCO2 adjusted for baseline  
• 
Mean postdose EtCO2 
• Incidence of reduced respiratory rate to <6 breaths/min (sustained for at least 30 seconds) 
• Mean time to each reduced respiratory rate episode of <6 breaths/min (sustained for at 
least 30 seconds) 


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• Mean duration of each reduced respiratory rate episode of <6 breaths/min (sustained for 
at least 30 seconds) 
• Maximum postdose decrease in respiratory rate adjusted for baseline  
• Mean postdose respiratory rate 
• Incidence, frequency, severity and relationship of AEs 
• Vital signs measurements (BP, HR, and oral temperature) 
• ECGs (12-lead safety ECGs, 12-lead dECGs, and ECG telemetry) 
• Clinical laboratory test results (clinical chemistry, hematology, coagulation, urinalysis) 
• Physical examination findings 
• Type of medical intervention used, summarized for each event of significantly increased 
EtCO2, reduced SpO2 or respiratory rate 
8.3.2. Safety Analysis 
 Respiratory Depression Analysis 
Summary statistics and inferential analysis for respiratory depression endpoints will be done 
using the Completer Population. 
Incidence of increased EtCO2 of at least >50 mmHg will be summarized by treatment and time 
point using frequency tables. Mean time to each increased EtCO2 episode of at least >50 mmHg, 
mean duration of each increased EtCO2 episode of at least >50 mmHg, and mean postdose 
EtCO2 will be summarized by treatment and time point using descriptive statistics. Maximum 
postdose increase in EtCO2 Emax (postdose – predose) will be summarized by treatment using 
descriptive statistics and inferential analysis. EtCO2 averages (predose average from Days 2 to 
15), and postdose average on Day 15 will also be summarized by treatment using descriptive 
statistics and inferential analysis. For each event of significantly increased ETCO2, type of 
medical intervention used will be listed. 
Incidence of reduction in SpO2 to <92% will be summarized by treatment and time point using 
frequency tables. Mean time to reduction in SpO2 to <92%, mean duration of reduction in SpO2 
to <92%, and mean postdose SpO2 will be summarized by treatment and time point using 
descriptive statistics. Maximum postdose reduction of SpO2 Emax (predose – postdose) will be 
summarized by treatment using descriptive statistics and inferential analysis. SpO2 averages 
(predose average from Days 2 to 15), and postdose average on Day 15 will also be summarized 
by treatment using descriptive statistics and inferential analysis. For each event of significantly 
reduced SpO2, type of medical intervention used will be listed. 
Incidence of reduced respiratory rate to <6 breaths/min will be summarized by treatment and 
time point using frequency tables. Mean time to each reduced respiratory rate episode of < 
6 breaths/min, mean duration of each reduced respiratory rate episode of <6 breaths/min, and 
mean postdose respiratory rate will be summarized by treatment and time point using descriptive 
statistics. Maximum postdose decrease in respiratory rate Emax (predose – postdose) will be summarized 
by treatment using descriptive statistics and inferential analysis. Respiratory rate averages 


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(predose average from Days 2 to 15), and postdose average on Day 15 will also be summarized 
by treatment using descriptive statistics and inferential analysis. 
For EtCO2, SpO2, and respiratory rate the following figures will be generated: 
1) Mean (± SD) treatment by time point for Day 1 Morphine alone matched to Day 15 
Morphine + AZD4041 
2) Mean (± SD) treatment by time point for Day 1 Morphine alone matched to Day 15 
Morphine + Placebo  
3) Mean (± SD) treatment by time point for Days 2-15 predose AZD4041 vs. Days 2-15 
predose Placebo  
4)  Boxplot for Emax Day 1 Morphine alone matched to Day 15 Morphine + AZD4041 
5) Boxplot for Emax Day 1 Morphine alone matched to Day 15 Morphine + Placebo  
6) Boxplot for Emax Day 15 Morphine + AZD4041 vs. Day 15 Morphine + Placebo  
For all inferential analysis on EtCO2, SpO2, and respiratory rate, mixed-effects models will be 
used for Emax and averaged measures. The models will include treatment as a fixed effect, and 
baseline as a covariate. Homogeneity of treatment variances will be explored to determine if 
subject may be considered a random effect. 
For maximum postdose increase in EtCO2 (Emax (postdose – predose)), maximum postdose reduction in 
SpO2 (Emax (predose – postdose)), and maximum postdose decrease in respiratory rate (Emax (predose – 
postdose)), the following contrasts will be explored in the mixed-effects models: 
1) E: Morphine + AZD4041 (Day 15) vs A: Morphine alone (Day 1) 
2) F: Morphine + Placebo (Day 15) vs B: Morphine alone (Day 1) 
3) E: Morphine + AZD4041 (Day 15) vs F: Morphine + Placebo (Day 15) 
For EtCO2, SpO2, and respiratory rate averages (predose average from Days 2 to 15), and 
postdose average on Day 15, the following contrasts will be explored in the mixed-effects 
models: 
1) E (postdose): Morphine + AZD4041 (postdose average Day 15) vs C + E (predose): 
AZD40401 (predose average Days 2-15) 
2) C + E (predose): Morphine + AZD4041 (predose average Days 2-15) vs D + F (predose): 
Morphine + Placebo (predose average Days 2-15) 
 12-lead digital ECG Statistical Methodology  
From the dECG data, the following parameters will be derived:  
1) QTcF will be calculated as QTcF = QT*RR-1/3, where the QT interval is in milliseconds 
and the RR interval is in seconds.  
2) Heart rate will be calculated, based on the RR interval as HR = 60/RR interval, where the 
RR interval is in seconds.  
3) Calculation of derived parameters will be performed after smoothing of QT and RR data.  


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The dECG data will be smoothed on an individual basis before performing the derivations above 
and prior to 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 provided that at 
least 4 measurements are present and the time between the first and last is greater than 2.75 
minutes or else, the smoothed value at the corresponding target time point will be set to missing.  
Digital ECG results will be listed by treatment (Morphine and AZD4041 vs Morphine and 
placebo) 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. All smoothed and derived 
parameters will have changes from baseline derived and presented.  
Descriptive statistics will be presented by treatment and time point for smoothed values and 
changes from baseline of smoothed values of PR, RR, QRS, QT; derived values and changes 
from baseline for QTcF and HR will also be included. The baseline for the dECG measurements 
will be the (smoothed) predose assessment on Day 1.   
Outliers with respect to PR, QRS, HR, RR and QTcF will also be tabulated for the following 
categories: 
For QTcF:  
• Absolute value > 450 ms and ≤ 480 ms  
• Absolute value > 480 ms and ≤ 500 ms  
• Absolute value > 500 ms  
• Increase from baseline > 30 ms and ≤ 60 ms  
• Increase from baseline > 60 ms   
The maximum postdose values for PR interval will be summarized by treatment according to the 
following categories:   
• ≤220 ms 
• 
>220 and ≤ 240 ms (all instances flagged in the listing*)  
• 
>240 ms (all instances flagged in the listing **)  
The maximum postdose values for QRS duration will be summarized by treatment according to 
the following categories:   
• ≤115 ms   
• 
>115 ≤ 119 ms (all instances flagged in the listing*) 
• 
>119 ms (all instances flagged in the listing**) 
The maximum/min postdose values for HR will be summarized by treatment according to the 
following categories:   
• <40 bpm (all instances flagged in the listing**)   
• 40 - <50 bpm (all instances flagged in the listing*) 
• ≥50 bpm and ≤100 bpm  
• >100 - ≤120 bpm (all instances flagged in the listing*)   
• >120 bpm (all instances flagged in the listing**)   
The maximum/min postdose values for RR will be summarized by treatment according to the 
following categories:   


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• <500 ms (all instances flagged in the listing**) 
• 500 ms - < 600 ms (all instances flagged in the listing*)  
• ≥ 600 ms ≤ 1200 ms 
• > 1200 ms ≤ 1500 ms (all instances flagged in the listing*)   
• >1500 ms (all instances flagged in the listing**) 
All calculations of dECG parameters and reporting described in this section will be performed by 
AltaSciences. 
 All Other Safety Analysis 
Summary statistics for all other safety analysis will be done using the Safety Population. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
characterized as pre-treatment and treatment-emergent according to the intake of the study drugs. 
The occurrence and incidence of TEAEs will be summarized by MedDRA system organ class 
and preferred term and by treatment. The occurrence and incidence of TEAEs will also be 
summarized by severity and by relationship to the study drugs. Adverse events leading to 
discontinuation and SAEs will be listed. 
Clinical laboratory parameters will be summarized by visit using descriptive statistics. Values 
within and outside the reference range will also be summarized using frequency tablets. Vital 
sign and ECG parameters and change from baseline (predose) will be summarized at each time 
point by treatment using descriptive statistics. Physical examination abnormalities and C-SSRS 
findings will be listed. 
8.4. Pharmacokinetics 
The PK analysis will be carried out according to AZ SOPs. Pharmacokinetic data handling and 
analysis will be further detailed in a SAP. 
8.4.1. Pharmacokinetic Parameters 
The PK parameters will be determined by non-compartmental analysis using appropriate 
software. The PK parameters for AZD4041, morphine, morphine-6-glucuronide and morphine-3-
glucuronide are presented in Table 8-1. 
Table 8-1 Pharmacokinetic Parameters in Plasma 
Parametera 
Definition 
For morphine, morphine-6-glucuronide and morphine-3-glucuronide (Day 1 and 15) 
Cmax 
Maximum observed concentration occurring at time tmax 
tmax 
Time of maximum observed concentration. If the maximum observed 
concentration is not unique, then the first maximum is used 
AUC0-t 
Area under the concentration time curve from the time of last dosing to the 
time of last quantifiable concentration (Tlast)  
AUC0-∞  
Area under the concentration time curve extrapolated to infinity, calculated as 
AUC0-T + Clast/λZ, where Clast is the last quantifiable concentration at time Tlast 
t1/2,z 
Terminal elimination half-life, calculated as ln(2)/λ 


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Parametera 
Definition 
Tlast 
Time of last measurable observed concentration 
CL 
Total body clearance, calculated as Dose/AUC0-∞ (parent drug only) 
Vz 
Volume of distribution based on terminal phase (parent drug only) 
For AZD4041 
Days 2 to 7 and Days 9 to 14: 
Ctrough 
Predose concentration observed immediately prior to the next successive dose 
Days 8 and 15 
Cmax,ss 
maximum observed plasma concentration 
tmax,ss 
time to maximum observed plasma concentration 
Ctrough 
Predose concentration observed immediately prior to the next successive dose 
AUCτ 
area under the concentration time curve over the dosing interval at steady-
state, calculated from 0 to 24 hours (dosing interval) 
Cav 
average concentration during a dosing interval, after the last dose of a multiple 
dose regimen, calculated as AUCτ/τ 
t1/2,z 
Terminal elimination half-life, calculated as ln(2)/λz (Day 15 only) 
CLss/F 
Apparent total body clearance at steady-state, calculated as Dose/AUCτ 
Vzss/F 
Apparent volume of distribution at steady-state, based on terminal phase  
a. 
A complete list of PK parameters that will be used for PK calculation and presented in the PK listings will be 
included in the SAP. 












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Society of Actuaries, 2019 
Opioid Epidemic Cost the U.S. Economy at Least $631 Billion Over Four Years: Society of 
Actuaries’ Analysis. Society of Actuaries https://www.soa.org/resources/announcements/press-
releases/2019/opioid-epidemic-cost-631-billion/ (2019). 
Stoops et al, 2010 
Stoops WW, Hatton KW, Lofwall MR, Nuzzo PA, Walsh SL. Intravenous oxycodone, 
hydrocodone, and morphine in recreational opioid users: abuse potential and relative potencies. 
Psychopharmacology (Berl). 2010 Oct;212(2):193-203. 
Thannickal et al, 2018 
Thannickal TC et al. Opiates increase the number of hypocretin-producing cells in human and 
mouse brain and reverse catalepsy in a mouse model of narcolepsy. Science Translational 
Medicine 10, doi:10.1126/scitranslmed.aao4953 (2018) 
Thompson et al. 1999 
Thompson PI, Joel SP, John L, Wedzicha JA, Maclean M, Slevin ML. Respiratory depression 
following morphine and morphine-6-glucuronide in normal subjects. Br J Clin Pharmacol. 1995 
Aug;40(2):145-52.  
Verbekt et al, 2017 
Verberkt CA, van den Beuken-van MH, Schols JM, Datla S, Dirksen CD, Johnson MJ, van 
Kuijk SM, Wouters EF, Janssen DJ. Respiratory adverse effects of opioids for breathlessness: a 
systematic review and meta-analysis. European Respiratory Journal. 2017 Nov 1;50(5). 
Viscusi et al, 2021 
Viscusi ER, Torjman MC, Munera CL, Stauffer JW, Setnik BS, Bagal SN. Effect of 
difelikefalin, a selective kappa opioid receptor agonist, on respiratory depression: a randomized, 
double‐blind, placebo‐controlled trial. Clinical and Translational Science. 2021 Sep;14(5):1886-
93. 
Waugh et al, 2011 
Waugh JB, Epps CA, Khodneva YA. Capnography enhances surveillance of respiratory events 
during procedural sedation: a meta-analysis. J Clin Anesth 2011;23(3):189-196. 
Wakeman et al, 2020 
Wakeman, S. E. et al. Comparative Effectiveness of Different Treatment Pathways for Opioid 
Use Disorder. JAMA network open 3, e1920622, doi:10.1001/jamanetworkopen.2019.20622 
(2020). 
Webster et al, 2011 
Webster LR, Johnson FK, Stauffer J, Setnik B, Ciric S. Impact of intravenous naltrexone on 
intravenous morphine-induced high, drug liking, and euphoric effects in experienced, 
nondependent male opioid users. Drugs R D. 2011 Sep 1;11(3):259-75. 




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10. 
APPENDIX 1: ETHICS 
10.1. Institutional Review Board 
This protocol and the ICF will be submitted to an IRB (or Independent Ethics Committee[IEC]) 
prior to initiation of the study and the study will not start until the Board has approved the 
documents. Notification of the Board’s approval will be appended to the final report. 
10.2. Ethical Conduct of the Study 
This study will be conducted in compliance with the study protocol, the ethical principles that 
have their origins in the Declaration of Helsinki, the International Council for Harmonisation 
(ICH) Guideline E6 for Good Clinical Practice (GCP), the FDA GCP Code of Federal 
Regulations (CFR) Title 21 (part 56), the EU Clinical Trial Directive (EC) No. 2001/20/EC, the 
European regulation EU 536/2014 and the Tri-Council Policy Statement (Canada). 
10.3. Subject Information and Consent 
Before screening activities commence, each volunteer will be given a copy of the ICF to read, as 
well as a full explanation of the purpose of the study, the procedures to be carried out, and the 
potential AE(s). Once this essential information is provided to the volunteer and the physician in 
charge or delegate has the conviction the volunteer understands the implications of participating 
in the study, and if the volunteer chooses to continue the screening process, they will be 
requested to sign and date a properly executed ICF prior to enrollment. Subjects will be assured 
they may withdraw from the study at any time without jeopardizing their medical care or future 
study participation (for which they qualify). 
Subjects will be given a signed copy of the ICF. If an amended or revised ICF is introduced 
during the study, each subject’s further consent must be obtained. 
10.4. Subject Confidentiality 
Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in the 
study, in accordance with GCP and local regulations. Subjects should be identified by a unique 
subject identifier on all study documents provided to the Sponsor. In compliance with Federal 
regulations/ICH GCP Guidelines, it is required an Investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and IRB access to review the 
subject’s original medical records for verification of study-related procedures and data. An 
Investigator is obligated to inform the subject that his/her study-related records will be reviewed 
by the above named representatives without violating the subject’s confidentiality. 


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11. 
APPENDIX 2: DATA COLLECTION, RETENTION, AND MONITORING 
11.1. Case Report Forms 
The subject level data is entered by the site from the source document into a study specific 
21 CFR Part 11 compliant electronic clinical database to accurately collect data for each subject 
included in a clinical trial. Screen failure data may be entered into the database at the discretion 
of the Sponsor, when included in the contracted scope of work. 
11.2. Data Management and Processing 
Data management develops documentation to define activities performed during the data 
management conduct of the study trial. The EDC system is the tool used to conduct all data 
management data cleaning activities for monitoring, data review and queries. Data management 
will use a combination of automated programmed edits and manual data review listings to issue 
queries for non-conforming or discrepant data. Data management activities are performed in 
accordance with the SOPs and study-specific data management documents. 
Database locking is guided by the Data Management Locking Checklist based on the concept 
that all site activities are complete, data are considered clean and without errors and CRF signoff 
by the Principal Investigator or delegate has been completed. User access is removed as part of 
the locking process. 
Data from the clinical database will be output as SAS® datasets. All data will be included with 
the final report provided to the Sponsor. 
11.3. Quality Control and Quality Assurance 
Designated personnel from the quality assurance (QA) unit(s) of the clinical, PK and statistical 
facilities will be responsible for maintaining QA systems to ensure that the trial is conducted and 
that clinical/PK/statistical data is generated, documented and reported in compliance with the 
protocol and the integrated addendum to ICH E6: Guideline for Good Clinical Practice E6 (R2). 
Designated personnel from each corresponding operation unit (eg, clinical, PK, and statistical 
facilities) will be responsible to maintain and assure the QC of all data generated and 
documented in compliance with the protocol. 
All parts of the bioanalytical phase of the study and all its documentation will be subject to 
inspection by the QA unit of the bioanalytical facility to ensure that the data are generated, 
documented and reported in compliance with the protocol and applicable requirements as 
outlined in the FDA and Organization for Economic Co-Operation and Development (OECD) 
Principles of GLP. 
11.4. Record Retention 
All essential documents and records will be maintained by the clinical site in accordance with, 
and for the period specified in the applicable regulatory requirement(s) (FDA CFR 312.57 [C]). 
11.5. Monitoring of the Study 
The sponsor or its representative may monitor the study in order to maintain current and personal 
knowledge of the study through review of the records, comparison with source documents, 
observation and discussion of the conduct and progress of the study. The clinical site will permit 
trial-related monitoring, audits, institutional review board (IRB)/independent ethics committee 


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(IEC) review, and regulatory inspection(s) by providing direct and/or virtual access, where 
possible, to source data/documents. 


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12. 
APPENDIX 3: ADMINISTRATIVE PROCEDURES 
12.1. Liabilities 
It is the Sponsor’s responsibility to guarantee sufficient insurance coverage should any serious 
events or deaths result, either directly or indirectly, from the execution of the present protocol. 
12.2. Adherence to Protocol 
Excluding an emergency situation in which proper treatment is required for the protection, safety 
and well-being of the study subjects, the study will be conducted as described in the approved 
protocol and performed according to ICH/GCP and the applicable regulatory requirements. Any 
deviation from the protocol will be recorded and explained. 
If amendments to the protocol and/or amendments or revisions to the ICF are required, the 
modifications will be documented and submitted to an IRB for approval. 
12.3. COVID-19 Response Plan 
Regulatory authorities have recognized that the Coronavirus Disease 2019 (COVID-19) 
pandemic may impact the conduct of clinical trials of medical products. Challenges may arise, 
for example, from quarantines, site closures, travel limitations, interruptions to the supply chain 
for the IP(s), or other considerations if site personnel or study participants become infected with 
COVID-19. These challenges may lead to difficulties in meeting protocol-specified procedures, 
including administering or using the IP or adhering to protocol-mandated visits and 
laboratory/diagnostic testing. To accommodate these challenges and mitigate safety risks 
associated with COVID-19, protocol modifications may be required which include (and are not 
limited to): 
• Conducting the study in multiple (smaller) subject groups; 
• Altering the timing of study procedures and subject confinement; 
• Modification of standard inclusion or exclusion criteria; 
The exact mitigations will be documented in the study Risk Assessment and Mitigation Plan. 
Additional health checks including COVID-19 testing, body temperature monitoring, etc. may be 
performed during the trial, even if not planned within the protocol. 
12.4. Statement of Investigator 
The form “Qualified Investigator Undertaking” will be signed by an Investigator responsible for 
the medical decisions and care provided to the subjects (being also referred to as the “qualified 
investigator”) prior to the commencement of his responsibilities with respect to the clinical trial, 
as required by the Food and Drug Regulations. The undertaking form will be maintained with the 
trial records and will be made available upon request. 
The FDA 1572 form, Statement of Investigator [Title 21, CFR Part 312], will be signed by the 
Investigator, and will be kept on file. 


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12.5. Delegation of Investigator Duties 
An Investigator will ensure all personnel involved in the trial are adequately qualified and 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
An Investigator will maintain a list of sub-investigator(s) and other appropriately-qualified 
persons to whom he/she delegates significant trial-related duties. 
Should an Investigator delegate the supervision of the IP administration to a designated person, 
this individual must have the appropriate professional-legal qualifications and certifications. An 
Investigator should also ensure key staff personnel have the appropriate medical qualifications to 
effectively conduct or supervise any potential resuscitation procedures. 
12.6. Premature Termination or Suspension of a Study 
The Sponsor or its representative may terminate the study at any time for scientific or corporate 
reasons. 
If the trial is prematurely terminated or suspended for any reason, the clinical site or an 
Investigator (or delegate) should promptly inform the trial subjects, should assure appropriate 
therapy and follow-up for the subjects and should inform the regulatory authority(ies) when 
required. 


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13. 
APPENDIX 4: PROTOCOL REVIEW AND APPROVALS 
 


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TITLE: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, FIXED 
SEQUENCE STUDY TO ASSESS THE EFFECT ON RESPIRATORY DRIVE OF 
MULTIPLE DOSES OF AZD4041 WHEN CO-ADMINISTERED WITH A SINGLE DOSE OF 
MORPHINE IN HEALTHY RECREATIONAL OPIOID USERS 
 
 
I have carefully read this study protocol and agree it contains all necessary information required 
to conduct this study. I agree to conduct the study according to this protocol and in accordance 
with GCP and the applicable regulatory requirements. 
___________________________ 
Principal Investigator Name (Please Print) 
___________________________ 
____________________ 
Principal Investigator Signature 
Date (yyyy/mm/dd) 
Altasciences Clinical Kansas Inc 




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14. 
APPENDIX 5: LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interests 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase  
AV 
Atrioventricular   
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per Minute 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficient Of Variation 
CYP 
Cytochrome P450 
dECG 
Digital Electrocardiogram 
DORA 
Dual Orexin Receptor Antagonist  
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
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 Centre 
EDC 
Electronic Data Capture 
EEG 
Electroencephalogram 
EtCO2 
End Tidal Carbon Dioxide 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 


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HBsAG 
Hepatitis B Surface Antigen 
HCl 
Hydrochloride 
HCVAb 
Hepatitis C Virus Antibody 
hERG 
Human Ether-A-Go-Go-Related Gene 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
kg 
Kilogram 
L 
Litre 
LH 
Luteinizing Hormone  
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Millilitres 
mmHG 
Millimetre of Mercury 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
ng 
Nanograms 
NIDA 
National Institutes on Drug Abuse  
NOAEL 
No-Observed-Adverse-Effect Level 
NSVT 
Non-Sustained Ventricular Tachycardia 
OECD 
Organization for Economic Co-Operation and Development 
OTC 
Over-The-Counter 
OUD 
Opioid Use Disorder 
OX1/2 
Orexin Receptor 
PK 
Pharmacokinetic 
PR (PQ) 
ECG interval measured from the onset of the P wave to the onset of the 
QRS complex 
PT 
Preferred Term 


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QA 
Quality Assurance 
QRS 
ECG Interval Measured from the onset of QRS Complex to the J-Point 
QT 
QT Interval is the time from the start of the Q Wave to the end of the T Wave, 
Time Taken for Ventricular Depolarization and Repolarization 
QTC 
Qt Interval Corrected for Heart Rate 
QTcF 
Qt Interval Corrected for Heart Rate Using Fridericia's Correction Formula 
RR 
Time Elapsed Between Two Successive R-Waves of the QRS Signal on the ECG 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SMP 
Safety Management Plan 
ST 
ST Segment of the ECG 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
T Wave of the ECG 
TEAE 
Treatment-Emergent Adverse Event 
THC 
Tetrahydrocannabinol 
ULN 
Upper Limit of Normal 
VPC 
Ventricular Premature Contractions 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


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15. 
APPENDIX 6: CLINICAL LABORATORY EVALUATIONS 
Laboratory Test Panel 
Description 
General biochemistry: 
Alanine aminotransferase, aspartate aminotransferase, albumin, alkaline phosphatase, bilirubin total, 
chloride, creatinine (including eGFR using the MDRD equation), glucose, potassium, sodium, BUN, 
magnesium, calcium 
Endocrinologya 
FSH 
Hematology: 
White cell count with differential (absolute values of neutrophil, lymphocyte, monocyte, eosinophil, and 
basophil), red cell count, hemoglobin, hematocrit, mean corpuscular volume, and platelet count 
Coagulation tests: 
Activated partial thromboplastin time, prothrombin time, INR 
Serologya: 
HIV Ag/Ab Combo, Hepatitis B surface antigen and Hepatitis C virus,  
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, glucose, ketones, bilirubin, blood, nitrite, 
urobilinogen. Microscopic examination will only be performed if the dipstick test is outside of the 
reference range for leukocyte, blood, nitrite or protein 
Urine drug screen: 
Amphetamines, barbiturates, cannabinoids, cocaine, opiates, benzodiazepines, ethanol, and 
phencyclidine 
Pregnancy test: 
Serum pregnancy test 
Abbreviations: BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; FSH = follicle stimulating hormone; INR = international normalization 
ratio; MDRD = Modification of Diet in Renal Disease 
 
 
a Screening visit only. 


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16. 
APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION 
The Columbia-Suicide Severity Rating Scale Baseline/Screening Version will be provided to the 
clinical site and is not included here in its entirety. 
 


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17. 
APPENDIX 8: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
SINCE LAST VISIT VERSION  
The Columbia-Suicide Severity Rating Scale Since Last Visit Version will be provided to the 
clinical site and is not included here in its entirety. 
 


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18. APPENDIX 9: CLINICAL OPIOID WITHDRAWAL SCALE (COWS) 
 


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19. 
APPENDIX 10: CONTRACEPTION GUIDANCE  
Non-sterilised males who are sexually active with a female partner of childbearing potential must 
use a condom for the duration of the treatment period and for no less than 120 days following the 
last administration of study drug. As a male condom is not considered to constitute a highly 
effective contraception method, it is recommended that female partners of a male study subject 
also use a highly effective method of contraception throughout the study and the 
protocol-specified follow-up period. A highly effective method of contraception is defined as 
one that results in a low failure rate (ie, less than 1% per year) when used consistently and 
correctly. The acceptable methods of contraception are described in the table below.  
 
Table 1 
Highly effective methods of contraception 
Barrier methods 
Hormonal methods 
Intrauterine device 
Intrauterine hormone-releasing system (UIS)a 
Bilateral tubal occlusion 
Vasectomyb 
Sexual abstinencec 
Combined (oestrogen and progestogen containing 
hormonal contraception) 
• 
Oral (combined pill) 
• 
Injectable 
• 
Transdermal (patch) 
Progestogen-only hormonal contraception 
associated with inhibition of ovulationd 
• 
Injectable 
• 
Implantable 
• 
Intravaginal 
a 
This is also considered a hormonal method. 
b 
With appropriate evidence of post-vasectomy surgical success. 
c 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject. 
d 
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action (eg, 
minipill), is not accepted as a highly effective method). 


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20. APPENDIX 11: PHYSICAL EXAMINATION FORM 


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21. APPENDIX 12: NEUROLOGICAL EXAMINATION FORM 
 

SAP_001.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
For:
AstraZeneca AB 
PROTOCOL No. D7460C00003 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, FIXED SEQUENCE 
STUDY TO ASSESS THE EFFECT ON RESPIRATORY DRIVE OF MULTIPLE DOSES OF 
AZD4041 WHEN CO-ADMINISTERED WITH A SINGLE DOSE OF MORPHINE IN 
HEALTHY RECREATIONAL OPIOID USERS 
Altasciences Project No. AZN-P1-265 
Prepared by: 
Altasciences Company Inc.
575 Armand-Frappier Boulevard 
Laval, Quebec 
Canada, H7V 4B3 
Version: 3.0 
Date: 2023/09/19 


Protocol No. D7460C00003 | Altasciences Project No. AZN-P1-265 | Version 3.0 | 2023/09/19
Page 2 of 34
We have carefully read this statistical analysis plan and corresponding shells and agree it 
contains the necessary information required to handle the statistical analysis of study data. 
Altasciences 
Date 
Altasciences 
Date 
On behalf of the Sponsor: 
 & Sponsor Representative
Date 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD




 
 
 
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STATISTICAL ANALYSIS PLAN AND SHELLS APPROVAL..............................................2 
VERSION CONTROL .............................................................................................................3 
TABLE OF CONTENTS ..........................................................................................................4 
TABLE OF TABLES ...............................................................................................................6 
ABBREVIATIONS ..................................................................................................................7 
1 
INTRODUCTION ...........................................................................................................9 
2 
STUDY OBJECTIVES....................................................................................................9 
3 
STUDY DESIGN .......................................................................................................... 11 
3.1 
General Description .................................................................................................. 11 
3.2 
Treatments ................................................................................................................ 11 
3.3 
Study Procedures ...................................................................................................... 11 
3.4 
Randomization and Unblinding Procedures................................................................ 11 
3.5 
Determination of Sample Size ................................................................................... 11 
4 
ANALYSIS POPULATIONS ........................................................................................ 11 
5 
DATA HANDLING AND PRESENTATION ................................................................ 12 
5.1 
Safety Analysis Presentation...................................................................................... 12 
5.2 
Methods for Handling Missing Data .......................................................................... 13 
6 
STUDY SUBJECTS ...................................................................................................... 13 
6.1 
Disposition ............................................................................................................... 13 
6.2 
Protocol Deviations................................................................................................... 14 
7 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................. 14 
8 
PHARMACOKINETIC ANALYSIS ............................................................................. 14 
8.1 
Handling of Measurements Below the Lower Limit of Quantification in the PK 
analysis..................................................................................................................... 14 
8.2 
Handling of Measurements Below the Lower Limit of Quantification in the TFLs ...... 15 
8.3 
Actual Time .............................................................................................................. 15 
8.4 
Non-Compartmental Analysis.................................................................................... 16 
8.4.1 
Urine PK Parameters ........................................................................................ 18 
8.4.2 
Plasma PK Parameters ..................................................................................... 18 
8.4.3 
Urine Concentration Data ................................................................................. 19 
8.5 
Pharmacokinetic Statistical Methodology................................................................... 19 
8.5.1 
PK Parameter Listings...................................................................................... 19 


 
 
 
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8.5.2 
PK Paramater Descriptive Statistics .................................................................. 19 
8.5.3 
Graphical Presentation of Pharmacokinetic Data Statistics................................. 20 
8.5.4 
Plasma Concentration Data............................................................................... 22 
8.5.5 
Pharmacokinetic Parameter Data ...................................................................... 22 
9 
SAFETY ANALYSIS ................................................................................................... 23 
9.1 
Respiratory Depression Analysis ............................................................................... 23 
9.2 
12-lead digital ECG Statistical Methodology.............................................................. 24 
9.3 
Clinical Laboratory Evaluations................................................................................. 26 
9.4 
Vital Signs ................................................................................................................ 26 
9.5 
12-lead Safety Electrocardiogram .............................................................................. 27 
9.6 
Telemetry Results ..................................................................................................... 27 
9.7 
Physical Examination Findings .................................................................................. 27 
9.8 
All Other Safety Analysis .......................................................................................... 27 
10 
EFFICACY ANALYSIS................................................................................................ 28 
11 
INTERIM ANALYSES................................................................................................. 28 
12 
GENERAL INFORMATION RELATED TO DATA PRESENTATIONS ...................... 28 
APPENDIX A 
STUDY SCHEDULE(S) ......................................................................... 29 


 
 
 
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Table 2-1 
Objectives and Related Endpoints.......................................................................9 
Table 8-1  
Pharmacokinetic Parameters of AZD4041......................................................... 16 
Table 8-2  
Pharmacokinetic Parameters of Morphine, morphine-6-glucuronide and 
morphine-3-glucuronide in Plasma (Days 1 and 15) .......................................... 17 
Table 8-3 
Diagnostic PK Parameters for all Analytes in Plasma ........................................18
Table 9-1  
List of Laboratory Tests ................................................................................... 26 
 
 


 
 
 
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AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating 
CV% 
Coefficient of Variation 
dECG 
Digital Electrocardiogram 
DSMB
Data Safety Monitoring Board 
DMP 
Data Management Plan 
DTS 
Deviation Tracking System  
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   
EOS 
End of Study 
ET 
Early Termination 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
LLOQ 
Lower Limit of Quantification  
ln 
Natural Logarithm
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
Max 
Maximum 
NCA 
Non-Compartmental Analysis  
pECG 
Paper Print-out Electrocardiogram 
PK 
Pharmacokinetic(s) 
PR (PQ) 
The interval measured from the onset of the P complex to the onset of the Q 
complex 
PT 
Preferred Term 
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 
QT interval corrected for heart rate 
QTcF 
 


 
 
 
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RR 
The time elapsed between 2 consecutive R waves as measured by 
electrocardiogram 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE
Treatment-Emergent Adverse Event
TFLs 
Tables, Figures, and Listings 
WHODrug 
World Health Organization Drug Dictionary
 
 
 






 
 
 
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3 
STUDY DESIGN  
3.1 
General Description 
The target population is adults who use opioids recreationally. The design of the study is a 2-arm 
fixed-sequence, double-blind study performed at a single site. The IP being investigated is 
AZD4041 alone and in combination with morphine. 
3.2 
Treatments 
The active and placebo treatment groups are presented as two sequences: Sequence 1 and 
Sequence 2. In Sequence 1, subjects are administered
 of morphine on Day 1, then 
 
of AZD4041 on Days 2 through 14, then both 
 of morphine and 
 of AZD4041 on 
Day 15. Sequence 2 is similar to Sequence 1, but with AZD4041 replaced with a placebo. 
Sequence 2 subjects receive 
 of morphine on Day 1, then placebo on Days 2 through 14, 
then both 
 of morphine and placebo on Day 15. 
3.3 
Study Procedures 
For complete details on the study assessments to be performed for each study period, refer to 
APPENDIX A.  
3.4 
Randomization and Unblinding Procedures 
Subjects will be randomized into treatments as Sequence 1 or Sequence 2, as described in section 
3.2. Sequence 1 will include 28 subjects total and Sequence 2 will include 16 subjects total. The 
total 44 subjects will be assigned into 6 Blocks, with Block 1 including 4 subjects (Sequence 1 to 
Sequence 2, 1:1), Blocks 2 through 5 including 8 subjects each (Sequence 1 to Sequence 2, 5:3), 
and Block 6 includes 8 subjects (Sequence 1 to Sequence 2, 3:1). Replacements may be made if 
subjects drop out of the study before completion. 
The randomization code must not be broken except in emergency situations where the 
the subject or to complete a SAE report. Randomization information will be held by designated 
individual(s). The date and reason for breaking the blind must be recorded. 
Unblinding of the data will occur after database lock except in cases of emergency. 
3.5
Determination of Sample Size
No formal sample size calculation was performed for this Phase 1 study. 
4 
ANALYSIS POPULATIONS 
The following populations are defined for this study: 
 Randomized Population: The randomized population will include all subjects who are 
randomized to the Treatment phase. 
 Safety population: The safety population will include all subjects who received at least 1 
dose of morphine, placebo, or AZD4041. 
 Completer Population: The completer population will include all subjects in the safety 
population who completed the entire Treatment phase and the follow-up period (up to at 
least Day 22). This population will be used for inferential analysis of maximum postdose 
CCI
CCI
CCI
CCI
CCI
CCI


 
 
 
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increase in EtCO2 (Emax (postdose  predose)), maximum postdose reduction in SpO2 (Emax (predose 
 postdose)), and maximum postdose decrease in respiratory rate (Emax (predose  postdose)). 
 Pharmacokinetic Population: All subjects in the safety population who received at least 
1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing will be 
included in the PK population.
5 
DATA HANDLING AND PRESENTATION 
5.1 
Safety Analysis Presentation 
Adverse events and medical history will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology as defined in the study Data Management Plan 
(DMP).  
Prior and concomitant medications will be coded with the World Health Organization Drug 
Dictionary (WHODrug) as defined in the study DMP. 
In general, all safety summary tables will be presented for the safety population. Summaries for 
AEs will be presented by treatment and treatment sequence. Summaries for other safety 
endpoints will be presented by treatment if the endpoints are measured at the end of each period 
or by treatment sequence if the endpoints are not measured at the end of each period (End of
Study only). 
In general, the data listings will include all subjects in the safety population up to the point of 
study completion or discontinuation; exceptions will be listings pertaining to a subset of subjects 
only (eg, subjects with protocol deviations) or a subset of records/events (eg, abnormal 
laboratory values). Limited data for those not included in the safety population, eg, who failed 
screening, may be presented, as appropriate. 
Categorical variables will be summarized using sample size (N), number of available data (n), 
and the percentage of available data (%) for each class. Continuous variables will be summarized 
using descriptive statistics, including N, n, arithmetic mean (mean), standard deviation (SD), 
minimum (min), median, and maximum (max).  
The following general considerations may be applied: 
 Study Day will be derived from the reference date (eg, the day of the first dose of study 
drug) and date of event as: 
Study Day = (date of event  reference date) +1, if event is on or after the reference date; 
Study Day = date of event  reference date, if event is before the reference date. 
 Duration will be calculated using the general formula: (end date - start date) +1. 
 If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (eg, a character string is reported for a parameter of the numerical type), a 
coded value may be appropriately determined and used in the statistical analyses. In 
general, a value below the lowe
treated as half of the lower limit, 5
2.
, respectively, and a value above the upper 
limit of normal range 
replaced with a number deemed 
scientifically reasonable, eg, 101. However, the actual values as reported in the database 
will be presented in data listings. 


 
 
 
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 Unscheduled assessments will not be included in descriptive summary, except for 
baseline consideration. When assessments are repeated for a given timepoint or 
performed at unscheduled times, only the result which is the closest to the assessment 
time will be included in summary tables.
In general, summary statistics for raw variables (ie, variables measured at the study site or 
central laboratory) will be displayed as follows:  
 Minima and maxima will be displayed to the same number of decimal places as the raw 
data  
 Means, medians, and quartiles (if presented) will be displayed to 1 additional decimal 
place  
 Standard deviations will be displayed to 2 additional decimal places 
 Percentages will be displayed to 1 decimal place; Percentages between 0 and 0.1 
  
 P-values will be displayed to 3 decimal places; p-values that are less than .001 will be 
 
Derived variables (ie variables that are not measured by the study site but are calculated for 
analysis based on other measured variables) will be displayed with the same precision as the raw 
data, as appropriate, then will follow similar rules in presentation of summary statistics. 
All outputs will be generated using SAS software version 9.4 or higher. 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock and/or prior to breaking the blind. Any analyses performed subsequent to database 
lock and/or breaking the blind will be considered post hoc and exploratory, and will be identified 
in the Clinical Study Report (CSR). 
5.2 
Methods for Handling Missing Data  
No imputation of missing data will be performed on data that is not PK. 
6 
STUDY SUBJECTS 
Unless otherwise specified, all available data will be listed and summary table for disposition 
will be presented for the safety population.  
6.1 
Disposition 
Subject disposition will be summarized by treatment sequence and overall, including: 
 Number of subjects screened 
 Number of subjects randomized 
 Number of subjects who received any treatment compound (morphine, AZD4041 or 
placebo) 
 Number of subjects who received IP (i.e. AZD4041 or placebo) 
 Number (%) of subjects who completed the study 


 
 
 
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 Number (%) of subjects discontinued from the study overall and by primary reason for 
discontinuation 
 Number (%) of subjects included in each of the analysis populations 
The percentages will be calculated using the number of subjects who received at least one dose 
of a treatment.  
Listings 
and subjects included in each of the analysis populations will be 
provided. 
6.2 
Protocol Deviations 
Deviations will be collected in the clinic deviation tracking system (DTS) and presented in a 
general protocol deviation listing.  
7 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Unless otherwise specified, all available data will be listed and summary tables for demographics 
and other baseline characteristics will be presented for the safety population.  
Medical history will be recorded during screening. 
Demographic and baseline characteristics including age, height, weight (at screening), and body 
mass index (BMI) will be listed and summarized by treatment sequence and overall. Descriptive 
statistics will be presented for age, height, weight, and BMI, while frequency counts and 
percentages will be presented for sex, ethnicity, and race.  
The following will be presented in listings: 
 Medical history 
 Prior and concomitant medications 
 Childbearing potential and contraceptive method 
 Alcohol habits  
 Smoking habits 
 Recreational drug use history (Amphetamines, barbiturates, cannabinoids, cocaine, 
opiates, benzodiazepines, ethanol, and phencyclidine)
 
8 
PHARMACOKINETIC ANALYSIS 
The pharmacokinetic (PK) parameters from the concentration data for AZD4041, morphine, 
morphine-6-glucuronide and morphine-3-glucuronide will be derived using non-compartmental 
methods in Phoenix® WinNonlin® Version 8.3 or higher (Certara) by the Clinical PK Scientist 
from AstraZeneca. 
8.1 
Handling of Measurements Below the Lower Limit of Quantification in the PK 
analysis 
For each PK sampling period, plasma concentrations that are non-quantifiable (NQ) from the 
time of pre-dose sampling (t=0) up to the time of the first quantifiable concentration is set to a 
value of zero. After this time point, NQ plasma concentrations are set to missing for all 


 
 
 
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concentration profiles. Where 2 or more consecutive concentrations are NQ at the end of a 
profile, the profile is deemed to have terminated and therefore any further quantifiable 
concentrations are set to missing for the calculation of the PK parameters unless it is considered 
to be a true characteristic of the profile of the drug. 
If an entire concentration-time profile is NQ, the profile is excluded from the PK analysis. 
Cmax, tmax, and tlast are taken directly from the concentration-time profiles.  
8.2 
Handling of Measurements Below the Lower Limit of Quantification in the TFLs 
Individual concentrations below the LLOQ of the bioanalytical assay are reported as NQ in the 
listings with the LLOQ defined in the footnotes of the relevant TFLs. Individual plasma 
concentrations that are Not Reportable are reported as NR and those that are missing are reported 
as NS (No Sample) in the listings. Plasma concentrations that are NQ, NR or NS are handled as 
follows for the provision of descriptive statistics: 
 Any values reported as NR or NS are excluded from the summary tables and 
corresponding figures. 
 At a time point where less than or equal to 50% of the concentration values are NQ, all 
NQ values are set to the LLOQ, and all descriptive statistics are calculated accordingly. 
 At a time point where more than 50% (but not all) of the values are NQ, the gmean and 
gCV% are set to Not calculable (NC). The maximum value is reported from the 
individual data, and the minimum and median are set to NQ. 
 If all concentrations are NQ at a time point, no descriptive statistics are calculated for that 
time point. The gmean, minimum, median and maximum are reported as NQ and the 
gCV% as NC. 
 The number of values below LLOQ (n < LLOQ) are reported for each time point together 
with the total number of collected values (n). 
 
Three observations > LLOQ are required as a minimum for a plasma concentration or PK 
parameter (e.g. Cmax, Cmax,ss) to be summarised. Two observations > LLOQ are presented as 
minimum and maximum with the other summary statistics as NC. 
8.3 
Actual Time 
PK analysis is, where data allow, carried out using actual elapsed times determined from the PK 
sampling and dosing times recorded in the database. If actual elapsed times are missing, nominal 
times may be used at the discretion of the PK Scientist with approval from the AZ Clinical 
Pharmacology Scientist (CPS). Nominal sampling times may be used for any agreed interim PK 
parameter calculations.  








 
 
 
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The following descriptive statistics are presented for plasma concentrations:  
 n 
 n below LLOQ 
 geometric mean (gmean) 
 geometric coefficient of variation (%) (gCV) 
 arithmetic mean (mean) 
 arithmetic standard deviation (Std Dev) 
 median 
 minimum (min)  
 maximum (max) 
 
 
The gCV is calculated as 100 x sqrt[exp(s2)-1], where s is the Std Dev of the data on the natural 
log scale. 
the data on the natural log scale. The gmean ± gSD (gmean-gSD and gmean+gSD) are calculated 
 
Protocol scheduled times are used to present the PK concentration summary tables and 
corresponding gmean concentration-time figures. 
8.4.3 Urine Concentration Data 
Urine concentration and volume/weight data are listed only and not summarised. Any individual 
data excluded from the PK analysis are flagged with an appropriate footnote in the listing by the 
PK Scientist. 
8.5 
Pharmacokinetic Statistical Methodology 
8.5.1 PK Parameter Listings 
All reportable PK parameters, including individual diagnostic and lambda z related parameters, 
are listed for each subject by PK Day and Treatment sequence, for each analyte separately. 
8.5.2 PK Paramater Descriptive Statistics 
All PK parameters are summarised for each analyte by PK Day and Treatment sequence using 
appropriate descriptive statistics. Similar parameter data (e.g. single dose or multiple dose for the 
same dosing regimen) from different PK Days may also be summarised together. 
The descriptive statistics for PK parameters are presented as follows: 


 
 
 
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-t, AUC0-
Vzss/F, CLR, Ae and fe: present n, geometric mean, geometric standard deviation (Geo 
Std Dev), arithmetic mean of non log-transformed data (mean), arithmetic standard 
deviation (Std Dev), gCV(%), median, min and max. 
 tmax, and tlast: present n, median, min and max. 
 
AUCextr): present n, arithmetic mean, Std Dev, gmean, gCV%, median, min and max. 
Three values are required as a minimum for PK parameters to be summarised. Two values are 
presented as a min and max with the other summary statistics as NC. 
If one or more values for a given parameter is zero, then no geometric statistics are calculated for 
that parameter and the results for geometric statistics are set to NA (Not Applicable). 
The point estimate and associated two-sided 90% confidence intervals for the ratio of PK 
parameters (for AZD4041: AUC , Cmax,ss, Ctrough,ss; for morphine and metabolites: Cmax, 
AUC0-t, AUC0- ) for each comparison of interest will be calculated: 
For treatment sequence 1: 
 AZD4041 in the absence of Morphine - Day 8 and AZD4041 in the presence of 
Morphine  Day 15 
 Morphine in the absence of AZD4041  Day 1 and Morphine in the presence of 
AZD4041  Day 15 
 Morphine metabolites in the absence of AZD4041  Day 1 and Morphine metabolites in 
the presence of AZD4041  Day 15 
For treatment sequence 2: 
 Morphine on Day 1 and 15. 
 Morphine metabolites on Day 1 and 15. 
8.5.3 Graphical Presentation of Pharmacokinetic Data Statistics 
All mean (arithmetic mean and/or gmean) plots or combined plots showing all subjects by 
treatment and treatment sequence are based on the PK analysis set. Individual plots by subject 
are based on the Safety analysis set.  
For consistency, the plasma concentration values used in the mean (arithmetic mean and/or 
gmean) data graphs are those given in the descriptive statistics summary table for each time 
point. 
For gmean concentration-time plots, NQ values are handled as described for the descriptive 
statistics; if the geometric mean is NQ, the value plotted is zero for linear plots and missing for 


 
 
 
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semi-logarithmic plots. Any gmean±gSD error bar values that are negative are truncated at zero 
on linear concentration-time plots and omitted from semi-logarithmic plots. 
For individual plots, plasma concentrations which are NQ prior to the first quantifiable 
concentration are set to a value of zero (linear plots only). After the first quantifiable 
concentration, any NQ plasma concentrations are regarded as missing. 
Data permitting, the following figures are presented as appropriate:  
Figures for the mean (arithmetic mean and/or gmean) plasma concentration-time data (with 
±Std Dev and/or ±gSD error bars) presented on both linear and semi-logarithmic scales using 
scheduled post-dose time as follows: 
AZD4041 in both the presence and absence of Morphine 
Day 8 and 15
 Morphine in the absence and presence of AZD4041  Day 1 and 15 
 Morphine metabolites in the absence and presence of AZD4041  Day 1 and 15 
Individual subject plasma concentration-time data graphically presented on both linear and semi-
logarithmic scales using actual time post-dose as: 
 AZD4041 in the absence of Morphine - Day 8 and AZD4041 in the presence of 
Morphine  Day 15 
 Morphine and its metabolites in the absence of AZD4041  Day 1 and Morphine and its 
metabolites in the presence of AZD4041  Day 15 
Combined individual plasma concentration versus actual time after dose will be plotted on both 
the linear and semi-logarithmic scale, with the individual profiles for the same analyte in the 
different periods overlaid on the same plot as described below: 
For treatment sequence 1: 
 AZD4041 in the absence of Morphine - Day 8 and AZD4041 in the presence of 
Morphine  Day 15 
 Morphine in the absence of AZD4041  Day 1 and Morphine in the presence of 
AZD4041  Day 15 
 Morphine metabolites in the absence of AZD4041  Day 1 and Morphine metabolites in 
the presence of AZD4041  Day 15 
For treatment sequence 2: 
Morphine on Day 1 and 15. 
Morphine metabolites on Day 1 and 15. 
 


 
 
 
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These plots will be based on the PK 
analysis set. Focus plots may be provided if there will be no clear distinction among profiles. 
Geometric mean (± gSD) plasma trough concentration (Ctrough) of AZD4041 versus study 
day will be plotted on linear scale. Additional plots may be produced if deemed appropriate to 
summarise and present PK data. 
Figures presenting the point estimate and associated two-sided 90% confidence intervals for the 
ratio of PK parameters (for AZD4041: AUC , Cmax,ss, Ctrough,ss; for morphine and 
metabolites: Cmax, AUC0-t, AUC0- ) for each comparison as mentioned above. 
Figures for the arithmetic mean urine concentration-time data (with ±Std Dev error bars) 
presented on both linear and semi-logarithmic scales using scheduled post-dose time as follows:
 Arithmetic mean of accumulated fraction (%) of AZD4041 
8.5.4 Plasma Concentration Data 
PK concentration data listings present to the same number of significant figures as the data 
received from the bioanalytical laboratory (usually but not always to 3 significant figures) and 
against the same units as received. 
PK concentration descriptive statistics present 4 significant figures with the exception of the min 
and max which present 3 significant figures and n and n<LLOQ which present as integers. 
8.5.5 Pharmacokinetic Parameter Data 
PK parameter listings are presented according to the following rules:  
 Cmax, Ctrough: present to the same number of significant figures as received from 
the bioanalytical laboratory 
 Tmax and tlast: present as received in the data, usually to 2 decimal places 
 AUCinf, AUC(0-
ss/F, Vzss/F, Vz, , all ratios 
of PK, Rsq adj, Ae, fe and CLR: present to 3 significant figures 
 n obs: present as an integer (no decimals) 
 
The descriptive statistics for PK parameter data are presented to 4 significant figures with the 
exception of the min and max which are presented to 3 significant figures apart from the 
following: 
 
 
 tmax and tlast: present as received in the data, usually to 2 decimal places 
 number of values (n): present as an integer 
 


 
 
 
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9 
SAFETY ANALYSIS  
9.1 
Respiratory Depression Analysis 
Summary statistics and inferential analysis for respiratory depression endpoints will be presented 
for all subjects who completed all etCO2 assessments in addition to the Safety Population, when 
possible. Incidence of increased EtCO2 of at least >50 mmHg will be summarized by treatment 
and time point using frequency tables. Mean time to each increased EtCO2 episode of at least 
>50 mmHg, mean duration of each increased EtCO2 episode of at least >50 mmHg, and mean 
postdose EtCO2 will be summarized by treatment and time point using descriptive statistics. 
Maximum postdose increase in EtCO2 Emax (postdose  predose) will be summarized by treatment using 
descriptive statistics and inferential analysis. EtCO2 averages (predose average from Days 2 to 
15), and postdose average on Day 15 will also be summarized by treatment using descriptive 
statistics and inferential analysis. For each event of significantly increased ETCO2, type of 
medical intervention used will be listed.
Incidence of reduction in SpO2 to <92% will be summarized by treatment and time point using 
frequency tables. Mean time to reduction in SpO2 to <92%, mean duration of reduction in SpO2 
to <92%, and mean postdose SpO2 will be summarized by treatment and time point using 
descriptive statistics. Maximum postdose reduction of SpO2 Emax (predose  postdose) will be 
summarized by treatment using descriptive statistics and inferential analysis. SpO2 averages 
(predose average from Days 2 to 15), and postdose average on Day 15 will also be summarized 
by treatment using descriptive statistics and inferential analysis. For each event of significantly 
reduced SpO2, type of medical intervention used will be listed. 
Incidence of reduced respiratory rate to <6 breaths/min will be summarized by treatment and 
time point using frequency tables. Mean time to each reduced respiratory rate episode of < 
6 breaths/min, mean duration of each reduced respiratory rate episode of <6 breaths/min, and 
mean postdose respiratory rate will be summarized by treatment and time point using descriptive 
statistics. Maximum postdose decrease in respiratory rate Emax (predose  postdose) will be summarized 
by treatment using descriptive statistics and inferential analysis. Respiratory rate averages 
(predose average from Days 2 to 15), and postdose average on Day 15 will also be summarized 
by treatment using descriptive statistics and inferential analysis. 
For EtCO2, SpO2, and respiratory rate the following figures will be generated: 
1) Sequence 1: Mean (± SD) treatment by time point for Day 1 Morphine alone matched to 
Day 15 Morphine + AZD4041 
2) Sequence 2: Mean (± SD) treatment by time point for Day 1 Morphine alone matched to 
Day 15 Morphine + Placebo  
3) Mean (± SD) treatment by time point for Days 2-15 predose AZD4041 vs. Days 2-15 
predose Placebo  
4) Boxplot for Emax Day 1 Morphine alone matched to Day 15 Morphine + AZD4041 
5) Boxplot for Emax Day 1 Morphine alone matched to Day 15 Morphine + Placebo  
6) Boxplot for Emax Day 15 Morphine + AZD4041 vs. Day 15 Morphine + Placebo  


 
 
 
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For all inferential analysis on EtCO2, SpO2, and respiratory rate, mixed-effects models will be 
used for Emax and averaged measures. The models will include sequence, time (as a ordered 
factor variable), and the sequence-by-time interaction as fixed effects and baseline as a covariate, 
with 95% confidence intervals reported along with p-values. Homogeneity of treatment variances 
will be explored to determine if subject may be considered a random effect. The covariance 
structure for the mixed models will be heterogeneous compound symmetry. If the heterogeneous 
compound symmetry model does not converge, then a compound symmetry structure will be 
used and a footnote will be added to identify the results as using a different covariance structure 
than usual. The kenwood-roger adjustment for the degrees of freedom with be used when 
calculating p-values due to the small sample size. 
The maximum postdose decrease in respiratory rate (Emax (predose  postdose)) is the primary criterion. 
In addition to the primary criterion, maximum postdose reduction in SpO2 (Emax (predose  postdose)) 
and The maximum postdose increase in EtCO2 (Emax (postdose  predose))  will have the following 
contrasts calculated in the mixed-effects models:
1) Morphine + AZD4041 (Day 15) vs Morphine alone (Day 1) [Sequence 1] 
2) Morphine + Placebo (Day 15) vs Morphine alone (Day 1) [Sequence 2] 
3) Morphine + AZD4041 (Day 15) vs Morphine + Placebo (Day 15) [Sequence 1 vs 
Sequence 2] 
For EtCO2, SpO2, and respiratory rate averages (predose average from Days 2 to 15), and 
postdose average on Day 15, the following contrasts will be explored in the mixed-effects 
models: 
1) (postdose): Morphine + AZD4041 (postdose average Day 15) vs (predose): AZD40401 
(predose average Days 2-15) 
2) (predose): Morphine + AZD4041 (predose average Days 2-15) vs (predose): Morphine + 
Placebo (predose average Days 2-15) 
9.2 
12-lead digital ECG Statistical Methodology  
From the dECG data, the following parameters will be derived:  
1) QTcF will be calculated as  QTcF = QT*RR-1/3, where the QT interval is in milliseconds 
and the RR interval is in seconds.  
2) Heart rate will be calculated, based on the RR interval as HR = 60/RR interval, where the 
RR interval is in seconds.  
3) Calculation of derived parameters will be performed after smoothing of QT and RR data.  
The dECG data will be smoothed on an individual basis before performing the derivations above 
and prior to 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 provided that at 
least 4 measurements are present and the time between the first and last is greater than 2.75 
minutes or else, the smoothed value at the corresponding target time point will be set to missing.  
Digital ECG results will be listed by treatment (Morphine and AZD4041 vs Morphine and 
placebo) 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. All smoothed and derived 


 
 
 
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parameters will have changes from baseline derived and presented within subject and treatment 
group. 
Descriptive statistics will be presented by treatment arm andtime point for smoothed values and 
changes from baseline of smoothed values of PR, RR, QRS, QT; derived values and changes 
from baseline for QTcF and HR will also be included. The baseline for the dECG measurements 
will be the (smoothed) predose assessment on Day 1.   
Outliers with respect to PR, QRS, HR, RR and QTcF will also be tabulated for the following 
categories, described below. 
For QTcF these values will be reported per time point:  
 
 
 
 
 Absolute value > 500 ms  
 
 
 Increase from baseline > 60 ms   
The maximum postdose values for PR interval will be summarized by treatment according to the 
following categories:   
 
 
 
 
 
>240 ms (all instances flagged in the listing **)  
The maximum postdose values for QRS duration will be summarized by treatment according to 
the following categories:   
 
 
 
 
 
>119 ms (all instances flagged in the listing**) 
The maximum/min postdose values for HR will be summarized by treatment according to the 
following categories:   
 <40 bpm (all instances flagged in the listing**)   
 40 - <50 bpm (all instances flagged in the listing*) 
 
 
 >100 - 
 
 >120 bpm (all instances flagged in the listing**)   
The maximum/min postdose values for RR will be summarized by treatment according to the 
following categories:   
 <500 ms (all instances flagged in the listing**) 
 500 ms - < 600 ms (all instances flagged in the listing*)  
 
 
 
 
 >1500 ms (all instances flagged in the listing**) 


 
 
 
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All calculations of dECG parameters and reporting described in this section will be performed by 
AltaSciences who also will produce tables, box plots and graphs presenting the results. An 
Exposure Response (ER) analysis may be conducted that may include modelling of digital ECG 
variable data versus PK data of Morphine and/or morphine metabolites with and without 
AZD4041 co-administration and/or versus PK data of AZD4041 with and without morphine co-
administration. This potential analysis will be described in a separate technical document and 
reported outside the final CSR for the study. 
9.3 
Clinical Laboratory Evaluations 
Laboratory data will be presented using units as reported by the clinical laboratory. 
The laboratory categories and parameters as defined in the protocol will include the tests listed 
in Table 9-1  
List of Laboratory Tests. 
The following listings will be presented:  
 All laboratory values by category  
 Out-of-range laboratory values 
 Clinically significant laboratory values 
For protocol-specified laboratory parameters, summary tables on observed and change from 
baseline values will be presented by treatment and visit for each category. Summary statistics 
will be presented for each laboratory test. 
Table 9-1  
List of Laboratory Tests 
Laboratory Test Panel 
Description 
General biochemistry: 
Alanine aminotransferase, aspartate aminotransferase, albumin, alkaline 
phosphatase, bilirubin total, chloride, creatinine (including eGFR using 
the MDRD equation), glucose, potassium, sodium, BUN, magnesium, 
calcium
Endocrinology 
FSH 
Hematology: 
White cell count with differential (absolute values of neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil), red cell count, 
hemoglobin, hematocrit, mean corpuscular volume, and platelet count 
Coagulation tests: 
Activated partial thromboplastin time, prothrombin time, INR 
Serology: 
HIV Ag/Ab Combo, Hepatitis B surface antigen and Hepatitis C virus,  
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, glucose, ketones, 
bilirubin, blood, nitrite, urobilinogen. Microscopic examination will only 
be performed if the dipstick test is outside of the reference range for 
leukocyte, blood, nitrite or protein 
Abbreviations: BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; FSH = follicle stimulating 
hormone; INR = international normalization ratio; MDRD = Modification of Diet in Renal Disease 
9.4 
Vital Signs 
Vital signs will include systolic and diastolic blood pressures, pulse rate, and body temperature. 


 
 
 
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The following listings will be presented:  
 All vital signs 
 Clinically significant vital signs 
Summary tables on observed and change from baseline values will be presented by treatment, 
visit, and/or timepoint. 
9.5 
12-lead Safety Electrocardiogram 
Resting 12-lead safety Electrocardiogram results: Standard safety 12-lead ECGs will be 
performed as described in the CSP.  
The 12-lead safety ECG results will be listed for each subject. All 12-lead safety ECGs will be 
evaluated for HR, and for PR, time elapsed between two successive R-waves of the QRS signal 
on the ECG (RR), QRS, QT, and QTcF intervals, and an investigator will judge the overall 
interpretation as normal or abnormal. If abnormal, it will be decided whether 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 electronic CRF (eCRF), and the paper printouts will be stored at the site. An investigator 
(or designee) will evaluate the printout of the 12-lead ECG in real time, and with particular 
attention to the effects of clinical importance on the PR, QRS, and QTcF intervals. Timepoints 
for 12-lead safety ECG measurements are specified in the CSP. The results per time point and 
for extra unscheduled ECGs requested by PI (Normal/Abnormal and CS or NCS, if CS it will be 
specified) from the 12-lead safety ECG will be listed for each subject. 
The following listings will be presented:  
 All ECGs  
 Clinically significant ECGs  
Summary tables on observed and change from baseline values will be presented by treatment, 
visit, and/or timepoint. 
9.6 
Telemetry Results 
 Telemetry results will be reviewed by the investigator, listed by date and time, described and 
reported, if considered clinically significant.   
9.7 
Physical Examination Findings 
The following listings will be presented:  
 All physical examination  
 Clinically significant physical examination 
9.8 
All Other Safety Analysis 
Summary statistics for all other safety analysis will be done using the Safety Population. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
characterized as pre-treatment and treatment-emergent according to the intake of the study drugs. 
The occurrence and incidence of TEAEs will be summarized by MedDRA system organ class 
and preferred term and by treatment. The occurrence and incidence of TEAEs will also be 


 
 
 
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summarized by severity and by relationship to the study drugs. Adverse events leading to 
discontinuation and SAEs will be listed. 
Values within and outside the reference range will also be summarized using frequency tablets. 
Physical examination abnormalities and C-SSRS findings will be listed. 
Unless otherwise specified, all available data will be listed and summary tables for safety 
assessments will be presented for the safety population.   
10 EFFICACY ANALYSIS 
There is no efficacy assessment defined in the protocol. 
11 INTERIM ANALYSES 
Interim review on blinded safety and/or PK data may be performed near the end of the study.
These reviews will also ensure 
are not unblinded. 
12 GENERAL INFORMATION RELATED TO DATA PRESENTATIONS 
The formats and layouts of TFLs are provided in a separate document as common displays. Their 
numbering and general content follow the International Conference on Harmonisation (ICH) E3 
guidelines. Actual formats and layouts may be altered slightly from those presented as necessary 
to accommodate actual data or statistics.