Conditions: Opioid Use Disorder (OUD)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: yes

Brief summary:
This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, multiple ascending doses (MAD) study in healthy male and female adult participants.

The study will include up to 48 participants (12 participants per cohort) who will be randomized 9:3 to active drug or placebo. Each cohort will receive AZD4041 or placebo in a MAD study.

A sequential cohort MAD design will be employed to assure that higher doses are administered to healthy participants only after lower doses have demonstrated an acceptable safety profile.

The total study duration will be up to 59 days (including Screening) per participant.

Detailed description:

Arms:
arm 1: Participants will receive oral solution of AZD4041 dose level 1 once daily (QD) directly into the mouth using a syringe from Days 1 to 14. arm 2: Participants will receive oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14. arm 3: Participants will receive oral solution of AZD4041 dose level 3 QD directly into the mouth using a syringe from Days 1 to 14. arm 4: Participants will receive oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.

Interventions: intervention 1: AZD4041 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive oral solution of AZD4041 as stated in arm description. intervention 2: Participants will receive oral solution of placebo as stated in arm description.

Protocol document:
Prot_000.pdf: 
 
 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, 
and Pharmacokinetics of Multiple Ascending Doses of AZD4041 in Healthy Adult Subjects 
Protocol Number: 
D7460C00002 
Altasciences Project Number: 
AZN-P3-000 
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 
2.0 
(Amendment 1) 
03 February 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. 


Protocol No: D7460C00002 
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PROTOCOL AMENDMENT 01  SUMMARY OF CHANGES 
Description of Change Made 
Section/Location 
Rationale 
Safety laboratory assessment for 
sentinel dosing group changed from 
Day 3 (in text) to Day 2 to align 
with Schedule of Activities (SOA) 
Table 
Synopsis (Study 
Design) and Section 3.1 
 
Corrected for accuracy 
Clarification of the evaluation of the 
endpoint:  
 
 
 
  
 
 
 
 
Added to align with study 
objectives and design 
Updated cross reference for 
inclusion criteria regarding men who 
are biologically capable of fathering 
children  
From: 
 Table 16-1  
To: 
 Appendix 7 
Section 4.1 
To align with the changes in 
Section 4.7 
Contraception Guidance heading 
added and text changed. 
Section 4.7 
To correct formatting errors  
Changed:  
Men who are biologically capable 
of fathering children must agree and 
commit to use of adequate forms of 
double-barrier contraception and 
refrain from sperm donation for the 
duration of the treatment period and 
for no less than 120 days (4 months) 
after the last administration of study 
drug. A male subject is considered 
capable of fathering children even if 
his sexual partner is sterile or using 
contraceptives.  
To:  
Section 4.7 
Updated to improve 
understanding and clarity   
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and female subjects can be found 
 
The text in Section 5.2.3 Method of 
Assigning Subjects to Treatment 
groups was updated:  
Deleted: 
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, receive the study 
treatment, and subsequently 
withdraw, or are withdrawn or 
discontinued from the study, will not 
be replaced
 
Added:  
Subjects who sign the ICF, are 
randomized, receive the study 
treatment, and subsequently 
withdraw, or are withdrawn or 
discontinued from the study, should 
not generally be replaced. However, 
consideration may be given to the 
replacement of such subjects in 
order to enable the completion of at 
least 10 subjects for the purposes of 
Safety Review Committee and dose 
escalation decisions. Replacement 
of subjects under these 
circumstances 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 cohort 
stopping rules (Section 4.4.2.1) or 
otherwise jeopardise the safe 
 
 
Section 5.2.3 
To ensure that a sufficient 
number of evaluable 
subjects complete each 
cohort. 


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Administration of Study Drug: 
with approximately 240 mL 
of non-carbonated room 
temperature  
Section 5.3 
To align with the process 
followed in the preceding 
SAD study 
Changed: 
On Days 1 and 14, water will be 
permitted as needed except from 
1 hour pre-dose until 1 hour after 
dosing. 
To: 
On Days 1 and 14, water will be 
permitted as needed except from 
1 hour pre-dose until 1 hour after 
dosing (with the exception of the 
water to be administered during 
drug administration). 
 
Section 5.5 
To align with the revised 
text for section 5.3 (above) 
Addition of Footnote to the SOA 
table for activities that need to be 
performed on Days -2 and -1.  
Activities need to be completed 
only once and should be performed 
based on the order of assessments 
and timing defined for specific 
 
Table 6.1 Schedule of 
Activities 
This was to provide clarity 
on the timings and order of 
assessments for each 
specific assessment. 
Study assessments were adjusted for 
Endocrinology, pregnancy test, 
blood sampling for investigative 
metabolite, and PD biomarker 
sampling to reflect accurate time 
points for each assessment.  
Change: Endocrinology assessments 
added to day 1 and removed from 
days 2, 3-13, 15, 16 and 17.    
Change: Footnote for endocrinology 
assessment added: 
Male hormones (FSH, 
testosterone, LH, Inhibin B) are to 
be collected: Day-1 (1 sample 
preferably in the morning); Day 1 
(2 samples: pre-dose and 1.5 hours 
Table 6.1 Schedule of 
Activities 
To provide clarity on 
sampling timepoints 


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post-dose); Day 14 (2 samples: pre-
dose and 1.5 hours post-
 
Added: To 12-lead dECG footnote 
-lead digital Holter is used for 
 
Change: Serum Pregnancy test 
added to Day -2 to -1 
Change: Blood sample for 
metabolite investigation was added 
to Day 1 
Change: PD blood sample removed 
from day 14 and added to Day 15 
since the timepoint falls on day 15.  
Physical Examination worksheets 
for physical and neurological 
examination Appendices were 
updated from Appendix 11 and 12 to 
Appendix 12 and 13 for accuracy. 
Section 6.2.2  
Corrected for accuracy  
ECG Recording Table 6-4 Updated: 
Added 
Day -1: in the morning at the start 
of 24-hour continuous wired ECG 
monitoring  
Day7 timepoint.  
Table 6-4 
Updated to add clarity and 
improve safety data 
evaluation 
The dECG acceptable window of 
assessments Appendix Cross-links 
were updated from Appendix 10 to 
Appendix 11 for accuracy.  
Section 6.2.5  
Corrected for accuracy  
Addition of text to Section 6.2.5 
Section 6.2.5 
 
 
 
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Added: Telemetry Updated 
Added: Footnote to Table 6-7 
telemetry on Day 1 and Day 14 
should be continued for up to 48 
hours post dose when subjects are 
 
Table 6-7 
To ensure accurate data 
capture and guidance to the 
investigators  
Table 6-14 The number  of 
endocrinology samples was reduced 
(from 8 to 5). However, of the 5 
samples, only 3 sample timepoints 
will require additional blood from 
the subject (other samples are 
included in the standard 
biochemistry/hematology 
assessments). As such the volume of 
blood required for the assessments 
has been reduced from 32 mL to 
10.5 mL.  
 
Table 6-14 
To provide clarity on 
sampling volumes 
Added:  
Modified The following text:  
Section 8.6.3  
For clarification purposes 
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Appendix 6 Endocrinology 
Assessment for TSH footnote was 
updated to remove footnote b. This 
was done to ensure that all subjects 
(not just women) have their TSH 
evaluated during screening.   
Footnote d was also updated to: 
Males only at Day -1, Day 1 and 
Day 14 
Appendix 6  
Corrected for accuracy 
Appendix 7: Male contraception 
guidance was updated from 90 days 
to 120 days to align with Study 
Inclusion/Exclusion Criteria 
(Section 4) 
Appendix 7  
Corrected for accuracy  
Append 11 Digital ECG Updated to 
include Day 7 procedure to align 
with protocol 
Appendix 11 
Update for consistency 
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TABLE OF CONTENTS ............................................................................................................................................ 2 
STUDY SYNOPSIS ................................................................................................................................................... 13 
STUDY ADMINISTRATIVE STRUCTURE ......................................................................................................... 19 
1. 
INTRODUCTION .............................................................................................................................................. 21 
1.1. Background ................................................................................................................................................... 21 
1.2. 
 
1.3. Risk/Benefit Assessment ............................................................................................................................... 22 
1.3.1. Known Potential Benefits....................................................................................................................... 22 
1.3.2. Important Potential Risks ....................................................................................................................... 23 
1.3.3. Risk/Benefit Summary and Conclusion ................................................................................................. 28 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................................... 29 
3. 
STUDY DESIGN ................................................................................................................................................ 31 
3.1. Overall Study Design .................................................................................................................................... 31 
3.2. Adaptive Features and Risk Management of Study Design .......................................................................... 32 
3.2.1. Maximum Tolerated Dose ...................................................................................................................... 33 
4. 
SUBJECT POPULATION ................................................................................................................................ 35 
4.1. Inclusion Criteria ........................................................................................................................................... 35 
4.2. Exclusion Criteria .......................................................................................................................................... 36 
4.3. Rescreening Criteria ...................................................................................................................................... 39 
4.3.1. Subjects within the Original Screening Window ................................................................................... 39 
4.3.2. Subjects Outside the Original Screening Window ................................................................................. 39 
4.4. Withdrawal Criteria ....................................................................................................................................... 39 
4.4.1. Before First Treatment Administration .................................................................................................. 39 
4.4.2. After First Treatment Administration..................................................................................................... 40 
4.5. Lifestyle and/or Dietary Requirements ......................................................................................................... 43 
4.6. Concomitant Treatment ................................................................................................................................. 43 
5. 
STUDY TREATMENTS .................................................................................................................................... 44 
5.1. Investigational Products ................................................................................................................................ 44 
5.2. Investigational Product Management ............................................................................................................ 44 
5.2.1. Packaging, Labelling, and Dispensing ................................................................................................... 44 
5.2.2. Storage and Handling ............................................................................................................................. 44 
5.2.3. Method of Assigning Subjects to Treatment Groups ............................................................................. 44 
5.2.4. Blinding .................................................................................................................................................. 45 
5.2.5. Study Drug Accountability..................................................................................................................... 45 
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5.3. Administration of Study Drug ....................................................................................................................... 46 
5.3.1. Treatment Compliance ........................................................................................................................... 46 
5.4. Meals ............................................................................................................................................................. 46 
5.5. Fluids ............................................................................................................................................................. 46 
5.6. Other Protocol Restrictions ........................................................................................................................... 46 
6. 
STUDY PROCEDURES .................................................................................................................................... 47 
6.1. Order of Assessments .................................................................................................................................... 51 
6.2. Safety Assessments ....................................................................................................................................... 51 
6.2.1. Medical History ...................................................................................................................................... 51 
6.2.2. Physical Examination ............................................................................................................................. 51 
6.2.3. Vital Signs .............................................................................................................................................. 51 
6.2.4. 12-Lead Safety Electrocardiogram ......................................................................................................... 52 
6.2.5. Electronic Capture of 12-lead Continuous Digital Electrocardiogram ................................................... 53 
6.2.6. Telemetry ............................................................................................................................................... 58 
6.2.7. Laboratory Evaluations .......................................................................................................................... 58 
6.2.8. Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................................... 58 
6.3. Pharmacokinetic and Pharmacodynamic Specimen Sampling ...................................................................... 59 
6.3.1. Pharmacokinetic Blood Sampling .......................................................................................................... 59 
6.3.2. 
 
6.3.3. 
 
6.3.4. Lumbar Puncture for CSF Sample (Cohorts 2 and 3 only) .................................................................... 61 
6.3.5. Pharmacodynamic Assessments ............................................................................................................. 61 
6.3.6. Pharmacokinetics and Pharmacodynamic Sample Handling ................................................................. 61 
6.4. Total Specimen Collection ............................................................................................................................ 62 
7. 
ADVERSE EVENTS DOCUMENTATION .................................................................................................... 62 
7.1. Definitions ..................................................................................................................................................... 62 
7.2. Severity Assessment ...................................................................................................................................... 64 
7.3. Causality Assessment .................................................................................................................................... 64 
7.4. Adverse Event Monitoring ............................................................................................................................ 64 
7.5. Serious Adverse Event Reporting ................................................................................................................. 65 
7.6. Reporting of Pregnancy ................................................................................................................................. 66 
7.6.1. Pregnancy in Female Subjects ................................................................................................................ 67 
7.6.2. Pregnancy in Female Partners of Male Subjects .................................................................................... 67 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................................................... 67 
8.1.1. Safety Population ................................................................................................................................... 67 
8.1.2. Pharmacokinetic Population ................................................................................................................... 67 
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8.1.3. Pharmacodynamic Population ................................................................................................................ 67 
8.2. Demographic Data and Other Baseline Characteristics ................................................................................. 67 
8.3. Safety............................................................................................................................................................. 68 
8.3.1. Safety Endpoints .................................................................................................................................... 68 
8.3.2. Safety Statistical Methodology .............................................................................................................. 68 
8.4. Pharmacokinetics .......................................................................................................................................... 68 
8.4.1. Missing Values ....................................................................................................................................... 68 
8.4.2. Measurements Below the Lower Limit of Quantitation ......................................................................... 68 
8.4.3. Actual Time ............................................................................................................................................ 68 
8.4.4. Baseline Reference Timepoint ............................................................................................................... 69 
8.4.5. Non-Compartmental Analysis ................................................................................................................ 69 
8.4.6. Cerebrospinal Fluid ................................................................................................................................ 72 
8.4.7. 
 
8.4.8. Data Handling ........................................................................................................................................ 72 
8.4.9. Pharmacokinetic Statistical Methodology .............................................................................................. 72 
8.5. Planned Interim Pharmacokinetic Analyses .................................................................................................. 73 
8.6. 12-Lead Digital ECG Analysis ...................................................................................................................... 73 
8.6.1. 12-Lead Digital ECG Statistical Methodology ...................................................................................... 73 
8.6.2. 
 
8.6.3. 
 
8.7. Determination of Sample Size ....................................................................................................................... 75 
9. 
REFERENCES ................................................................................................................................................... 76 
10. APPENDIX 1: ETHICS ..................................................................................................................................... 82 
10.1. Institutional Review Board ............................................................................................................................ 82 
10.2. Ethical Conduct of the Study ......................................................................................................................... 82 
10.3. Subject Information and Consent .................................................................................................................. 82 
10.4. Subject Confidentiality .................................................................................................................................. 82 
10.5. Safety Oversight ............................................................................................................................................ 82 
11. APPENDIX 2: DATA COLLECTION, RETENTION, AND MONITORING ............................................ 84 
11.1. Case Report Forms ........................................................................................................................................ 84 
11.2. Data Management and Processing ................................................................................................................. 84 
11.3. Quality Control and Quality Assurance......................................................................................................... 84 
11.4. Record Retention ........................................................................................................................................... 84 
11.5. Monitoring of the Study ................................................................................................................................ 84 
12. APPENDIX 3: ADMINISTRATIVE PROCEDURES .................................................................................... 85 
12.1. Liabilities ....................................................................................................................................................... 85 
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12.2. Adherence to Protocol ................................................................................................................................... 85 
12.3. COVID-19 Response Plan ............................................................................................................................. 85 
12.4. Statement of Investigator ............................................................................................................................... 85 
12.5. Delegation of Investigator Duties .................................................................................................................. 85 
12.6. Premature Termination or Suspension of a Study ......................................................................................... 86 
13. APPENDIX 4: PROTOCOL REVIEW AND APPROVALS ......................................................................... 87 
14. APPENDIX 5: LIST OF ABBREVIATIONS .................................................................................................. 90 
15. APPENDIX 6: CLINICAL LABORATORY EVALUATIONS ..................................................................... 94 
16. APPENDIX 7: CONTRACEPTION GUIDANCE .......................................................................................... 95 
17. APPENDIX 8: STUDY SPECIFIC RESTRICTIONS .................................................................................... 96 
18. APPENDIX 9: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)  
BASELINE/SCREENING VERSION .............................................................................................................. 97 
19. APPENDIX 10: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)  SINCE LAST VISIT 
VERSION ............................................................................................................................................................ 98 
20. APPENDIX 11: DIGITAL ELECTROCARDIOGRAM ................................................................................ 99 
21. APPENDIX 12: PHYSICAL EXAMINATION ............................................................................................. 101 
22. APPENDIX 13: NEUROLOGICAL EXAMINATION ................................................................................ 102 


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LIST OF IN-TEXT TABLES 
Synopsis Table 1-1. Proposed Dose Levels .................................................................................. 15 
Table 1-1. 
 
Table 1-2. 
 
Table 3-1 
Proposed Dose Levels ........................................................................................... 31 
Table 3-2 
Adaptive Features and Boundaries ....................................................................... 32 
Table 5-1 
Study Treatments .................................................................................................. 44 
Table 6-1 
Schedule of Activities ........................................................................................... 48 
Table 6-2 
Vital Sign Recording Schedule ............................................................................. 52 
Table 6-3 
Acceptable Windows for Vital Sign Assessments Procedures ............................. 52 
Table 6-4 
12-Lead Safety ECG ............................................................................................. 53 
Table 6-5. 
Acceptable Windows for 12-Lead Safety Electrocardiogram Assessments 
Procedures ............................................................................................................. 53 
Table 6-6 
: .................... 55 
Table 6-7 
Telemetry Schedule .............................................................................................. 58 
Table 6-8 
Pharmacokinetic Blood Sampling Schedule ......................................................... 59 
Table 6-9 
Acceptable Windows for Timed PK Blood Specimen Collection Procedures ..... 59 
Table 6-10 
 
Table 6-11 
 
Table 6-12 
 
Table 6-13 
 
Table 6-14 
 Specimen Collected and Total Amount per subject ............................................. 62 
Table 7-1 
Adverse Event Relationship to Study Drug .......................................................... 64 
Table 8-1 
Pharmacokinetic Parameters of AZD4041 in Plasma ........................................... 69 
Table 16-1. 
Highly Effective Methods of Contraception ......................................................... 95 
Table 17-1. 
Restricted medications/products ........................................................................... 96 
Table 17-2. 
Prohibited medications.......................................................................................... 96 
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Name of 
Sponsor/Company:
AstraZeneca AB 
Name of Product: 
AZD4041 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of Multiple Ascending Doses of AZD4041 
in Healthy Adult Subjects 
Study 
Development 
Phase: 
Phase 1 
Objectives: 
Primary objective: 
 To evaluate the safety and tolerability of orally administered AZD4041 in 
healthy subjects following daily doses for 14 days (or to steady state). 
Secondary objectives: 
 To characterize the multiple dose pharmacokinetics (PK) of AZD4041 and 
assess the time required to reach steady state, the degree of accumulation, 
and the time dependency of its PK. 
 
 
 
 
 To assess the central nervous system (CNS) penetration potential of 
AZD4041 by quantification of AZD4041 concentration in the 
cerebrospinal fluid (CSF) at steady state. 
Exploratory objective: 
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Endpoints: 
Primary endpoints: 
 
Adverse events (AEs) 
 
Vital signs 
 
Clinical laboratory tests 
 
12-lead electrocardiogram (ECG) (digital ECG [dECG] and safety 
ECG) and telemetry 
 
Columbia Suicide Severity Rating Scale (C-SSRS) questionnaire 
 
Physical and neurological examination 
 
Measurement of male hormone levels: testosterone, luteinizing 
hormone (LH), follicle stimulating hormone (FSH), and inhibin B. 
Secondary endpoints: 
The following AZD4041 PK endpoints will be estimated: 
 
Plasma: Cmax, Tmax, AUC0-24, AUC0-t, AUC0-inf, AUC , Ctrough, C , 
t1/2,z, t1/2Eff, CL/F, Vz/F, RAC(Cmax), and RAC(AUC), z 
 
Urine: Ae , fe/F, and CLR 
 
CSF (Cohorts 2 and 3 only): CSF concentration (ng/mL) reported as a 
percentage of total and free plasma concentration 
 
 
 
 
Exploratory endpoints: 
Investigational 
Product, Dose, and 
Mode of 
Administration 
(proposed): 
 
 
Manufacturer of Drug Substance: AstraZeneca 
Mode of administration: Oral 
Placebo, Dose, and 
Mode of 
Administration: 
 
 
Manufacturer: MEDISCA 
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Mode of administration: Oral 
Study Design: 
This is a Phase 1, randomized, double-blind, placebo-controlled, multiple 
ascending dose (MAD) study in healthy male and female adult subjects. 
The study will include up to 48 subjects (12 subjects per cohort) who will be 
randomized 9:3 to active drug or placebo. Each cohort will receive AZD4041 or 
placebo in a MAD order or until a maximum tolerated dose (MTD) is defined. 
If the MTD has not been defined and the maximum allowed exposure has not 
been reached after 3 cohorts, 1 additional cohort may be added. Enrolment of 
an additional cohort will be subject to a review of safety, tolerability and PK 
data from completed preceding cohorts, and will be based on the scientific 
rationale to explore additional dose levels with respect to predicted therapeutic 
dose levels and agreed exposure limits. 
Screening will occur within 28 days prior to the first study drug administration. 
Screening data will be reviewed to determine subject eligibility prior to the first 
study drug administration. Subjects who meet all inclusion criteria and none of 
the exclusion criteria and who consent to participation will be admitted to the 
study site the evening of Day -2 for baseline evaluations before dosing on the 
morning of Day 1. All baseline safety evaluation results should be available 
prior to first study drug administration and continued eligibility should be 
confirmed. 
The protocol makes provision for the evaluation of AZD4041 across 3 cohorts 
of subjects (N=12 subjects per cohort). For each cohort, 9 subjects will be 
randomly assigned to receive AZD4041 and 3 subjects will be assigned to 
receive placebo (see Synopsis Table 1-1). Within each cohort, 2 subjects will 
be randomized initially to AZD4041 or placebo (1:1 ratio) to allow a sentinel 
dosing approach. Providing no clinically significant issues have been noted 
after the first 3 doses of the initial 2 (sentinel) subjects in a cohort and provided 
the Day 2 safety laboratory tests for the 2 subjects have been reviewed, the 
remaining 10 subjects will be randomised to AZD4041 or placebo in an 8:2 
ratio and dosed in 2 separate groups with at least 24 hours between groups to 
monitor for safety and tolerability. All subjects will receive either AZD4041 or 
placebo administered once daily for 14 days.  
Synopsis Table 1-1. Proposed Dose Levels  
Cohorta 
Nb 
Dosec 
Regimen 
1 
9:3 
Adaptive 
Oral solution of 
AZD4041 or 
placebo once daily 
for 14 consecutive 
days (Day 1 to Day 
14) 
2 
Adaptive 
3 
Adaptive 
a. An additional cohort may be added if the maximum tolerated dose has not been defined and the 
maximum allowed exposure has not been reached after 3 cohorts 


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b. Active:Placebo 
c. Or until maximum tolerated dose is defined 
Safety will be assessed during the study through physical and neurological 
examinations, vital signs, ECGs (safety and dECG), telemetry, C-SSRS 
questionnaires, clinical laboratory assessments, and AE questioning. 
 
 
 
 In addition, subjects from Cohorts 2 and 3 will have lumbar punctures 
performed on one occasion to evaluate CSF levels of AZD4041
 
 
. 
Subjects are confined to the clinical site from the evening of Day -2 to Day 17. 
A follow-up visit will occur 10 to 14 days after discharge (Days 27 to 31). 
Subjects who terminate the study early will perform Day 17 scheduled 
procedures at the time of Early Termination. 
The Safety Review Committee (SRC) will review the safety and PK data of the 
previous cohort prior to initiating dosing of the subsequent cohort. Complete 
safety, tolerability and PK datasets from at least 10 subjects in the previous 
cohort must be reviewed during any safety meeting. Scope for dose escalation 
will be determined by the SRC based on an evaluation of the observed 
AZD4041 safety, tolerability and PK data from the completed cohort. Where 
dose escalation is not possible following completion of a given dose-level 
cohort, the protocol makes provision for an evaluation of the same dose or a 
lower dose in the next scheduled cohort at the discretion of the SRC.  
Duration of 
Treatment and 
Subject 
Confinement: 
Duration of clinical trial (per subject): 
Screening: Day -28 to Day -1 (up to 28 days) 
Treatment period: Subjects will be confined to the clinical site from the evening 
of Day -2 until 72 hours following the last study drug administration (Day 17). 
Follow-up visit: Subjects will return to the clinical site approximately 
10 to 14 days after discharge for a follow-up visit (Days 27 to 31). 
Total study duration: Up to 59 days (including Screening) 
Safety Meetings 
for Dose Escalation 
and Adjustments: 
Following completion of each cohort, a SRC will review all safety, tolerability, 
and PK data to evaluate scope for progression to the next dose cohort. Data 
from at least 10 subjects in the previous cohort must be reviewed before dose 
escalation can take place. 
The SRC will be comprised, at a minimum, of the 
(CRU) Principal Investigator, Study Manager, Medical Monitor and the 
Study Physician. 
During the study, each prescheduled cohort may be conducted at the dose 
outlined in the protocol or may be adjusted to allow for an evaluation of a 
lower dose level or for a repeat-evaluation of the same dose level based on 
safety, tolerability, and PK data reported in the previous cohorts. 
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The highest dose level tested will be based on an ongoing review of cumulative 
safety, tolerability and PK data from completed preceding dose-level cohorts, 
with due respect to the maximum permitted limits for human systemic 
exposure. 
Study Population: 
Healthy male or female adult subjects 
Planned Number 
of Subjects: 
Up to 48 subjects will be randomized (12 subjects per cohort). 
Pharmacokinetic 
Analysis: 
Plasma and urine samples for determination of AZD4041 concentration will be 
collected at various timepoints throughout the study. 
PK analyses will be performed by non-compartmental analysis and will be 
further detailed in the statistical analysis plan (SAP). 
The following PK parameters in plasma will be estimated for AZD4041, data 
permitting: 
Day 1: Cmax, Tmax, AUC0-24, AUC0-t, AUC0-inf, t1/2,z, and CL/F 
Days 3 to 13: Ctrough 
Day 14: Ctrough, Cmax, Tmax, C , AUC , AUC0-t, t1/2,z, t1/2Eff, CL/Fss, , RAC(Cmax), 
RAC(AUC) 
The following PK parameters in urine will be estimated for AZD4041, data 
permitting: 
Day 1 and Day 14: Ae, fe, and CLR 
AZD4041 CSF concentrations on Day 14 will be calculated as a percentage of 
the total and free plasma concentration (For cohorts 2 and 3 only) 
Additionally, the following biomarker will be measured prior to dosing on 
Day 1 and Day 14: plasma 4- -hydroxy-cholesterol. 
 
 
 
 
 
 
 
 
 
 
 
Statistical 
Analysis: 
Descriptive statistics will be used to summarize the safety endpoints. 
Descriptive statistics will be calculated for AZD4041 concentrations in plasma, 
urine, CSF, and safety parameters (dECG intervals), at each individual 
timepoint (or time interval, for urine) and for all PK parameters; individual and 
mean concentration-time profiles will also be presented. 
The appropriate PK parameters (Cmax, AUCs) will be assessed statistically for 
dose proportionality. Proportionality analysis will be done using a power 
model. 
Ctrough will be displayed graphically and summarized descriptively to assess for 
steady state. 
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The statistical analyses will be further detailed in the SAP. 
 


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Biopharmaceuticals Research and Development 
AstraZeneca 
Aaron Klug Building, Granta Park 
Cambridge CB21 6GH 
United Kingdom 
Tel: +44 7469 119060 
CLINICAL RESEARCH UNIT: 
Altasciences 
1200 Beaumont Ave. 
Mount-Royal, Quebec, Canada 
H3P 3P1 
SCREENING FACILITY: 
 
Altasciences 
1100 Beaumont Ave. 
Mount-Royal, Quebec, Canada 
H3P 3H5 
BIOANALYTICAL FACILITIES: 
LabCorp 
 
 
 
 
3402 Kinsman Blvd.  
 
 
 
 
 
Madison, WI US 53704 
 
 
 
 
 
USA 
 
 
 
 
 
 
Altasciences  
 
 
 
 
 
575 Armand-Frappier Blvd 
 
 
 
 
 
Laval, Quebec, Canada 
 
 
 
 
 
H7V 4B3 
URINE MARKER FACILITIES: 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
SCIENTIFIC AFFAIRS: 
 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
STATISTICAL FACILITY: 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
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ECG CORE LABORATORY:  
   AstraZeneca ECG Centre 
AZ R&D Gothenburg 
Pepparedsleden 1 
43183 Molndal 
Sweden 
C QTc Analysis 
 
 
 
 
    AstraZeneca  
Aaron Klug Building, Granta Park 
Cambridge CB21 6GH 
United Kingdom 
 
  
 
 
 
 
 
 
DATA MANAGEMENT FACILITY: Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
BIOBANKING FACILITY  
 
AstraZeneca  
 
 
 
 
 
Raul Rios (Operations Manager) 
 
 
 
 
 
SSF Biobank 
 
 
 
 
 
121 Oyster Point Blvd 
 
 
 
 
 
South San Francisco, CA 94080 
 
 
 
 
 
USA 
 
 
 
 
 
SDM@astrazeneca.com 
PROJECT MANAGEMENT: 
 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3
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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 (Centers for Disease Control and Prevention [CDC], National Center for Health 
Statistics, 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 Medicaid billed OUD treatment alone costing over $8 
billion in 2013 (Leslie et al, 2019). 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) 
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 
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 (Mancher 
et al, 2019; Hall et al, 2008; Leslie et al, 2019), unpleasant side effects (Chen and Ashburn, 
2015) that reduce compliance, including withdrawal symptoms of withdrawal (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 National 
Institute of Drug Abuse (NIDA) has identified several high priority drug targets for rapid 
therapeutic development (Rasmussen et al, 2019). Orexin 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 (GPCRs), the OX1 and OX2 receptors. Orexin A 
has high affinity for both receptors whereas orexin B has higher affinity for OX2 over OX1 
receptors. Orexin transmission has been implicated in a diverse range of physiological functions, 
including feeding and energy homeostasis (Sakurai et al, 1998), the sleep/wake cycle (Gotter et 
al, 2016), neuroendocrine homeostasis, cardiovascular functions (Samson et al, 2007), and 
motivated behaviours (Kodadek and Cai, 2010). 
 
 
 
 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 (Pantazis 
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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 
1.3. 
Risk/Benefit Assessment 
1.3.1. Known Potential Benefits 
As the study treatment is not being given to subjects to treat any symptoms or illness, there will 
be no direct medical benefit from participation in this trial. 
 
 
. Supporting the 
feasibility of developing a safe and potent OX1 receptor antagonist for OUD is the fact that two 
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dual OX1/OX2 receptor antagonists (so-called DORAs) have 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 demonstrate 
mechanism-related toxicity in humans 
, 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. 
1.3.2. Important Potential Risks 
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 (see Section 7.1). 
1.3.2.1. Justification for Dose selection 
For the purposes of predicting human exposures following multiple dosing with AZD4041 over a 
 oral dose range, steady-state profiles were simulated using nonparametric 
superposition in Phoenix-WinNonlin
 using data achieved in the single-dose study over the 
dose range 
. Results from steady-state profiles were used to estimate the 
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geometric mean for Cmax and AUC0-24 using noncompartmental analysis for the proposed MAD 
study. Comparable results were obtained from physiologically-based PK (PBPK) modelling 
using simCYP simulation software after dosing for a 2-week period, every 24 hours. The current 
PBPK model fitted dose ranges 
 in the single-dose study (see AZD4041 
 for details).  
 
 
 
 
 
 
Table 1-1. 
 
Table 1-2. 
 
The MAD study is designed to enable an exploration of safety and systemic exposure 
relationships over a dose-range that is predicted to be relevant to expected therapeutic exposures 
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for 
 opioid-use disorder. The rationale for the planned AZD4041 
starting dose level 
 and higher provisional dose levels 
 is based on an 
understanding of data accumulated across non-clinical studies and clinical experience to-date 
summarised as follows: 
 
 
 
 
 
 
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1.3.3. Risk/Benefit Summary and Conclusion 
 
 
 
 
 
 
 
. Dosing of subjects will be staggered appropriately and 
includes sentinel subjects for each cohort. 
 
 
 
 
 
 
 
 
. The requirement for healthy volunteer 
subjects to use highly effective methods of contraception (APPENDIX 7) has been implemented 
into the study protocol. 
Based on the considerations regarding the potential risks of AZD4041, as well as the risk-
mitigation precautions included in the clinical study protocol, exposure of healthy volunteer 
subjects to repeat doses of AZD4041 is considered justifiable in relation to the significant unmet 
need for patients in opioid-use disorder. It is expected that the safety, tolerability and PK data 
acquired in the current repeat dose study in health volunteer subjects 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 
. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To evaluate the safety and tolerability of orally 
administered AZD4041 in healthy subjects 
following daily doses for 14 days (or to steady 
state) 
 
AEs 
 
Vital signs 
 
Clinical laboratory tests 
 
12-lead ECG (dECG and safety ECG) and 
telemetry (bedside cardiac monitoring) 
 
C-SSRS questionnaire 
 
Physical and neurological examination 
 
Measurement of male hormone levels: 
testosterone, LH, FSH, and inhibin B 
Secondary 
 
 
To characterize the multiple dose PK of 
AZD4041 and assess the time required to 
reach steady state, the degree of 
accumulation, and the time dependency of 
its PK 
 
 
 
 
 
 
 
To assess the CNS penetration potential of 
AZD4041 by quantification of AZD4041 
concentration in the CSF at plasma steady 
state 
The following AZD4041 PK endpoints will be 
estimated, data permitting: 
 
Plasma: Cmax, Tmax, AUC0-24, AUC0-t, AUC0-inf, 
AUC , Ctrough, C , t1/2,z, t1/2Eff, CL/F, Vz/F, 
RAC(Cmax), and RAC(AUC), z 
 
Urine: Ae fe/F, and CLR 
 
CSF (Cohorts 2 and 3 only): CSF concentration 
(ng/ml) reported as a percentage of total and free 
plasma concentration 
Additional PK parameters (as noted in Section 8.4) 
may be estimated as appropriate to support the main 
PK endpoints. 
 
 
 
 
 
Exploratory
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OBJECTIVES 
ENDPOINTS 
Abbreviations: AEs= adverse events; CNS =central nervous system C-SSRS = Columbia Suicide Severity Rating 
Scale; CSF = cerebrospinal Fluid; CSR = Clinical Study Report; dECG = digital electrocardiogram; 
ECG = electrocardiogram; 
 FSH = follicle stimulating hormone; LH = luteinizing hormone; 
; 
; 
; PK = 
Pharmacokinetics; 
; 
; 
 
 
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3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, MAD study in 
healthy male and female adult subjects. 
The study will include up to 48 subjects (12 subjects per cohort) who will be randomized 9:3 to 
active drug or placebo. Each cohort will receive AZD4041 or placebo in a MAD study. 
However, the need for an additional cohort will be based primarily on the scientific need to 
explore a range of doses in Phase 1 that are anticipated to span a therapeutic exposure level that 
is predicted to be relevant to any subsequent Phase 2 efficacy evaluation of AZD4041 in patients 
with OUD. 
Screening will occur within 28 days prior to the first study drug administration. Screening data 
will be reviewed to determine subject eligibility prior to the first study drug administration. 
Subjects who meet all inclusion criteria and none of the exclusion criteria and who consent to 
participation will be admitted to the study site for baseline evaluations before dosing (Day -2). 
All baseline safety evaluation results should be available prior to the first study drug 
administration and continued eligibility confirmed. 
The protocol makes provision for the evaluation of AZD4041 across 3 cohorts of subjects (N=12 
subjects per cohort). For each cohort, 9 subjects will be randomly assigned to receive AZD4041 
and 3 subjects will be assigned to receive placebo (see Table 3-1 below). Within each cohort, 2 
subjects will be randomized initially to AZD4041 or placebo (1:1 ratio) to allow a sentinel 
dosing approach. Providing no clinically significant issues have been noted after the first 3 doses 
of the initial 2 (sentinel) subjects in a cohort and provided the Day 2 safety laboratory tests for 
the 2 subjects have been reviewed, the remaining 10 subjects will be randomised to AZD4041 or 
placebo in an 8:2 ratio and will be dosed in 2 separate groups with at least 24 hours between 
groups to monitor for safety and tolerability. All subjects will receive either AZD4041 or 
placebo administered 
 for 14 days. 
Table 3-1 
Proposed Dose Levels 
Cohorta 
Nb 
Dosec 
Regimen 
1 
9:3 
Adaptive 
Oral solution of 
AZD4041 or placebo 
 for 
14 consecutive days 
(Day 1 to Day 14) 
2 
Adaptive 
3 
Adaptive 
a. An additional cohort may be added if the maximum tolerated dose has not been defined and the maximum 
allowed exposure has not been reached after 3 cohorts 
b. Active:Placebo 
c. Or until maximum tolerated dose is defined 
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A sequential cohort MAD design will be employed to assure that higher doses are administered 
to healthy subjects only after lower doses have demonstrated an acceptable safety profile as 
assessed by physical and neurological examination, vital signs, ECG (dECG and safety ECG), 
telemetry, C-SSRS questionnaires, clinical laboratory testing, and AE monitoring. 
 
 
. In addition, subjects from Cohorts 2 and 3 will have lumbar punctures 
performed to evaluate CSF levels of AZD4041. 
 
 
 
Subjects will be confined to the clinical site from 36 hours prior to the first study drug 
administration until 72 hours after the last study drug administration (Days -2 to 17). A 
follow-up visit will occur 10 to 14 days after discharge (Days 27 to 31). 
Subjects who terminate the study early will perform the Day 17 scheduled procedures at the time 
of Early Termination. 
The total study duration will be up to 59 days (including Screening). 
The SRC will review the safety, tolerability, and PK data of the previous cohort prior to initiating 
dosing of the subsequent cohort. Data sets from at least 10 subjects from the previous cohort 
must be reviewed during any safety meeting. Based on observed AZD4041 safety, tolerability, 
and available PK data, the dose escalation will be approved prior to dosing the next cohort. The 
study makes provision for dose-adjustment, with all due respect to exposure limits, such that 
each prescheduled cohort may be conducted at the dose outlined in the protocol or may be 
adjusted, at the discretion of the SRC, to allow for an evaluation of a lower dose level or for a 
repeat-evaluation of the same dose level an intermediate (lower) or equivalent dose, based on 
safety, tolerability, and PK data. 
The study schema is presented in Figure 3-1. 
The schedule of activities is presented in Table 6-1. 
3.2. 
Adaptive Features and Risk Management of Study Design 
The study design may be adapted as described in Table 3-2. 
Table 3-2 
Adaptive Features and Boundaries 
Adaptive study 
design category 
Adaptive Features 
Boundaries 
Dose levels 
Doses will be 
determined/adapted 
in accordance with 
available safety, 
tolerability, and PK 
data collected in 
previous cohorts. 
The planned AZD4041 starting dose level will be 
, 
oral, 
. 
Exploration of subsequent dose levels will be based on a 
review of available safety, tolerability, and PK data from 
the previous cohorts. Complete data sets from at least 
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Adaptive study 
design category 
Adaptive Features 
Boundaries 
10 subjects in the previous cohort must be reviewed 
during the safety meetings. 
Doses are intended to escalate; however, they may be 
adjusted to an intermediate (lower) or equivalent dose, 
based on safety, tolerability, and PK data reported in the 
previous cohort(s), at the discretion of the SRC. 
Human exposure limits in the MAD will be based on 
those which have been achieved in the SAD study. 
The number of 
MAD cohorts 
The number of MAD 
cohorts may be 
adapted. 
Three cohorts of 12 subjects each are planned. However, 
if the MTD has not been defined and the maximum 
allowed exposure has not been reached after 3 cohorts, up 
to 1 additional MAD cohort may be added, at the 
discretion of the SRC 
Abbreviations: GLP = Good Laboratory Practices; MAD = multiple ascending dose; MTD = maximum tolerated 
dose; NOAEL = no-observed-adverse-effect level; PK = pharmacokinetics; SAD = single ascending dose; SRC= 
Safety Review Committee 
The decision-making process for the above adaptive study categories will be as follows: 
 Interim review of safety, tolerability, and PK data of AZD4041 from previous cohorts in 
a blinded fashion by the SRC. Complete data sets from at least 10 subjects in the previous 
cohort must be reviewed before dose escalation can take place. 
 Outcome on the adaptive study (cohort by cohort) category will be documented by the 
SRC. 
The SRC will be comprised of, at a minimum, the Principal Investigator at the Investigational 
site, the Study Manager, Medical Monitor, 
Study Physician. 
Based on the above, progression to the next dose cohort may be performed without delay 
(ie, without prior approval from the Research Ethic Committee or regulatory authorities), unless 
the adaptive features are outside of the prespecified boundaries.  
3.2.1. Maximum Tolerated Dose 
The MTD definition of transient, mild, or moderate AEs occurring at a given dose level will be 
 3 subjects at a given 
dose level, dose escalation may be ceased and this dose level or the next lower one will be 
considered the MTD, or an intermediate dose level can be investigated. If such AEs occurred in 
 2 subjects depending on the particular adverse effects observed, the current dose level may be 
considered the MTD, or dose escalation may proceed. 
If the MTD has not been defined and the maximum allowed exposure has not been reached after 
3 cohorts, up to 1 additional MAD cohort may be added. 


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Figure 3-1.  
Study Schema 
Visit 1a 
Enrolment 
 
Visit 2 
In patient period 
 
Visit 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
 
Admission to 
study unit 
 
 
 
Discharge from 
study unit 
 
Follow up 
 
 
 
 
 
 
 
 
 
Screening 
period 
 
 
Randomization 
 
 
 
 
Multiple dose administration 
(Once daily) 
 
 
 
 
 
 
 
 
 
 
 
 
 
-28 days 
 
Day -2 
Day 1 
 
 
Day 14 
Day 17 
 
Days 27 
to 31 
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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 entered in the study. 
4.1. 
Inclusion Criteria 
1. Provision of signed and dated written informed consent form (ICF) prior to any 
study-specific procedures 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
3. Healthy adult male or female subjects. Female subjects must be of non-childbearing 
potential (postmenopausal and/or surgically sterile) 
4. If female, meets one of the following criteria: 
(1) Physiological postmenopausal status, defined as the following: 
a) absence of menses for at least 12 months following cessation of all exogenous 
hormonal treatments (without an alternative medical condition) at Screening and 
prior to the first study drug administration; and 
b) 
 mIU/mL at Screening; and 
c) must have a negative pregnancy test result at screening and check-in. 
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; and must have a negative pregnancy test result at screening and 
check-in. 
If postmenopausal and has an FSH of < 40 mIU/mL, but meets all other criteria in (1) or 
(2) above as well as all the other inclusion criteria, screening oestradiol serum level must 
be equal to or below 150 pmol/L.  
5. Men who are biologically capable of fathering children must agree and commit to use an 
adequate form of contraception (APPENDIX 7) for the duration of the treatment period 
and for no less than 120 days (4 months) after the last administration of study 
intervention. A male subject is considered capable of fathering children even if his sexual 
partner is sterile or using contraceptives. 
6. Men who are biologically capable of fathering children must also agree to refrain from 
sperm donation for the duration of the treatment period and for at least 90 days after the 
last administration of study intervention. 
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8. Body mass index (BMI) within 18.0 kg/m2 to 30.0 kg/m2, inclusive 
9. Body weight of within 50 kg to 100 kg, inclusive 
10. Non- or ex-smoker (An ex-smoker is defined as someone who completely stopped using 
nicotine products for at least 180 days prior to the first study drug administration) 
11. Have no clinically significant diseases captured in the medical history or evidence of 
clinically significant findings on the physical or neurological examination (including vital 
signs) and/or ECG and/or safety laboratory tests, as determined by an Investigator 
12. Suitable veins for cannulation or repeated venepuncture 
4.2. 
Exclusion Criteria 
1. Female who is lactating 
2. Female who is pregnant according to the pregnancy test at Screening or prior to the first 
study drug administration 
3. Male subjects with a history of oligospermia or azoospermia or any other disorder of the 
reproductive system 
4. Male subjects who are undergoing treatment or evaluation for infertility. 
5. History of significant allergy/ hypersensitivity to AZD4041 or products related to 
AZD4041 (including excipients of the formulation) as well as severe 
allergy/hypersensitivity reactions (like angioedema) to any drugs 
6. Presence or history of significant gastrointestinal, liver or kidney disease, or any other 
condition that is known to interfere with drug absorption, distribution, metabolism, or 
excretion, or known to potentiate or predispose to undesired effects 
7. History of any significant disease, including [but not necessarily limited to] significant 
cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, 
immunologic, or dermatologic disease 
8. Maintenance therapy with any drug or significant history of drug dependency or alcohol 
abuse (> 21 units/week or > 3 units/day for men; > 14 units/week or > 2 units/day for 
women; intake of excessive alcohol, acute or chronic) 
9. History of any significant psychiatric disorder according to the criteria of the Diagnostic 
and Statistical manual of Mental Disorders, 5th Edition (American Psychiatric 
Association 2013) which, in the opinion of the Investigator, could be detrimental to 
subject safety or could compromise study data interpretation. 
10. History of substance use disorder, other than nicotine or caffeine (as per DSM-5 criteria) 
11. Use of any prescription drugs, including hormone replacement therapy in the 28 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 
12. U
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13. Positive test result for alcohol and/or drugs of abuse at Screening or prior to the first 
study drug administration 
14. Any clinically significant illness, medical/surgical procedure or trauma within the 
28 days prior to the first study drug administration 
15. Any abnormal or clinically significant findings 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 
16. Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen, or 
hepatitis C virus tests 
17. Showing suicidal tendency as per the C-SSRS questionnaire administered at Screening 
(APPENDIX 9) 
18. Any abnormal vital signs, after 10 minutes supine rest, as defined in the list below, at the 
Screening Visit/or Day -2 Out of range tests may be repeated once for each visit at the 
discretion of an Investigator.  
a. Systolic BP < 90 mmHg or >140 mmHg 
b. Diastolic BP < 50 mmHg or > 90 mmHg 
c. Heart Rate <45 or >85 beats per minute (bpm) 
19. 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 an 
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 results may be repeated once for each visit at the discretion of an 
Investigator) 
20. Prolonged QT interval corrected for HR 
 (QTcF) > 440 ms at 
Screening or prior to the first study drug administration 
21. Shortened QTcF < 340 ms at Screening or prior to first study drug administration 
22. Known family history of long QT syndrome 
23. ECG interval measured from the onset of the P wave to the onset of the complex between 
Q and S waves (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 the first study drug administration 
24. 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 the first study drug administration 
25. Persistent or intermittent complete bundle branch block, incomplete bundle branch block, 
or intraventricular conduction delay (IVCD) with ECG interval measured from the onset 


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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 the first study drug administration 
26.  In the pre-dose 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 VPC (ventricular couplets) or other repetitive ventricular rhythms, including non-
sustained or sustained (> 30 second duration), slow (< 100bpm), 
 100 bpm) 
ventricular tachycardias. 
27. Vaccination with the Coronavirus disease 2019 (COVID-19) vaccine less than 14 days 
prior to first study dose administration 
28. Scheduled immunization with a COVID-19 vaccine (first or second dose) during the 
study that, in the opinion of an Investigator, could potentially interfere with subject 
participation, subject safety, study results, or any other reason 
29. Use of any prescribed or nonprescribed oral and topical inhibitors/inducers of CYP3A4 
(including shampoo). 
30. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as 
judged by an Investigator 
31. Subjects who have previously received AZD4041 
32. Any history of tuberculosis 
33. Involvement of any AstraZeneca or study site employee or their close relatives 
34. Judgment by an Investigator that the subject should not participate in the study if they 
have any ongoing or recent (ie, during the Screening period) minor medical complaints 
that may interfere with the interpretation of study data or are considered unlikely to 
comply with study procedures, restrictions, and requirements  
35. Presence of any tongue piercings or history of any tongue piercings in the last 90 days 
prior to the first study drug administration 
36. Subjects who have medical dietary restrictions 
37. Subjects who cannot communicate reliably with the Investigator 
38. Inclusion in a previous group for this clinical study 
39. Intake of an investigational product (IP) within at least 28 days or 5 half-lives; whichever 
is longer, prior to the first study drug administration 
40. Donation of 50 mL or more of blood in the 28 days prior to the first study drug 
administration 
41. Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical 
studies, etc.) in the 56 days prior to the first study drug administration 


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4.3. 
Rescreening Criteria 
Subjects may be required to be re-screened 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.  
4.3.1. Subjects within the Original Screening Window 
A subject within the original screening window may enrol in any open cohort as long as he/she 
meets all eligibility criteria with the following conditions  
 All Day -1 procedures (Table 6-1) must be repeated 
 The Subject will retain his/her original subject identification number.  
4.3.2. Subjects Outside the Original Screening Window 
Subjects outside of the original screening window may be randomized for the next available 
cohort if the following conditions are met and he/she is deemed eligible:  
The following screening procedures must be repeated to determine eligibility:  
 Signed ICF (applicable only if there has been a revision to the original ICF)  
 Recent medical/surgical history 
 C-SSRS assessment  
 Concomitant medication 
 Physical examination 
 Neurological examination 
 Laboratory tests (between Day -14 and Day -3) expect for HIV, Hepatitis B and C, and 
 
 Vital Signs 
 12-lead ECG  
All Day -1 procedures (Table 6-1) must be repeated. 
Subjects who are outside of initial screening window will 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 eligibility of 
subjects to be enrolled into the study and dosed. Subjects withdrawn before first treatment 
administration will not be followed up and will not undergo Early Termination assessments. 
Other safety assessments may be performed if required. 


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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 the Sponsor. An Investigator may withdraw a subject at any 
time if it is determined that continuing the study would result in a significant safety risk to the 
subject or if the 
 behaviour 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 
study documents. 
An Investigator may remove a subject from the study on the recommendation of the PK facility 
and/or Sponsor due to an unanticipated event that could result in an inadequately characterized 
PK profile (eg, a missed blood draw, an AE, meal deviation, concomitant medication intake). 
In the case of a clinically significant illness detected during the trial (including COVID-19 
diagnosis), the Principal Investigator (or delegate) will, in concert with the Sponsor, determine 
the most appropriate course of action on an individual basis. Evaluations will include but are not 
limited to: 
 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 analysed 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 (CSR). 
Attempts should be made to have such subjects complete the Early Termination assessments. 
Early Termination assessments (assessments from Day 17 in Table 6-1) 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, registered letters, etc.). 


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4.4.2.1. Stopping Rules 
4.4.2.1.1. Individual Subject Stopping Rules 
Participation in the clinical study may be discontinued by the physician 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 noncompliance (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 > 2 × ULN 
 Aspartate aminotransferase (AST) > 3 x ULN 
 Alanine aminotransferase (ALT) > 3 × ULN 
 Creatinine > 1.5 × ULN 
 Meets either of the following criteria: 
QTc prolongation defined as QTcF > 500 ms or a prolongation from baseline of >60 ms 
(persisting for at least 5 minutes) confirmed and determined post dose either during 
continuous 12-lead ECG monitoring or on a repeat 12-lead ECG. 
4.4.2.1.2. Cohort Stopping Rules 
If any of the following safety concerns are observed, dosing of all subjects at the given dose level 
or higher will be suspended/halted and all available data will be evaluated by the SRC. Dose 
continuation (remaining subjects within a cohort or remaining dosing for a subject) or escalation 
should not proceed for any of, but not limited to, the following reasons: 
 If 1 AZD4041 related serious adverse event (SAE) (based on Investigator or Sponsor 
assessment) (Grade 3, 4, or 5) occurs in a cohort 
 Moderate or severe AEs in 50% or more of the subjects in a cohort 
 Two or more subjects that 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 during continuous 12-lead ECG monitoring or 
on a repeated 12-lead ECG 
 Two or more subjects, who received AZD4041, have tachycardia defined as resting 
supine heart rate > 125 bpm persisting for at least 10 minutes 
 Two or more subjects, who received AZD4041, have a non-
 
 


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 One or more subjects, who received AZD4041, have a sustained ventricular tachycardia 
(ie, >30 second duration, or leading to haemodynamic consequences requiring immediate 
intervention to terminate the arrhythmia) 
 Two or more subjects, who receive AZD4041, have symptomatic bradycardia defined as 
resting supine heart rate < 40 bpm or asymptomatic bradycardia defined as resting supine 
heart rate < 30 bpm while awake and persisting for at least 10 minutes 
 Two or more subjects, who receive AZD4041, develop hypertension defined as an 
increase in resting supine systolic BP > 40 mmHg to above 180 mmHg and persisting for 
at least 10 minutes 
 Two or more subjects, who receive AZD4041, develop hypotension defined as an 
asymptomatic fall in systolic blood pressure (SBP) > 20 mmHg to below 70 mmHg 
persisting for at least 10 minutes, or a symptomatic fall in resting supine SBP > 20 
mmHg (excluding vasovagal reaction). 
 Clinically significant laboratory abnormalities including, but not necessarily limited to: 
o One or more subjects, who receive AZD4041, fulfil 
increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
 
× ULN, where no 
other reason can be found to explain the combination of increases; eg, elevated 
serum alkaline phosphatase (ALP) indicating cholestasis, viral hepatitis, or 
 at the same time or within a 
specified time frame.  
o Two or more subjects, who receive AZD4041, have >3× ULN of either ALT or 
AST, or >2× ULN for TBL or ALP. 
Dose escalation will be discussed during the SRC meeting and may be stopped depending on the 
Principal Investigator
(or delegate) 
 to the 
following: 
 New clinically significant abnormalities in physical examination; including neurological 
examination, 12-lead ECG, or vital signs in 2 or more subjects 
 Overall pattern of clinical changes or symptoms that may have appeared minor in terms 
of an individual AE or subject, but which collectively present a safety concern 
 Clinically significant changes in organ-specific laboratory parameters (eg, liver function 
enzymes, renal function studies in 1 or more subjects) 
 Pattern of laboratory changes (eg, a consistent increase or decrease within 2 or more 
subjects or within or across dosing groups) which might indicate an overall safety 
concern 


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4.4.2.1.3. Trial Stopping Rules 
Clinical trial stopping rules: 
 
If 2 AZD4041-related SAEs (based on Investigator or Sponsor assessment) (Grade 3, 4, or 5) 
occur in a cohort 
 
Occurrence of 1 death attributable to the study treatment 
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 study drug administration and during the study. 
 Subjects will be prohibited from consuming alcohol for 48 hours prior to the first study 
drug administration and during the study. Throughout the study (including the follow-up 
visit), in case of any doubt about alcohol consumption, a test for alcohol may be 
performed if requested by the physician. 
 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 
study drug administration and during the study. 
 Subjects will eat only the food provided by the study site during confinement at the 
clinical research unit (CRU). 
4.6. 
Concomitant Treatment 
In addition to the drugs prohibited as per the exclusion criteria (Section 4.2), subjects will also be 
prohibited from taking any over-the-counter (OTC) products for 14 days prior to the first study 
drug administration and during the study. Specifically restricted and prohibited medications are 
detailed in APPENDIX 8. 
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 study drug 
administration until all study activities and evaluations have been completed. 
Subjects will be instructed to notify the study site about any new medications taken after the start 
of the study treatment. All medications and significant nondrug therapies (including physical 
therapy and blood transfusions) administered after the subject has received the study treatment 
must be listed in the subject  case report form (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. 
Medication other than those described above
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate section of the eCRF. 
4.7. 
Contraceptive Guidance 
Contraception guidance for male and female subjects can be found in APPENDIX 7. 


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5. 
STUDY TREATMENTS 
5.1. 
Investigational Products 
All IPs will be provided by the Sponsor. The study treatments are presented in Table 5-1. 
Table 5-1 
 
5.2. 
Investigational Product Management 
5.2.1. Packaging, Labelling, and Dispensing 
The Sponsor will be responsible for ensuring that the IP is prepared (where applicable) in 
accordance with applicable current Good Manufacturing Practice regulations and requirements. 
The IPs will be labelled according to the requirements of local law and legislation. The IPs will 
prelabelled 
individual dosing samples. 
5.2.2. Storage and Handling 
y. 
AZD4041 should be stored under conditions as described on the label. The products should not 
be used if expired and should not be frozen. 
restricted area), and dispensed. Investigational products will be provided to study subjects only. 
5.2.3. Method of Assigning Subjects to Treatment Groups 
The CRU will generate the randomization code with a computer program according to the study 
design, the number of subjects, and the number of treatments. Eligible subjects within each 
cohort will be randomly assigned in a ratio of 9:3 to Active: Placebo. Once generated, the 
randomization code will be final and will not be modified. 
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Subjects who sign the ICF, are randomized, receive the study treatment, and subsequently 
withdraw, or are withdrawn or discontinued from the study, should not generally be replaced. 
However, consideration may be given to the replacement of such subjects in order to enable the 
completion of at least 10 subjects for the purposes of Safety Review Committee and dose 
escalation decisions. Replacement of subjects under these circumstances 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 cohort stopping rules (Section 4.4.2.1) or otherwise jeopardise the safe 
conduct of the study. 
 
5.2.4. Blinding 
The treatment assignment will not be known by the study participants; however, the taste 
between the IP and placebo is distinguishable and unable to be masked. Therefore, it is possible 
that subjects will know the treatment to which they have been assigned. 
The randomization code will not be available to the personnel of the bioanalytical facility until 
the bioanalytical phase of the study has been completed. 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, including the pharmacokineticist(s) and statistician(s) (or delegate), until all the 
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 
by an Investigator for further treatment to 
the subject or to complete a SAE report. Randomization information will be held by designated 
individual(s). In the event of a medical emergency requiring identification of the study drug 
administered to an individual subject, an Investigator will make every attempt to contact the 
Sponsor  Study Physician to explain the need for breaking the blind within 24 hours of doing 
so. The date and reason for breaking the blind must be recorded. 
The results of the PK and safety analyses will be made available only to the personnel 
responsible for evaluating the safety data before proceeding with the next dose level. The 
bioanalytical facility will preserve the blind by reassigning alternative subject numbers to the 
interim data before they are made available to the PK facility and Sponsor; these alternative 
subject numbers will be assigned by the lab at the time of sample analysis. 
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. 


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The labelling and storage conditions shall comply with the current FDA rules and regulations. 
Drug accountability will be performed at the completion of the trial. 
5.3. 
Administration of Study Drug 
Study drug will be administered in the morning. The date and time of each dose will be recorded. 
For each subject, all scheduled postdose activities and assessments will be performed relative to 
the time of each study drug administration. 
5.3.1. Treatment Compliance 
The IP will be dispensed only to eligible subjects and administered under the supervision of 
study personnel. 
The following measures will be employed to ensure treatment compliance: 
 All doses will be administered under the supervision of an Investigator (or delegate). 
 
the study drug was swallowed. 
5.4. 
Meals 
Food intake will be controlled for the confinement period and for all subjects. 
On Days 1 and 14, subjects will be required to fast (abstain from food) for at least 10 hours prior 
to dosing and for at least 4 hours following dosing. 
No fasting requirements will be implemented for the study drug administrations on Days 2 to 13. 
5.5. 
Fluids 
Fluid intake other than water will be controlled for the confinement period and for all subjects. 
On Days 1 and 14, water will be permitted as needed except from 1 hour pre-dose until 1 hour 
after dosing (with the exception of the water to be administered during drug administration)  
No water restriction will be implemented for the study drug administrations on Days 2 to 13. 
5.6. 
Other Protocol Restrictions 
On Days 1 and 14, subjects will remain seated or kept in minimal ambulatory movement for the 
first 4 hours following study drug administration, avoiding both vigorous exertion and complete 
rest. On Days 2 to 13, 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). 
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Subjects will not engage in strenuous activity at any time during the confinement periods. 
6. 
STUDY PROCEDURES 
An overview of the study activities for each participant is detailed in Table 6-1. 
Unless otherwise stated in the protocol, the Standard Operating Procedures (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. 
Any deviation from protocol procedures should be noted in the source documentation and 
compiled for reporting in the CSR. 
 


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Table 6-1  Schedule of Activities 
Day 
Screening 
-28 to -1 
-2 to -1
1 
1 
2 
3-13 
14 
15 
16 
17
2 
Follow-
up 
27 to 31 
Informed Consent
3 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History, including Height 
X 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
 
X 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
Clinic Confinement 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Discharge 
 
 
 
 
 
 
 
 
X
4 
 
Study Drug Administration
5 
 
 
X 
X 
X 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
C-SSRS Questionnaire
6 
X 
X 
 
X 
 
X 
 
 
X 
 
Vital Signs
7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination
8 
X 
X 
 
 
 
X 
 
 
 
X 
 
1 Activities need to be completed only once and should be performed based on the order of assessments and timing defined for specific assessments.  
2 For subjects who terminate early from the study, the assessments scheduled on Day 17 will be performed as soon as possible upon termination. 
3 The latest version of the consent form must be signed prior to a subject's inclusion (prior to any study-related procedures). 
4 Subjects will be discharged from the clinical site approximately 72 hours following the last study drug administration. 
5 Subjects will be administered an oral dose of AZD4041 or placebo 
 for 14 consecutive days. Timing of clinical activities are relative to dose 
administration on Day 1. 
6 On dosing days, the C-SSRS questionnaire should be completed prior to AZD4041 administration and at approximately the same time each day ( ±2 hours).The 
Baseline/Screening version (APPENDIX 9) will be used at Screening 
APPENDIX 10) will be used at all other timepoints. 
7 Vital signs at Screening and prior to each study drug administration include blood pressure, pulse rate, and body temperature. Vital signs after each study drug 
administration and at the follow-up visit include blood pressure and pulse rate. Vital sign assessments timepoints are specified in Section 6.2.3. 
8 A complete physical examination and modified neurological examination will be performed on all instances except for Day -1, where a symptom-oriented 
physical examination will be performed.  
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Day 
Screening 
-28 to -1 
-2 to -1
1 
1 
2 
3-13 
14 
15 
16 
17
2 
Follow-
up 
27 to 31 
General Biochemistry, Haematology, 
and Urinalysis
9 
X 
X 
 
X 
X
10 
X 
 
 
X 
X 
Endocrinology
11 
X 
X 
X 
 
 
X 
 
 
 
 
Serology (HIV, HbsAg, and HCV) 
X 
 
 
 
 
 
 
 
 
 
Serology (Severe Acute Respiratory 
Syndrome Coronavirus-2)
12 
 
X 
 
 
 
 
 
 
 
 
Safety 12-Lead Electrocardiogram
13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead Digital ECG
14 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Telemetry
17 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Alcohol and Drugs of Abuse Screen 
X 
X 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (Females Only) 
X 
X 
 
 
 
 
 
 
 
 
 
9 Clinical laboratory parameters are detailed in APPENDIX 6. On dosing days, the clinical laboratory tests will be performed prior to study drug administration. 
10 Day 7 only. 
11 Endocrinology parameters are detailed in APPENDIX 6. Male hormones (FSH, testosterone, LH, Inhibin B) are to be collected: Day-1 (1 sample preferably in 
the morning); Day 1 (2 samples: pre-dose and 1.5 hours post-dose); Day 14 (2 samples: pre-dose and 1.5 hours post-dose). 
12 May be done up to 72 hours prior to Day 1. 
13 The 12-lead electrocardiogram assessment timepoints are specified in Section 6.2.4. Assessments may be conducted at additional timepoints according to 
Principal Investigator judgment. 
14 Timepoints and extraction times for the 12-lead dECG (extracted from 
) are specified in Section 6.2.5. 
 is used 
for dECG extraction on Day 17 
 
  
17 The telemetry timepoints are specified in Section 6.2.6 
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Day 
Screening 
-28 to -1 
-2 to -1
1 
1 
2 
3-13 
14 
15 
16 
17
2 
Follow-
up 
27 to 31 
Blood Sampling for Pharmacokinetics
18 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Lumbar Puncture for CSF Sample 
(Cohorts 2 and 3 only) 
 
 
 
 
 
X
21 
 
 
 
 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
22 
Concomitant Medication Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: CSF = Cerebrospinal fluid; C-SSRS = Columbia Suicide Severity Rating Scale; dECG = digital electrocardiogram; ECG= electrocardiogram; 
HbsAg = Hepatitis B surface antigen; HCV = Hepatitis C virus; HIV = Human Immunodeficiency Virus 
 
18 The pharmacokinetic blood sample timepoints are specified in Section 6.3. 
21 Lumbar puncture for CSF sample timepoint is specified in Section 6.3.4. 
22 Adverse events check must be done at the last scheduled study visit. 
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6.1. 
Order of Assessments  
As PK and PD samples occur at the same time as other schedule assessments, the following 
sequence should be followed to ensure that PK and PD sampling occurs as close as possible to 
the scheduled timepoints.  
The sequence of assessment at any particular timepoint is: 
1. ECG  dECG/safety ECG 
2. Vital Signs (systolic and diastolic blood pressures, pulse rate) 
3. PK 
 blood sampling (to be drawn at the specified timepoints) 
4. PD blood sampling (to be drawn at the specified timepoints) 
5. For Cohorts 2 and 3, Day 14 Lumbar Puncture for CSF  
6.2. 
Safety Assessments 
Safety assessments will include physical examination, neurological examination, vital signs, 
ECG (dECG and safety ECG), telemetry, clinical laboratory tests, C-SSRS questionnaires, and 
AE monitoring. At the discretion of an Investigator, additional safety assessments may be 
performed as needed to ensure subject safety. 
The physician in charge will be present at the clinical site for at least the first 4 hours following 
the first study drug administration on Day 1 and will remain available at all times throughout the 
study. 
6.2.1. Medical History 
The medical history at Screening will include all queries by the medical and clinical staff related 
-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. 
6.2.2. Physical Examination 
A physical and neurological 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, neurological, and general 
appearance, unless a symptom-oriented physical exam is indicated. The sponsor provides 
worksheets to facilitate a standardised approach to the physical and neurological examination at 
the study site (APPENDIX 12 and APPENDIX 13). 
6.2.3. Vital Signs 
Vital signs will be measured as outlined in Table 6-1. Timepoints for vital sign measurements are 
presented in Table 6-2. 
 
 
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Table 6-2 
Vital Sign Recording Schedule 
Vital Sign Recording - Scheduled Timepoints 
Screening 
Day -2 to Day -1 
Days 1 and 14: predose and 1, 2, 3, 4, 8, 12, 24, and 48 hours postdose 
Days 3 to 13: predose 
Day 17: prior to discharge 
Follow-up visit 
Vital signs measured: 
 at Screening and prior to each dosing will include BP, pulse rate, and body temperature. 
 at all other times will include BP and pulse rate. 
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 
No window specified 
24 hours 
± 30 minutes 
72 hours 
± 1 hour 
 
6.2.4. 12-Lead Safety Electrocardiogram 
The 12-lead safety ECGs will be performed on study days as outlined in Table 6-1. 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 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 Table 6-4. 


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Table 6-4 
12-Lead Safety ECG 
ECG Recording - Scheduled Timepoints 
Screening 
Day -1: In the morning at the time of start of 24-hour continuous wired ECG monitoring 
Day 1: Prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 postdose,  
Days 3, 5, 7, 8, 11, and 13: Prior to dosing 
Day 14: Prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours postdose 
Day 17: Prior to discharge 
Follow-up visit 
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 
No window specified 
 
± 30 minutes 
72 hours 
± 1 hour 
 
6.2.5. Electronic Capture of 12-lead Continuous Digital Electrocardiogram 
The AstraZeneca ECG Centre 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. 
On clinical study protocol (CSP)-indicated time points in Table 6-6, 12-lead 
continuous dECG files will be recorded using the 
 
according to AstraZeneca ECG 
 standard procedures for settings/configuration, 
recording and transfer of dECGs.
will be sent to the 
AstraZeneca ECG Centre with an agreed courier. 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 
 equipment at the start of each study 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 AstraZeneca central dECG files repository have 
correct metadata. 
 
 
 
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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 10 minutes before the start of each recording. A shorter resting period (at least 5 minutes) 
may be agreed 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. Detailed 
description of the dECG data collection, handling of the devices and transfer of the data for the 
study centre staff is available in the ECG Manual. Acceptable window of assessment for dECG 
are detailed in APPENDIX 11.  
From the continuous dECG files received at the AstraZeneca ECG Centre, the EClysis© system 
will extract continuous files of at least 5 minutes in length at CSP -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 analysed by the software. The ECG 
Scientific Advisor will perform all necessary manual corrections of the ECG annotations 
provided automatically by EClysis©. All dECGs from one subject will be analysed by a single 
reader in a blinded manner. 
The AstraZeneca ECG Centre cardiologist will review the data and provide, when requested, 
the dECG safety report to support dose escalation decisions by the SRC. 
The AstraZeneca ECG Centre cardiologist will 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 AstraZeneca dECG central repository to accredited data management specialists for 
conversion into SAS® files. 
The following dECG variables will be reported by the AstraZeneca ECG 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, heart rate, and others, as applicable) are calculated by the study 
statistician or delegate. 
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Table 6-6 
: 
Study 
Day 
Visit 
Number 
ECG 
Number
Time:  
Start of the 
Extraction 
Window,  
Hour:Minute 
aError! Reference 
source not found.b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Minute 
Duration of 
Extraction 
window from 
continuous 
filesb, c, d  
Other  
1 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
1 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 
1 
2 
1 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
1 
2 
 
00:00 
IP 
administration
 
 
 
 
 
 
 
 
 
 
 
1 
2 
2 
00:25 
 
00:30 
5 min 
d 
1 
2 
3 
00:55 
 
01:00 
5 min 
d 
1 
2 
4 
01:25 
 
01:30 
5 min 
d 
1 
2 
5 
01:55 
 
02:00 
5 min 
d 
1 
2 
6 
02:55 
 
03:00 
5 min 
d 
1 
2 
7 
03:55 
 
04:00 
5 min 
d 
1 
2 
8 
05:55 
 
06:00 
5 min 
d 
1 
2 
9 
07:55 
 
08:00 
5 min 
d 
1 
2 
10 
11:55 
 
12:00 
5 min 
d 
2 
2 
11 
23:55 
 
24:00 
5 min 
d 
2 
2 
 
 
IP 
administration
 
 
 
2 
2 
12 
35:55 
 
36:00 
5 min 
d 
3 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
3 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 
3 
2 
13 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
3 
2 
 
00:00 
IP 
administration
 
 
 
5 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
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Study 
Day 
Visit 
Number 
ECG 
Number
Time:  
Start of the 
Extraction 
Window,  
Hour:Minute 
aError! Reference 
source not found.b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Minute 
Duration of 
Extraction 
window from 
continuous 
filesb, c, d  
Other  
5 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 
5 
2 
14 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
5 
2 
 
00:00 
IP 
administration
 
 
 
7 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
7 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 
7 
2 
15 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
7 
2 
 
00:00 
IP 
administration
 
 
 
8 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
8 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 
8 
2 
16 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
8 
2 
 
00:00 
IP 
administration
 
 
 
11 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
11 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 
11 
2 
17 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
11 
2 
 
00:00 
IP 
administration
 
 
 
13 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
13 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 


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Study 
Day 
Visit 
Number 
ECG 
Number
Time:  
Start of the 
Extraction 
Window,  
Hour:Minute 
aError! Reference 
source not found.b 
Dose 
Time:  
Stop of the 
Extraction 
Window,  
Hour:Minute 
Duration of 
Extraction 
window from 
continuous 
filesb, c, d  
Other  
13 
2 
18 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
13 
2 
 
00:00 
IP 
administration
 
 
 
14 
2 
 
-02:00 
 
-01:30 
 
Apply 
electrodes  
14 
2 
 
-01:10 
 
-01:00 
 
Rest in bed 
c 
14 
2 
19 
-01:00 (within 
60 min prior 
to dosing) 
Pre-dose 
-00:50 
10 min 
d 
14 
2 
 
00:00 
IP 
administration
 
 
 
 
 
 
 
 
 
 
 
14 
2 
20 
00:25 
 
00:30 
5 min 
d 
14 
2 
21 
00:55 
 
01:00 
5 min 
d 
14 
2 
22 
01:25 
 
01:30 
5 min 
d 
14 
2 
23 
01:55 
 
02:00 
5 min 
d 
14 
2 
24 
02:55 
 
03:00 
5 min 
d 
14 
2 
25 
03:55 
 
04:00 
5 min 
d 
14 
2 
26 
05:55 
 
06:00 
5 min 
d 
14 
2 
27 
07:55 
 
08:00 
5 min 
d 
14 
2 
28 
11:55 
 
12:00 
5 min 
d 
15 
2 
29 
23:55 
 
24:00 
5 min 
d 
15 
2 
30 
35:55 
 
36:00 
5 min 
d 
16 
2 
31 
47:55 
 
48:00 
5 min 
d 
17 
2 
32 
71:55 
 
72:00 
5 min 
d 
a 
Time points for Extraction window from continuous dECG files 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 min before the first continuous dECG recording. 
d 
The subjects must rest in bed for at least 10 min prior to each Extraction window from the continuous file 
(dECG time point). 
e 
The subject must remain awake. 


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Abbreviations: dECG: Digital electrocardiogram, ECG: Electrocardiogram; h: Hour, IP: Investigational product; 
min: Minute; PK: Pharmacokinetics. 
6.2.6. Telemetry 
Subjects will be monitored using a 5-lead bedside wired cardiac telemetry with real-time 
interpretation and safety feedback as outlined in Table 6-1. Subjects will be able to ambulate 
short distances during the scheduled intervals for telemetry specified in Table 6-7. 
Table 6-7 
Telemetry Schedule 
Telemetry - Scheduled Intervals 
Day -1: Full 24 hours (Start 24 hours prior to first dose)   
Days 1 and 14: Start at least 30 minutes prior to dosing to at least 24 hours postdose and up to 
48 hours postdose (Day 3 and Day 16)1 
Day 7: Start at least 30 minutes prior to dosing to 24 hours postdose (Day 8) 
1 It is recommended that ECG telemetry on Day 1 and Day 14 should be continued for up to 48 hours post dose 
when subjects are at rest.  
6.2.7. 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 physician in charge (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 physician in charge (or delegate). Verification of collection for all 
laboratory test panels will be saved in the clinical database. 
6.2.8. 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. 
The C-SSRS will assess suicidality over the month preceding screening as well as over the 
 and 
 the 
 or French) 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 9 for a sample C-SSRS  Baseline/Screening 
version assessment and APPENDIX 10 for a sample postdose C-SSRS  Since Last Visit version 
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If there is a positive result for suicidality on the C-SSRS after Screening (defined by a subject 
 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. 
6.3. 
Pharmacokinetic and Pharmacodynamic Specimen Sampling 
6.3.1. Pharmacokinetic Blood Sampling  
The complete PK blood sampling schedule is presented in Table 6-8. 
Table 6-8 
Pharmacokinetic Blood Sampling Schedule 
Pharmacokinetic Blood Sampling - Scheduled Timepointsa 
Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose 
Days 3 to 10: Predose 
Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose 
Blood samples will be collected by direct venepuncture into a labelled 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 (stylet catheter that requires no flushing), which will be placed in the vein of the subject. 
The time of PK blood sample collection will be calculated relative to the time of treatment 
administration. 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 6-9. PK samples 
collected outside of the prespecified 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. 


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Table 6-9 
Acceptable Windows for Timed PK Blood Specimen Collection Procedures 
Elapsed Time  
Accepted Window 
Predose 
No window specified 
> 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 
AZD4041 concentrations for PK assessments will be obtained through bioanalysis of the plasma 
derived from the blood samples drawn during this study, using a validated bioanalytical method. 
6.3.2. 
 
 Table 6-10. 
Table 6-10 
 
6.3.3. 
 
 Table 6-11. 
Table 6-11 
 
 
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. 
 Table 6-12. 
Table 6-12 
 
6.3.4. Lumbar Puncture for CSF Sample 
For cohorts 2 and 3 only, subjects will have a single lumbar puncture performed on Day 14 post 
dose (approximately 3 hours ± 1 hour). The samples will be collected by insertion of an 
atraumatic spinal needle (eg, Whitacre atraumatic, 22G 0.7 mm needle between vertebrae L3 and 
L5). Approximately 10 mL will be collected.  
Samples will be processed, stored, and shipped according to the sample processing instructions 
supplied by the bioanalytical facility. 
6.3.5. Pharmacodynamic Assessments 
 
 
 
 Table 6-13. 
Table 6-13 
 
Blood samples will be collected by direct venepuncture into a labelled 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 (stylet catheter that requires no flushing), which will be placed in the vein of the subject. 
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6.3.6. Pharmacokinetics and Pharmacodynamic Sample Handling 
Blood, urine and CSF samples for PK determination will be processed, stored and shipped 
according to the sample processing instructions supplied by the bioanalytic facilities.  
Blood and CSF samples for PD determination will be processed to plasma and PBMCs according 
to the local lab SOP. Sample processing must start within 1 hour of blood draw. Samples should 
be stored at -70ºC or lower. Once EOS has been achieved, samples will be shipped on dry ice 
and shipped to the AZ biobank for biomarker analysis. 
6.4. 
Total Specimen Collection  
Total specimen collection volumes per subject for blood, urine, and CSF are detailed in
Table 6-14. 
Table 6-14 
 Specimen Collected and Total Amount per subject 
Per cohort sample volume 
(mL) 
Male 
Female 
Screening clinical lab tests (including pregnancy and 
serology) 
8 
8 
On study General Biochemistry and Haematology (6 
samples x 4 mL) 
24 
24 
On study Endocrinology (3 cohorts) (3 samples per 
subject × 3.5 mL) 
10.5 
0 
PK blood samples (37 samples per cohort x 4 mL per 
sample) 
148 
148 
Additional PK blood samples (13 samples per cohort x 4 
mL per sample) 
52 
52 
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End of study clinical lab tests  
6.5 
6.5 
Total Blood donation 
313 
313 
Total Urine donation 
200 
200 
Total Cerebrospinal Fluid 
10 
10 
 
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 study drug. An AE can therefore be any 
unfavourable 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 caus
relationship between the drug and the AE. A SAR 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; 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 drug administration. In the latter case, the condition 
should be reported as medical history. 
An AE of Special Interest (AESI) (serious or nonserious) is one of scientific and medical 
monitoring and rapid communication by the investigator to the sponsor. Such an event might 
warrant further investigation in order to characterize and understand it. 
The following AESI(s) have been identified for the study intervention(s) in this protocol: 
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) 
Non-serious AESIs are to be recorded in EDC within 72 hours, and serious AESIs are to be 
reported to the sponsor within 24 hours. 
A SAE or reaction is any untoward medical occurrence that at any dose: 
 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 
 
 Is a congenital anomaly or birth defect 
 Is an important medical event 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) 
7.2. 
Severity Assessment 
All AEs will be graded per the current version of the 
Terminology Criteria for Adverse Events (NCI-CTCAE). Every effort will be made to obtain an 
adequate evaluation of the severity. 
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. 
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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 
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 aetiology 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 17 days after the last study drug administration (ie, stop registration on 
new AEs on follow-up visit Day 31 in case last AZD4041 dose was administered on Day 14).  
Subjects will be questioned on their health status from the beginning of the study, before 
departure from the clinical site, and at each follow-up visit until Day 31. 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 CSR, 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 
without stating an intention to withdraw, Investigator should show "due diligence" by 


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documenting in the source records steps taken to contact the subject, (eg, dates of at least three 
telephone call attempts, registered letters, etc). 
experiencing AEs receive appropriate 
follow-up, treatment where required, and that every action is well documented. 
Classification of AEs will be performed by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA), version 24.1 or higher. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
Enhanced (WHO-DDE March 2021 or later). 
7.5. 
Serious Adverse Event Reporting 
The CRU will report all SAEs to the Sponsor, which includes the AstraZeneca study physician 
(or designee) and MMS Holdings, Inc., without regard to causality, within 24 hours after 
becoming aware of its occurrence using the SAE Report Form provided by MMS Holdings. The 
study-specific Safety Management Plan (SMP) will provide further details on SAE distribution.  
Registration of new AEs will start from the moment of ICH signature and will stop 17 days after 
the last study drug administration (ie, stop registration on new AEs on follow-up visit Day 31 in 
case last AZD4041 dose was administered on Day 14). SAE with a suspected causal relationship 
to the AZD4041 should be registered even if occur after the end of the clinical trial. The 
investigator does not need to actively monitor subjects for AEs once the clinical trial has ended 
with regard to the subjects treated by him/her. 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, 
that AE should be recorded as a new SAE. 
Any SAE which remains unresolved as of the last study visit will require an evaluation and 
follow-up until the SAE has been resolved, stabilized or a reasonable explanation for its 
persistence found, or is deemed mild and safely resolving. 
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the IP(s). 
Information not available at the time of the initial report (eg, an end date for the AE, laboratory 
values received after the report, or hospital discharge summary) must be documented. All 
follow-up information must be reported as soon as the relevant information is available. 
The appropriately completed SAE Report Form should be directe
 
 MMS Holdings, Inc. 
 Email: 
 
 Facsimile: 
 
Any SAE reports should be made using the SAE Report Form provided by MMS Holdings. It is 
not a
Sponsor in lieu of completion of the SAE report forms.  
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There may be instances when copies of medical records for certain cases are requested by AZ. In 
this case, all subject identifiers, with the exception of protocol number, site number and the 
subject number, will be redacted on the copies of the medical records before submission to AZ.  
safety information 
section of current IB or is not listed at the specificity or severity that has been observed. 
"Unexpected", as used in this definition, also refers to AEs that are mentioned in the IB as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug 
but are not specifically mentioned as occurring with the AZD4041. 
If reports of any new suspected unexpected serious adverse reactions (SUSARs) become 
available to the Sponsor or their designee during the clinical portion of this study (related or not 
to the present study), the Sponsor or their designee has to advise the CRU, through its clinical 
Investigator, of those events. 
The CRU will determine whether suspected unexpected serious adverse reactions (SUSARs) 
must be reported to the Institutional Review Board (IRB). If so, the event will be reported via fax 
 
All details on SUSAR reporting to regulatory authorities will be specified in the SMP. 
7.6. 
Reporting of Pregnancy 
All pregnancies and the subsequent outcome of any conception (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality/birth defect) 
that occurs from the first study drug administration until 16 weeks after study drug 
administration will be recorded and should be reported to 
 within 24 hours 
of knowledge: 
 MMS Holdings, Inc. 
 Email: 
 
 Facsimile: 
 
Pregnancy reports should be made using the MMS Pregnancy Notification and Outcome Form. 
Pregnancies should be followed until resolution of pregnancy with any abnormal outcomes of the 
mother or the child being reported. Should a female study participant become pregnant during 
the study, outcomes can be categorized into the following (1. Normal Outcome before end of the 
Study, 2. Abnormal outcome before end of study, 3. Normal outcome after end of study, or 4. 
Abnormal outcome after end of study). Congenital abnormalities/birth defects, spontaneous 
miscarriages, and any other SAEs experienced during pregnancy should be recorded and 
reported as an SAE according to Section 7.5. New-borns with congenital abnormalities/birth 
defects will be followed up until 3-month age with follow-up SAE reports submitted monthly. 
No follow up is required for the healthy at birth new-borns (no reported anomaly). 
7.6.1. Pregnancy in Female Subjects 
Pregnancy in a female study subject shall be reported as specified above in Section 7.6 within 
24 hours of the knowledge of its occurrence by an Investigator or delegate. Because of the 
possibility the foetus/embryo could have been exposed to the study drug through the parent and 
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spontaneous or voluntary termination, details of birth, presence or absence of any birth defects, 
congenital anomalies, or maternal and/or newborn complications. 
7.6.2. Pregnancy in Female Partners of Male Subjects 
Pregnancy in a female partner of a male study subject shall be reported as specified above in 
Section 7.6 within 24 hours of the knowledge of its occurrence by the clinical site. Because of 
the possibility that the foetus/embryo could have been exposed to the study drug through the 
parent and for the safety 
determine its outcome, including spontaneous or voluntary termination, details of birth, presence 
or absence of any birth defects, congenital anomalies, or maternal and/or newborn complications 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Unless otherwise specified below, listings and statistical summaries will be presented by 
AZD4041 dose level and pooled placebo, and by scheduled time, as appropriate. Continuous 
variables and endpoints will be summarized using descriptive statistics (n, mean, SD, min 
median, max). Categorical variables will be summarized in contingency tables (by frequency and 
proportion)  
The number of subjects who were included, who discontinued, and who completed the study will 
be tabulated. The primary reasons for discontinuation will be provided. 
8.1.1. Safety Population 
The safety population will include all subjects who received at least 1 dose of the IP or placebo. 
8.1.2. Pharmacokinetic Population 
The PK population will include all subjects who have received at least 1 dose of AZD4041 and 
have at least 1 PK concentration after dosing. 
8.1.3. Pharmacodynamic Population 
The PD population will include all subjects who have received at least 1 dose of AZD4041 and 
have at least 1 
 
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. 
Further details of the statistical presentations for demographic and baseline data will be given in 
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8.3. 
Safety 
8.3.1. Safety Endpoints 
The safety endpoints include the incidence of AEs and the assessments of vital signs, clinical 
laboratory tests, ECG (dECG and safety ECG), telemetry, C-SSRS questionnaire, and physical 
and neurological examination. 
These parameters will be used to perform the safety statistical analysis.  
8.3.2. Safety Statistical Methodology 
Simple descriptive statistics as described above will be used to summarize the safety endpoints. 
Further details of the statistical analysis of AEs and other safety results will be given in the SAP. 
In addition, AESIs as defined in Section 7.1 will also be summarized. 
8.4. 
Pharmacokinetics 
The PK analysis will be carried out according to Altasciences  SOPs. Pharmacokinetic data 
handling and analysis will be further detailed in the SAP. 
 
.  
8.4.1. Missing Values 
The lack of concentration values due to failure to collect the sample, a lost or compromised 
sample, 
dataset, and no imputation will be done. For urine data, if a subject has failed to void over a 
particular collection interval, the amount excreted will be set to zero. 
If the actual collection time of a postdose plasma PK sample is unknown, but a valid 
concentration value has been measured, the sample will be set to missing in the PK analysis and 
will be presented in listing excluded from descriptive statistics. Unknown predose collection 
times will be handled on a case-by-case basis. 
8.4.2. Measurements Below the Lower Limit of Quantitation 
Concentration values below the lower limit of quantitation (LLOQ) associated with predose and 
postdose collection times will be replaced with zero for the non-compartmental analyses (NCA). 
Concentration values below the LLOQ will be replaced with zero for mean PK profile 
representations as well as for descriptive statistic calculations. 
8.4.3. Actual Time 
The plasma NCA analysis will be based on the actual sampling times, except for predose 
samples, which will always be reported as zero, regardless of time deviations. 
The individual plasma concentration/time profiles will be presented using actual sampling times 
whereas the mean plasma concentration/time profiles and tables presenting summary statistics of 
concentration -time series will be presented using nominal sampling times. 
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Actual times for plasma PK sample collections will be listed in the report. 
Urine PK analysis and data presentation will utilize the nominal collection interval times; CSF 
concentration and biomarker data will be presented based on nominal collection time. 
8.4.4. Baseline Reference Timepoint 
Unless otherwise specified, the baseline value will be defined as the last non-missing evaluation 
prior to the first study drug administration. 
8.4.5. Non-Compartmental Analysis 
The following configuration for the NCA analysis (with Phoenix® WinNonlin® version 8, or 
higher) will be used: 
 Data: 
Serial sampled data 
 Model/Dose options Type:  Plasma (200 202) and Urine (210  212)/Extravascular 
 AUC Calculation Method: 
Linear up/Log down (applicable to plasma only) 
 Lambda Z ( z) calculation: 
z Linear-Log regression 
Reasons for excluding PK parameters will include the following: 
 AUC: AUC parameters will not be estimated if less than 3 consecutive measurable 
concentrations are observed. 
 PK 
eg, AUC0-  and t1/2) will be set to Not Reported 
(NR) in the Tables and Listings if they meet one of the following: 
 R2 < 0.8 
 Extrapolated area > 20% 
The PK parameters for AZD4041 are presented in Table 8-1. 
Table 8-1 Pharmacokinetic Parameters of AZD4041 in Plasma 
PK Parameter 
Definition 
Plasma, Day 1 
Cmax 
Maximum observed concentration 
Tmax 
Time of maximum observed concentration 
AUC0-24 
Area under the concentration time curve from time 0 (dose administration) to 
24 hours 
(The nominal time will be used to estimate partial AUC using the NCA built-in 
tool in Phoenix® WinNonlin®. This means that actual times off by more than 1 
minute from the partial end-hour timepoint will be extrapolated/interpolated as 
per Phoenix® WinNonli
-in formulas. If extrapolation/interpolation is 
not possible, then no value is reported by the software.) 


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AUC0-t 
Area under the concentration time curve from time 0 (dose administration) to 
the time of last quantifiable concentration (tlast) 
AUC0-inf 
Area under the concentration time curve extrapolated to infinity, calculated as 
AUC0-t + Clast
Z, where Clast is the measured concentration at time tlast 
t1/2,z 
Terminal elimination half-
Z 
CL/F 
Apparent total clearance, calculated as Dose/AUC0-inf 
Vz/F 
Z * AUC0-inf 
Cmax/D 
Dose-normalized Cmax 
AUC0-t/D 
Dose-normalized AUC0-t 
AUC0-inf/D 
Dose-normalized AUC0-inf 
Plasma, Day 14: 
Cmax 
Maximum observed concentration 
Tmax 
Time of maximum observed concentration; if it occurs at more than one 
timepoint, tmax is defined as the first timepoint with this value 
C  
Concentration at the end of the dosing interval. Observed concentration, 
otherwise the predicted concentration value will be calculated as per Phoenix® 
WinNonlin®
-in rules for interpolation/extrapolation, and subject to the 
criteria for 
z estimation. 
AUC  
Area under the concentration time curve over the dosing interval at steady state, 
calculated from 0 to 24 hours (dosing interval)  
(The nominal time will be used to estimate AUC  using the NCA built-in tool in 
Phoenix® WinNonlin®. This means that actual times off by more than 1 minute 
from the dosing interval end-hour timepoint will be extrapolated/interpolated 
as per Phoenix® 
-in formulas. If extrapolation/interpolation 
is not possible, then no value is reported by the software.) 
AUC0-t 
Area under the concentration time curve from time 0 (dose administration) to 
the time of last quantifiable concentration (tlast) 
t1/2,z 
Terminal elimination half-
Z 
t1/2Eeff 
Effective half-life, calculated as 
(AUC)/( Rac(AUC)-1)
1 
CL/Fss 
Apparent total clearance at steady state, calculated as Dose/AUC   
Vz/Fss 
Z * AUC  
Cmax/D 
Dose-normalized Cmax 
AUC /D 
Dose-normalized AUC  
AUC0-t/D 
Dose-normalized AUC0-T 
RAC(Cmax) 
Accumulation ratio evaluated by comparing Day 14 Cmax to Day 1 Cmax 
RAC(AUC) 
Accumulation ratio evaluated by comparing Day 14 AUC  to Day 1 AUC0-24* 


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*Day 1 AUC0-t may be used if AUC0-24 cannot be estimated, provided that the 
24-hour sample was collected within 10% of nominal time. 
Plasma, Various Days: 
Ctrough 
Observed concentration at the end of the dosing interval (predose 
concentrations on Day 2 [Day 1, 24-hours] through Day 14) 
The following plasma PK parameters will be used for PK calculation and presented in the PK 
listings only 
tlast 
Time of last measurable observed concentration 
Clast 
Observed concentration corresponding to tlast 
Z 
Apparent elimination rate constant, estimated by linear regression of the 
terminal linear portion of the log concentration versus time curve 
Z Upper 
z 
Z Lower 
Lower limit on time for 
z 
Number of Points 
Z 
R2 
Goodness of fit for the terminal phase 
Residual area 
Extrapolated area (ie, percentage of AUC0-  due to extrapolation from tlast to 
infinity: AUC0-
- AUC0-t/ AUC0- *100) 
Urine, Day 1, and Day 14: 
Ae 
Amount of drug excreted in urine 
The Ae at each urine collection interval will be calculated as follows:  
Concentration * Volume of urine during that time interval (t1 to t2) 
Cumulative Ae will be calculated as the sum of all urine collection interval Aes 
Note: The Ae at pre-dose will not be included in the calculation of cumulative 
Ae. 
fe 
Cumulative fraction of unchanged drug excreted in urine over all time 
intervals, calculated as 
(Ae / Dose)*100 (expressed in %) 
Note: The Ae at pre-dose will not be included in the calculation of fe. 
CLr 
Apparent renal clearance, calculated as: 
Ae (0-24) / AUC0-24 on Day 1 and as Ae (0-24) / AUC  on Day 14 
A different time interval may be used providing not all single intervals are 
usable. 
*Day 1 AUC0-t may be used if AUC0-24 cannot be estimated, provided that the 
24-hour sample was collected within 10% of nominal time. 
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8.4.6. Cerebrospinal Fluid 
For cohorts 2 and 3 only, AZD4041 CSF concentrations (ng/ml) on Day 14 will be calculated as 
a percentage of plasma concentration. 
8.4.7. 
 
 
 
8.4.8. Data Handling 
Precision for individual values will be display as follows: 
 Raw data will be displayed with the same precision as received from the bioanalytical 
laboratory 
 Concentration-related PK parameters (eg, Cmax, AUCs) will be displayed with the same 
precision as the raw PK concentration data 
 Parameters associated with time will be displayed with 2 decimal places 
 Percentages will be displayed with 2 decimal places 
 R2 a
z will be displayed with 4 decimal places 
8.4.9. Pharmacokinetic Statistical Methodology 
All tables, figures, and listings, when appropriate, will be stratified by cohort (dose level) and by 
study day, as applicable. 
8.4.9.1. Summary Statistics 
Summary statistics of the individual AZD4041 plasma, urine, and CSF concentration data and 
derived parameters as well as biomarker data will be calculated for the PK population. Summary 
statistics will be calculated for concentration at each individual timepoint and for all PK 
parameters. 
Concentration data will be summarized by group using the following statistics: number of 
observations (N), arithmetic mean (mean), standard deviation (SD), minimum (min), median, 
maximum (max), and coefficient of variation (CV). PK parameters will be summarized using 
these same statistics, as well as geometric mean and geometric mean CV. 
Summary statistics will be displayed with the same precision as the individual values 
(Section 8.4.8), with the exception of N and CV which will be presented with 0 and 1 decimal 
places, respectively. 
If PK parameters can only be estimated in a limited number of subjects, the following criteria 
will be applied for reporting descriptive statistics: 
 If a PK parameter value is reportable in less than 3 subjects for a given study part and 
day, then SD, CV, and geometric mean CV will be considered not reportable 
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 If a PK parameter value is only reportable in 1 subject for a given study part and day, 
only minimum and maximum will be reported 
8.4.9.2. Statistical Analysis 
Dose Proportionality for Day 1 and Day 14 
Inferential statistical analysis will be performed with SAS. 
Appropriate dose normalized PK parameters (Cmax and appropriate AUCs) will be assessed 
graphically for dose-proportionality. 
Natural log-transformed PK parameters (Cmax and appropriate AUCs) will be assessed 
statistically for proportionality. Proportionality analysis will be done using a power model. The 
power model is defined as: 
 
normal error term. A linear model with ln-
transformed dose as a continuous effect will be fitted. A point estimate and a 90% confidence 
interval (CI) 
 
Dose proportionality may be assessed within different dose ranges if deemed appropriate with at 
least three doses. 
Steady State 
Ctrough will be displayed graphically and summarized descriptively by day to assess for steady 
state. 
8.5. 
Planned Interim Pharmacokinetic Analyses 
Interim PK analysis may be performed after each cohort to support dose selection and safety 
assessments. 
The SAP will describe the planned interim analyses in greater detail. 
8.6. 
12-Lead Digital ECG Analysis 
8.6.1. 12-Lead Digital ECG Statistical Methodology 
From the dECG data, the following parameters will be derived: 
 
QTcF will be calculated as QTcF = QT*RR-1/3, where the QT interval is in milliseconds and 
the RR interval is in seconds. 
 
Heart rate will be calculated, based on the RR interval as HR = 60/RR interval, where the 
RR interval is in seconds. 
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 


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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 (dose level of AZD4041 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 (dose level of AZD4041 and pooled 
placebo) 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) pre-dose assessment 
on Day 1. 
Outliers with respect to QTcF will also be tabulated for the following categories: 
 
 
 
 
 
Absolute value > 500 ms 
 
 
 
Increase from baseline > 60 ms 
All calculations of dECG parameters and reporting described in this section will be performed by 
Altasciences. 
8.6.2. 
  
 
 
8.6.3. 
 
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8.7. 
Determination of Sample Size 
No formal sample size analysis was performed. It is estimated that 12 subjects per cohort should 
be sufficient to meet the objectives of the study. 
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doi:S0197-0186(09)00264-2[pii]10.1016/j.neuint.2009.08.012 (2009). 
Rasmussen et al, 2019 
Rasmussen, K., White, D. A. & Acri, J. B. NIDA's medication development priorities in 
response to the Opioid Crisis: ten most wanted. Neuropsychopharmacology 44, 657-659, 
doi:10.1038/s41386-018-0292-5 (2019). 
Sakurai et al, 1998 
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al. Orexins and orexin 
receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate 
feeding behavior. Cell 1998;92(4):573-85. 
Salvadore et al, 2019 
Salvadore G, Brooks S, Cathy B, et al. JNJ-61393215 in male healthy volunteers. 74th Annu 
Meet Soc Biol Psychiatry (SOBP) 2019 May 16-18, Chicago Abst F13. 
Samson et al, 2007 
Samson WK, Bagley SL, Ferguson AV, White MM. Hypocretin/orexin type 1 receptor in brain: 
role in cardiovascular control and the neuroendocrine response to immobilization stress. Am J 
Physiol Regul Integr Comp Physiol 2007 Jan;292(1):R382-7. 
Society of Actuaries 
Opioid Epidemic Cost the U.S. Economy at Least $631 Billion Over Four Years: Society of 
https://www.soa.org/resources/announcements/press-
releases/2019/opioid-epidemic-cost-631-billion/ (2019). 


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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) 
Vanderstichele et al, 2012 
Vanderstichele H, Bibl M, Engelborghs S, Le Bastard N, Lewczuk P, Molinuevo JL, et al. 
 
disease diagnosis: A consensus paper from the 
Initiative. 
2012;8:65 73. 
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). 
Willie et al, 2003 
Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, et al. Distinct 
narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection 
of Non-REM and REM sleep regulatory processes. Neuron 2003;38(5):715-30. 
Yan et al, 1999 
Yan W, Linderborg J, Suominen J, Toppari J. Stage-specific regulation of stem cell factor gene 
expression in rat seminiferous epithelium. Endocrinology 1999;140(3):1499-1504. 
Yan et al, 2000 
Yan W, Suominen J, Toppari J. Stem cell factor protects germ cells from apoptosis in vitro. 
J Cell Sci 2000;113:161-8. 


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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. Notificat
 
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 European Union (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 subject 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 subject and the physician in 
charge (or delegate) has the conviction the subject understands the implications of participating 
in the study, and if the subject chooses to continue the screening process, they will be requested 
to sign and date a properly executed ICF prior to enrolment. 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 
 
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 
-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 r
 
10.5. Safety Oversight 
Safety oversight will be under the direction of a SRC composed of individuals with the 
appropriate expertise, including the Principal Investigator 
nitor. 
Additional reviewers with expertise in clinical pharmacology, PK, statistics, or other clinical 
disciplines may be included as deemed appropriate. The SRC will review the safety, tolerability, 
and PK data prior to proceeding to the next dose level in a blinded fashion. After each cohort, the 


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SRC will assess available data to decide on the next dose level. Data from at least 10 subjects in 
the previous cohort must be reviewed during the safety meeting. 


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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 electronic data capture (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 nonconforming 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 each corresponding operation 
unit will be responsible for maintaining QA to ensure that the trial is conducted and data are 
generated, documented, and reported in compliance with the protocol, ICH Guideline E6 for 
GCP, applicable requirements as outlined in the FDA and OECD Principles of GLP, and the 
 Reflection paper for laboratories that perform the 
analysis or evaluation of clinical trial samples (EM/INS/GCP/532137/2010). 
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, IRB/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
events or deaths result, either directly or indirectly, from the execution of the present protocol. 
12.2. Adherence to Protocol 
Excluding an emergency in which proper treatment is required for the protection, safety, and 
wellbeing 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 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(s) 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 (eg, COVID-19 testing, body temperature monitoring) may be 
performed during the trial, even if not planned within the protocol. 
12.4. Statement of Investigator 
the commencement of his/her responsibilities with respect to the clinical 
trial, as required by FDA regulations. The undertaking form will be maintained with the trial 
records and will be made available upon request. 
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 treatment, and their 
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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 and 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, assure appropriate therapy 
and follow-up for the subjects, and 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 Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of Multiple Ascending Doses of AZD4041 in Healthy Adult 
Subjects 
 
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 Company Inc. 
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TITLE: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of Multiple Ascending Doses of AZD4041 in Healthy Adult 
Subjects 
On behalf of the Sponsor, I am aware of, and agree to comply with, all the procedures contained 
within this protocol. 
___ 
____ 
 
 
 
 
 
 
 
 
 
 
 
 
Date (yyyy/mm/dd) 
 
, Clinical Development, Neuroscience 
Neuroscience Biopharmaceuticals Research and Development 
Sponsor's Representative 
AstraZeneca 
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14. 
APPENDIX 5: LIST OF ABBREVIATIONS 
AE 
AESI 
Adverse Event 
Adverse Event of Special Interest  
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase  
AV 
Atrioventricular   
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPM 
Beats per Minute 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CSF 
Cerebrospinal Fluid 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficient Of Variation 
 
 
DECG 
Digital Electrocardiogram 
DORA 
Dual Orexin Receptor Antagonist  
DSM 
and Statistical Manual of Mental 
Disorders 
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 
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EMA 
European Medicines Agency 
 
 
EU 
European Union 
FDA 
Food and Drug Administration 
FIH 
First-in-Human 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPCR 
G Protein Coupled Receptors 
HBSAG 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HERG 
Human Ether-A-Go-Go-Related Gene 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
 
 
IC50 
Half Maximal Inhibitory Concentration 
IC90 
Ninety Percent (90%) Inhibitory Concentration 
IB 
 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IU 
International Unit 
IVCD 
Intraventricular Conduction Delay 
KG 
Kilogram 
L 
Litre 
LH 
luteinizing Hormone  
LLOQ 
Lower Limit of Quantitation 
LN 
Napierian Log Transformation 
MAD 
Multiple Ascending Dose 
MEDDRA 
Medical Dictionary for Regulatory Activities 
MG 
Milligram 
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MIN 
Minute 
ML 
Millilitres 
MMHG 
Millimetre of Mercury 
MTD 
Maximum Tolerated Dose 
N/A 
Not Applicable 
NCA 
Non-Compartmental Analysis 
NCI-CTCAE 
for Adverse Events 
NG 
Nanograms 
NIDA 
National Institutes on Drug Abuse  
NOAEL 
No-Observed-Adverse-Effect Level 
NREM 
Non-Rapid Eye Movement 
 
 
OECD 
Organization for Economic Co-Operation and Development 
OTC 
Over-The-Counter 
OUD 
Opioid Use Disorder 
OX1/2 
Orexin Receptor 
PBMC 
Peripheral blood mononuclear cells 
PBPK 
Physiologically based PK 
PD 
Pharmacodynamics 
PH 
The Logarithm, On the Base 10, of the Reciprocal of the Hydrogen Ion Concentration 
PK 
Pharmacokinetic 
PR 
Time Between P and R Wave 
PR (PQ) 
Prolongation of the PR (PQ) interval  
PT 
Preferred Term 
QA 
Quality Assurance 
QD 
Daily Dosing 
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 
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SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SMP 
Safety Management Plan 
SRC 
Safety Review Committee 
ST 
ST Segment of the ECG 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
T Wave of the ECG 
TBL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
 
 
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 
Clinical Laboratory Test 
Panel 
Description 
General biochemistry: 
Alanine aminotransferase, albumin, alkaline phosphatase, bilirubin total and 
unconjugated, C-reactive protein, chloride, creatinine, creatine kinase, 
gamma glutamyl transferase, protein total, glucose (fasting), calcium, 
potassium, magnesiuma, and sodium 
Endocrinology: 
Follicle stimulating hormonede, oestradiola,b, thyroid stimulating hormonea, 
T4a,c, luteinising hormoned, testosteroned, and inhibin Bd 
Haematology: 
White cell count with differential (absolute values of neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil), red cell count, 
haemoglobin, haematocrit, mean corpuscular volume, and platelet count 
Serology: 
Human immunodeficiency virus Ag/Ab Combo, hepatitis B surface antigen, 
hepatitis C virus, and Severe Acute Respiratory Syndrome Coronavirus-2 
Urinalysis: 
Colour, 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, cotinine, opiates, and 
phencyclidine 
Pregnancy test (females 
only): 
Serum pregnancy test 
Alcohol screen: 
Alcohol breathalyser or urine screen 
a. At Screening only  
b. Postmenopausal women only 
c. Reflex only (if TSH is abnormal) 
d. Males only at Day -1, Day 1 and Day 14 
e. FSH for females at screening only 
 


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16. 
APPENDIX 7: CONTRACEPTION GUIDANCE 
Females 
Only females of non-childbearing potential will be considered for eligibility in this study. 
Females of non-childbearing potential are defined as those who are surgically sterile (ie, women 
who have had a hysterectomy, bilateral ovariectomy [oophorectomy], bilateral salpingectomy, or 
bilateral tubal ligation) or those who are postmenopausal (defined as 12 months or more with no 
menses without an alternative medical cause). (See Inclusion Criterion# 4, Section 4.1) 
Males 
Non-sterilized 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 after 
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, including 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 Table 16-1. 
Table 16-1. 
Highly Effective Methods of Contraception 
Barrier methods 
Hormonal methods 
Intrauterine device 
Intrauterine hormone-releasing system (UIS)a 
Bilateral tubal occlusion 
Vasectomized partnerb 
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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17. 
APPENDIX 8: STUDY SPECIFIC RESTRICTIONS 
Table 17-1. 
Restricted medications/products 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situation in which it is allowed) 
Antacids 
Analgesics other than paracetamol/acetaminophen 
Herbal remedies 
Megadose (20 to 600 times recommended daily dose) 
vitamins 
Megadose minerals 
In the 2 weeks prior to administration of IP, or longer if 
the medication has a long half-life, use of any of these 
medications constitutes a basis for exclusion from the 
study. 
Table 17-2. 
Prohibited medications 
Prohibited medication/class of drug: 
Any other investigational product (other than provided in this study) 
 
Hormone replacement therapy 
 
Vaccination with COVID-19 vaccine less than 14 days prior to the proposed date of randomization 
 
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18. 
APPENDIX 9: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)  
BASELINE/SCREENING VERSION 
 


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19. 
APPENDIX 10: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)  
SINCE LAST VISIT VERSION 
 
 
 


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20. 
APPENDIX 11: DIGITAL ELECTROCARDIOGRAM  
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21. 
APPENDIX 12: PHYSICAL EXAMINATION 
 
 


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22. 
APPENDIX 13: NEUROLOGICAL EXAMINATION 
 


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SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
For: 
AstraZeneca AB  
 
 
PROTOCOL No. D7460C00002 
 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of Multiple Ascending Doses of AZD4041 in Healthy Adult Subjects  
 
Altasciences Project No. AZN-P3-000 
 
Prepared by: 
Altasciences Company Inc. 
575 Armand-Frappier Boulevard 
Laval, Quebec 
Canada, H7V 4B3 
 
 
Version: Final 1.0 
Date: 2022-05-12 
 


 
 
 
Protocol No. D7460C00002|Altasciences Project No. AZN-P3-000| Version Final 1.0 | 2022/05/12 
Page 2 of 34
STATISTICAL ANALYSIS PLAN APPROVAL 
We have carefully read this statistical analysis plan and agree it contains the necessary information 
required to handle the statistical analysis of study data. 
 
 
 
 
Biostatistician II 
 
Date  
 
 
 
 
Altasciences 
 
 
Date  
 
 
On behalf of the Sponsor: 
 
 
 
 
 
 Statistician 
 
Date  
 
 
PPD
PPD
PPD
PPD
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VERSION CONTROL 
Version 
Date 
Author 
Description of Changes 
1.0 
12-05-2022 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
VERSION CONTROL ....................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
TABLE OF TABLES ......................................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
1 
INTRODUCTION ..................................................................................................................9 
2 
STUDY OBJECTIVES ........................................................................................................10 
3 
STUDY DESIGN .................................................................................................................13 
3.1 
General Description .........................................................................................................13 
3.2 
Treatments .......................................................................................................................13 
3.3 
Study Procedures .............................................................................................................13 
3.4 
Randomization and Unblinding Procedures ....................................................................13 
4 
ANALYSIS POPULATIONS ..............................................................................................15 
5 
STUDY SUBJECTS ............................................................................................................16 
5.1 
Disposition .......................................................................................................................16 
5.2 
Protocol Deviations .........................................................................................................16 
6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...............................18 
7 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES .............................19 
7.1 
Missing Values ................................................................................................................19 
7.2 
Measurements Below the Lower Limit of Quantitation ..................................................19 
7.3 
Actual Time .....................................................................................................................19 
7.4 
Baseline Reference Timepoint ........................................................................................19 
7.5 
Non-Compartmental Analysis .........................................................................................19 
7.6 
Cerebrospinal Fluid .........................................................................................................22 
7.7 
 
7.7.1 
 
7.7.2 
 
7.8 
Summary Statistics ..........................................................................................................23 
7.9 
Statistical Analysis ..........................................................................................................23 
8 
SAFETY ANALYSIS ..........................................................................................................24 
8.1 
Adverse Events ................................................................................................................24 
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8.2 
Clinical Laboratory Evaluations ......................................................................................25 
8.3 
Vital Signs .......................................................................................................................26 
8.4 
Physical and Neurological Examination Findings ..........................................................26 
8.5 
12-Lead Digital ECG Statistical Methodology ...............................................................26 
8.6 
12-lead Safety Electrocardiogram ...................................................................................27 
8.7 
Telemetry Results ............................................................................................................28 
8.8 
 
8.9 
C-SSRS Results ...............................................................................................................28 
9 
DATA HANDLING AND PRESENTATION ....................................................................29 
9.1 
Safety Analysis Presentation ...........................................................................................29 
9.2 
Pharmacokinetic Analysis ...............................................................................................30 
9.3 
Analysis Timepoints ........................................................................................................30 
9.4 
Methods for Handling Missing Data ...............................................................................30 
10 
INTERIM ANALYSES AND DATA SAFETY MONITORING .......................................31 
11 
GENERAL INFORMATION RELATED TO DATA PRESENTATIONS ........................32 
APPENDIX A 
STUDY SCHEDULE(S) ..............................................................................33 
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TABLE OF TABLES 
Table 1: 
Objectives and Related Endpoints ........................................................................... 10 
Table 2: 
Cohort and Treatment Information .......................................................................... 13 
Table 3: 
Data Presentations for Study Subject Information................................................... 16 
Table 4: 
Acceptable Windows for Timed PK Blood Specimen Collection Procedures ........ 17 
Table 5: 
Data Presentations for Demographic and Other Baseline Characteristics ............... 18 
Table 6: 
Pharmacokinetic Parameters of AZD4041 in Plasma .............................................. 20 
Table 8: 
Data Presentations for Safety Assessments ............................................................. 24 
Table 9: 
Clinical Laboratory Evaluations .............................................................................. 25 
 


 
 
 
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ABBREVIATIONS 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV% 
Coefficient of Variation 
 
 
dECG 
Digital Electrocardiogram 
DSMB 
Data Safety Monitoring Board 
DMP` 
Data Management Plan 
ECG 
Electrocardiogram 
EOS 
End of Study 
ET 
Early Termination 
 
 
ICF 
Informed Consent Form 
ICH 
International conference on Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
LN 
Natural Log 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic(s) 
PR(PQ) 
ECG interval measured from the onset of the P wave to the onset of the QRS 
complex 
PT 
Preferred Term 
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 
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SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TFLS 
Tables, Figures, and Listings 
 
  
WHO-DDE 
World Health Organization Drug Dictionary- enhanced 
 
 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides a detailed description of the statistical methods and 
procedures to be implemented for the analyses of data from protocol D7460C00002. Pre-planning 
of analyses reduces the potential for bias and often reduces disputes between sponsor and the 
regulatory authority regarding the validity of the results. The same principles apply to supportive 
and/or sensitivity analyses. These analyses must be prospectively specified. (Good Review 
Practice: Clinical Review of Investigational New Drug Applications, December 2013).  
The analyses described in the SAP are based upon the final protocol version 2.0 (Amendment 1) 
dated 2022/02/03. 
 
 


 
 
 
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2 
STUDY OBJECTIVES 
The objectives of the study and corresponding study endpoints are detailed in Table 1. 
Table 1: Objectives and Related Endpoints 
Objective 
Endpoint 
Analysis 
Primary  
To evaluate the safety and 
tolerability of orally 
administered AZD4041 in 
healthy subjects following daily 
doses for 14 days (or to steady 
state). 
• Adverse events (AEs) 
• Vital signs 
• Clinical laboratory tests 
• 12-lead electrocardiogram 
(ECG) (digital ECG [dECG] and 
safety ECG) and telemetry 
• Columbia Suicide Severity 
Rating Scale (C-SSRS) 
questionnaire 
• Physical and neurological 
examination 
• Measurement of male hormone 
levels: testosterone, luteinizing 
hormone (LH), follicle 
stimulating hormone (FSH), and 
inhibin B. 
Refer to Section 8 
Secondary 
x 
To characterize the multiple 
dose pharmacokinetics (PK) 
of AZD4041 in plasma and 
urine and assess the time 
required to reach steady 
state, the degree of 
accumulation, and the time 
dependency of its PK. 
The following AZD4041 PK 
endpoints will be estimated, data 
permitting: 
x 
Plasma: Cmax, Tmax, AUC0-24, 
AUC0-t, AUC0-inf, AUCss, 
Ctrough, Cτ, t1/2,z, t1/2Eff, CL/F, 
Vz/F, RAC(Cmax), and 
RAC(AUC), λz 
x 
Urine: CmaxU, TmaxU AUC0-
infU, Ae τ, fe/F, and CLR 
Additional PK parameters may 
be estimated as appropriate to 
support the main PK endpoints. 
 
Refer to Section 7 


 
 
 
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Objective 
Endpoint 
Analysis 
x 
 
 
 
 
 
  
 
x 
To assess the central nervous 
system (CNS) penetration 
potential of AZD4041 by 
quantification of AZD4041 
concentration in the 
cerebrospinal fluid (CSF) at 
plasma steady state. 
CSF (Cohorts 2 and 3 only): CSF 
concentration (ng/ml) reported as 
a percentage of total and free 
plasma concentration 
 
Exploratory 
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Objective 
Endpoint 
Analysis 
 
 
 
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3 
STUDY DESIGN  
3.1 
General Description 
This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, multiple ascending 
dose (MAD) study in healthy male and female adult subjects. 
The study will include up to 48 subjects (12 subjects per cohort) who will be randomized 9:3 to 
active drug or placebo. Each cohort will receive AZD4041 or placebo in a MAD study. Screening 
will occur within 28 days prior to the first study drug administration. Screening data will be 
reviewed to determine subject eligibility prior to the first study drug administration. 
For each cohort, 9 subjects will be randomly assigned to receive AZD4041 and 3 subjects will be 
assigned to receive placebo. Within each cohort, 2 subjects will be randomized initially to 
AZD4041 or placebo (1:1 ratio) to allow a sentinel dosing approach. Providing no clinically 
significant issues have been noted after the first 3 doses of the initial 2 (sentinel) subjects in a 
cohort and provided the Day 2 safety laboratory tests for the 2 subjects have been reviewed, the 
remaining 10 subjects will be randomised to AZD4041 or placebo in a 8:2 ratio and will be dosed 
in 2 separate groups with at least 24 hours between groups to monitor for safety and tolerability. 
All subjects will receive either AZD4041 or placebo administered 
 for 14 days. 
3.2 
Treatments 
All investigational products (IPs) will be provided by the Sponsor. The study treatments are 
presented in Table 2: 
Cohort and Treatment Information 
.  
Table 2: Cohort and Treatment Information 
 
Cohorta 
Treatment 
N 
Doseb 
1 
AZD4041 or Placebo 
12 (9:3) 
Adaptive 
2 
3 
a. = An additional cohort may be added if the maximum tolerated dose has not been defined and 
the maximum allowed exposure has not been reached after 3 cohorts. 
b. = Or until maximum tolerated dose is defined. 
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 
The CRU will generate the randomization code with a computer program according to the study 
design, the number of subjects, and the number of treatments. Eligible subjects within each cohort 
will be randomly assigned in a ratio of 9:3 to Active: Placebo. Once generated, the randomization 
code will be final and will not be modified. 
Subjects who sign the ICF, are randomized, receive the study treatment, and subsequently 
withdraw, or are withdrawn or discontinued from the study, should not generally be replaced. 
However, consideration may be given to the replacement of such subjects in order to enable the 
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completion of at least 10 subjects for the purposes of Safety Review Committee and dose 
escalation decisions. Replacement of subjects under these circumstances 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 cohort stopping rules (Section 4.4.2.1) or otherwise jeopardise the safe conduct of the 
study.  
Blinding 
The treatment assignment will not be known by the study participants; however, the taste between 
the IP and placebo is distinguishable and unable to be masked. Therefore, it is possible that 
subjects will know the treatment to which they have been assigned.  
The randomization code will not be available to the personnel of the bioanalytical facility until the 
bioanalytical phase of the study has been completed. 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, 
including the pharmacokineticist(s) and statistician(s) (or delegate), until all the 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). In the event of a medical emergency requiring identification of the study drug 
administered to an individual subject, an Investigator will make every attempt to contact the 
Sponsor’s Study Physician to explain the need for breaking the blind within 24 hours of doing so. 
The date and reason for breaking the blind must be recorded. 
The results of the PK and safety analyses will be made available only to the personnel responsible 
for evaluating the safety data before proceeding with the next dose level. The bioanalytical facility 
will preserve the blind by reassigning alternative subject numbers to the interim data before they 
are made available to the PK facility and Sponsor; these alternative subject numbers will be 
assigned by the lab at the time of sample analysis. 
 
 


 
 
 
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4 
ANALYSIS POPULATIONS 
The following populations will be defined: 
x Safety population: The safety population will include all subjects who received at least 1 
dose of the IP or placebo. 
x Pharmacokinetic Population: The PK population will include all subjects who have 
received at least 1 dose of AZD4041 and have at least 1 PK concentration after dosing. 
Subjects administered matching placebo will not be included in the PK population. 
Subjects who do not complete the sampling schedule may be included in the PK analysis 
for only the PK parameters that are judged not to be affected by the missing sample(s). 
x 
 
 
 
 
 
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5 
STUDY SUBJECTS 
Disposition data, analysis population information and protocol deviations will be listed and 
summarized as described in Table 3.   
Table 3: Data Presentations for Study Subject Information  
Data 
Variables 
Presentation 
Disposition and analysis 
population 
Subject, completion status (i.e., 
completed or withdrawn), reason for 
withdrawal, analysis population 
determination 
Listings: 
x Randomization 
x Disposition 
x Analysis population 
Table: 
x Disposition 
Protocol deviations 
Protocol deviations 
Listings: 
x 
Protocol deviations 
x 
Pharmacokinetic (PK) 
sample collection time 
deviations 
5.1 
Disposition 
Subject disposition will be summarized for all subjects randomized. The following will be 
presented: 
x Number (N) of subjects screened 
x N of subjects randomized 
x N and % of subjects who completed the study 
x N and % of subjects who withdrew from the study by primary reason for withdrawal 
x N and % of subjects included in each analysis population 
The percentages will be calculated using the number of randomized subjects as the denominator. 
The summary will be presented by treatment (dose level of AZD4041 and pooled placebo).  
5.2 
Protocol Deviations 
Deviations identified at the site will be collected in the clinic deviation tracking system (DTS) and 
presented in a protocol deviation listing. Protocol deviations will be reviewed by the 
Sponsor, principal investigator, lead statistician and study scientist(s) and finalized before 
unblinding the study. Protocol deviations will be listed for the Safety Population. 
For PK sampling time deviations, information will be derived programmatically and presented in a 
separate listing. Allowable windows for PK blood samples are shown in Table 4. 
 
 


 
 
 
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Table 4: Acceptable Windows for Timed PK Blood Specimen Collection Procedures 
Elapsed Time 
Accepted Window 
Predose 
No window specified 
> 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 
 
 
 


 
 
 
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6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Unless otherwise specified, all available data will be listed, summarized, for demographics and 
other baseline characteristics and presented for the safety population as detailed in Table 5.   
Table 5: Data Presentations for Demographic and Other Baseline Characteristics  
Data 
Variables 
Presentation 
Demographic and Other 
Baseline Characteristics 
Sex, age, ethnicity, race, height, 
weight and body mass index (BMI) 
Listing  
Table 
Medical history 
All medical history findings 
Listing 
Prior and Concomitant 
medications 
All medications taken prior to 
study drug administration 
and concomitant medications 
(including vaccines, prescription 
medications, nonprescription 
medications, dietary supplements, 
vitamins, or herbal medications) 
Listing 
 
Contraception 
Contraceptive method 
Listing 
 
 
 


 
 
 
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7 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
The PK analysis will be carried out according to Altasciences Standard Operating Procedures (SOPs). 
Unless otherwise specified, all available PK data and analysis results will be presented for the PK 
Population. 
 
7.1 
Missing Values 
The lack of concentration values due to failure to collect the sample, a lost or compromised 
sample, or due to the subject’s early termination from the study will be termed “missing” in the 
dataset, and no imputation will be done. For urine data, if a subject has failed to void over a 
particular collection interval, the amount excreted will be set to zero. 
If the actual collection time of a postdose plasma PK sample is unknown, but a valid concentration 
value has been measured, the sample will be set to missing in the PK analysis and will be 
presented in listings but excluded from descriptive statistics. Unknown predose collection times 
will be handled on a case-by-case basis. 
7.2 
Measurements Below the Lower Limit of Quantitation 
Concentration values below the lower limit of quantitation (LLOQ) associated with predose 
collection times will be replaced with zero for the non-compartmental analyses (NCA); however, 
postdose collection times will be replaced using conditional substitutions that considers zero  
before Tmax and likelihood estimations after Tmax. 
Concentration values below the LLOQ will be replaced with zero for mean PK profile 
representations as well as for descriptive statistic calculations. 
7.3 
Actual Time 
The plasma NCA analysis will be based on the actual sampling times, except for predose samples, 
which will always be reported as zero, regardless of time deviations. 
The individual plasma concentration/time profiles will be presented using actual sampling times 
whereas the mean plasma concentration/time profiles and tables presenting summary statistics of 
concentration -time series will be presented using nominal sampling times. 
Actual times for plasma PK sample collections will be listed in the report. 
Urine PK analysis and data presentation will utilize the nominal collection interval times; CSF 
concentration and biomarker data will be presented based on nominal collection time. 
7.4 
Baseline Reference Timepoint 
Unless otherwise specified, the baseline value will be defined as the last non-missing evaluation 
prior to the first study drug administration. 
7.5 
Non-Compartmental Analysis 
The following configuration for the NCA analysis (with Phoenix® WinNonlin® version 8, or 
higher) will be used: 
x Data: 
                              Serial sampled data 
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x Model/Dose options Type:  
Plasma (200 202) and Urine (210 – 212)/Extravascular 
x AUC Calculation Method: 
Linear up/Log down (applicable to plasma only) 
x Lambda Z (λz) calculation: 
Best fit method for λz Linear-Log regression 
Reasons for excluding PK parameters will include the following: 
x AUC: AUC parameters will not be estimated if less than 3 consecutive measurable 
concentrations are observed. 
x PK parameters requiring λz estimation (eg, AUC0-inf and t1/2) will be set to Not Reported 
(NR) in the Tables and Listings if they meet one of the following: 
 R2 < 0.8 
 Extrapolated area > 20% 
The PK parameters for AZD4041 are presented in Table 6 
Table 6: Pharmacokinetic Parameters of AZD4041 in Plasma  
PK Parameter 
Definition 
Plasma, Day 1 
Cmax 
Maximum observed concentration 
Tmax 
Time of maximum observed concentration 
AUC0-24 
Area under the concentration time curve from time 0 (dose administration) to 
24 hours 
(The nominal time will be used to estimate partial AUC using the NCA built-in 
tool in Phoenix® WinNonlin®. This means that actual times off by more than 1 
minute from the partial end-hour timepoint will be extrapolated/interpolated as 
per Phoenix® WinNonlin®’s built-in formulas. If extrapolation/interpolation is 
not possible, then no value is reported by the software.) 
AUC0-t 
Area under the concentration time curve from time 0 (dose administration) to 
the time of last quantifiable concentration (tlast) 
AUC0-inf 
Area under the concentration time curve extrapolated to infinity, calculated as 
AUC0-t + Clast/λZ, where Clast is the measured concentration at time tlast 
t1/2,z 
Terminal elimination half-life, calculated as ln(2)/λZ 
CL/F 
Apparent total clearance, calculated as Dose/AUC0-inf 
Vz/F 
Apparent volume of distribution, calculated as Dose/λZ * AUC0-inf 
Cmax/D 
Dose-normalized Cmax 
AUC0-t/D 
Dose-normalized AUC0-t 
AUC0-inf/D 
Dose-normalized AUC0-inf 
Plasma, Day 14: 
Cmax 
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Tmax 
Time of maximum observed concentration; if it occurs at more than one 
timepoint, tmax is defined as the first timepoint with this value 
Cτ 
Concentration at the end of the dosing interval. Observed concentration, 
otherwise the predicted concentration value will be calculated as per Phoenix® 
WinNonlin®’s built-in rules for interpolation/extrapolation, and subject to the 
criteria for PK parameters requiring λz estimation. 
AUCss 
Area under the concentration time curve over the dosing interval at steady state, 
calculated from 0 to 24 hours (dosing interval)  
(The nominal time will be used to estimate AUCss using the NCA built-in tool in 
Phoenix® WinNonlin®. This means that actual times off by more than 1 minute 
from the dosing interval end-hour timepoint will be extrapolated/interpolated 
as per Phoenix® WinNonlin®’s built-in formulas. If extrapolation/interpolation 
is not possible, then no value is reported by the software.) 
AUC0-t 
Area under the concentration time curve from time 0 (dose administration) to 
the time of last quantifiable concentration (tlast) 
t1/2,z 
Terminal elimination half-life, calculated as ln(2)/λZ 
t1/2Eff 
Effective half-life, calculated as 
τ * ln2 /ln(Rac(AUC)/( Rac(AUC)-1)), where τ is 24 hours1 
CL/Fss 
Apparent total clearance at steady state, calculated as Dose/AUCτ  
Vz/Fss 
Apparent volume of distribution at steady state, calculated as Dose/λZ * AUCτ  
Cmax/D 
Dose-normalized Cmax 
AUCτ/D 
Dose-normalized AUCτ 
AUC0-t/D 
Dose-normalized AUC0-T 
RAC(Cmax) 
Accumulation ratio evaluated by comparing Day 14 Cmax to Day 1 Cmax 
RAC(AUC) 
Accumulation ratio evaluated by comparing Day 14 AUCτ to Day 1 AUC0-24* 
*Day 1 AUC0-t may be used if AUC0-24 cannot be estimated, provided that the 
24-hour sample was collected within 10% of nominal time. 
Plasma, Various Days: 
Ctrough 
Observed concentration at the end of the dosing interval (predose 
concentrations on Day 2 [Day 1, 24-hours] through Day 14) 
The following plasma PK parameters will be used for PK calculation and presented in the PK 
listings only 
tlast 
Time of last measurable observed concentration 
Clast 
Observed concentration corresponding to tlast 
λZ 
Apparent elimination rate constant, estimated by linear regression of the 
terminal linear portion of the log concentration versus time curve 
λZ Upper 
Upper limit on time for values included in the calculation of λz 
λZ Lower 
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Number of Points 
Number of data points in computing ȜZ 
R2 
Goodness of fit for the terminal phase 
Residual area 
Extrapolated area (ie, percentage of AUC0- due to extrapolation from tlast to 
infinity: AUC0- - AUC0-t/ AUC0-*100) 
Urine, Day 1, and Day 14: 
AeĲ 
Amount of drug excreted in urine 
The Ae at each urine collection interval will be calculated as follows:  
Concentration * Volume of urine during that time interval (t1 to t2) 
Cumulative Ae will be calculated as the sum of all urine collection interval Aes 
Note: The Ae at pre-dose will not be included in the calculation of cumulative 
Ae. 
fe/F 
Cumulative fraction of unchanged drug excreted in urine over all time 
intervals, calculated as 
(Ae / Dose)*100 (expressed in %) 
Note: The Ae at pre-dose will not be included in the calculation of fe. 
CLR 
Apparent renal clearance, calculated as: 
Ae (0-24) / AUC0-24 on Day 1 and as Ae (0-24) / AUCĲ on Day 14 
A different time interval may be used providing not all single intervals are 
usable. 
*Day 1 AUC0-t may be used if AUC0-24 cannot be estimated, provided that the 
24-hour sample was collected within 10% of nominal time. 
CSF, Day 14: 
CCSF% 
AZD4041 CSF concentration (Cohorts 2 and 3 only), calculated as a percentage 
of plasma concentration (i.e. Kp(CSF) = CSF /total plasma concentration *100 
and Kp,u(CSF) = CSF/free plasma concentration *100)  
1 Sources: Error! Reference source not found. and Error! Reference source not found. 
7.6 
Cerebrospinal Fluid 
For Cohorts 2 and 3 only, AZD4041 CSF concentrations (ng/ml) on Day 14 will be calculated as a 
percentage of plasma concentration collected at the corresponding time. 
7.7 
 
 
 
 
7.7.1 
 
 
  
 
 
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7.7.2 
 
7.8 
Summary Statistics 
All tables, figures, and listings, when appropriate, will be stratified by cohort (dose level) and by 
study day, as applicable.Summary statistics of the individual AZD4041 plasma, urine, and CSF 
concentration data and derived parameters as well as biomarker data will be calculated for the PK 
population. Summary statistics will be calculated for concentration at each individual timepoint 
and for all PK parameters. 
Concentration data will be summarized by group using the following statistics: number of 
observations (N), arithmetic mean (mean), standard deviation (SD), minimum (min), median, 
maximum (max), and coefficient of variation (CV). PK parameters will be summarized using these 
same statistics, as well as geometric mean and geometric mean CV. 
If PK parameters can only be estimated in a limited number of subjects, the following criteria will 
be applied for reporting descriptive statistics: 
x If a PK parameter value is reportable in less than 3 subjects for a given study part and day, 
then SD, CV, and geometric mean CV will be considered not reportable 
x If a PK parameter value is only reportable in 1 subject for a given study part and day, only 
minimum and maximum will be reported 
7.9 
Statistical Analysis 
Dose Proportionality for Day 1 and Day 14 
Inferential statistical analysis will be performed with SAS. 
Appropriate dose–normalized PK parameters (Cmax and appropriate AUCs) will be assessed 
graphically for dose-proportionality. 
Natural log-transformed PK parameters (Cmax and appropriate AUCs) will be assessed statistically 
for proportionality. Proportionality analysis will be done using a power model. The power model is 
defined as: 
ln(PK parameter) = Į + ȕ • ln(Dose) + İ 
where Į is the intercept, ȕ is the slope and İ is the normal error term. A linear model with ln-
transformed dose as a continuous effect will be fitted. A point estimate and a 90% confidence 
interval (CI) will be derived for the slope (ȕ). 
Dose proportionality may be assessed within different dose ranges if deemed appropriate with at 
least three doses. 
Steady State 
Ctrough will be displayed graphically and summarized descriptively by day to assess for steady state. 
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8 
SAFETY ANALYSIS 
Unless otherwise specified, all available data will be listed and summary tables for safety 
assessments will be presented by treatment (dose level of AZD4041 and pooled placebo) per 
cohort for the Safety population as detailed in Table 7.  
Continuous variables will be summarized (absolute values) using descriptive statistics (n, mean, 
SD, minimum, median and maximum). 
Table 7: Data Presentations for Safety Assessments  
Data 
Variables 
Presentation 
Adverse events 
Adverse event (AE) 
description, date and time (start 
and end), 
intensity, relationship to study 
drug, action taken, study days 
and outcome 
Listing  
Table  
Extent of exposure 
Study drug administration dose, 
units, date, time, Cohort 
Listing 
Clinical laboratory 
evaluations 
Laboratory results (refer to section 
8.2 for parameters) 
Listing  
Table  
Vital signs 
Blood pressure, pulse, and body 
temperature 
Listing  
Table  
Physical and 
neurological 
examinations 
Physical and neurological 
examinations findings 
Listings  
12-Lead 
Electrocardiograms 
(ECGs) 
ECG interpretations and findings 
Listings 
Table 
Digital 
Electrocardiograms 
(ECGs) 
Digital ECG interpretations and 
findings 
Listings 
Table 
Figures 
Telemetry 
Telemetry findings 
Listings 
Columbia-Suicide 
Severity Rating 
Scale (C-SSRS) 
C-SSRS Suicide Ideation 
score 
Listing for individual items 
 
8.1 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are adverse events (AEs) that are not present prior to 
the exposure to study treatment or AEs that are already present that worsen in intensity or 
frequency following exposure to study treatment. All AEs reported following exposure to study 
treatment are considered TEAEs.  


 
 
 
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AEs will be assessed for treatment emergence with respect to the study cohort. All TEAEs will be 
coded using MedDRA Version 24.0. The listing and summaries will include coded System Organ 
Class (SOC) and Preferred Term (PT). 
An overall summary by treatment (dose level of AZD4041 and pooled placebo) will present the 
number and percentage of subjects with: 
x At Least One TEAE 
x At Least One Drug-Related TEAE 
x Maximum Intensity 
o Mild 
o Moderate 
o Severe 
x  At Least One SAE 
x  At Least One Drug-Related SAE 
x  Death 
For the study, the following AE tables will also be presented: 
x TEAEs by SOC and PT 
x Drug-Related TEAEs by SOC and PT 
x TEAEs by SOC, PT, and Maximum Intensity (Mild, Moderate, Severe) 
Events will be listed by treatment, subject and AE onset date. Treatment-emergent Adverse Event 
(TEAE) duration (stop date/time - start date/time) will be included in the listing; where applicable, 
imputed data will be used for the calculation of TEAE duration, but the original dates/time 
information will be presented in the listing. 
8.2 
Clinical Laboratory Evaluations 
Laboratory data will be presented using units as reported by the clinical laboratory. Specific 
hematology, clinical chemistry, urinalysis, endocrinology, serology parameters are listed in Table 
8. 
Table 8: Clinical Laboratory Evaluations 
Clinical Laboratory Test Panel  
Description  
General biochemistry:  
 
Alanine aminotransferase, albumin, alkaline 
phosphatase, bilirubin total and unconjugated, C-
reactive protein, chloride, creatinine, creatine 
kinase, gamma glutamyl transferase, protein total, 
glucose (fasting), calcium, potassium, magnesiuma, 
and sodium  
Endocrinology: 
Follicle stimulating hormoned,e, oestradiola,b, 
thyroid stimulating hormonea , T4a,c, luteinising 
hormoned, testosteroned, and inhibin Bd  
Haematology:  
White cell count with differential (absolute values 
of neutrophil, lymphocyte, monocyte, eosinophil, 
and basophil), red cell count, haemoglobin, 
haematocrit, mean corpuscular volume, and platelet 
count  
Serology:  
 
Human immunodeficiency virus Ag/Ab Combo, 
hepatitis B surface antigen, hepatitis C virus, and 
Severe Acute Respiratory Syndrome Coronavirus-2  


 
 
 
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Urinalysis:  
Colour, 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, cotinine, opiates, and phencyclidine  
Pregnancy test (females only):  
Serum pregnancy test 
Alcohol screen:  
Alcohol breathalyser or urine screen  
a. At Screening only  
b. Postmenopausal women only  
c. Reflex only (if TSH is abnormal)  
d. Males only at Day -1, Day 1 and Day 14 
e. FSH for females at screening only 
Absolute values for ‘continuous’ parameters (hematology, chemistry and urinalysis) will be 
summarized using descriptive statistics by treatment (dose level of AZD4041 and pooled placebo). 
Serology, alcohol/drug screen, Pregnancy test and Endocrinology results will be presented in 
separate listings. 
Data listings will include out-of-range flags (L, H) and whether the abnormal values are clinically 
significant or not. 
8.3 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, temperature and pulse. 
Absolute values in vital signs measurements will be summarized descriptively by treatment (dose 
level of AZD4041 and pooled placebo) and time point.  
Data listings will identify if values are “abnormal, clinically significant” or “abnormal, not 
clinically significant”.  
8.4 
Physical and Neurological Examination Findings 
The physical examination will include a general review of the following body systems (at 
minimum): head and neck, cardiovascular, respiratory, gastrointestinal, and general appearance, 
unless a symptom-oriented physical exam is indicated.  
The neurological examination includes a review of basic mental status, cranial nerves, motor 
function, sensation and proprioception, reflexes, co-ordination and gait 
Physical and neurological examination results will be listed as normal or abnormal. Abnormal 
findings of clinical significance will be included in the listings.  
8.5 
12-Lead Digital ECG Statistical Methodology 
From the digital electrocardiogram (dECG) data, the following parameters will be derived: 
QTcF = QT*RR-1/3, where the QT interval is in milliseconds and the RR interval is in seconds. 
Heart rate (HR) = 60/RR interval, where the RR is Time Elapsed between Two Successive R-
Waves of the QRS Signal on the ECG i.e. interval in seconds. 
Calculation of derived parameters will be performed after smoothing of QT and RR data. 
The digital electrocardiogram (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 


 
 
 
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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 (dose level of AZD4041 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 (dose level of AZD4041 and pooled placebo) 
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) pre-dose assessment on Day 1. 
Outliers with respect to QTcF will also be tabulated for the following categories: 
 
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 
Outliers in other ECG variables (absolute values either below or above the reference ranges): 
 
PR interval < 110 ms or > 220 ms 
 
QRS duration < 75 ms or > 115 ms 
 
Heart rate < 50 bpm or > 100 bpm 
 
QT < 320 ms or > 450 ms 
 
QTcF < 320 ms or > 450 ms 
8.6 
12-lead Safety Electrocardiogram  
Resting 12-lead Safety Electrocardiogram: Standard safety 12-lead ECGs will be performed as 
described in the CSP protocol section 6.2.4. 
The 12-lead 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 
CCI


 
 
 
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clinical importance on the PR, QRS, and QTcF intervals. Timepoints for 12-lead Safety ECG 
measurements are specified in the protocol Table 6-4 in the CSP. 
8.7 
Telemetry Results 
Telemetry results will be reviewed by the Investigator, listed by date and time, described and 
reported, if considered clinically significant.  
8.8 
 
 
8.9 
C-SSRS Results 
C-SSRS, results will be listed by date and time, described and reported, if considered clinically 
significant.  
 
 
 
 
 
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9 
DATA HANDLING AND PRESENTATION 
All safety and statistical outputs will be generated using SAS software, version 9.4. 
All programs used to generate statistical analyses will be validated according to Altasciences 
SOPs). 
Draft tables, figures and listings will be provided in RTF and PDF formats. 
9.1 
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 WHO-DDE (March 2021) as defined in 
the study DMP. 
Generally, summaries will be presented by treatment (dose level of AZD4041 and pooled placebo). 
Some summaries will also be presented to include all subjects (i.e., subject disposition and 
demographics).  
Summaries for data collected at scheduled times specified by the protocol will be presented by 
treatment (dose level of AZD4041 and pooled placebo), visit and, where applicable, time point. 
In general, the data listings will include data from all subjects who receive at least one dose of 
either AZD4041 or placebo.  
Study days will be included in adverse event and concomitant medication listings in addition to 
dates. Study days will be calculated relative to the first day of double-blind treatment (Day 1) 
derived as (event date - first day of AZD4041 or placebo dosing) +1 for events after the first day of 
dosing and (event date - first day of AZD4041 or placebo dosing) for events before the first day of 
dosing. 
The following general comments also apply to all statistical analyses and data presentations: 
x Duration variables will be calculated using the general formula: (end date - start date) +1. 
x If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical type), a 
coded value must be appropriately determined and used in the statistical analyses.  In 
general, a value or lower and upper limit of normal range such as ‘<10’ or ‘≤5’ will be 
treated as ‘10’ or ‘5’ respectively, and a value such as ‘>100’ will be treated as ’100’.  
However, the actual values as reported in the database will be presented in data listings. 
x When assessments are repeated for a given time point or performed at unscheduled times, 
only the result which is the closest to the dosing time will be included in summary tables. 
In general, summary statistics for raw variables (i.e., variables measured at the study site or central 
laboratory) will be displayed as follows:  
x Minima and maxima will be displayed to the same number of decimal places as the raw 
data.  
x Means, medians, and quartiles will be displayed to 1additional decimal place.  
x Standard deviations will be displayed to 2 additional decimal places.   


 
 
 
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x Percentages will be displayed to 1 decimal place. Percentages between 0 and 0.1 
(exclusive) will be displayed as ‘<0.1’.   
x P-values will be displayed to 3 decimal places. P-values that are less than 0.001 will be 
displayed as ‘<0.001’. 
The number of decimal places for summary statistics of derived variables (i.e., variables that are 
not measured by the study site but are calculated for analysis based on other measured variables) 
will be determined on a case by case basis.  In general:  
x Minima and maxima will be displayed to the commonly used unit of precision for the 
parameter.  
x Means, medians, quartiles, and confidence limits will be displayed to 1 additional decimal 
place.  
x Standard deviations will be displayed to 2 additional decimal places.  
9.2 
Pharmacokinetic Analysis 
In general, all PK summary tables will be presented for the PK population. 
Individual raw PK concentrations will be displayed with the same precision as received from the 
bioanalytical laboratory. 
Precision for individual PK data will be displayed as follows:  
x Concentration-related PK parameters (eg, Cmax, AUCs) will be displayed with the same 
precision as the raw PK concentration data, 
x Apparent clearance (CL/F, CL/Fss) and volume of distribution (Vz/F, Vz/Fss) will be 
reported to 3 significant figures, 
x Parameters associated with time (e.g. Tmax and t1/2) will be displayed with 2 decimal places, 
x Percentages will be displayed with 2 decimal places, 
x R2 and λZ will be displayed with 4 decimal places. 
Summary statistics for concentration and PK parameters will be displayed with the same precision 
as the individual values, with the exception of number of observations (N) and CV% which will be 
presented with 0 and 1 decimal place, respectively. 
9.3 
Analysis Timepoints  
Unless otherwise specified, the baseline value will be defined as the last non-missing evaluation 
prior to the first dose of study medication. 
9.4 
Methods for Handling Missing Data  
No imputations of values for missing data (ie, blank, “Not Done”, “Not Applicable”, etc) will be 
performed and data presentations will reflect the data point as it appears in the case report form 
(CRF) or electronic data file.  


 
 
 
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10 INTERIM ANALYSES AND DATA SAFETY MONITORING 
In order to inform dose selection for the next expected cohort, interim PK analysis will be 
performed and available at the time of the safety review meeting, prior to the next dose escalation, 
for Cohort 1,Cohort 2 and Cohort 3. (Note: PK analysis for Cohort 3 is required for the Cohort 3 
safety review meeting in the event that a Cohort 4 is initiated for the study). These preliminary PK 
results will be performed on plasma concentration data only, as outlined in Section 7.1 through 
Section 7.5, with the exception those nominal times will be used in the analysis instead of actual 
times.  
To preserve the study blind, bioanalytical facility will preserve the blind by reassigning alternative 
subject numbers to the interim data before they are made available to the PK facility and Sponsor; 
these alternative subject numbers will be assigned by the lab at the time of sample analysis. 
Mean plasma concentration-time profiles as well as parameter summary tables of the key (e.g. 
Cmax, Tmax, and AUCs) PK endpoints will be generated.  
 
 


 
 
 
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11 GENERAL INFORMATION RELATED TO DATA PRESENTATIONS 
The formats and layouts of TFLs are provided in a separate document and are 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.  
Minor format changes will not require updates to the SAP; rather they may be documented in a 
Note to SAP. 


 
 
 
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APPENDIX A STUDY SCHEDULE(S) 
  
 


 
 
 
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