A Randomised, Double-blind, Placebo-controlled Study to Evaluate Cortisol Reserve in Response to Adrenocorticotropic Hormone Stimulation Test Following Treatment With Baxdrostat for 8 Weeks in Participants With Uncontrolled Hypertension
Phase: PHASE2
Conditions: Uncontrolled Hypertension
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study 
Intervention 
Baxdrostat 
Study Code 
D6970C00011 
Version 
3.0 
Date 
26 August 2024 
IND Number 
146112 
A Randomised, Double-blind, Placebo-controlled Study to Evaluate 
Cortisol Reserve in Response to Adrenocorticotropic Hormone 
Stimulation Test Following Treatment with Baxdrostat for 8 Weeks 
in Participants with Uncontrolled Hypertension  
Sponsor Name: AstraZeneca AB 
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden 
Regulatory Agency Identifier Number: IND 146112 
 
This protocol has been subject to a peer review according to AstraZeneca standard procedures. 
The protocol is publicly registered and the results are disclosed and/or published according to 
the AstraZeneca Global Standard - Bioethics and in compliance with prevailing laws and 
regulations. 

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Version Scope: Global 
Brief Title: A Study to Evaluate Cortisol Reserve in Response to Adrenocorticotropic 
Hormone Stimulation Test Following Baxdrostat Treatment Compared to Placebo in 
Participants with Uncontrolled Hypertension 
Study Phase: Phase II 
Study Clinical Lead Name and Contact Information will be provided separately. 
Study Clinical Lead is responsible for the clinical integrity of the study (for example, the 
study physician or scientist). 

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SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY 
Document 
Date 
Clinical Study Protocol Version 3.0 (Amendment 2.0) 
26-August-2024 
Clinical Study Protocol Version 2.0 (Amendment 1.0) 
05-June-2024 
Clinical Study Protocol Version 1.0 
05-March-2024 
 
Clinical Study Protocol (CSP) Version 3.0, 26 August 2024 
Overall Rationale for the Modification: 
The primary rationale for this amendment is 
 
 and to correct and/or clarify details related to 
some procedures, statistical analysis details, and tests as listed below. Additionally, some 
minor editorial and typographical corrections have been made throughout this protocol which 
have not been listed in the summary of change. 
Summary of Changes: 
List of Non-substantial Modifications 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis; 
Section 1.3, Schedule of 
Activities; Section 4.1, 
Overall Design. 
Addition of Table 3 “Schedule of Cortisol 
Measurements” and providing description 
of different cortisol measurements during 
the study throughout. 
To provide additional clarification. 
Section 1.3, Schedule of 
Activities. 
Addition of clarification to Table 1 
footnote “b” to read “In rare incidence that 
participant has abnormal ACTH stimulated 
cortisol level, the participant will be asked 
to remain on treatment and to undergo 
repeat ACTH stimulated cortisol 
measurements during an unscheduled visit. 
See Footnote “g”. If applicable, the repeat 
tests shall be rescheduled as soon as 
possible to keep the duration of the 
treatment within 10 weeks. The IMP will 
be discontinued immediately following the 
completion of the repeated ACTH 
stimulation test”. 
To provide additional clarification. 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.3, Schedule of 
Activities. 
Amendment to Table 1 footnote “g” to read 
“If the cortisol level is abnormal at EoT 
(Visit 6, Week 8), the test will be repeated 
during an unscheduled visit (prior to 
ACTH stimulation test, 
 minutes 
after ACTH stimulation test, and 
 
minutes after ACTH stimulation test) for 
confirmation. See Table 3 for more 
details.” 
To clarify and align the language 
around the unscheduled visit 
throughout. 
Section 1.3, Schedule of 
Activities. 
Addition for clarification to Table 1 
footnote “h” that “Participants must have a 
morning cortisol (measured at 
08:00 AM ± 2 hours) ≥ µg/dL, 
determined as per central laboratory to be 
eligible for the study”. 
To provide additional clarification. 
Section 1.1, Synopsis; 
Section 4.1, Overall 
Design. 
Addition of clarification note “10 weeks is 
not the targeted duration of the treatment 
period, but only intends to provide 
flexibility in case of unforeseen event. The 
last date of treatment can be later than the 
EoT Visit date.” 
Deletion of duplicated sentence “this 
period can be extended up to 10 weeks if 
waiting for ACTH results.” 
To clarify and to provide the 
needed time flexibility in case of 
an unforeseen event such as 
waiting for ACTH stimulation test 
results. 
Section 1.1, Synopsis; 
Section 4.1, Overall 
Design. 
Addition for clarification that “If 
applicable, the repeat tests shall be 
rescheduled as soon as possible to keep the 
duration of the treatment within 10 weeks” 
AND that “The IMP will be discontinued 
immediately following the completion of 
the repeated ACTH stimulation test.” 
To provide clarification on the 
duration of treatment. 
Section 1.1, Synopsis; 
Section 4.1, Overall 
Design. 
Amendment of cortisol cut-off amount 
from “≤ 
 μg/dL” to “< 
 μg/dL” for 
baseline (Visit 2), EoT Visit (Visit 6), and 
Unscheduled Visit for the repeat 
post
 minute ACTH stimulation test.  
 
 
 
Section 1.1, Synopsis; 
Section 4.1, Overall 
Design; Section 7.1, 
Discontinuation of Study 
Intervention. 
Addition of clarification that “In case of 
abnormal ACTH stimulated cortisol values 
at baseline, participant discontinues the 
study intervention and follows steps as 
described in the protocol.” 
To provide clarification. 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis; 
Section 4.1, Overall 
Design; Section 8.6.2, 
ACTH Stimulation Test 
and Cortisol Level 
Measurement. 
Amendment of abnormal cortisol level 
definition to this effect that Cortisol level at 
 minutes after ACTH stimulation 
that is < 
 μg/dL at baseline (Visit 2) 
and EoT (Visit 6, Week 8) will be 
considered abnormal, indicating impaired 
cortisol reserve. An abnormal cortisol level 
after ACTH stimulation test at baseline 
(Visit 2), will result in the participant’s 
discontinuation of the study intervention. 
At EoT (Visit 6, Week 8), in the rare 
incidence of an abnormal ACTH stimulated 
cortisol level, the participant will be asked 
to remain on treatment and to undergo 
repeat ACTH stimulated cortisol 
measurements during an unscheduled visit 
which includes cortisol measurements 
 minutes after ACTH stimulation test 
(with 
 µg/dL cut-off) and 
 
minutes after ACTH stimulation test (with 
 µg/dL cut-off). To be considered an 
abnormal repeat ACTH stimulated cortisol 
result, post-ACTH cortisol must 
be < 
 µg/dL at 
 minutes post-ACTH 
stimulation and < 
 µg/dL at 
 minutes 
post-ACTH stimulation. If only one of the 
two results is abnormal, the overall test will 
be considered normal. The results from the 
repeat test will supersede the original 
Week 8 results. 
 
 
Section 1.1, Synopsis; 
Section 9.4.2.1, Primary 
and Secondary Endpoints. 
Amendment of the incidence of abnormal 
stimulated cortisol to read “serum total 
cortisol below the pre-specified threshold 
after 
 minutes.” 
To correct a typographical error. 
Section 1.1, Synopsis; 
Section 9.4.2.1, Primary 
and Secondary Endpoints. 
Addition of clarification that “Those 
discontinued participants will be listed and 
plotted separately. If performed, the results 
of the repeat ACTH stimulation test at the 
unscheduled visit will be used for the 
analysis”. 
To provide clarification. 
Section 3.0, Objectives, 
Endpoints, and 
Estimands. 
Update of the primary estimand treatment 
condition and intercurrent events and 
strategies. 
To improve estimand strategy. 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis; 
Section 9.4.2.1, Primary 
and Secondary Endpoints. 
Addition of clarification that 
 
 
 
 
The data collected after the other 
intercurrent events will be included in the 
data analyses (Treatment Policy Strategy)”. 
To provide clarification. 
Section 5.2, Exclusion 
Criteria; Section 6.9.1, 
Prohibited Concomitant 
Medications; 
Section 6.9.2., Restricted 
Concomitant 
Medications. 
Amendment of exclusion criterion 
number 25 to read “Treatment with 
medications that 
 
 within 8 weeks prior to 
Screening.” 
AND expansion of the list of prohibited 
medications to include “
 
 
 
;
 
 
 and Once enrolled, treatment 
with any form of 
 
therapy or on over the counter 
 while enrolled in the 
study, treatment with 
 
 at any dose”. 
Removed repetition of prohibited 
medications from Section 6.9.2. 
To define concomitant medications 
 
Section 8.1, 
Administrative and 
General/Baseline 
Procedures. 
Addition of “Cortisol values” to the list of 
data collected at the Screening. 
To provide clarification. 
Section 8.2.1, Efficacy 
Assessments. 
Moving the subheading to new subheading 
8.6.2 under Pharmacodynamics. 
Accordingly, Section 8.2 is now changed to 
“Not applicable”. 
To correct a template 
misalignment. 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 8.3.4, Clinical 
Safety Laboratory Tests. 
Revision of Table 7 title to “Laboratory 
variables” 
Amendment of Table 7, footnote “a” to 
indicate that eGFR will be calculated every 
time creatinine is collected. 
Amendment of Table 7, footnote “b” to 
indicate Creatinine, K+, and Na+ will be 
measured between “Screening (Visit 1)” 
and End of Treatment (EoT) (Visit 6). 
Amendment of Table 7 footnote “d” to 
include “serum pregnancy test will be 
performed centrally”. 
To provide clarification and 
prevent misinterpretation during 
sampling and analysis. 
Section 9.4.3.1, Adverse 
Events. 
Removal of mention of “other significant 
AEs”. 
To align with the SAP. 
Appendix E6, Laboratory 
Tests. 
Removal of the current IgM anti-HSV test 
and replacement with the HSV-1 and 
HSV-2 IgM testing OR HSV-1 and 
HSV-2 PCR testing depending on regional 
requirements 
This operational update is meant to 
improve diagnostic accuracy 
without impacting the study's 
primary or secondary objectives, 
patient safety, or the overall 
management of the study. 
Appendix F, Protocol 
Version History. 
Addition of protocol version history to the 
CSP appendices. 
To align with the protocol template 
requirement. 
ACTH = Adrenocorticotropic hormone; AE = Adverse event; 
 CSP = Clinical Study 
Protocol; eGFR = Estimated Glomerular Filtration Rate; EoT = End of treatment; FDA = Food and Drug 
Administration; HSV-1 = Herpes Simplex Virus type 1; HSV-2 = Herpes Simplex Virus type 2 
IgM = Immunoglobulin M; PCR = Polymerase chain reaction; K+ = Potassium; N+ = Sodium; 
PK = Pharmacokinetic(s); SAP = Statistical Analysis Plan. 
 
List of Substantial Modifications 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis; 
Section 3.0, Objectives, 
Endpoints, and 
Estimands. 
Amendment of secondary endpoint to read 
“Incidence of abnormal stimulated cortisol 
at Week 8 in the baxdrostat and placebo 
groups. In the event that the routine 
stimulated cortisol at Week 8 is abnormal 
(< 
 μg/dL at 
 minutes), an 
abnormal result for repeat stimulated 
cortisol is defined as < 
 μg/dL at 
 minutes AND < 
 μg/dL at 
 minutes. Participants with 
abnormal stimulated cortisol (< 
 μg/dL 
at 
 min) at baseline will not be 
considered”. 
To provide clarification on the 
abnormal cortisol values and 
exclusion of participants with 
abnormal results at Randomisation. 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis; 
Section 3.0, Objectives, 
Endpoints, and 
Estimands; Section 9.3, 
Populations for 
Analysis; Section 9.4.2, 
Pharmacodynamic 
Analysis; Section 9.4.3, 
Safety. 
Amendment of “Pharmacodynamic 
Analysis Set” to “Full Analysis Set”. 
Correction of analysis set. 
Section 1.1, Synopsis; 
Section 4.1, Overall 
Design. 
Addition of a test timepoint as 
“
 minutes after ACTH stimulation 
test (with 
 µg/dL cut-off)” to 
unscheduled repeat ACTH stimulation test 
when retesting in case of abnormal 
stimulated cortisol value at EoT Visit 
(Visit 6). 
 
 
 
 
Section 1.1, Synopsis; 
Section 9.4.2.1, 
Primary and Secondary 
Endpoints. 
Amendment of the statistical methods to 
align with the updated secondary 
objectives and endpoints and to include 
details about the repeat ACTH stimulation 
testing, as well as indicating that 
participants with abnormal cortisol levels 
at baseline will be excluded from the 
analysis. 
To provide clarification for the 
analyses. 
Section 5.1, Inclusion 
Criteria. 
Correction of inclusion criterion 7 to read 
“Participants must have a morning cortisol 
(measured at 08:00 AM ± 2 hours) 
≥ µg/dL”. 
Correction of acceptable morning 
cortisol level. 
ACTH = Adrenocorticotropic hormone; EoT = End of Treatment; FDA = Food and Drug Administration. 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES TABLE ....................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................... 13 
1 
PROTOCOL SUMMARY .................................................................................... 16 
1.1 
Synopsis ................................................................................................................ 16 
1.2 
Schema .................................................................................................................. 22 
1.3 
Schedule of Activities ........................................................................................... 23 
2 
INTRODUCTION ................................................................................................ 29 
2.1 
Study Rationale ..................................................................................................... 29 
2.2 
Background ........................................................................................................... 30 
2.3 
Benefit/Risk Assessment ...................................................................................... 30 
2.3.1 
Risk Assessment ................................................................................................... 31 
2.3.2 
Benefit Assessment ............................................................................................... 33 
2.3.3 
Overall Benefit/Risk Conclusion .......................................................................... 34 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ............................................ 35 
4 
STUDY DESIGN ................................................................................................. 37 
4.1 
Overall Design ...................................................................................................... 37 
4.2 
Scientific Rationale for Study Design .................................................................. 39 
4.2.1 
Justification for Placebo Control .......................................................................... 39 
4.2.2 
Justification for Study Length .............................................................................. 39 
4.3 
Justification for Dose ............................................................................................ 39 
4.4 
End-of-study Definition ........................................................................................ 40 
5 
STUDY POPULATION ....................................................................................... 40 
5.1 
Inclusion Criteria .................................................................................................. 40 
5.2 
Exclusion Criteria ................................................................................................. 42 
5.3 
Lifestyle Considerations ....................................................................................... 45 
5.3.1 
Meals and Dietary Restrictions ............................................................................. 45 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................................................ 45 
5.4 
Screen Failures...................................................................................................... 45 
5.4.1 
Rescreening........................................................................................................... 45 
5.5 
Criteria for Temporarily Delaying Enrolment/Randomisation/ Administration of 
Study Intervention ................................................................................................ 46 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................... 46 
6.1 
Study Interventions Administered ........................................................................ 46 
6.2 
Preparation, Handling, Storage, and Accountability ............................................ 48 
6.3 
Assignment to Study Intervention ........................................................................ 48 
6.3.1 
Incorrectly Enrolled/Randomised Participants ..................................................... 49 

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6.4 
Blinding ................................................................................................................ 49 
6.5 
Study Intervention Compliance ............................................................................ 50 
6.6 
Dose Modification ................................................................................................ 50 
6.7 
Continued Access to Study Intervention After the End of the Study ................... 51 
6.8 
Treatment of Overdose ......................................................................................... 51 
6.9 
Prior and Concomitant Therapy ............................................................................ 51 
6.9.1 
Prohibited Concomitant Medications ................................................................... 52 
6.9.2 
Restricted Concomitant Medications .................................................................... 52 
6.9.3 
Rescue Medicine ................................................................................................... 53 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................. 53 
7.1 
Discontinuation of Study Intervention ................................................................. 53 
7.1.1 
Liver Chemistry Stopping Criteria ....................................................................... 53 
7.1.2 
QTc Stopping Criteria ........................................................................................... 53 
7.1.3 
Temporary Interruption of Study Intervention ..................................................... 54 
7.1.4 
Permanent Discontinuation of Study Intervention ............................................... 55 
7.1.5 
Rechallenge........................................................................................................... 56 
7.1.5.1 
Study Intervention Restart or Rechallenge After Liver Stopping Criteria Are Met
 .............................................................................................................................. 56 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................................... 57 
7.3 
Lost to Follow-up ................................................................................................. 58 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 58 
8.1 
Administrative and General/Baseline Procedures ................................................ 59 
8.1.1 
Demographics ....................................................................................................... 60 
8.1.2 
Medical/Surgical History ...................................................................................... 60 
8.2 
Efficacy Assessments ............................................................................................ 60 
8.3 
Safety Assessments ............................................................................................... 61 
8.3.1 
Physical Examinations .......................................................................................... 61 
8.3.2 
Vital Signs ............................................................................................................. 61 
8.3.2.1 
Seated Blood Pressure Measurements .................................................................. 61 
8.3.3 
Electrocardiograms ............................................................................................... 62 
8.3.4 
Clinical Safety Laboratory Tests ........................................................................... 62 
8.3.4.1 
Potassium Laboratory Measurements ................................................................... 64 
8.4 
AEs, SAEs, and Other Safety Reporting .............................................................. 64 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 65 
8.4.2 
Follow-up of AEs and SAEs ................................................................................. 65 
8.4.3 
Causality Collection.............................................................................................. 66 
8.4.4 
AEs Based on Examinations and Tests ................................................................. 66 
8.4.5 
AEs Based on Signs and Symptoms ..................................................................... 66 
8.4.5.1 
 ................................................. 67 
8.4.6 
Adverse Events of Special Interest ....................................................................... 67 
8.4.6.1 
Hyperkalaemia ...................................................................................................... 67 
8.4.6.2 
Hyponatraemia ...................................................................................................... 68 
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8.4.6.3 
Hypotension .......................................................................................................... 68 
8.4.7 
Hy’s Law ............................................................................................................... 68 
8.4.8 
Reporting of SAEs ................................................................................................ 68 
8.4.9 
Pregnancy ............................................................................................................. 69 
8.4.9.1 
Maternal Exposure ................................................................................................ 69 
8.4.9.2 
Paternal Exposure ................................................................................................. 70 
8.4.10 
Medication Error, Drug Abuse, and Drug Misuse ................................................ 70 
8.4.10.1 
Timelines .............................................................................................................. 70 
8.4.10.2 
Medication Error ................................................................................................... 70 
8.4.10.3 
Drug Abuse ........................................................................................................... 70 
8.4.10.4 
Drug Misuse.......................................................................................................... 70 
8.4.11 
Reporting of Overdose .......................................................................................... 70 
8.5 
Pharmacokinetics .................................................................................................. 71 
8.5.1 
Collection of Samples for Pharmacokinetics ........................................................ 72 
8.5.2 
Determination of Drug Concentration .................................................................. 72 
8.6 
Pharmacodynamics ............................................................................................... 72 
8.6.1 
Collection of Samples for Pharmacodynamics ..................................................... 72 
8.6.2 
ACTH Stimulation Test and Cortisol Level Measurement ................................... 72 
8.7 
 ................................................................................ 73 
8.8 
Biomarkers ............................................................................................................ 74 
8.9 
Immunogenicity Assessments ............................................................................... 74 
8.10 
Medical Resource Utilisation and Health Economics .......................................... 74 
8.11 
Study Participant Feedback Questionnaire ........................................................... 74 
9 
STATISTICAL CONSIDERATIONS ................................................................... 74 
9.1 
Statistical Hypotheses ........................................................................................... 74 
9.2 
Sample Size Determination .................................................................................. 74 
9.3 
Populations for Analyses ...................................................................................... 75 
9.4 
Statistical Analyses ............................................................................................... 75 
9.4.1 
General Considerations ......................................................................................... 75 
9.4.2 
Pharmacodynamic Analysis .................................................................................. 75 
9.4.2.1 
Primary and Secondary Endpoints ....................................................................... 75 
9.4.3 
Safety .................................................................................................................... 76 
9.4.3.1 
Adverse Events ..................................................................................................... 76 
9.4.3.2 
Vital Signs ............................................................................................................. 77 
9.4.3.3 
Clinical Safety Laboratory Tests ........................................................................... 77 
9.4.3.4 
Electrocardiogram................................................................................................. 78 
9.4.4 
Other Exploratory Analyses .................................................................................. 78 
9.5 
Interim Analyses ................................................................................................... 78 
9.6 
Data Monitoring/Other Committee ...................................................................... 78 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ............................................................................................ 79 
11 
REFERENCES ................................................................................................... 107 
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LIST OF FIGURES 
Figure 1 
Study Design ............................................................................................... 22 
 
LIST OF TABLES 
Table 1 
Schedule of Activities ................................................................................. 23 
Table 2 
Schedule of Laboratory Samples ................................................................ 26 
Table 3 
Schedule of Cortisol Measurements ............................................................ 28 
Table 4 
Risk Assessment .......................................................................................... 31 
Table 5 
Objectives and Estimands/Endpoints .......................................................... 35 
Table 6 
Study Intervention and Procedure ............................................................... 46 
Table 7 
Laboratory Variables ................................................................................... 62 
Table 8 
Populations for Analysis ............................................................................. 75 
List of Non-Substantial Modifications .................................................................................. 105 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .......................... 79 
Appendix B 
AEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting .............................................................................................. 87 
Appendix C 
Handling of Human Biological Samples ..................................................... 92 
Appendix D 
 ...................................................... 95 
Appendix E 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .............................................................................. 99 
Appendix F 
Protocol Version History ........................................................................... 105 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation or special 
term 
Explanation 
ACEI 
Angiotensin-converting Enzyme Inhibitor 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AI 
Adrenal insufficiency  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase/Transaminase 
AOBPM 
Automated Office Blood Pressure Measurement 
ARB 
Angiotensin-receptor Blocker 
AST 
Aspartate Aminotransferase/Transaminase 
AxMP 
Auxiliary Medicinal Product 
β-hCG 
Beta-human Chorionic Gonadotropin 
BP 
Blood Pressure 
CIRB 
Central Institutional Review Board 
CKD 
Chronic Kidney Disease 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organisation 
CSR 
Clinical Study Report 
CTT 
Clinical Trial Transparency 
CYP 
Cytochrome P450 
DAE 
Discontinuation due to Adverse Event(s) 
DBP 
Diastolic Blood Pressure 
DES 
Data Entry Site 
DILI 
Drug Induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
DUS 
Disease Under Study 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EoT 
End of Treatment 
FDA 
Food and Drug Administration 

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Abbreviation or special 
term 
Explanation 
FOCBP 
Female(s) of Child-bearing Potential 
FSH 
Follicle Stimulating Hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
HbA1c 
Glycated Haemoglobin 
HBS 
Human Biological Sample(s) 
HF 
Heart Failure 
HSV-1 
Herpes Simplex Virus Type 1 
HSV-2 
Herpes Simplex Virus Type 2 
HTN 
Hypertension 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
K+ 
Potassium 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRA 
Mineralocorticoid Receptor Antagonist 
N/A 
Not Applicable 
Na+ 
Sodium 
NIMP 
Non-investigational Medicinal Product  
NSAID 
Non-steroidal Anti-inflammatory Drug 
NYHA 
New York Heart Association 
OD 
Once Daily 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QT 
QT Interval 
QTcF 
Fridericia’s Corrected QT 
R 
Randomisation 

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Abbreviation or special 
term 
Explanation 
RAAS 
Renin-angiotensin-aldosterone System 
RBC 
Red Blood Cells 
RTSM 
Randomisation and Trial Supply Management 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SFU 
Safety Follow-up Visit 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
TBL 
Total Bilirubin 
uHTN 
Uncontrolled Hypertension 
ULN 
Upper Limit of Normal 
 

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1 
PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title: 
A Randomised, Double-blind, Placebo-controlled Study to Evaluate Cortisol Reserve in 
Response to Adrenocorticotropic Hormone Stimulation Test Following Treatment with 
Baxdrostat for 8 Weeks in Participants with Uncontrolled Hypertension 
Brief Title: 
A Study to Evaluate Cortisol Reserve in Response to Adrenocorticotropic Hormone 
Stimulation Test Following Baxdrostat Treatment Compared to Placebo in Participants with 
Uncontrolled Hypertension 
Regulatory Agency Identifier Number(s): IND 146112 
Rationale: 
This Phase II study is intended to evaluate the cortisol reserve in response to 
adrenocorticotropic hormone (ACTH) stimulation test following treatment with baxdrostat 
administered at 2 mg once daily (OD) orally versus placebo, in participants aged ≥ 18 years 
with uncontrolled hypertension (uHTN) despite a stable regimen of ≥ 1 antihypertensive agent 
(including a diuretic). 
Baxdrostat (previously referred as RO6836191 and CIN-107) is a highly potent, selective, and 
competitive inhibitor of human aldosterone synthase (encoded by CYP11B2 gene), being 
developed specifically to address the unmet need in participants whose blood pressure (BP) is 
refractory to 2 or more therapies in order to lower their BP. 
The synthesis pathway of cortisol is catalysed by 11β-hydroxylase (CYP11B1), which shares 
high sequence homology with aldosterone synthase (CYP11B2). Undesired inhibition of 
11β-hydroxylase leads to suppression of cortisol levels leading to subclinical or clinical 
adrenal insufficiency. Therefore, the selectivity of baxdrostat to aldosterone synthetase has 
been evaluated in vitro, in nonclinical and in Phase I clinical studies. 
Prior data do not show baxdrostat to cause reduced cortisol response to ACTH stimulation. 
Although baxdrostat is a highly selective competitive aldosterone synthase inhibitor with no 
evidence from prior studies of inhibition of 11β-hydroxylase nor ACTH stimulated cortisol 
secretion, this double-blind, placebo-controlled study is proposed to further evaluate cortisol 
reserve in response to ACTH stimulation test after prolonged exposure of 8 weeks to 
baxdrostat treatment in participants with uHTN. This study, along with results from other 
studies, will allow a comprehensive evaluation of cortisol reserve following baxdrostat 
treatment. 

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Objectives, Endpoints, and Estimands: 
Objectives 
Estimands/Endpoints 
Primary 
• 
To characterise the total serum cortisol before 
and after ACTH stimulation test at baseline and 
Week 8. 
• 
Individual cortisol level before and after ACTH 
stimulation test at baseline and Week 8. 
Secondary 
• 
To evaluate the total serum cortisol response 
after ACTH stimulation test at Week 8. 
• 
Incidence of abnormal stimulated cortisol at 
Week 8 in the baxdrostat and placebo groups. In 
the event that the routine stimulated cortisol at 
Week 8 is abnormal (< 
 μg/dL at 
 min), an abnormal result for repeat 
stimulated cortisol is defined as < 
 μg/dL at 
 minutes AND < 
 μg/dL at 
 minutes. Participants with abnormal 
stimulated cortisol (< 
 μg/dL at 
 minutes) at baseline will not be 
considered. 
Exploratory 
• 
To evaluate 
  
• 
  
• 
To assess the pharmacokinetics of baxdrostat. 
• 
Plasma concentrations of baxdrostat. 
• 
To explore how 
 
 
 
 
 a 
• 
To explore how 
 
 
 
 
 a 
• 
Exploratory endpoints 
 
 
 
 
 
• 
Exploratory endpoints 
 
 
 
 
Safety 
• 
To assess the safety and tolerability of 
baxdrostat as compared to placebo. 
• 
Outcome variables: safety and tolerability will 
be evaluated in terms of: 
• 
AEs, SAEs, and DAEs. 
• 
Vital signs (BP, pulse rate, body weight). 
• 
Safety investigations and laboratory tests (ECG, 
clinical chemistry, haematology). 
• 
AESIs (hyperkalaemia, hyponatraemia, and 
hypotension 
 
based on Investigator reported AEs). 
a 
. Results will not be reported 
in the CSR. 
ACTH = Adrenocorticotropic hormone; AE = Adverse event; AESI = Adverse event of special interest; 
 BP = Blood pressure; CSR = Clinical study report; DAE = Discontinuation due to 
adverse event(s); 
 ECG = Electrocardiogram; SAE = Serious adverse event. 
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For estimands description, please see Section 3 of the protocol. 
Overall Design Synopsis: 
This is a Phase II, randomised, double-blind, placebo-controlled study to evaluate cortisol 
reserve after ACTH stimulation test following treatment with 2 mg baxdrostat versus placebo, 
administered OD orally on top of standard-of-care, in approximately 45 participants 
≥ 18 years of age with uHTN (seated systolic BP [SBP] ≥ 130 mmHg at screening, 
≥ 130 mmHg at Randomisation) despite a stable regimen of ≥ 1 antihypertensive agent 
(including a diuretic). 
The study is planned to be conducted in the United States in approximately 12 study sites. 
Brief Summary: 
The purpose of this study is to evaluate cortisol reserve after ACTH stimulation test following 
treatment with 2 mg baxdrostat compared to placebo in participants with uHTN. 
The study duration will be up to 16 weeks, including: 
• 
A 4-week screening period. 
• 
An 8-week double-blind treatment period. The end-of-study assessment will be at Visit 6 
(Week 8), at which data will be collected and an ACTH stimulation test will be 
performed. Participants can be on treatment for up to 10 weeks*, while waiting for the 
ACTH stimulation test result to be available. 
*10 weeks is not the targeted duration of the treatment period, but only intends to provide 
flexibility in case of unforeseen event. The last date of treatment can be later than the End 
of Treatment (EoT) Visit date. 
• 
A safety follow-up 2 weeks after last dose. 
 
Disclosure Statement: This is a randomised, double-blind, placebo-controlled, parallel group 
study with 2 arms that is participant, Investigator and Sponsor blind. 
Number of Participants: 
Approximately 45 participants will be randomised and assigned to study intervention such 
that, with an estimated 10% drop-out rate, approximately 40 evaluable participants complete 
the study. 
Note: ‘Screened’ means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 

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but are not randomised/assigned in the study, are considered ‘screen failures’, unless 
otherwise specified by the protocol. 
Study Arms and Duration: 
After an up to 4-week screening period, eligible participants will be randomised in a 2:1 ratio 
to one of 2 treatment arms: 
• 
2 mg baxdrostat (target number of participants: 30). 
• 
Placebo (target number of participants: 15). 
 
During the 8-week double-blind treatment period, participants should remain on their 
background antihypertensive treatment regimen. Doses of background medications should not 
be changed during this period unless participants experience SBP < 
 mmHg with 
symptoms of hypotension. Rescue therapy is permitted if the SBP exceeds 170 mmHg or 
diastolic BP (DBP) exceeds 105 mmHg. The choice of rescue therapy is based on the 
Investigator’s best clinical judgement; however, the use of K+-sparing diuretics and 
mineralocorticoid receptor antagonists (MRAs) is prohibited. 
An ACTH stimulation test using 250 µg ACTH will be performed at Visit 2 (Randomisation) 
prior to the first dose of study intervention and Visit 6 (Week 8) with cortisol measured before 
and after the stimulation test (
 minutes after injection). The ACTH stimulation testing 
procedure will be done locally at the site, but the serum cortisol measurement pre- and 
post-ACTH stimulation testing will be processed centrally. Participants need to be on 
treatment until the ACTH stimulation test result is available, ie, treatment may last up to 
10 weeks depending on the availability of the ACTH stimulation test result or in case the test 
needs to be repeated. If applicable, the repeat tests shall be rescheduled as soon as possible to 
keep the duration of the treatment within 10 weeks. The Investigational Medicinal Product 
(IMP) will be discontinued immediately following the completion of the repeated ACTH 
stimulation test. 
Cortisol analysis will be performed using the 
 measured at a 
central laboratory. Cortisol level at 
 minutes after ACTH stimulation that is 
< 
μg/dL at baseline (Visit 2) and EoT (Visit 6, Week 8) will be considered abnormal, 
indicating impaired cortisol reserve. An abnormal cortisol level after ACTH stimulation test at 
baseline (Visit 2), will result in the participant’s discontinuation of the study intervention. At 
EoT (Visit 6, Week 8), in the rare incidence of an abnormal ACTH stimulated cortisol level, 
the participant will be asked to remain on treatment and to undergo repeat ACTH stimulated 
cortisol measurements during an unscheduled visit which includes cortisol measurements 
 minutes after ACTH stimulation test (with 
 µg/dL cut-off) and 
 minutes 
after ACTH stimulation test (with 
 µg/dL cut-off). To be considered an abnormal repeat 
ACTH stimulated cortisol result, post-ACTH cortisol must be < 
µg/dL at 
 minutes 
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post-ACTH stimulation and < 
µg/dL at 
minutes post-ACTH stimulation. If only one 
of the two results is abnormal, the overall test will be considered normal. The results from the 
repeat test will supersede the original Week 8 results. 
The following is a summary of different types of cortisol measurements at different 
timepoints: 
• 
AM serum cortisol without ACTH stimulation (8 AM ± 2 hours) 
− 
Cortisol level ≥ μg/dL is considered normal.  
• 
Routine serum cortisol collected before and 
 minutes after ACTH stimulation 
− 
Cortisol level ≥ 
μg/dL at 
minutes after ACTH is considered normal. 
• 
Retest serum cortisol collected before, 
 minutes AND 
 minutes after 
ACTH stimulation  
− 
Cortisol level ≥ 
 μg/dL at 
 minutes after ACTH stimulation is considered 
normal. Cortisol level ≥ 
μg/dL at 
 minutes after ACTH stimulation is 
considered normal.  
Note: If only one of the two results is abnormal, the overall test will still be 
considered normal. 
 
Further evaluation and management of the participant should be at the discretion of the 
Investigator, and if needed, in consultation with an endocrinologist. 
Laboratory and safety visits are outlined in the schedule of assessments. 
After completing the 8-week double-blind treatment period (this period can be extended up to 
10 weeks if waiting for ACTH results, or in the situation that a repeat test is needed) or if 
participants permanently discontinue treatment earlier than 8 weeks, participants will return 
for a safety follow-up, 14 days after the last dose. 
Data Monitoring/Other Committee: 
No data monitoring committee has been appointed for this study. However, all cases of 
abnormal ACTH stimulation test will be reviewed by an independent blinded adrenal expert.  
Statistical Methods: 
Statistical analyses will be descriptive in nature, without formal statistical hypothesis testing. 
This study is planning to randomise approximately 45 participants using a 2:1 ratio to either 
receive 2 mg baxdrostat OD or placebo OD, in addition to a stable regimen of 
≥ 1 antihypertensive agent (including a diuretic) in the double-blind treatment period of 
8 weeks. The sample size is considered to be adequate for supporting descriptive analysis of 
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the cortisol response to ACTH, based on previous experience with baxdrostat. 
Cortisol response to ACTH stimulation test will be assessed on individual level via line plot of 
total serum cortisol values prior to ACTH stimulation testing and after 
 minutes, both 
at baseline and at Week 8. In the event of abnormal ACTH stimulated cortisol results at Week 
8, an unscheduled visit with repeat pre-ACTH stimulated and 
 minutes and 
 
minutes post-ACTH cortisol measurements will be performed for each treatment group. An 
abnormal result is defined as abnormal repeat stimulated cortisol (< 
 μg/dL at 
 
minutes AND < 
μg/dL at 
 minutes) obtained in the event that the routine stimulated 
cortisol at Week 8 is abnormal (< 
μg/dL at 
 minutes). If performed, the results of 
the repeat ACTH stimulation test at the unscheduled visit will be used for the analysis.  
Participants with abnormal cortisol levels at baseline will not be considered. Those 
discontinued participants will be listed and plotted separately. 
The baseline values are the last non-missing values prior to the administration of the first dose 
of IMP. 
 
 The data collected after the other 
intercurrent events will be included in the data analyses (Treatment Policy Strategy). 
Incidence of abnormal stimulated cortisol (ie, total serum cortisol above below the 
pre-specified threshold after 
 minutes) at baseline and Week 8 by treatment group will 
be assessed via frequency table, in participants with normal stimulated cortisol at baseline. Of 
note, participants with abnormal stimulated cortisol at baseline will be reported separately. If 
performed, the results of the repeat ACTH stimulation test at the unscheduled visit will be 
used for the analysis. 
The primary and secondary endpoints will be analysed in the Full Analysis Set, defined as all 
randomised participants who received at least one dose of study intervention (treatment 
classification will be based on the study intervention that participants were randomly assigned 
to). 
The safety endpoint aims to assess the safety and tolerability of baxdrostat as compared to 
placebo; the safety data will be presented using descriptive statistics unless otherwise 
specified. Safety analyses will be performed in the Full Analysis Set. 
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1.2 
Schema  
Figure 1 
Study Design  
 
* Participants can be on treatment for up to 10 weeks, while waiting for the ACTH stimulation test results to be 
available. 
ACTH = Adrenocorticotropic hormone; FU = Follow-up; OD = Once daily; R = Randomisation. 
 

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1.3 
Schedule of Activities  
Table 1 
Schedule of Activities  
Procedure 
Screening 
Randomisation 
Double-blind period 
EoT a,b 
Safety FU 
Details in 
protocol section 
or appendix 
Visit 
1 
2 
3 
(Laboratory 
Visit) 
4 
(Laboratory 
Visit) 
5 
6 
SFU c 
 
Week 
(-4 to 0) 
0 
1 
2 
4 
8 b 
 
 
Day 
(-28 to -1) 
1 
8 (+ 4) 
16 (± 3) 
29 (± 3) 
57 (± 4) b 
14 days from 
last dose (± 4) 
 
Signed informed consent 
X 
 
 
 
 
 
 
Section 5.1 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Section 5.1 
Section 5.2 
Section 5.4.1 
Enrolment in IRT/RTSM 
X 
 
 
 
 
 
 
Section 6.3 
Demography 
X 
 
 
 
 
 
 
Section 8.1.1 
Randomisation 
 
X 
 
 
 
 
 
Section 6.3 
Complete physical examination d 
X 
X 
 
 
 
X 
 
Section 8.3.1 
Targeted physical examination e 
 
 
 
 
 
 
X 
Section 8.3.1 
Medical/surgical history 
X 
 
 
 
 
 
 
Section 8.1.2 
Concomitant medications 
X 
X 
 
 
X 
X 
X 
Section 6.1 
Section 6.9 
ACTH stimulation test b,f  
 
X 
 
 
 
X 
 
Table 3 and 
Section 8.6.2 
Serum cortisol measurement f,  
Xh 
Xg 
 
 
 
Xg 
 
Table 3 and 
Section 8.6.2 
Collect sample for clinical safety 
analysis 
X 
X 
X 
X 
X 
X 
X 
Table 2 
and Section 8.3.4 

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Procedure 
Screening 
Randomisation 
Double-blind period 
EoT a,b 
Safety FU 
Details in 
protocol section 
or appendix 
Visit 
1 
2 
3 
(Laboratory 
Visit) 
4 
(Laboratory 
Visit) 
5 
6 
SFU c 
 
Week 
(-4 to 0) 
0 
1 
2 
4 
8 b 
 
 
Day 
(-28 to -1) 
1 
8 (+ 4) 
16 (± 3) 
29 (± 3) 
57 (± 4) b 
14 days from 
last dose (± 4) 
 
12-lead ECG 
X 
 
 
 
 
X 
X 
Section 8.3.3 
Vital signs i 
X 
X 
 
 
X 
X 
X 
Section 8.3.2 
IMP dispensation 
 
X j 
 
 
X j 
 
 
Section 6.1 
IMP accountability 
 
 
 
 
X 
X 
X 
Section 6.2 
Section 6.5 
Adverse events k 
X (SAE only) 
X 
 
 
X 
X 
X 
Section 8.4 
a 
Participants who prematurely withdraw study intervention will undergo an EoT Visit, ideally scheduled as soon as possible at the time of premature 
withdrawal from study intervention. Following the EoT Visit, the participant will then proceed to complete the final SFU Visit as per SoA. If the EoT Visit 
is conducted > 10 days after the last administered dose, all assessments (except the PK sampling) required at EoT and SFU Visits are to be conducted within 
the same visit (inclusive of the ACTH stimulation testing, serum cortisol measurement, and K+ only testing) and a complete physical examination will be 
performed. 
b 
Participants need to stay on treatment until ACTH stimulation test results are available ie, up to 10 weeks. In rare incidence that participant has abnormal 
ACTH stimulated cortisol level, the participant will be asked to remain on treatment and to undergo repeat ACTH stimulated cortisol measurements during 
an unscheduled visit. See Footnote “g”. If applicable, the repeat tests shall be rescheduled as soon as possible to keep the duration of the treatment within 
10 weeks. The IMP will be discontinued immediately following the completion of the repeated ACTH stimulation test. The participant will be informed by 
a telephone call to stop treatment after ACTH stimulation test results are available.  
c 
The SFU Visit will be performed 14 days after the participant receives the last IMP dose. 
d 
A complete physical examination will be performed by the Investigator or a suitably qualified medical designee and include assessments of the following: 
general appearance, respiratory, cardiovascular, abdomen, skin, head and neck, lymph nodes, thyroid, musculoskeletal/extremities, and neurological 
systems. Additionally, height will be measured during screening. 
e 
A targeted physical examination should include, at a minimum, cardiovascular and lung evaluations, and examination of any peripheral oedema. 
f 
ACTH stimulation testing procedure will be done locally at the site (at 8.00 AM [± 2 hours]), but the serum cortisol measurement pre- and post-ACTH 
stimulation testing will be processed centrally. See Table 3 for more details. 
g 
Blood samples will be collected to measure serum total cortisol prior to the ACTH stimulation test and 
 minutes after. If the cortisol level is 
abnormal at EoT (Visit 6, Week 8), the test will be repeated during an unscheduled visit (prior to ACTH stimulation test, 
 minutes after ACTH 
stimulation test, and 
 minutes after ACTH stimulation test). See Table 3 for more details. 
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h 
Morning serum total cortisol to ensure inclusion criteria are met. Blood sample should be collected at site (at 8.00 AM [± 2 hours]) but it will be processed 
centrally. Participants must have a morning cortisol (measured at 08:00 AM ± 2 hours) ≥ µg/dL, determined as per central laboratory to be eligible for the 
study. 
i 
Including seated attended office automated BP, pulse rate and body weight measurements. 
j 
One IMP-containing blister pack will be dispensed at Visit 2 (Randomisation) and 2 IMP-containing blister packs, at Visit 5. 
k 
Adverse events will be collected from randomisation throughout the study intervention period, including at the SFU Visit but excluding at Visits 3 and 4. 
Serious adverse events will be collected from the time of signing informed consent and onward. 
ACTH = Adrenocorticotropic hormone; BP = Blood pressure; ECG = Electrocardiogram; EoT = End of treatment; FU = Follow-up; IMP = Investigational 
medicinal product; IRT = Interactive response technology; RTSM = Randomisation and trial supply management; SAE = Serious adverse event; SFU = Safety 
follow-up; SoA = Schedule of activities. 
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Table 2 
Schedule of Laboratory Samples  
Procedure 
Screening 
Randomisation 
Double-blind period 
EoT 
Safety FU 
Details in 
protocol section 
or appendix 
Visit 
1 
2 
3 
(Laboratory 
Visit) 
4 
(Laboratory 
Visit) 
5 
6 
SFUg 
 
Week 
(-4 to 0) 
0 
1 
2 
4 
8 
 
 
Day 
(-28 to -1) 
1 
8 (+ 4) 
16 (± 3) 
29 (± 3) 
57 (± 4) 
14 days from 
last dose (± 4) 
 
Whole safety panel (central 
laboratory) a 
X 
X 
 
 
X 
X 
X 
Section 8.3.4 
Dipstick urinalysis 
 
X 
 
 
 
 
 
Section 8.3.4 
Safety laboratory: 
Only creatinine, eGFR, K+, and 
Na+ (central laboratory) b 
 
 
X 
X 
 
 
 
Section 8.3.4 
K+ only (local laboratory) 
 
X 
X 
X 
X 
X 
 
Section 8.3.4.1 
PK sampling (pre-dose) c 
 
 
 
 
X 
(X) c 
 
Section 8.5.1 
 
 
 
 
X 
 
 
 
 
 
Section 8.7 
Appendix D 
HbA1c test d 
X 
 
 
 
 
 
 
Section 8.3.4 
FSH test (for female 
participants only) e 
X 
 
 
 
 
 
 
Section 8.3.4 
Urine pregnancy test (FOCBP 
only) f 
X 
X 
 
 
X 
X 
X 
Section 8.3.4 
a 
The whole safety panel includes haematology and clinical chemistry analyses (see Table 7 in Section 8.3.4 for further details). This assessment will include 
creatinine analysis (for eGFR calculation) and the measurement of Na+ and K+ levels in blood. 
b 
At Visits 3 and 4, only creatinine (for eGFR calculation), K+ and Na+ are tested by the central laboratory. Additionally, these analytes are also included in 
the whole safety panel during the respective visits. eGFR calculation is required at all visits. 
c 
Pharmacokinetic samples will be collected pre-dose from all participants at Visit 5. For participants who are discontinued from study intervention due to 
hyperkalaemia, a PK sample should be collected at the EoT Visit. 
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d 
The HbA1c test will be performed to exclude poorly controlled diabetes at screening. 
e 
For confirmation of postmenopausal status of women aged < 50 years only. Females aged < 50 years old will be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more, following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range. 
f 
Urine pregnancy test can be replaced by a serum pregnancy test. Additional ad-hoc test to be used at the discretion of the Investigator during the treatment 
period if there is a suspected pregnancy. 
g 
If the EoT Visit is conducted > 10 days after the last administered dose, all assessments required at EoT and SFU Visits are to be conducted within the same 
visit (inclusive of K+ only testing) (see Table 1 for a complete list of tests). 
eGFR = Estimated glomerular filtration rate; EoT = End of treatment; FOCBP = Female(s) of child-bearing potential; FSH = Follicle stimulating hormone; 
FU = Follow-up; HbA1c = Glycated haemoglobin; K+ = Potassium; Na+ = Sodium; PK = Pharmacokinetic(s); SFU = Safety follow-up. 
 

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Table 3 
Schedule of Cortisol Measurements  
Timing of 
Assessment 
Cortisol 
Measurement 
ACTH Stimulation 
Time for ACTH 
Stimulation 
Time for Cortisol 
Collection 
Normal Value 
Purpose of Test 
Screening (Visit 1) 
AM Serum Cortisol 
No 
N/A 
8 AM ± 2 hours 
≥ µg/dL 
Part of screening 
procedure with 
results as part of 
Inclusion/Exclusion 
criteria 
Visit 2 
Routine Serum 
Cortisol Collection 
before and after 
ACTH 
Yes 
8 AM ± 2 hours 
 min 
after ACTH 
stimulation 
≥ 
 µg/dL 
Assess cortisol 
response prior to 
starting intervention 
Visit 6 
Routine Serum 
Cortisol Collection 
before and after 
ACTH 
Yes 
8 AM ± 2 hours 
 min 
after ACTH 
stimulation 
≥ 
µg/dL 
Assess cortisol 
response after 
completing 
intervention 
Unscheduled 
(Retests ONLY 
when Visit 6 results 
are abnormal) 
Retest Serum 
Cortisol Collection 
before and after 
ACTH 
Yes 
8 AM ± 2 hours 
 min  
And 
 
 min 
after ACTH 
stimulation 
≥ 
µg/dL at 
 min after 
ACTH 
 
≥ 
µg/dL at 
 min after 
ACTH 
Retesting procedure 
if routine cortisol 
collection before 
and after ACTH 
stimulation is 
abnormal at Visit 6. 
ACTH = Adrenocorticotropic Hormone; Min = Minute. 
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2 
INTRODUCTION  
2.1 
Study Rationale  
This Phase II study is intended to evaluate the cortisol reserve in response to ACTH 
stimulation test following treatment with baxdrostat administered at 2 mg OD orally versus 
placebo, in participants aged ≥ 18 years with uHTN despite a stable regimen of 
≥ 1 antihypertensive agent (including a diuretic). 
Baxdrostat (previously referred as RO6836191 and CIN-107) is a highly potent, selective, and 
competitive inhibitor of human aldosterone synthase (encoded by CYP11B2 gene), being 
developed specifically to address the unmet need in participants whose BP is refractory to 2 or 
more therapies in order to lower their BP. 
The synthesis pathway of cortisol is catalysed by 11β-hydroxylase (CYP11B1), which shares 
high sequence homology with aldosterone synthase (CYP11B2). Undesired inhibition of 
11β-hydroxylase leads to suppression of cortisol levels leading to subclinical or clinical 
adrenal insufficiency (Oelkers, 1996, Wagner and White, 1984, Wagner et al, 1984).  
Adrenal insufficiency has an incidence of 1:10,000 in the global population. The evaluation of 
AI is based on clinical context i.e. an initial assessment of clinical signs and symptoms (e.g., 
weight loss, anorexia, hyperpigmentation, hypotension and constitutional symptoms). If 
identified, a morning serum cortisol is measured, which can be followed up by dynamic 
evaluation such as an ACTH stimulation or insulin tolerance test with cortisol measurement. 
Importantly, all the available cutoffs of abnormal cortisol response to ACTH have been 
established in populations with moderate-high pre-test probability of AI (Javorsky et al, 2021). 
The selectivity of baxdrostat to aldosterone synthetase has been evaluated in vitro, in 
nonclinical and in Phase I clinical studies. 
In humans, the maximum suppression of plasma and urine aldosterone levels is achieved at a 
dose of 10 mg baxdrostat and the ability of baxdrostat to lower aldosterone without affecting 
cortisol levels was previously confirmed following administration of baxdrostat at well above 
the anticipated therapeutic dose range. In healthy subjects, single doses of baxdrostat up to 
360 mg (180-fold the maximum dose in Phase III HTN studies), ACTH stimulated cortisol 
levels remained unchanged at all doses tested, up to and inclusive of 360 mg. Furthermore, no 
increase in the precursors 11-deoxycorticosterone and 11-deoxycortisol were present at doses 
≤ 90 mg, roughly a 44-fold higher exposure than achieved with 2 mg dose 
(Bogman et al, 2017). 
In a multiple ascending dose study in participants treated with baxdrostat, while there was 
expected dose-dependent reduction of aldosterone, there was no significant suppression of 
ACTH stimulated plasma cortisol (Freeman et al, 2023a). In vitro, baxdrostat exhibited a high 
selectivity ratio for aldosterone synthase compared to 11β-hydroxylase (cortisol synthesis). In 

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cynomolgus monkey, baxdrostat decreased aldosterone production but had no effect on 
cortisol levels (Bogman et al, 2017). Taken together, prior data do not show baxdrostat to 
cause reduced cortisol response to ACTH stimulation. Although baxdrostat is a highly 
selective competitive aldosterone synthase inhibitor with no evidence from prior studies of 
inhibition of 11β-hydroxylase nor ACTH stimulated cortisol secretion, this double-blind, 
placebo-controlled study is proposed to further evaluate cortisol reserve in response to ACTH 
stimulation test after prolonged exposure of 8 weeks to baxdrostat treatment in participants 
with uHTN. This study, along with results from other studies, will allow a comprehensive 
evaluation of cortisol reserve following baxdrostat treatment. 
2.2 
Background  
Aldosterone is a steroid hormone that contributes to the regulation of Na+ reabsorption, 
volume retention and BP control. Aldosterone is the principal mineralocorticoid in humans, 
synthesised in the adrenal cortex by the enzyme aldosterone synthase and acts as a critical 
regulator of fluid and electrolyte homeostasis through its agonism of the mineralocorticoid 
receptor. 
Baxdrostat (also known as CIN-107) is a highly potent, selective, and competitive inhibitor of 
human aldosterone synthase (encoded by CYP11B2 gene), being developed specifically to 
address the unmet need in participants whose BP is refractory to other therapies in order to 
lower their BP. Aldosterone synthase converts 11-deoxycorticosterone to aldosterone via a 
multistep biosynthetic pathway. Baxdrostat is 100-fold more active against aldosterone 
synthase (CYP11B2) than the closely related enzyme that produces cortisol, 11β-hydroxylase 
(CYP11B1). 
In Phase I and II studies, baxdrostat has demonstrated high selectivity for aldosterone synthase 
(selectivity ratio 100:1) as compared to the enzyme required for cortisol synthesis 
(Bogman et al, 2017, Freeman et al, 2023a, Freeman et al, 2023b), resulting in significantly 
lowered aldosterone levels without affecting cortisol levels over a wide dose range. In a 
Phase II study of baxdrostat versus placebo in participants with rHTN, baxdrostat elicited 
statistically and clinically significant SBP reductions compared to placebo 
(Freeman et al, 2023b). In addition, in the Phase II HALO Study (CIN-107-124), baxdrostat 
substantially reduced aldosterone levels and increased plasma renin activity in a 
dose-dependent manner in the adherent patient population. Based on these findings, baxdrostat 
may be a novel treatment for uHTN. 
For a detailed description of the chemistry, pharmacology, efficacy, and safety of baxdrostat, 
please refer to the IB. 
2.3 
Benefit/Risk Assessment  
The primary benefit for participants with uHTN, randomised to baxdrostat, is expected to be 

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the reduction of BP. Baxdrostat safety and efficacy have been demonstrated in previous 
completed studies conducted in participants with rHTN. It is expected to be better tolerated 
than spironolactone, the guidelines recommended therapy for rHTN. 
For detailed information about previous clinical studies, the known and expected benefits and 
risks and reasonably expected AEs of baxdrostat, please see latest baxdrostat IB. 
2.3.1 
Risk Assessment  
A summary of the potential risks with baxdrostat is presented in Table 4. 
Table 4 
Risk Assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk  
Mitigation strategy 
Study intervention (baxdrostat)-related risks 
Important identified risk of 
hyperkalaemia 
Baxdrostat is an aldosterone 
synthase inhibitor, leading to 
decreased renal K+ excretion and 
increased serum K+ levels due to 
lowered circulating aldosterone. 
In clinical studies with 
baxdrostat, increases from 
baseline in mean serum K+ were 
observed. In the BrigHTN Study 
(CIN-107-121), mean increases 
from baseline to EoT at 12 weeks 
were 0.36 and 0.29 mEq/L in the 
1- and 2-mg groups, respectively. 
In the HALO Study 
(CIN-107-124), mean increases 
from baseline to EoT at 8 weeks 
were 0.26 and 0.12 mEq/L in the 
1- and 2-mg groups, respectively. 
In the 
 
 
 
 
 
 
 
 
• 
Hyperkalaemia is considered an 
AESI 
 
 
 
• 
Serum K+ level and minimum 
baseline renal function are 
included as inclusion criterion 
(see inclusion criterion 6 
[serum K+ level ≥ 3.5 and 
< 5.0 mmol/L at screening] and 
inclusion criterion 5 
[eGFR ≥ 45 mL/min/1.73 m² at 
screening]; Section 5.1). 
• 
Certain drugs known to 
increase serum K+ are 
prohibited in the study (see 
Section 6.9). 
• 
Serum K+ will be monitored at 
all visits (see Section 8.3.4.1). 
• 
 
 
 
(see Section 7.1.3). 
Important potential risk of 
hyponatraemia 
Baxdrostat leads to increased 
natriuresis due to lowered 
circulating aldosterone, resulting 
in a minor decrease in serum Na+ 
level. 
• 
Hyponatraemia is considered 
an AESI 
 
 
 
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Table 4 
Risk Assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk  
Mitigation strategy 
Additionally, hyponatraemia is a 
known complication to diuretics, 
a common background 
medication in this study 
population. 
In clinical studies with 
baxdrostat, clinically insignificant 
decreases from baseline in mean 
serum Na+ were observed. In the 
BrigHTN Study (CIN-107-121), 
mean decreases from baseline to 
EoT at 12 weeks were 1.1 and 
2.4 mEq/L in the 1- and 2-mg 
groups, respectively. In the 
 
 
 
 
 
In the baxdrostat BrigHTN Study, 
10 (3.6%) participants developed 
moderate hyponatraemia (serum 
Na+ < 130 mEq/L), whereof one 
in the placebo group. 
• 
Serum Na+ level is an exclusion 
criterion (see exclusion 
criterion 4; Section 5.2). 
• 
Serum Na+ will be monitored at 
Visits 3 and 4, in addition to 
when these analytes are 
measured as part of the whole 
safety panel (see Section 8.3.4). 
• 
 
 
(see Section 7.1.3). 
Important potential risk of 
hypotension 
Hypotension is reported as a risk 
with all classes of 
antihypertensives. As a 
consequence of the urinary Na+ 
loss, osmotic water loss can lead 
to hypovolemia and, 
consequently, to orthostatic 
hypotension with a corresponding 
increase in heart rate. 
In the baxdrostat Phase II 
BrigHTN and HALO Studies 
(CIN-107-121 and CIN-107-124), 
 
were considered related to 
baxdrostat. Pooled data from 
these 2 studies also revealed a 
higher frequency of headache, 
dizziness, and nausea on 
baxdrostat than on placebo (all 
• 
Hypotension is considered an 
AESI 
 
 
 
• 
Seated BPs will be monitored 
throughout the study (see 
Section 8.3.2). 
• 
Discontinuation/restarting 
criteria are provided (see 
Section 7). 
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Table 4 
Risk Assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk  
Mitigation strategy 
possible symptoms of 
hypotension). 
There was a small decrease from 
seated BP to standing BP in the 
2-mg group in the BrigHTN 
Study of approximately 2 mmHg 
at EoT at 12 weeks. One 
non-serious AE of orthostatic 
hypotension was reported in the 
2-mg group. 
Study procedure (ACTH stimulation test)-related risks 
Potential risks of adverse 
reactions on cosytropin 
Cosyntropin injection 
hypersensitivity reactions 
including anaphylaxis have been 
reported. 
• 
Participants must be asked 
about allergies hypersensitivity 
to cosyntropin injection, 
synthetic ACTH, or to any of 
the excipients before use (see 
exclusion criterion 19; 
Section 5.2) 
• 
Monitoring of participants for 
hypersensitivity reactions and 
treatment as needed will 
performed following ACTH 
stimulation testing procedure 
prior to blood sampling for 
cortisol measurements (see 
Section 8.6.2) 
ACTH = Adrenocorticotropic hormone; AE = Adverse event; AESI = Adverse event of special interest; 
BP = Blood pressure; eGFR = Estimated glomerular filtration rate; EoT = End of treatment; K+ = Potassium; 
Na+ = Sodium. 
 
2.3.2 Benefit Assessment  
Participants enrolled in this study could benefit from the BP lowering effect of baxdrostat, 
which acts as an aldosterone synthase inhibitor. 
Aldosterone synthase inhibition is a new therapeutic option. The aldosterone synthase 
inhibition lowering effect on BP is expected to be greater than the non-steroidal MRAs and 
not associated with the endocrine adverse side effects seen with steroidal MRAs usage, which 
include gynaecomastia and menstrual irregularities (Lainscak et al, 2015). Aldosterone 
regulates blood volume and pressure by regulating salt and water retention. Serum aldosterone 
levels are often elevated in response to chronic ACEIs/ARBs, which can diminish BP control 
and have an associated progression of end organ damage (Bomback and Klemmer, 2007). This 
is a physiological response from the RAAS and thus, it is expected that direct aldosterone 

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synthase inhibition, lowering serum aldosterone levels, may provide additional benefit on top 
of the established standard-of-care. 
Taken together, the preclinical data and existing clinical data support the efficacy and safety of 
baxdrostat and its continued clinical evaluation. 
2.3.3 Overall Benefit/Risk Conclusion  
Considering the measures taken to minimise risk to participants in this study, the potential 
risks identified in association with baxdrostat are justified by the anticipated benefits that may 
be afforded to participants with HTN. 

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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Study objectives and endpoints are presented in Table 5. 
Table 5 
Objectives and Estimands/Endpoints  
Objectives 
Estimands/Endpoints 
Primary 
• 
To characterise the total serum cortisol before 
and after ACTH stimulation test at baseline and 
Week 8. 
• 
Individual cortisol level before and after ACTH 
stimulation test at baseline and Week 8. 
Secondary 
• 
To evaluate the total serum cortisol response 
after ACTH stimulation test at Week 8. 
• 
Incidence of abnormal stimulated cortisol at 
Week 8 in the baxdrostat and placebo groups. In 
the event that the routine stimulated cortisol at 
Week 8 is abnormal (< 
μg/dL at 
 minutes), an abnormal result for repeat 
stimulated cortisol is defined as < 
 μg/dL at 
 min AND < 
μg/dL at 
 minutes. 
Participants with abnormal stimulated cortisol 
(< 
μg/dL at 
 min) at baseline will not 
be considered. 
Exploratory 
• 
  
• 
 
• 
To assess the pharmacokinetics of baxdrostat. 
• 
Plasma concentrations of baxdrostat. 
• 
To explore how 
 
 
 
 
 a 
• 
To explore how 
 
 
 
 
 a 
• 
Exploratory endpoints 
 
 
 
 
• 
Exploratory endpoints 
 
 
 
 
Safety 
• 
To assess the safety and tolerability of 
baxdrostat as compared to placebo. 
• 
Outcome variables: safety and tolerability will 
be evaluated in terms of: 
• 
AEs, SAEs and DAEs. 
• 
Vital signs (BP, pulse rate, body weight). 
• 
Safety investigations and laboratory tests (ECG, 
clinical chemistry, haematology). 
• 
AESIs (hyperkalaemia, hyponatraemia, and 
hypotension 
; 
based on Investigator reported AEs). 
a 
 Results will not be reported 
in the CSR. 
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ACTH = Adrenocorticotropic hormone; AE = Adverse event; AESI = Adverse event of special interest; 
 BP = Blood pressure; CSR = Clinical study report; DAE = Discontinuation due to 
adverse event(s); 
 ECG = Electrocardiogram; SAE = Serious adverse event. 
 
Primary Estimand 
The primary clinical question of interest is to evaluate the serum total cortisol response after 
ACTH stimulation test after 8 weeks. 
The estimand is described by the following attributes: 
• 
Population: Participants with uHTN, as defined by the inclusion/exclusion criteria. 
Implemented in the Full Analysis Set, excluding participants with abnormal ACTH 
stimulated cortisol at baseline. 
• 
Endpoint: Individual cortisol level before and after ACTH stimulation test at baseline and 
Week 8. If applicable, the unscheduled visit results will be included. 
• 
Treatment condition: 
− 
2 mg baxdrostat  
− 
Placebo 
• 
Intercurrent events: The intercurrent events and the handling strategies are described 
below: 
• 
Population-level summary: Descriptive statistics on individual cortisol level before and 
after ACTH stimulation. 
Intercurrent Event 
Strategy 
Initiation of 
 
 (See Section 6.9.1 for list of 
medication). 
  
The data collected after this intercurrent event 
 
 
Treatment discontinuation; use of antihypertensive 
rescue therapy; other intercurrent events that do not 
interfere with cortisol production.  
Treatment Policy Strategy:  
The data collected after this intercurrent event will be 
included in the data analyses. 
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4 
STUDY DESIGN  
4.1 
Overall Design  
This is a Phase II, randomised, double-blind, placebo-controlled study to evaluate cortisol 
reserve after ACTH stimulation test following treatment with 2 mg baxdrostat versus placebo, 
administered OD orally on top of standard-of-care, in approximately 45 participants 
≥ 18 years of age with uHTN (seated SBP ≥ 130 mmHg at screening, ≥ 130 mmHg at 
Randomisation) despite a stable regimen of ≥ 1 antihypertensive agent (including a diuretic). 
The study duration will be up to 16 weeks, including: 
• 
A 4-week screening period. 
• 
An 8-week double-blind treatment period. The end-of-study assessment will be at Visit 6 
(Week 8), at which data will be collected and an ACTH stimulation test will be 
performed. Participants can be on treatment for up to 10 weeks*, while waiting for the 
ACTH stimulation test result to be available. 
*10 weeks is not the targeted duration of the treatment period, but only intends to provide 
flexibility in case of an unforeseen event. The last date of treatment can be later than the 
EoT Visit date. 
• 
A safety follow-up 2 weeks after last dose. 
 
Consenting participants will be screened up to 4 weeks and then randomised in a 2:1 ratio to 
one of 2 treatment arms: 
• 
2 mg baxdrostat (target number of participants: 30). 
• 
Placebo (target number of participants: 15). 
 
During the 8-week double-blind treatment period, participants should remain on their 
background antihypertensive treatment regimen. Doses of background medications should not 
be changed during this period unless participants experience SBP < 
 mmHg with 
symptoms of hypotension. Rescue therapy is permitted if the SBP or DBP exceeds 170 mmHg 
or 105 mmHg, respectively. The choice of rescue therapy is based on the Investigator’s best 
clinical judgement, however the use of K+-sparing diuretics and MRAs is prohibited. 
An ACTH stimulation test using 250 µg ACTH will be performed at Visit 2 (Randomisation) 
prior to the first dose of study intervention and Visit 6 (Week 8) with cortisol measured before 
and after the stimulation test (
 minutes after injection) (Fragoso Perozo et al, 2023). The 
ACTH stimulation testing procedure will be done locally at the site, but the serum cortisol 
measurement pre- and post-ACTH stimulation testing will be processed centrally. Participants 
need to be on treatment until ACTH stimulation test result is available, ie, treatment may last 
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up to 10 weeks depending on the availability of the ACTH stimulation test result or in case the 
test needs to be repeated. If applicable, the repeat tests shall be rescheduled as soon as 
possible to keep the duration of the treatment within 10 weeks. The IMP will be discontinued 
immediately following the completion of the repeated ACTH stimulation test. 
Cortisol analysis will be performed using the 
 measured at a 
central laboratory. Cortisol level at 
 minutes after ACTH stimulation that is < 
μg/dL at 
baseline (Visit 2) and EoT (Visit 6, Week 8) will be considered abnormal, indicating impaired 
cortisol reserve (Fragoso Perozo et al, 2023). An abnormal cortisol level after ACTH 
stimulation test at baseline (Visit 2), will result in the participant’s discontinuation of the study 
intervention (See Section 7 for discontinuation details). At EoT (Visit 6, Week 8), in the rare 
incidence of an abnormal ACTH stimulated cortisol level, the participant will be asked to 
remain on treatment and to undergo repeat ACTH stimulated cortisol measurements during an 
unscheduled visit which will include cortisol measurements 
 minutes after ACTH 
stimulation test (with 
 µg/dL cut-off) and 
 minutes after ACTH stimulation test 
(with 
µg/dL cut-off). To be considered an abnormal repeat ACTH stimulated cortisol 
result, post-ACTH cortisol must be < 
 µg/dL at 
minutes post-ACTH stimulation 
and < 
µg/dL at 
minutes post-ACTH stimulation. If only one of the two results is 
abnormal, the overall test will be considered normal. The results from the repeat test 
supersedes the original Week 8 results. 
The following is a summary of different types of cortisol measurements at different 
timepoints: 
• 
AM serum cortisol without ACTH stimulation (8 AM ± 2 hours) 
− 
Cortisol level ≥ μg/dL is considered normal.  
• 
Routine serum cortisol collected before and 
 minutes after ACTH stimulation  
− 
Cortisol level ≥
 μg/dL at 
minutes after ACTH is considered normal. 
• 
Retest serum cortisol collected before, 
 minutes AND 
 minutes after 
ACTH stimulation  
− 
Cortisol level ≥ 
μg/dL at 
 minutes after ACTH stimulation is considered 
normal. Cortisol level ≥ 
μg/dL at 
 minutes after ACTH stimulation is 
considered normal.  
Note: If only one of the two results is abnormal, the overall test will still be 
considered normal. 
 
Further evaluation and management of the participant should be at the discretion of the 
Investigator, and if needed, in consultation with an endocrinologist. 
Laboratory and safety visit timepoints are provided in the SoA Table 1. 
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After completing the 8-week double-blind treatment period (this period can be extended up to 
10 weeks if waiting for ACTH results) or if participants permanently discontinue treatment 
earlier than 8 weeks, participants will return for an SFU, 14 days after the last dose. 
A study diagram is presented in Figure 1 and study randomisation details are presented in 
Section 6.3. 
The study is planned to be conducted in the United States in approximately 12 study sites. 
4.2 
Scientific Rationale for Study Design  
The study design is developed to evaluate cortisol reserve in response to ACTH stimulation 
test in participants treated with baxdrostat. 
4.2.1 
Justification for Placebo Control  
In this study, placebo is chosen as control to objectively assess the response after ACTH 
stimulation while on baxdrostat and to maintain the blind in this study design. In addition, 
inclusion of placebo control will ensure that any potential variations in cortisol reserve is 
accounted for. This will allow the evaluation of cortisol reserve in response to ACTH 
stimulation test in participants with uHTN. 
4.2.2 
Justification for Study Length  
Baxdrostat maximal inhibition of CYP11B2 occurs by steady state over roughly 7 days 
(Freeman et al, 2023b). Thus, if cortisol suppression was to occur through inhibition of the 
enzyme, it should have occurred by steady state. Additionally, according to ICH guidance on 
technical requirements for clinical evaluation of new antihypertensive drugs (ICH E12, 2000), 
in studies involving a placebo group, participants cannot be without antihypertensive 
medications for more than 12 weeks. In this study, because it is a double-blind, 
placebo-controlled study with a 4-week screening period, this guideline is being adhered to by 
selecting an 8-week treatment period. 
Thus, considering the baxdrostat mechanism of action, its PK/PD as well as efficacy/safety 
profiles, and the regulatory limitation on the duration of a placebo-controlled group needed to 
characterise cortisol reserve, AstraZeneca has designed the study with an 8-week treatment 
exposure. 
4.3 
Justification for Dose  
Baxdrostat doses up to 2 mg OD were well-tolerated in participants in Phase II studies 
(CIN-107-121 and CIN-107-124), with a mild to moderate increase in serum K+, mild 
hyponatraemia (decrease in Na+) and a slight decrease in eGFR observed. More significant 
laboratory changes such as mild to moderate hyperkalaemia (K+ level above normal range) or 
hyponatraemia were infrequent and well managed in the majority of instances. In less frequent 

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cases, brief dosing interruption was required and resulted in a return of electrolytes to normal 
levels. These laboratory parameter changes were not associated with significant clinical AEs. 
Sporadic hypotension and associated dizziness appeared to be mild. 
The highest dose of baxdrostat being tested in the Phase III studies (D6970C00002 and 
D6970C00009 studies) is 2 mg. Therefore, the 2-mg dose was selected to evaluate the effects 
of baxdrostat on the cortisol reserve in the current study. 
4.4 
End-of-study Definition  
For the purpose of CTT, the FDA regulatory requirements define 2 completion dates for the 
end of the study: 
• 
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure 
with different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes. 
• 
Study Completion Date – the date the final participant is examined or receives an 
intervention for purposes of final collection of data for the primary and secondary 
outcome measures and AEs (for example, last participant’s last visit), whether the clinical 
study concludes according to the pre-specified protocol or is terminated. 
 
A participant is considered to have completed the study if they have completed all phases of 
the study including the last visit or the last scheduled procedure shown in the SoA (see 
Section 1.3). 
5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1 
Male or female participant must be ≥ 18 years old, at the time of signing the informed 
consent. 
 

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Type of Participant and Disease Characteristics 
2 
Participants with mean seated SBP on AOBPM ≥ 130 mmHg and < 170 mmHg at 
screening (participants who do not meet this criterion may be rescreened at the 
Investigator’s discretion, see Section 5.4.1). 
3 
Participants with mean seated SBP on AOBPM of ≥ 130 mmHg and < 170 mmHg at 
Randomisation (participants who do not meet this criterion may be rescreened at the 
Investigator’s discretion, see Section 5.4.1). 
4 
Participants must have a stable regimen of ≥ 1 antihypertensive medication (at least one 
should be a diuretic), for at least 4 weeks prior to screening (participants who do not meet 
this criterion may be rescreened at the Investigator’s discretion, see Section 5.4.1). 
Beta-blockers used to treat other conditions (ie, migraine, HF, coronary artery disease) 
should not be counted as an antihypertensive medication for the purpose of qualifying for 
this study. 
5 
Participants must have an eGFR ≥ 45 mL/min/1.73 m² at screening (participants who 
have an eGFR < 45 mL/min/1.73 m² may be rescreened at the Investigator’s discretion, 
see Section 5.4.1). 
6 
Participants must have a serum K+ level ≥ 3.5 and < 5.0 mmol/L at screening, determined 
as per central laboratory (participants who have serum K+ levels < 3.5 mmol/L or 
≥ 5.0 mmol/L may be rescreened at the Investigator’s discretion, see Section 5.4.1). 
7 
Participants must have a morning cortisol (measured at 08:00 AM ± 2 hours) ≥ µg/dL, 
determined as per central laboratory. 
 
Sex and Contraceptive/Barrier Requirements 
8 
Specific to only female participants 
Contraceptive used by female participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
(a) Females not of child-bearing potential are defined as females who are either 
permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Females will be considered 
postmenopausal if they have been amenorrhoeic for 12 months prior to the planned 
date of randomisation without an alternative medical cause. The following age 
specific requirements apply: 
(i) Females < 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and FSH levels in the postmenopausal range. 
(ii) Females ≥ 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment. 
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(b) Female participants of child-bearing potential must use one highly effective form of 
birth control. A highly effective method of contraception is defined as one that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. 
Females of child-bearing potential who are sexually active with a non-sterilised male 
partner must agree to use one highly effective method of birth control, as defined 
below, from 30 days before enrolment and throughout the study, and until at least 
30 days after last dose of study intervention. 
(i) The following are not acceptable methods of contraception: periodic abstinence 
(calendar, symptom-thermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only and lactational amenorrhoea. Female condom and 
male condom should not be used together. 
(ii) All FOCBP must have a negative urine pregnancy test result at screening and not 
be at stage of breastfeeding. Urine pregnancy test may be replaced by a serum 
pregnancy test if required by local authorities. 
(iii) Highly effective birth control methods include: total sexual abstinence is an 
acceptable method provided it is the usual lifestyle of the participant (defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study interventions); a vasectomised partner; bilateral tubal 
occlusion; intrauterine device/levonorgestrel intrauterine system; Implanon®; 
Depo-Provera™ injections. 
 
 
 as it may affect the accuracy of the ACTH stimulation 
test. Therefore, progesterone only contraceptive methods are acceptable; 
however, oestrogen-containing contraceptive methods are not acceptable for the 
study. 
 
Informed Consent 
9 
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
10 Provision of signed and dated written 
 Information 
and Consent Form prior to collection of samples for 
 
 that supports the 
 (see Appendix D 2). 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
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Medical Conditions 
1 
As judged by the Investigator, any evidence which in the Investigator’s opinion makes it 
undesirable for the participant to participate in the study. 
2 
Mean seated DBP on AOBPM ≥ 110 mmHg at Randomisation (participants who meet 
this criterion may be rescreened at the Investigator’s discretion, see Section 5.4.1). 
3 
Prior treatment (within the 4 weeks before screening) with ARBs and ACEIs (both taken 
simultaneously). 
4 
Serum Na+ level < 135 mmol/L at screening, determined as per central laboratory 
(participants who meet this criterion may be rescreened at the Investigator’s discretion, 
see Section 5.4.1). 
5 
Participant with the following known secondary causes of HTN: renal artery stenosis, 
uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, 
pheochromocytoma, Cushing’s syndrome, aortic coarctation. 
6 
NYHA functional HF Class IV at screening. 
7 
Medical history of stroke, acute coronary syndrome, hypertensive encephalopathy, or 
hospitalisation for HF within 6 months prior to randomisation or within the screening 
period. 
8 
Planned percutaneous coronary intervention/coronary artery bypass grafting or 
percutaneous coronary intervention/coronary artery bypass grafting done within 6 months 
prior to screening. 
9 
Known current severe left ventricular outflow obstruction, such as obstructive 
hypertrophic cardiomyopathy and/or severe aortic valvular disease. 
10 Left bundle branch block and any cardiac arrhythmia requiring treatment. 
11 Known severe hepatic impairment, defined as Child-Pugh Class C, based on records that 
confirm documented medical history. 
12 Uncontrolled diabetes with HbA1c > 10.0% (86 mmol/mol) at screening. 
13 QTcF value > 470 ms at screening, unless having a pacemaker. 
14 Family history of long QT syndrome. 
15 Heart rate < 45 or > 110 beats/minute in a resting position, as per vital signs assessment. 
16 Participants suspected to have severe cardiac hypertrophy. 
17 Participants who are pregnant or breastfeeding. 
18 Participants with a diagnosis of adrenal insufficiency or other disease affecting the 
adrenal gland. 
19 Hypersensitivity reaction to cosyntropin injection, synthetic ACTH, or to any of the 
excipients. 
20 Any of the following related to COVID-19 infection (participants who meet this criterion 
may be rescreened at the Investigator’s discretion, see Section 5.4.1): 

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(a) Suspected (as judged by the Investigator) or confirmed COVID-19 infection within 
the last 4 weeks prior to screening or at Randomisation. 
(b) Hospitalisation for COVID-19 within the last 12 weeks prior to screening. 
 
Prior/Concomitant Therapy 
21 Prior medical treatment with any MRAs, antiarrhythmic medications, or K+-sparing 
diuretic used within 4 weeks prior to screening. 
22 Treatment with K+ binders within 8 weeks prior to screening. 
23 Participant expected to receive or receiving any of the exclusionary drugs such as strong 
inducers of 
, chronic use of NSAIDs (taken more than 3 times a week for more 
than 3 months). 
24 Treatment with 
 prior to screening. 
25 Treatment with 
 prior 
to Screening. See Section 6.9.1 for the list of medications. 
26 Drugs that prolong QT should be avoided, if possible, and if there are other alternatives 
without the QT liability, these should be preferred. If such QT prolonging drugs are still 
needed, the Investigator must ensure appropriate monitoring of ECGs and electrolytes are 
performed, as per clinical judgement. 
27 Current or prior treatment within 6 months prior to screening with cytotoxic therapy. 
28 Treatment with K+ supplements are not prohibited but should be continuously assessed 
and monitored throughout the study. 
 
Prior/Concurrent Clinical Study Experience 
1. Participation in another clinical study with an investigational product administered in the 
3 months prior to randomisation in this study. 
2. Participants with a known hypersensitivity to baxdrostat or drugs of the same class or any 
of its excipients. 
 
Other Exclusions 
3. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site). 
4. Judgement by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements. 
5. Previous enrolment or randomisation in the present study. 
6. Participants working shifts (ie, shifts that comprise working hours at different times on 
different days). 
 
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5.3 Lifestyle Considerations  
No lifestyle restrictions such as diet, smoking habits, alcohol restrictions, etc are required to 
participate in this study. 
Restrictions relating to concomitant medications are described in Section 6.9. 
5.3.1 
Meals and Dietary Restrictions  
Generally, no dietary restrictions are required. Participants can take the study intervention 
with or without food. If participants have abnormal K+ and/or Na+, dietary counselling may be 
provided. Hyperkalaemia should be managed as per local standard-of-care (see Section 7.1). 
Participants should be instructed to maintain their usual fluid intake as best as possible, unless 
additional oral hydration is needed. If the participant is suspected to be dehydrated, closer 
supervision, including K+ monitoring is warranted (see Section 8.3.4.1 for K+ monitoring). 
Investigators should also consider encouraging participants to limit K+ rich foods intake and to 
follow other main guidelines, such as: 
• 
Avoid drinking liquid from canned fruits or vegetables. 
• 
Eat a variety of foods but in moderation. 
• 
Moderate serving size for each meal. 
• 
Always read the labels of any prepared foods. 
• 
Leach one’s favourite high K+ vegetable to remove some of the K+. 
 
5.3.2 
Caffeine, Alcohol, and Tobacco  
Participants should not smoke or consume caffeinated beverages or food 30 minutes prior to 
assessment of AOBPM (see Section 8.3.2.1). 
5.4 
Screen Failures  
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from Regulatory 
Authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, any SAE(s) and any concomitant medication(s) related to the SAE(s). 
Data collected at screening are detailed in Section 8.1. 
5.4.1 
Rescreening  
Individuals who do not meet the following criteria for participation in this study (screen 

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failures) may be rescreened, at the Investigator’s discretion and only if the other criteria are 
met: 
• 
Inclusion criteria 2, 3, 4, 5 and 6: Have a mean seated SBP on AOBPM ≥ 130 mmHg and 
< 170 mmHg at screening and at Randomisation; have a stable regimen of 
≥ 1 antihypertensive medication (at least one should be a diuretic) for at least 4 weeks 
prior to screening; have an eGFR ≥ 45 mL/min/1.73 m² and a serum K+ level ≥ 3.5 and 
< 5.0 mmol/L at screening, determined as per central laboratory. 
• 
Exclusion criteria 2, 4 and 20: Have a mean seated DBP on AOBPM ≥ 110 mmHg at 
Randomisation; have a serum Na+ level < 135 mmol/L at screening, determined as per 
central laboratory and any of the following related to COVID-19 infection: 
− 
Suspected (as judged by the Investigator) or confirmed COVID-19 infection within 
the last 4 weeks prior to screening or at Randomisation. 
− 
Hospitalisation for COVID-19 within the last 12 weeks prior to screening. 
 
Rescreening is only allowed twice in the study. Rescreened participants should be assigned the 
same participant number as for the initial screening. A new informed consent is required to be 
signed for each rescreening. 
Individuals who do not meet the eGFR, Na+ and/or K+ inclusion/exclusion criteria at screening 
for participation in the study, may have these laboratory parameters retested once at the 
Investigator’s discretion. 
5.5 
Criteria for Temporarily Delaying Enrolment/Randomisation/ 
Administration of Study Intervention  
Not applicable. 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study interventions are all pre-specified IMPs and NIMPs intended to be administered to the 
study participants during the study conduct. 
6.1 
Study Interventions Administered  
Study interventions and procedures to be administered and investigated in this study are 
described in Table 6. 
Table 6 
Study Intervention and Procedure  
Arm name 
2 mg baxdrostat 
Placebo 
Intervention name 
Baxdrostat 
Placebo 

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Table 6 
Study Intervention and Procedure  
Arm name 
2 mg baxdrostat 
Placebo 
Type  
Drug 
Drug 
Dose formulation 
Tablet 
Tablet 
Unit dose strengths 
2 mg per tablet 
N/A 
Dosage levels 
2 mg baxdrostat OD 
Placebo OD 
Route of administration 
Oral 
Oral 
Regimen 
One tablet per day, 
preferably in the morning 
One tablet per day, 
preferably in the morning 
Use 
Experimental 
Placebo 
IMP or NIMP/AxMP 
IMP 
IMP 
Sourcing 
Provided centrally by 
AstraZeneca 
Provided centrally by 
AstraZeneca 
Packaging and labelling 
Study intervention will be 
provided in blister packs 
containing IMP tablets. Each 
blister pack will be labelled as 
required per country requirement. 
Study intervention will be 
provided in blister packs 
containing IMP tablets. Each 
blister pack will be labelled as 
required per country requirement. 
The external label and appearance of all tablets, for all study interventions, will be the same in order to keep the 
blind. 
AxMP = Auxiliary medicinal product; IMP = Investigational medicinal product; N/A = Not applicable; 
NIMP = Non-investigational medicinal product; OD = Once daily. 
 
Study intervention will be given to participants at the study visits summarised in the SoA (see 
Section 1.3) and participants will self-administer doses of 2 mg baxdrostat or placebo orally 
OD at home during the non-study visits. 
The following medicinal products are defined as NIMP/AxMP in this study and will be 
obtained by the study participants. 
• 
Background antihypertensive medications: The stable regimen of background 
antihypertensive medication that participants receive when they are enrolled in this study 
(see Section 4.1 for more details) and which they will continue receiving after they are 
randomised to study intervention. Doses of background medications should not be 
changed during this period unless participants experience SBP < 
 mmHg with 
symptoms of hypotension. 
• 
Rescue antihypertensive medications: Rescue therapy is permitted if the SBP or DBP 
exceeds 170 mmHg or 105 mmHg, respectively. The choice of rescue therapy is based on 
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the Investigator’s best clinical judgement; however, the use of K+-sparing diuretics and 
MRAs is prohibited. 
 
The ACTH stimulation test performed to assess the cortisol reserve is also defined as 
NIMP/AxMP and will be either sourced locally (by the site) or provided centrally by the CRO 
(as needed). This test will be performed with a single intravenous injection of 250 µg ACTH 
(cosyntropin injectable solution) at Visit 2 (Randomisation) and Visit 6 (EoT). 
All NIMPs/AxMPs used in this clinical study are authorised and are to be used in accordance 
with the terms of their marketing authorisations. 
6.2 
Preparation, Handling, Storage, and Accountability  
The IMP should be stored in accordance with the product labelling. Temperature monitoring is 
required at the storage location to ensure that the investigational product is maintained within 
an established temperature range. 
The Investigator or designee (eg, unblinded pharmacist) must confirm appropriate conditions 
(eg, temperature) have been maintained during transit for all study intervention received at the 
site and throughout the entire study until authorisation is provided for on-site destruction or 
removal of the IMP, reflecting completion of the study. In the event of a temperature excursion 
detected at any time during the study, sites will follow the reporting procedures for notifying 
AstraZeneca (or designated party); release of IMP for clinical use can only occur once the 
event has been reviewed and approval is provided by AstraZeneca (or designated party). 
Only participants enrolled in the study may receive study intervention, and only authorised 
site staff may supply, prepare, or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the Investigator and 
authorised site staff. 
The Investigator or authorised site staff are responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition 
records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Study Reference Manual. Additionally, concomitant medication compliance 
will be verified as per local standards/guidelines. 
6.3 
Assignment to Study Intervention  
All participants who meet all the eligibility criteria (see Section 5.1) and none of the exclusion 
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automated IRT/RTSM system that will allocate participants into 2:1 ratio to one of the 
2 treatment arms: 
• 
2 mg baxdrostat (target number of participants: 30). 
• 
Placebo (target number of participants: 15). 
 
Randomisation will be performed in balanced blocks of fixed size. The randomisation codes 
will be computer generated and loaded into the IRT/RTSM database. 
All randomisations will be performed by the Investigator directly using the IRT/RTSM 
system. No randomisation codes are to be reused. 
Randomisation information will be concealed from the Investigators, the participants, and the 
study team until all participants have completed the study, except for an emergency situation 
involving a participant that requires unblinding of the treatment assignment (see Section 6.4). 
Before the study is initiated, the telephone number and call-in directions for the IRT and/or the 
log in information and directions for the RTSM will be provided to each site. 
6.3.1 
Incorrectly Enrolled/Randomised Participants  
In the event that a participant is incorrectly enrolled/randomised, the Study Medical Monitor 
will discuss with the Sponsor the risk/benefit for the participant of continuing in the study 
(please refer to Section 7.1.3 and Section 7.1.4 for temporary interruption and permanent 
interruption of study intervention). 
6.4 
Blinding  
This is a randomised, double-blind study where neither the participants nor the Sponsor or 
Investigator will know which intervention participants are receiving until study completion. 
During the 8-week double-blind treatment period, the IRT/RTSM will provide to the 
Investigators, the kit identification number to be allocated to each participant at the dispensing 
visit. Routines for this will be described in the IRT/RTSM user manual that will be provided to 
each site. 
The IRT/RTSM will be programmed with blind-breaking instructions. The randomisation code 
should not be broken except in medical emergencies when the appropriate management of the 
participant requires knowledge of the treatment randomisation. Participant safety must always 
be the first consideration in making such a determination. The Investigator will document and 
report any blind break to AstraZeneca, without revealing the treatment given to the participant 
to other clinical site or blinded study personnel. If a participant’s intervention assignment is 
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AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to a study intervention and that potentially require expedited 
reporting to Regulatory Authorities. Randomisation codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented. 
Pharmacokinetic samples will be analysed by the bioanalytical laboratory performing the 
bioanalyses only for participants on active treatment, as referenced in Section 8.5.2. To allow 
for the appropriate selection of samples, the bioanalytical laboratory will, therefore, have 
access to the treatment codes but will not share the codes with the Sponsor or others involved 
in the study until the blinding is broken for the study. 
Pharmacokinetic and PD results from the central laboratory will be blinded. 
6.5 
Study Intervention Compliance  
When participants are dosed at the site, during on-site visits specified in the SoA (see 
Section 1.3), they will receive study interventions directly from the Investigator or designee, 
under medical supervision. The date, and time if applicable, of dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
When participants self-administer study interventions at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning 
and counting returned tablets during the site visits and documented in the source documents 
and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
A record of the quantity of IMPs dispensed to and administered by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates will also be recorded in the eCRF. 
Compliance with study intervention will be documented in the source documents and eCRF as 
follows: 
• 
Study intervention exposure measured by treatment interruptions and/or treatment 
discontinuation will be recorded in the eCRF using the exposure form. Intervention start 
and stop dates will also be recorded in the eCRF. 
 
6.6 
Dose Modification  
Dose modification of baxdrostat is not permitted in this study. For stopping study intervention 
due to safety or other reasons, please see Section 7. 

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6.7 
Continued Access to Study Intervention After the End of the 
Study  
Participants will have no access to study intervention beyond completion of the study. The 
recommendation will be to treat the participant according to guidelines. 
6.8 
Treatment of Overdose  
Overdose refers to the administration of a quantity of the study intervention given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. 
For this study, any dose of baxdrostat greater than 2 mg per day will be considered an 
overdose. 
The most likely manifestations of an overdose based on the mechanism of baxdrostat action 
would be hypotension, hypovolaemia, and hyperkalaemia, which would require supportive 
measures to maintain hydration, electrolyte balance and vital functions. 
In the event of an overdose, the Investigator should: 
• 
Evaluate the participant to determine, in consultation with the Study Clinical Lead, if 
possible, whether study intervention should be interrupted or whether the dose should be 
reduced. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate and at least until the next scheduled Follow-up Visit. Refer to 
Section 8.4.11 for details of AE/SAE reporting related to overdose. 
• 
Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
study intervention if requested by the Study Clinical Lead (determined on a case-by-case 
basis). 
• 
Document the quantity of the excess dose as well as the duration of the overdose. 
• 
Treat overdose symptoms using clinical judgement. 
 
6.9 
Prior and Concomitant Therapy  
Any medication or vaccine (including over the counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant (except for screen failures) is receiving at the time of enrolment or receives during 
the study must be recorded in the eCRF along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 

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• 
Dosage information including dose, frequency, and route. 
 
The Study Clinical Lead should be contacted if there are any questions regarding concomitant 
or prior therapy. 
6.9.1 
Prohibited Concomitant Medications  
The medications and supplements listed below are prohibited during this study: 
• 
Potassium-sparing diuretics (eg, amiloride, triamterene) and direct renin inhibitor (eg, 
aliskiren). 
• 
Mineralocorticoid receptor antagonists or aldosterone antagonists (eg, eplerenone, 
finerenone, spironolactone). 
• 
 
 
• 
 
• 
Once enrolled, treatment with any form of 
 or on 
over the counter 
 while enrolled in the study, and treatment with 
 at any dose. 
 
6.9.2 
Restricted Concomitant Medications  
The medications and supplements listed below are restricted during this study: 
• 
 
• 
Simultaneous use of ARBs and ACEIs (participants should be on stable dose of either 
drug class; any changes to drug dose or class must be closely monitored). 
• 
Potassium binders (prohibited at screening but can be started as a corrective action during 
the study). 
• 
Tacrolimus, calcineurin inhibitors and cyclosporin (topical/inhaled immunosuppressants 
are permitted). 
• 
Chronic NSAID use (taken more than 3 times a week for more than 3 months. Occasional 
NSAID usage is permitted; however, closer monitoring is warranted at these times). 
• 
Strong 
 
 
• 
Treatment with K+ supplements is not prohibited but should be continuously assessed and 
monitored throughout the study (see Section 8.3.4.1 for K+ laboratory measurements). 
 
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6.9.3 Rescue Medicine  
The study sites will be responsible for prescribing rescue antihypertensive medications, which 
are categorised as NIMP/AxMP in this study (see Section 6.1). 
Rescue therapy is permitted if the SBP or DBP exceeds 170 mmHg or 105 mmHg, 
respectively. The choice of rescue therapy is based on the Investigator’s best clinical 
judgement; however, the use of K+-sparing diuretics and MRAs is prohibited. 
The start date of rescue antihypertensive medication administration as well as the name and 
dosage regimen of the rescue antihypertensive medication must be recorded. 
During this study, participants should remain blinded to the study intervention while receiving 
rescue therapy. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study as a whole is handled as described in 
Appendix A. 
7.1 
Discontinuation of Study Intervention  
Note that discontinuation from study intervention is not the same thing as a discontinuation or 
withdrawal from the study (see Section 7.2). 
In case of abnormal ACTH stimulated cortisol values at baseline, participant discontinues the 
study intervention and follows steps as described below. 
If study intervention is permanently discontinued, the participant should, if at all possible, 
remain in the study in order to complete the EoT Visit and the SFU Visit, for details see 
Section 7.1.4. See the SoA for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
7.1.1 
Liver Chemistry Stopping Criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator 
when a participant meets one of the conditions outlined in the algorithm (see Appendix E) or 
in the presence of abnormal liver chemistries not meeting protocol-specified stopping rules, or 
if the Investigator believes that it is in best interest of the participant. 
7.1.2 
QTc Stopping Criteria  
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline [which is the Screening Visit value] in QT interval corrected using QTcF) after 
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on the study intervention and if any change in participant management is needed. This review 
of the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
Any QTcF value ≥ 
 ms should be evaluated thoroughly for accuracy of the ECG 
measurement and the electrolytes should be corrected, if needed. If the QTcF value decreases 
and there is another explanation for the QT prolongation, eg, another drug with QT 
prolongation effect, the restart of the study intervention may be considered, and study 
intervention will not be permanently stopped (see Section 7.1.3). On the contrary, if there are 
no other factors that could explain the QTcF value being 
 ms or higher, study intervention 
will have to be permanently discontinued (see Section 7.1.4). 
7.1.3 
Temporary Interruption of Study Intervention  
Study intervention will be temporarily interrupted in the following situations: 
• 
If a participant has a QTcF ≥ 
 ms, study intervention will be temporarily interrupted at 
first and may be permanently discontinued afterwards. See details in Section 7.1.2. 
• 
Hypotension: If the participant’s SBP is ≤ 
 mmHg, the study intervention should be 
temporarily interrupted and may be restarted only if an alternative aetiology for 
symptomatic hypotension has been identified and the event has fully resolved. If study 
intervention is resumed, SBP should be re-checked at an unscheduled visit within 
7-10 days (± 4 days) from restart of study intervention but can be re-checked at the next 
study visit if it falls within the suggested window. 
• 
Hyponatraemia: If the participant’s Na+ level is < 
 mmol/L, the participant may 
remain on study intervention; however, the Na+ should be re-checked within 72 hours by 
the central laboratory and the participant should be instructed to reduce free water 
consumption prior to retesting. If the laboratory retest confirms Na+ < 
 mmol/L, the 
study intervention should be temporarily interrupted. The study intervention may be 
restarted when the Na+ has increased to > 
 mmol/L. Sodium should then be re-checked 
by the central laboratory within 7-10 days (± 4 days) from restart of study intervention. 
• 
Hyperkalaemia should be managed as per local standard-of-care. Participants may be 
treated acutely or chronically with K+ binding agents, at the discretion of the Investigator 
and treating physicians. 
Study-specific discontinuation criteria and management regarding K+ are described 
below. Inappropriate sample handling/storage or lengthy transport time to local/central 
laboratory may result in falsely elevated K+ levels in analysed blood samples. It is 
expected that local laboratory results (from either serum/plasma samples) will be 
available prior to central laboratory results and expected to take priority for 
decision-making/monitoring: 
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− 
If K+ is ≥ 
 to < mmol/L, the participant may remain on study intervention; 
however, the K+ should be re-checked within 72 hours by the local and/or central 
laboratory and if confirmed ≥ 
 mmol/L, the study intervention should be 
temporarily interrupted. 
− 
If K+ is ≥ 
 mmol/L, immediately temporarily interrupt study intervention, manage 
as per local standard-of-care and re-check K+ within 72 hours by the local and/or 
central laboratory. If the repeated K+ measurement is also ≥ 
 mmol/L, refer to 
Section 7.1.4 for permanent study intervention discontinuation details. 
− 
The study intervention may be restarted when K+ level is ≤ 
 mmol/L. Potassium 
should then be re-checked by the local and/or central laboratory within 2-7 days from 
restart of study intervention. 
For further details on K+ laboratory measurements see Section 8.3.4.1. 
• 
Participants with signs and symptoms of AI should remain on treatment (either baxdrostat 
or placebo), unless severe signs and symptoms of adrenal insufficiency are present, in 
which case the treatment should be temporarily discontinued. In any case of AI signs and 
symptoms, an ACTH stimulation test should be performed (see Section 8.4.5.1). If the 
ACTH stimulation test: 
− 
has an abnormal result, and the participant is diagnosed with AI, the participant is 
recommended to be referred to an endocrinologist for management and treatment 
should be permanently discontinued, see Section 7.1.4.  
− 
has a normal result, the participant will not undergo additional workup for AI and 
he/she will continue the study as planned.  
 
7.1.4 
Permanent Discontinuation of Study Intervention  
Participants may be permanently discontinued from the study intervention in the following 
situations: 
• 
Participant decision: The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. 
• 
An AE that, in the opinion of the Investigator or AstraZeneca, warrants discontinuation 
from further dosing. 
• 
Severe non-compliance with the CSP. Safety reasons as judged by the Investigator where 
continued treatment may put participant at undue risk. 
• 
If the participant becomes pregnant during the study (see Section 8.4.9). 
• 
The participant has a mean seated SBP and seated DBP that exceeds 170 mmHg and 
105 mmHg, respectively, in 2 separate occasions, despite rescue therapy being given after 
each of these 2 occasions (see Section 6.9.3). See Section 8.3.2.1 for BP measurement 
procedures. 
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• 
Hypotension: If the participant’s SBP is ≤ 
 mmHg and the participant has symptoms 
that do not have an alternative aetiology for symptomatic hypotension other than the 
study intervention, the study intervention must be permanently discontinued. 
• 
Hyponatraemia: Permanently discontinue study intervention if a participant experiences a 
recurrent hyponatraemia event (post-randomisation Na+ level is < 
 mmol/L) after a 
previous event (see Section 7.1.3), if there was no explanation for the recurring event 
other than restarting study intervention. 
• 
Hyperkalaemia: Permanently discontinue study intervention if a participant experiences a 
recurrent hyperkalaemia event (K+ ≥ 
 mmol/L) after a previous event (see 
Section 7.1.3), if there was no explanation for the recurring event other than restarting 
study intervention. See Section 8.3.4.1 for further details on K+ laboratory measurements. 
• 
Participants who develop adrenal insufficiency during the study, confirmed as per the 
ACTH stimulation test (see Section 7.1.3), should discontinue the study intervention, 
and remain in the study for continued safety surveillance. In this situation an attempt 
should be made to establish whether the participant has primary, secondary or tertiary 
adrenal insufficiency. Refer to Section 8.3.4 for additional details. 
• 
Participants who are under temporary interruption of the study intervention when they 
reach Visit 5, and for which the Investigator deems not possible to restart the study 
intervention during that specific visit, need to be permanently discontinued from the study 
intervention. Details for this permanent discontinuation should be recorded in the eCRF. 
 
If the study intervention is permanently discontinued, the participant will undergo an EoT 
Visit (including ACTH stimulation cortisol testing), ideally scheduled as soon as possible at 
the time of discontinuation or premature withdrawal from the study intervention. Following 
the EoT Visit, the participant will then proceed to complete the final SFU Visit as per SoA (see 
Section 1.3). If the EoT Visit is conducted > 10 days after the last administered dose, the 
assessments outlined in the SFU Visit will be performed during the EoT Visit. 
7.1.5 
Rechallenge  
7.1.5.1 
Study Intervention Restart or Rechallenge After Liver Stopping Criteria Are 
Met  
Study intervention restart, after liver chemistry stopping criteria are met, is allowed in this 
study. If the participant meets liver chemistry stopping criteria, do not restart the participant 
with study intervention unless: 
• 
Sponsor approval is granted. 
• 
IEC and/or IRB approval is obtained, if required. 
 
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NOTE: If study intervention was interrupted for suspected intervention-induced liver injury, 
the participant should be informed of the risk of death, liver transplantation, hospitalisation, 
and jaundice. 
Refer to Appendix E for details on the study intervention restart process. 
If the Sponsor approval to restart the participant with study intervention is not granted, then 
the participant must permanently discontinue study intervention and may continue in the study 
for protocol-specified follow-up assessments. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation from the study describes specific situations where the Investigator ends the 
individual’s participation in the study. Withdrawal from the study describes a participant’s 
voluntary decision to end their participation in the study. 
Discontinuation of the participant from the study by the Investigator: 
• 
A participant may be discontinued from the study at any time at the discretion of the 
Investigator for behavioural or compliance reasons. 
• 
At the time of discontinuing from the study, if the participant has not been discontinued 
from the study intervention, see Section 7.1. 
 
Voluntary withdrawal from the study by the participant may occur in the following situations: 
• 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). A participant who prematurely 
withdraws consent from the study will have an early EoT Visit performed at the time of 
the withdrawal or as soon as possible, preferable with 2 weeks. 
• 
A participant who wishes to withdraw from the study must be informed by the 
Investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records). If a participant agrees 
to a modified follow-up until the end of the study, he/she will not be considered 
withdrawn from the study. 
• 
If the participant withdraws consent for disclosure of future information, AstraZeneca 
may retain and continue to use any data collected before such a withdrawal of consent. 
• 
If the participant withdraws from the study, AstraZeneca may retain and continue to use 
any samples collected before such a withdrawal of consent for the purposes the 
participant originally consented unless the participant withdraws consent for use of 
samples already collected. If the participant specifically withdraws consent for any use of 
samples, it must be documented in the site study records by the Investigator and the 

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Investigator must inform the Local and Global Study Team. Destruction of any samples 
taken and not yet tested should be carried out in line with documented sample withdrawal 
wishes in conjunction with what was stated in the informed consent and local regulation. 
 
Participants who develop signs and symptoms, which may indicate adrenal insufficiency 
during the study should remain on treatment unless severe signs and symptoms develop, 
should undergo ACTH stimulation testing, and stay in the study for continued safety 
surveillance. Refer to Section 8.4.5.1 for additional details. 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the study site for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible. The participant should be counselled on the importance of maintaining the 
assigned visit schedule. At this time ascertain whether the participant should or wishes to 
or continue in the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, texts, 
emails, and if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• 
Should the participant continue to be unreachable, the participant will be considered to 
have been lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES  
• 
Study procedures and their timing are summarised in the SoA (see Section 1.3). Protocol 
waivers or exemptions are not allowed. Descriptions of the scheduled evaluations are 
outlined in the subsections below. Before study entry, throughout the study and at the 
follow-up evaluation, various clinical and diagnostic laboratory evaluations are outlined. 
The purpose of obtaining these detailed measurements is to ensure adequate safety and 
efficacy assessments. Clinical evaluations and laboratory studies may be repeated more 
frequently if clinically indicated. Such unscheduled assessments will be captured in the 
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• 
The Investigator ensures the accuracy and completeness of eCRFs, and timeliness of the 
data recorded and of the provision of answers to data queries according to the Clinical 
Study Agreement. The Investigator will electronically sign the completed eCRFs. A copy 
of the completed eCRFs will be archived at the study site. 
• 
Urgent safety concerns should be discussed with AstraZeneca immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• 
Instructions for the collection and handling of HBS will be provided in the study-specific 
Laboratory Manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on handling of HBS see 
Appendix C. 
 
In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may be 
implemented by AstraZeneca or the Investigator, as per local health authority/ethics 
requirements. 
Safety/laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
8.1 
Administrative and General/Baseline Procedures  
Screening and randomisation procedures will be performed as specified in the SoA (see 
Section 1.3). 
For all participants, the following data will be collected: 
• 
At screening: 
− 
Obtain informed consent 
− 
Eligibility criteria (see Section 5) 

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− 
Demography details 
− 
Participant’s medical/surgical history 
− 
Collection of concomitant medications (see Section 6.1 and Section 6.9) 
− 
Safety assessment data (complete physical examination, 12-lead ECG, and vital 
signs; see Section 8.3) 
− 
Safety laboratory collection (whole safety panel including creatinine analysis for 
eGFR calculation and measurement of Na+ and K+ blood levels), cortisol 
values,HbA1c, FSH, and urine pregnancy test (see Section 8.3.4) 
− 
Any SAEs occurring from the time of signing the ICF (see Section 8.4.8) 
 
• 
At randomisation: 
− 
Confirmation of eligibility criteria (see Section 5) 
− 
Reporting of concomitant medications (see Section 6.1 and Section 6.9) 
− 
Safety assessment data (complete physical examination and vital signs; see 
Section 8.3) 
− 
Safety laboratory collection (whole safety panel including creatinine analysis for 
eGFR calculation and measurement of Na+ and K+ blood levels), K+ measurements, 
urine pregnancy and dipstick tests (see Section 8.3.4) 
− 
Optional 
 samples for 
 research (see Section 8.7) 
− 
Any AEs occurring from randomisation throughout the study intervention period 
including the SFU period (see Section 8.4) 
 
The following data for screen failures will be collected at screening: demography details, 
eligibility criteria (reason for screen failure), any SAE(s), and any concomitant medication(s) 
related to the SAE(s). 
8.1.1 
Demographics  
The Investigator, or designee, will record the participant’s sex, age, race, and ethnicity at 
screening. 
8.1.2 
Medical/Surgical History  
The Investigator, or designee, will record, at screening, any significant medical or surgical 
history of the participant along with the year in which such medical issue began (if known) or 
when the medical surgery was performed. 
8.2 
Efficacy Assessments  
Not applicable. 
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8.3 
Safety Assessments  
Planned timepoints for all safety assessments are provided in the SoA (see Section 1.3). 
8.3.1 
Physical Examinations  
Physical examination will be performed at timepoints as specified in the SoA (see 
Section 1.3). 
A complete physical examination will be performed by the Investigator or a suitably qualified 
medical designee and include assessments of the following: general appearance, respiratory, 
cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph 
nodes, thyroid, musculoskeletal (including spine and extremities), and neurological systems. 
Additionally, height will be measured during the Screening Visit. 
A targeted physical examination will be conducted at the SFU Visit and will include, at a 
minimum, assessments of the lung and cardiovascular evaluations, and examination of any 
peripheral oedema. 
8.3.2 
Vital Signs  
Vital signs will be performed at timepoints as specified in the SoA (see Section 1.3). 
Vital signs will include seated attended office automated BP, pulse rate and body weight 
measurements. Blood pressure will be measured using the standardised procedures described 
in Section 8.3.2.1. 
Deterioration of vital signs compared to screening/randomisation values, should only be 
reported as AEs if these values meet the criteria listed in Section 8.4.4 and/or Section 8.4.6. 
8.3.2.1 
Seated Blood Pressure Measurements  
Seated BP measurements will be recorded using standardised automated BP machines and 
using the following standardised procedures: 
• 
Participants should not exercise, smoke, or consume caffeinated beverages or food 
30 minutes prior to assessment of AOBPM. 
• 
Participants should be seated for at least 5 minutes in the examination room with the back 
supported, feet flat on the floor. 
• 
Mean seated BP is defined as the average of 2 seated BP measurements. 
 
Extreme reduction of BP measurements between screening and randomisation values should 
only be reported as AEs if these meet the criteria listed in Section 8.4.4. 

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8.3.3 
Electrocardiograms  
Twelve-lead ECGs will be performed at timepoints as specified in the SoA (see Section 1.3). 
Electrocardiograms will be performed after the participant has been resting in supine position 
for at least 5 minutes. Twelve-lead ECGs will be printed and will be evaluated as soon as 
possible for the presence of abnormalities by a qualified physician. 
Standard 12-ECG parameters will be measured, and the following 12-ECG parameters will be 
recorded: 
• 
Heart rate and heart rhythm. 
• 
QRS, PR, RR, QT and QTc (QTcF) intervals (see Section 7.1.2 for QTc stopping criteria 
details). 
 
An ECG machine that automatically calculates the heart rate and rhythm, and measures PR, 
QRS, QT, and QTc intervals, will be used. Interpretation of the clinical safety ECG findings 
will be reviewed and confirmed by the Investigator. 
Investigators should contact AstraZeneca or designee if any clinically meaningful changes 
from baseline (Screening Visit value) are noted on review (see Section 8.4.4 for ECG-related 
abnormalities that should be reported as AEs). 
8.3.4 
Clinical Safety Laboratory Tests  
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the visits indicated in the SoA (see Table 2 in Section 1.3). 
The clinical chemistry and haematology analyses will be performed at a central laboratory. 
The date of sample collection will be recorded on the appropriate eCRF. Sample tubes and 
sample sizes will be described in the Laboratory Manual. Please see Section 8.3.4.1 for details 
on K+ measurements. 
The following laboratory variables will be measured (Table 7). 
Table 7 
Laboratory Variables  
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum) 
Haemoglobin 
Creatinine a,b 
Leukocyte count 
TBL 
Leukocyte differential count (absolute count) 
ALP 
Platelet count 
AST 
HbA1c c 
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Table 7 
Laboratory Variables  
RBC count 
Albumin 
Urinalysis (dipstick; urine) e 
K+ b 
Haemoglobin/Erythrocytes/Blood  
Calcium, total 
Protein/Albumin  
Na+ b 
Glucose 
Magnesium 
Leucocytes 
Bicarbonate 
Nitrites 
Phosphate 
Pregnancy test d 
Hormonal Analysis (serum) 
 
FSH c 
 
β-hCG d 
a 
eGFR will be calculated every time the creatine is collected (at all visits) using the creatinine results 
obtained from blood samples. 
b 
Creatinine, K+ and Na+ will be measured centrally at every study visit that is scheduled between Screening 
(Visit 1), and EoT(Visit 6). 
c 
Only measured at Screening (Visit 1). 
d 
Urine pregnancy tests will be performed at Screening (Visit 1), Randomisation (Visit 2), Double-blind 
Period (Visit 5), EoT (Visit 6), and Safety Follow-up (SFU Visit) for FOCBP. However, these can be 
replaced by serum pregnancy tests (serum pregnancy test will be performed centrally). 
e 
Dipstick urinalysis is only performed locally at Randomisation (Visit 2). 
ALP = Alkaline phosphatase; ALT = Alanine aminotransferase/transaminase; AST = Aspartate 
aminotransferase/transaminase; β-hCG = Beta-human chorionic gonadotropin; eGFR = Estimated glomerular 
filtration rate; EoT = End of treatment; FOCBP = Female(s) of child-bearing potential; FSH = Follicle 
stimulating hormone; HbA1c = Glycated haemoglobin; K+ =Potassium; Na+ = Sodium; RBC = Red blood cells; 
TBL = Total bilirubin. 
 
In case a participant shows an AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, please 
refer to Appendix E, for further instructions and see Section 8.4.4 for AEs based on 
examination tests. If TBL value is elevated, the laboratory should also report the direct and 
indirect bilirubin values. Further details are described in the Laboratory Manual. 
Potassium values measured in the local laboratories will prevail over the results obtained in 
the central laboratory to assess for hyperkalaemia. Potassium values will be collected in the 
eCRF if they meet the criteria for hyperkalaemia AE (see Section 8.4.6.1). 
The eGFR will be monitored systemically throughout the study by the central laboratory. The 
eGFR will be calculated using the creatinine results obtained from blood sample analysis and 
using the CKD-EPI 2021 equation, which is as follows: 
eGFR = 142 × min (Scr/κ,1)α × max (Scr/κ, 1)-1.209 × 0.9938age × 1.012 [if female] 

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Where, Scr is standardised serum creatinine (mg/dL); κ is 0.7 for females and 0.9 for males; α 
is -0.241 for females and -0.302 for males; min indicates the minimum of Scr/κ or 1 and max 
indicates the maximum of Scr/κ or 1. Age is expressed in years (Inker et al, 2021). 
8.3.4.1 
Potassium Laboratory Measurements  
Serum K+ levels will be monitored systemically throughout the study. Potassium will be 
measured in both, the central and local laboratories, and will be measured at the times 
specified in SoA (see Section 1.3). Both serum and plasma K+ tests will be acceptable, as per 
local practice. Local laboratory sample values will be used for safety decision-making at site 
level and central laboratory samples will be used for analysis purposes. Potassium results from 
the local laboratories will be recorded on the eCRF only if they meet AE criteria. 
Unscheduled assessments of K+ levels should be planned at the Investigator’s discretion 
(eg, for a follow-up of elevated K+ levels, after changing concomitant medications which may 
affect serum K+ levels and/or renal function [eg, NSAIDs/ACEIs/ARBs/nephrotoxic agents], 
following acute changes in the clinical condition or when there is suspected dehydration, 
vomiting/diarrhoea, etc). Patients taking K+ supplements must have closer supervision. 
Repeated and unscheduled testing for K+ should be measured at both, the local and central 
laboratories (see Section 7.1.3 and Section 7.1.4 for temporary interruption and permanent 
discontinuation criteria of the study intervention, respectively, based on K+ levels). 
Potassium levels will be reported in the eCRF in case of hyperkalaemia (see Section 8.4.6.1). 
8.4 
AEs, SAEs, and Other Safety Reporting  
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
Participants (or, when appropriate, a caregiver, surrogate, or the participant’s legally 
authorised representative) will notify the Investigator or designees of symptoms. These must 
then be assessed by the Investigator and if considered an AE it will be reported by the 
Investigator. 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
AE Variables 
The following variables will be collected for each AE: 
• 
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• 
The date when the AE started and stopped 
• 
Maximum intensity (mild, moderate, severe) 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IMPs (yes or no) 
• 
Action taken with regard to IMPs 
• 
AE caused participant’s withdrawal from the study (yes or no) 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of SAE 
• 
AE description 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information  
Adverse events will be collected from Randomisation (Visit 2) throughout the treatment 
period and including the SFU period but excluding at Visits 3 and 4. 
Serious adverse events will be recorded from the time of signing the ICF. 
If the Investigator becomes aware of an SAE with a suspected causal relationship to the IMP 
that occurs after the end of the clinical study in a treated participant, the Investigator shall, 
without undue delay, report the SAE to AstraZeneca (see Section 8.4.8 for details on reporting 
of SAEs). 
8.4.2 
Follow-up of AEs and SAEs  
Any AEs that are unresolved at the participant’s last AE assessment or visit in the study are 
followed up by the Investigator for as long as medically indicated, but without further 

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recording in the eCRF. AstraZeneca retains the right to request additional information for any 
participant with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
8.4.3 Causality Collection  
The Investigator should assess causal relationship between IMP and each AE, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by the IMP?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B. 
8.4.4 AEs Based on Examinations and Tests  
Deterioration as compared to baseline/randomisation in protocol-mandated laboratory values 
and/or vital signs should only be reported as AEs if they meet any of the following: 
• 
Fulfil any of the SAE criteria. 
• 
Are the reason for discontinuation of the study intervention. 
• 
Are clinically relevant as judged by the Investigator (which may include but is not limited 
to consideration as to whether intervention or non-planned visits were required or other 
action was taken with the study intervention, eg, dose adjustment or drug interruption). 
 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline/randomisation assessment will be reported as an AE unless 
unequivocally related to the DUS. 
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the CSR. 
8.4.5 AEs Based on Signs and Symptoms  
All signs or symptoms spontaneously reported by the participant or reported in response to the 
open question from the study site staff: ‘Have you had any health problems since the previous 

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visit’, or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
8.4.5.1 
  
 
 
 
 
 
 
8.4.6 
Adverse Events of Special Interest  
The Investigator will monitor each participant for clinical and laboratory evidence for 
pre-defined AESIs throughout his or her participation in this clinical study. 
The Investigator will assess and record any additional information on the AESI in detail on an 
AE form which must be submitted as per standard timelines for AEs. The Investigator should 
assess possible contributing factors to the AESI and record these in the eCRF. 
For this clinical study, AESIs include the following: hyperkalaemia, hyponatraemia and 
hypotension events 
. These events consist of high K+ in 
blood, abnormally low Na+ concentration in blood and abnormally low BP, respectively. These 
AESIs will be confirmed by a clinician. 
Potassium and Na+ levels will be measured in the clinical laboratory analysis (see 
Section 8.3.4), using the blood samples extracted at the timepoints specified in the SoA (see 
Table 2 in Section 1.3). Blood pressure will be measured as detailed in Section 8.3.2.1. During 
the course of the study, additional AESIs may be identified by AstraZeneca. All AESIs must 
be recorded in the eCRF. 
8.4.6.1 
Hyperkalaemia  
An AESI of hyperkalaemia is an event of high K+ levels 
 mmol/L) in serum 
 
 
Local laboratory K+ values for all events of hyperkalaemia that fulfil the AE reporting criteria 
should be recorded in the specific eCRF form (see Section 8.3.4.1 for K+ laboratory 
measurement details). 
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8.4.6.2 
Hyponatraemia  
An AESI of hyponatraemia is an event of low Na+ levels 
 mmol/L) in serum 
 
 
8.4.6.3 
Hypotension  
An AESI of hypotension is an event of low SBP (eg, 
 mmHg) 
 
 
8.4.7 
Hy’s Law  
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation, and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may 
need to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law. 
8.4.8 
Reporting of SAEs  
All SAEs must be reported whether or not considered causally related to the study 
intervention. All SAEs will be recorded in the eCRF. 
If any SAE occurs during the study, Investigators or other site personnel will inform the 
appropriate AstraZeneca representatives within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety DES within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.  
If the EDC system is not available, then the Investigator or other study site staff reports the 
SAE via secure method to the appropriate AstraZeneca representative. 
When the EDC is temporarily not accessible, the AstraZeneca Study Representative should 
confirm that the Investigator/site staff enters the SAE in the AstraZeneca EDC when access 
resumes. 
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For further guidance on the definition of an SAE, see Appendix B. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
IMP. 
8.4.9 
Pregnancy  
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
• 
If the pregnancy is discovered before the study participant has received any study 
intervention. 
• 
Pregnancies in the partner of male participants. 
 
Participants will give consent on enrolment that the Investigator will report any pregnancy to 
AstraZeneca and that further information will be collected until delivery. 
8.4.9.1 
Maternal Exposure  
If a participant becomes pregnant during the study, study intervention should be discontinued 
immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly/birth defect) should be followed up and documented even if the 
participant was discontinued from the study. 
If any pregnancy occurs during the study, then the Investigator or other site personnel informs 
the appropriate AstraZeneca representatives immediately but no later than 24 hours after he or 
she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety DES within one or 
5 calendar days for pregnancies associated with SAEs (see Section 8.4.8) and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 
Pregnancies will be reported in the eCRF. The PREGREP module in the eCRF is used to 
report the pregnancy and the paper based PREGOUT module is used to report the outcome of 
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8.4.9.2 
Paternal Exposure  
Male study participants do not require to use contraception. There is no restriction on male 
participants fathering children or donating sperm during the study. 
8.4.10 
Medication Error, Drug Abuse, and Drug Misuse  
8.4.10.1 
Timelines  
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when they become aware of 
it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or follow-up 
fatal/life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the event of medication error, drug abuse, or misuse (see Section 8.4.8) 
and within 30 days for all other events. 
8.4.10.2 
Medication Error  
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant. 
The full definition and examples of medication error can be found in Appendix B 4. 
8.4.10.3 
Drug Abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix B 4. 
8.4.10.4 
Drug Misuse  
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix B 4. 
8.4.11 
Reporting of Overdose  
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• An overdose with associated AEs is recorded as the AE diagnoses/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety DES within one or 
5 calendar days for overdoses associated with an SAE (see Section 8.4.8) and within 30 days 
for all other overdoses. 
8.5 
Pharmacokinetics  
Pre-dose plasma samples will be collected for measurement of plasma concentrations of study 
intervention at the central laboratory as specified in the SoA (see Section 1.3). 
Samples may be collected at additional timepoints during the study if warranted and agreed 
upon between the Investigator and AstraZeneca, eg, for urgent safety reasons, and this may be 
reflected as a protocol deviation. 
The timing of sampling may be altered during the study based on newly available data (eg, to 
obtain data closer to the time of peak or trough matrix concentrations) to ensure appropriate 
monitoring. 
Plasma samples will be used to analyse the exposure of baxdrostat. Samples collected for 
analyses of baxdrostat concentration in plasma may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
For storage, re-use, and destruction of samples for PK, see Appendix C. 
Pharmacokinetics samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier). 
Additional analyses may be conducted on the anonymised, pooled, or individual PK samples 
to further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR. 

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8.5.1 
Collection of Samples for Pharmacokinetics  
All PK samples will be collected pre-dose; thus, participants should be reminded not to take 
their study intervention at home on the day of Visit 5 (Week 4) as they will receive study 
intervention in clinic on that day. 
8.5.2 
Determination of Drug Concentration  
Samples for determination of drug concentration in plasma will be assayed by Labcorp, on 
behalf of AstraZeneca, using an appropriately validated bioanalytical method. Full details of 
the analytical method used will be described in a separate Bioanalytical Report. 
Drug concentration information that could unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 
Pharmacokinetic samples will be analysed only for participants on active treatment. Placebo 
samples will not be analysed unless there is a need to confirm that correct treatment has been 
given to study participants (please see Section 6.4). 
8.6 
Pharmacodynamics  
Blood sample collection for cortisol and ACTH stimulation test procedures are described in 
Section 8.6.1 and Section 8.6.2, respectively. 
8.6.1 
Collection of Samples for Pharmacodynamics  
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Blood samples will be collected for measurement of cortisol at timepoints planned in the SoA 
(see Section 1.3). 
For storage, re-use, and destruction of samples for PD, see Appendix C. 
8.6.2 
ACTH Stimulation Test and Cortisol Level Measurement  
An ACTH stimulation test using 250 µg ACTH will be performed at Visit 2 (randomisation) 
and Visit 6 (EoT; Week 8), with serum cortisol level measured before and 
 minutes after 
ACTH stimulation test, based on Butt et al, 2020. Please refer to Section 6.1 for further details 
on the ACTH stimulation injection kit. 
The cortisol analysis will be performed by a central laboratory using the 
 
 (Javorsky et al, 2021, Fragoso Perozo et al, 2023). A cortisol level 
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 minutes after ACTH stimulation test that is < 
μg/dL will be considered abnormal, 
indicating impaired cortisol reserve. The procedure steps are as follows: 
1 
Start ACTH (also called cosyntropin) stimulation testing at 8.00 AM (± 2 hours). 
2 
Perform blood draw to measure serum cortisol level prior to ACTH stimulation testing. 
3 
Dilute 250 µg cosyntropin in 2 to 5 mL of normal saline and inject intravenously over 
2 minutes. 
4 
Perform blood draw to measure serum cortisol level 
 minutes after ACTH 
stimulation testing. 
5 
Ship all blood samples (pre- and the two post-ACTH stimulation) to the central laboratory 
as per Laboratory Manual. 
 
If the participant has abnormal cortisol levels at Week 8, the participant should remain on 
treatment until a repeat ACTH testing has been performed, ie, treatment may last for up to 
10 weeks. It is recommended that participants with abnormal ACTH stimulation test results be 
referred to an endocrinologist for evaluation. The procedure steps are as follows for repeat 
ACTH stimulation and cortisol collection:  
1 
Start ACTH (also called cosyntropin) stimulation testing at 8.00 AM (± 2 hours). 
2 
Perform blood draw to measure serum cortisol level prior to ACTH stimulation testing. 
3 
Dilute 250 µg cosyntropin in 2 to 5 mL of normal saline and inject intravenously over 
2 minutes. 
4 
Perform blood draw to measure serum cortisol level
 minutes after ACTH 
stimulation testing. 
5 
Perform blood draw to measure serum cortisol level 
 minutes after ACTH 
stimulation testing. 
6 
Ship both blood samples (pre- and post-ACTH stimulation) to the central laboratory as 
per Laboratory Manual. 
 
8.7 
  
Collection of optional samples for 
 is also part of this study as 
specified in the SoA (see Section 1.3) and is subject to participant agreement in the optional 
 information ICF. 
 sample for 
 isolation will be collected from participants who 
have consented to participate in the 
 analysis component of the 
study. Participation is optional. Participants who do not wish to participate in 
 
 research may still participate in the study. 
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See Appendix D for information regarding the 
 
samples. Details on processes for collection and shipment and destruction of these samples 
can be found either in the appendices of this protocol or in the Laboratory Manual. 
8.8 
Biomarkers  
Not applicable, biomarkers are not evaluated this study. 
8.9 
Immunogenicity Assessments  
Not applicable, immunogenicity is not assessed in this study. 
8.10 
Medical Resource Utilisation and Health Economics  
Not applicable, health economics/medical resource utilisation and health economics 
parameters are not evaluated in this study. 
8.11 
Study Participant Feedback Questionnaire  
Participants feedback questionnaires will not be utilised in this study. 
9 
STATISTICAL CONSIDERATIONS  
Any changes to the methods described in the SAP will be described and justified as needed in 
the CSR. 
9.1 
Statistical Hypotheses  
Statistical analyses will be descriptive in nature, without formal statistical hypothesis testing. 
9.2 
Sample Size Determination  
This study is planning to randomise approximately 45 participants using a 2:1 ratio to either 
receive 2 mg baxdrostat OD or placebo OD, in addition to a stable regimen of 
≥ 1 antihypertensive agent (including a diuretic) in the double-blind treatment period of 
8 weeks. The sample size is considered to be adequate for supporting descriptive analysis of 
the cortisol response to ACTH, based on previous experience with baxdrostat, as described in 
Section 2. 
Approximately 45 participants will be randomised and assigned to study intervention such 
that, with an estimated 10% drop-out rate, approximately 40 evaluable participants complete 
the study. 
Note: ‘Screened’ means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomised/assigned in the study, are considered ‘screen failures’, unless 
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otherwise specified by the protocol. 
9.3 
Populations for Analyses  
The following populations are defined: 
Table 8 
Populations for Analysis  
Population/analysis set 
Description 
Screened 
All participants who sign the ICF. 
Randomised/assigned to study 
intervention  
All randomised participants. This population will be used for the purpose 
of participant disposition. 
Full Analysis Set 
All randomised participants who received at least one dose of study 
intervention. This population will be the primary population for all 
endpoints. 
PK Analysis Set 
All randomised participants who had at least one evaluable pre-dose 
plasma concentration data for PK analysis and who received active 
treatment. 
ICF = Informed consent form; PK = Pharmacokinetic(s). 
 
9.4 
Statistical Analyses  
9.4.1 
General Considerations  
The SAP will detail how baseline data will be described, which refers to all data collected at 
the beginning of the clinical study for all participants. These data will include demographics, 
such as age, sex, race and ethnicity and study-specific measures. 
Study-collected data will be summarised by treatment using descriptive statistics, graphs 
and/or data listings. Descriptive statistics for continuous variables will include number of 
participants (n), mean, SD, median, minimum, and maximum values. Analysis of categorical 
variables will include frequency and percentage. 
In this study, baseline is defined as the last assessment taken on or before first dose of study 
intervention. 
9.4.2 
Pharmacodynamic Analysis  
Statistical analyses will be descriptive in nature, and no formal statistical testing will be 
performed. The primary and secondary endpoints will be analysed in the Full Analysis Set. 
9.4.2.1 
Primary and Secondary Endpoints  
Cortisol response to ACTH stimulation test will be described on individual level via line plot 
of serum total cortisol values prior to ACTH stimulation testing and after 
 minutes, 
both at baseline and at Week 8. In the event of abnormal stimulate cortisol results at Week 8, 
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cortisol response to ACTH stimulation testing will be assessed 
 minutes and 
 minutes after ACTH stimulation at an unscheduled visit, for each treatment group. An 
abnormal result is defined as abnormal repeat stimulated cortisol (< 
 μg/dL at 
 minutes AND < 
 μg/dL at 
 minutes) obtained in the event that the routine 
stimulated cortisol at Week 8 is abnormal (< 
μg/dL at 
 minutes). If performed, the 
results of the repeat ACTH stimulation test at the unscheduled visit will be used for the 
analysis.  
Participants with abnormal cortisol levels at baseline will not be considered. Those 
discontinued participants will be listed and plotted separately. 
The baseline values are the last non-missing values prior to the administration of the first dose 
of IMP. 
 
 The data collected after the other 
intercurrent events will be included in the data analyses (Treatment Policy Strategy).  
Incidence of abnormal stimulated cortisol (ie, total serum cortisol below the pre-specified 
threshold after 
 minutes) at baseline and Week 8 by treatment group will be assessed 
via frequency table, in participants with normal stimulated cortisol at baseline. Of note, 
participants with abnormal stimulated cortisol at baseline will be reported separately. If 
performed, the results of the repeat ACTH stimulation test at the unscheduled visit will be 
used for the analysis. 
9.4.3 
Safety  
Safety analyses will be performed in the Full Analysis Set. Safety data will be presented using 
descriptive statistics unless otherwise specified. 
The safety endpoint aims to assess the safety and tolerability of baxdrostat as compared to 
placebo. This will be evaluated in terms of: 
• 
AEs, SAEs, and DAEs. 
• 
Vital signs (BP, pulse rate, body weight). 
• 
Safety investigations and laboratory tests (ECG, clinical chemistry, haematology). 
• 
AESIs (hyperkalaemia, hyponatraemia, and hypotension 
 
; based on Investigator reported AEs). 
 
9.4.3.1 
Adverse Events  
Adverse events will be coded using MedDRA. The most recent version of the dictionary will 
be used at study start and up-versioning will be performed during study conduct as applicable. 
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Adverse events will be presented for each treatment, by SOC and/or PT covering number and 
percentage of participants reporting at least one event and number of events where 
appropriate. 
An overview of AEs will be presented for each treatment group, by SOC and PT, along with 
the number and percentage of participants with any AE, AEs with outcome of death, SAEs and 
AEs leading to discontinuation of study intervention. Separate tables will be provided for 
AESIs. 
Separate AE tables will be provided, taking into consideration AE relationship to study 
intervention, as assessed by the Investigator, maximum intensity, seriousness, death, and 
DAEs. 
An additional table will present the number and percentage of participants with the most 
common AEs. Most common (eg, frequency of > x%, ≥ x%) will be defined in the SAP. 
Key participant information will be presented for participants with AEs with an outcome of 
death, SAEs and DAEs. 
Separate summaries will be presented for the on-treatment and on-study periods, where the 
on-treatment period is defined as up to the time of last study intervention administration and 
on-study period is defined as up to the SFU Visit. 
An AE listing for the Full Analysis Set will cover details for each individual AE. 
Full details of AE analyses will be provided in the SAP. 
9.4.3.2 
Vital Signs  
Vital sign parameters will be presented for each treatment group using summary statistics. 
Frequency tables and shift tables cover number and percentage of participants in respective 
categories will also be presented. 
For each scheduled post-Randomisation Visit, descriptive statistics for all vital sign 
parameters will be presented for observed values and change from baseline. For multiple 
results taken at the same timepoint the multiple results will be averaged before analysis. 
Details of vital sign analysis, including categories to be included in shift tables will be 
provided in the SAP. 
9.4.3.3 
Clinical Safety Laboratory Tests  
Laboratory parameters will be presented for each treatment group using summary statistics. 
For each scheduled post-Randomisation Visit, descriptive statistics for all clinical chemistry 

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and haematology parameters will be presented for observed values and change from baseline. 
A shift table presents laboratory status (eg, low, normal, high) from baseline to maximum and 
minimum post-randomisation value. 
Elevation in liver parameters for assessment of Hy’s Law will be done and reported 
appropriately if potential cases have been identified during the course of the study. 
Key participant information will be presented for participants with treatment-emergent 
changes in laboratory parameters outside predetermined criteria. 
Details of laboratory analyses will be provided in the SAP. 
9.4.3.4 
Electrocardiogram  
Electrocardiogram parameters will be presented for each treatment group using summary 
statistics. 
For each scheduled post-screening assessment, descriptive statistics for all ECG parameters 
will be presented for observed values and change from baseline. 
A table presents the interpretation of the ECG reading (normal, abnormal – clinically not 
significant, abnormal – clinically significant) at baseline and each post-screening timepoint. 
Details of ECG analyses will be provided in the SAP. 
9.4.4 
Other Exploratory Analyses  
Plasma concentrations of baxdrostat will be descriptively summarised based on the PK 
Analysis Set. Any additional PK analyses will be described in a separate data analysis plan 
and the results will be provided in a separate report. 
9.5 
Interim Analyses  
No interim analyses are planned for this study due to the short duration of the study. 
9.6 
Data Monitoring/Other Committee  
No data monitoring committee has been appointed for this study. However, all cases of 
abnormal ACTH stimulation test will be reviewed by an independent blinded adrenal expert.  

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
Appendix A Regulatory, Ethical, and Study Oversight Considerations  
A 1 
Regulatory and Ethical Considerations  
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013 and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, revised protocol, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• 
Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca. 
• 
The Investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR 312.120, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to AstraZeneca of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
AstraZeneca has a legal responsibility to notify both the local Regulatory Authority and 
other Regulatory Agencies about the safety of a study intervention under clinical 
investigation. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the Regulatory Authority, IRB/IEC, and Investigators. 

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• 
For all studies except those utilising medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
• 
Adherence to European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations. 
• 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
Regulatory Reporting Requirements for Serious Breaches of Protocol or GCP 
Prompt notification by the Investigator to AstraZeneca of any (potential) serious breach of the 
protocol or regulations is essential so that legal obligations and ethical obligations are met. 
• 
A “serious breach” means a breach likely to affect to a significant degree the safety and 
rights of a participant or the reliability and robustness of the data generated in the clinical 
study. 
AstraZeneca will comply with country-specific regulatory requirements relating to serious 
breach reporting to the Regulatory Authority, IRB/IEC, and Investigators. 
 
If any (potential) serious breach occurs in the course of the study, Investigators or other site 
personnel will inform the appropriate AstraZeneca representatives immediately. 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
Regulatory Authority and other Regulatory Agencies about such breaches. 
The Investigator should have a process in place to ensure that: 
• 
The site staff or service providers delegated by the Investigator/institution are able to 
identify the occurrence of a (potential) serious breach. 
• 
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca. 
 
A 2 
Financial Disclosure  
Investigators and sub-Investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 
financial certification or disclosure statements to the appropriate Regulatory Authorities. 
Investigators are responsible for providing information on financial interests during the study 
and for one year after completion of the study. 

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A 3 
Informed Consent Process  
• 
The Investigator or their representative will explain the nature of the study to the 
participant or their legally authorised representative and answer all questions regarding 
the study. 
• 
Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative, defined as an 
individual or judicial or other body authorised under applicable law to consent on behalf 
of a prospective subject to the subject's participation in the procedures involved in the 
study, will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study site. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
• 
If new information requires changes to the ICF, consider if participants must be 
reconsented and if so, this must be to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative. 
 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional HBS. The Investigator or authorised designee will explain to 
each participant the objectives of the analysis to be done on the samples and any potential 
future use. Participants will be told that they are free to refuse to participate in any optional 
samples or the future use and may withdraw their consent at any time and for any reason 
during the retention period. 
A 4 
Data Protection  
• 
Participants will be assigned a unique identifier by AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that their personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 

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• 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from Regulatory Authorities. 
• 
The participant must be informed that data will be collected only for the business needs. 
We will only collect and use the minimum amount of personal data to support our 
business activities and will not make personal data available to anyone (including internal 
staff) who is not authorised or does not have a business need to know the information. 
• 
The participant must be informed that in some cases their data may be pseudonymised. 
The General Data Protection Regulation (GDPR) defines pseudonymisation as the 
processing of personal data in such a way that the personal data can no longer be 
attributed to a specific individual without the use of additional information, provided that 
such additional information is kept separately and protected by technical and 
organisational measures to ensure that the personal data are not attributed to an identified 
or identifiable natural person. 
 
Personal Data Breaches 
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, 
stored or otherwise processed. 
• 
In compliance with applicable laws, the Data Controller1 for the processing activity where 
the personal data breach occurred (AstraZeneca or respectively the site), will notify the 
data protection authorities without undue delay within the legal terms provided for such 
notification and within the prescribed form and content. 
• 
While AstraZeneca has processes in place to deal with personal data breaches it is 
important that Investigators that work with AstraZeneca have controls in place to protect 
patient data privacy. 
 
 
 
 
 
 
1 The data controller determines the purposes for which and the means by which personal 
data are processed, as defined by the European Commission. 

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The Investigator should have a process in place to ensure that: 
• 
Allow site staff or service providers delegated by the Investigator/institution to identify 
the occurrence of a (potential) personal data breaches. 
• 
Any (potential) personal data breach is promptly reported to AstraZeneca or delegated 
party, through the contacts (email address or telephone number) provided by 
AstraZeneca. 
 
AstraZeneca and the site must demonstrate that they: 
• 
Have taken all necessary steps to avoid personal data breaches and  
• 
Have undertaken measures to prevent such breaches from occurring in the first place and 
to mitigate the impact of occurred data breaches (eg, applying encryption, maintaining, 
and keeping systems and IT security measures up-to-date, regular reviews and testing, 
regular training of employees, and developed security policies and standards). 
• 
Where possible, have developed an internal data breach reporting and investigation 
process and internal protocols with guidance on how to respond swiftly and diligently to 
the occurrence of a personal data breach. 
• 
Where it has not been possible to develop an internal data breach reporting and 
investigation process, the site follows AstraZeneca’s instructions. 
 
Notification of personal data breach to participants: 
• 
Notification to participants is done by the site for the data breaches that occurred within 
the processing activities for which the site is the Data Controller and for data breaches 
occurred within the processing activities of AstraZeneca as the Data Controller, the 
notification is done in collaboration with the site and is performed by the site and/or 
Principal Investigator, acting on behalf of AstraZeneca, so that AstraZeneca has no access 
to the identifying personal information of the participants. The site and/or Principal 
Investigator shall conduct the notification by contacting the participants using the 
information that they gave for communication purposes in clinical research. 
• 
If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course 
after discovering the breach notifies AstraZeneca and provides full cooperation with the 
investigation. In these cases, to the extent AstraZeneca is the Data Controller for the 
processing activity where the breach occurred, it will be responsible for the notification to 
data protection authorities and, if applicable, to participants. If the personal data breach 
needs to be notified to the participants, the notification to participants is done in 
collaboration with the site and is performed by the site and/or Principal Investigator, 

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acting on behalf of the Sponsor, so that AstraZeneca has no access to the identifying 
personal information of the participants. 
• 
If a personal data breach involving an AstraZeneca's representative device (ie, Study 
Monitor laptop), AstraZeneca representative will provide AstraZeneca with all of the 
information needed for notification of the breach, without disclosing data that allows 
AstraZeneca directly or indirectly to identify the participants. The notification will be 
done by AstraZeneca solely with the information provided by the Study Monitor and in 
no event with access to information that could entail a risk of re-identification of the 
participants. If the data breach must be notified to the data subjects, the notification will 
be done directly by the Study Monitor in collaboration with the site and/or Principal 
Investigator, acting on behalf of the Sponsor, so that AstraZeneca has no access to the 
identifying personal information of the participants. The contract between AstraZeneca 
and the Study Monitor shall expressly specify these conditions. 
• 
The contract between the site and AstraZeneca for performing the clinical research 
includes the provisions and rules regarding who is responsible for coordinating and 
directing the actions in relation to the breaches and performing the mandatory 
notifications to authorities and participants, where applicable. 
 
A 5 
Committees Structure  
No data monitoring committee, event adjudication committee or any other entities will be 
engaged in this study. 
A 6 
Dissemination of Clinical Study Data  
A description of this clinical study will be available on www.astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
A 7 
Data Quality Assurance  
• 
All participant data relating to the study will be recorded on eCRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
Regulatory Agency inspections and provide direct access to source data documents. 
• 
Quality tolerance limits (QTLs) will be predefined in the Risk Assessment Categorisation 
Tool (RACT) to identify systematic issues that can impact participant safety and/or 
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study, and important deviations from the QTLs and remedial actions taken will be 
summarised in the CSR. 
• 
Monitoring details describing strategy, including definition of study-critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-based Monitoring), methods, 
responsibilities, and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are included in the 
Monitoring Plan and Data Surveillance Plan. 
• 
AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Medical Monitoring Plan. 
• 
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
AstraZeneca assumes accountability for actions delegated to other individuals 
(eg, CROs). 
• 
Study monitors will perform ongoing source data verification as per the 
Monitoring Plan(s) to confirm that data entered into the eCRF by authorised site 
personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH 
GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca Global retention and Disposal 
(GRAD) Schedule. No records may be destroyed during the retention period without the 
written approval of AstraZeneca. No records may be transferred to another location or 
party without written notification to AstraZeneca. 
 
A 8 
Source Documents  
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• 
Definition of what constitutes source data, and its origin can be found in the monitoring 
guidelines. 

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A 9 
Study and Site Start and Closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
AstraZeneca designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of AstraZeneca. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by AstraZeneca or the Investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, AstraZeneca’s procedures, or GCP guidelines. 
• 
Inadequate recruitment of participants by the Investigator. 
• 
Discontinuation of further study intervention development. 
 
If the study is prematurely terminated or suspended, AstraZeneca shall promptly inform the 
Investigators, the IRBs/IECs, the Regulatory Authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
A 10 
Publication Policy  
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments. 
• 
AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca will generally 
support publication of multicentre studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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Appendix B AEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting  
B 1 
Definition of AEs  
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not it is considered 
related to the medicinal (investigational) product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
B 2 
Definition of SAEs  
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Adverse Events for malignant tumours reported during a study should generally be assessed 
as SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should 
be used. In certain situations, however, medical judgement on an individual event basis should 
be applied to clarify that the malignant tumour event should be assessed and reported as a 
non-SAE. For example, if the tumour is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 

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Life-threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the medicinal product would result in 
the participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study. 
Important Medical Event or Medical Treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability, or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
Intensity Rating Scale: 
• 
Mild (awareness of sign or symptom, but easily tolerated). 
• 
Moderate (discomfort sufficient to cause interference with normal activities). 
• 
Severe (incapacitating, with inability to perform normal activities). 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2. 

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B 3 
A Guide to Interpreting the Causality Question  
When assessing causality consider the following factors when deciding if there is a 
‘reasonable possibility’ that an AE may have been caused by the medicinal product. 
• 
Time Course. Exposure to suspect drug. Has the participant received the suspect drug? 
Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host, or environmental factors. 
• 
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
rechallenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the DUS has deteriorated due to lack of effect should be 
classified as ‘no reasonable possibility’. 

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B 4 
Medication Error, Drug Abuse, and Drug Misuse  
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error:  
• 
Occurred 
• 
Was identified and intercepted before the participant received the drug. 
• 
Did not occur, but circumstances were recognised that could have led to an error. 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion. 
• 
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the participant. 
• 
Drug not administered as indicated, eg, wrong route or wrong site of administration. 
• 
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet.  
• 
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature.  
• 
Wrong participant received the medication (excluding IRT/RTSM errors). 
• 
Wrong drug administered to participant (excluding IRT/RTSM errors). 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IRT/RTSM - including those which led to one of the 
above listed events that would otherwise have been a medication error. 
• 
Participant accidentally missed drug dose(s), eg, forgot to take medication. 
• 
Accidental overdose (will be captured as an overdose). 
• 
Participant failed to return unused medication or empty packaging. 
 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error. 

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Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 
• 
The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study). 
• 
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high. 
 
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant). 
Examples of drug misuse include but are not limited to: 
• 
The drug is used with the intention to cause an effect in another person. 
• 
The drug is sold to other people for recreational purposes. 
• 
The drug is used to facilitate assault in another person. 
• 
The drug is deliberately administered by the wrong route. 
• 
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole. 
• 
Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose. 
• 
Someone who is not enrolled in the study intentionally takes the drug. 

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Appendix C Handling of Human Biological Samples  
C 1 
Chain of Custody  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Investigator at each site keeps full traceability of collected biological samples from the 
participants while in storage at the site until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at the site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers. 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca team for the 
remainder of the sample life cycle. 
All appropriately consented samples will be retained for maximum 15 years from last subject 
last visit. 
Pharmacokinetic samples will be disposed after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner. 
C 2 
Withdrawal of Informed Consent for Donated Biological Samples  
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent. 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 

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The Investigator: 
• 
Ensures the participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 
• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented. 
• 
Ensures that the participant and AstraZeneca are informed about the sample disposal. 
 
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented, and study site is notified. 
C 3 
International Air Transport Association Guidance Document 62nd 
Edition  
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
The International Air Transport Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B, or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900. 
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
Are to be packed in accordance with UN 3373 and IATA 650 
 
Exempt Substances are substances which do not contain infectious substances, or substances 
which are unlikely to cause disease in humans or animals, are not subject to these regulations 
unless they meet the criteria for inclusion in another class. 

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• 
Clinical study samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/contentassets/b08040a138dc4442a4f066e6fb99fe2a/dgr-62-en-
pi650.pdf). 
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content. 

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Appendix D 
  
D 1 
Use/Analysis of 
  
• 
AstraZeneca intends to collect and store 
 (such as 
 and 
 for 
 and comprehensive 
 research (such as 
 
 and 
 which may include 
 
 analysis, to explore how 
 and timepoint 
 variations may 
affect clinical parameters, risk and prognosis of diseases, and the response to medicinal 
product. 
• 
This 
 research may lead to better understanding of diseases, 
better diagnosis of diseases or other improvements in health care, and to the discovery of 
new diagnostics, treatments, or medications. Therefore, where local regulations and 
IRB/IEC allow, a 
 sample will be collected for 
 analysis from 
consenting participants. 
• 
This optional 
 research may consist of the analysis of the 
structure of the participant’s 
, ie, the 
 
• 
The results of these 
 analyses may be reported in a separate study 
summary. 
• 
AstraZeneca will store the 
 samples in a secure storage space 
with adequate measures to protect confidentiality. 
 
D 2 
 Research Plan and Procedures  
Selection of 
 Research Population 
All participants will be asked to participate in this 
 research. 
Participation is voluntary and if a participant declines to participate there will be no penalty or 
loss of benefit. The participant will not be excluded from any aspect of the main study. 
Inclusion Criteria 
For inclusion in this 
 research, participants must fulfil all of the 
inclusion criteria described in the main body of the protocol and: Provide informed consent 
for the 
 sampling and analyses. 
Exclusion Criteria 
Exclusion from this 
 research may be for any of the exclusion 
criteria specified in the main study or any of the following:  
• 
 
• 
 sample collection. 
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• 
Healthy volunteers and paediatric participant samples will not be collected for the 
 
 
Withdrawal of Consent for 
 Research 
• 
Participants may withdraw from this 
 research at any time, 
independent of any decision concerning participation in other aspects of the main study. 
Voluntary withdrawal will not prejudice further treatment. Procedures for withdrawal are 
outlined in Section 7.2 of the main protocol. 
 
Collection of Samples for 
 Research 
• 
The 
 sample for this 
 research will be obtained from the 
participants at 
 Although 
 is stable, early sample collection 
is preferred to avoid introducing bias through excluding participants who may withdraw 
due to an AE. If for any reason the sample is not drawn at 
 it may be taken at any 
visit until the last study visit. Only one sample should be collected per participant for 
 research during the study. 
 
Coding and Storage of 
 Samples 
The processes adopted for the coding and storage of samples for 
 
analysis are important to maintain participant confidentiality. Samples will be stored for a 
maximum of 15 years from the date of last subject last visit, after which they will be 
destroyed. 
 are a finite resource that will be used up during 
analyses. Samples will be stored and used until no further analyses are possible or the 
maximum storage time has been reached. 
• 
An additional second code will be assigned to the samples either before or at the time of 
sample processing, replacing the information on the sample tube. Thereafter, the sample 
will be identifiable only by the second, unique number. This number is used to identify 
the sample and corresponding data at the AstraZeneca analysis laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the 
 
 
• 
The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
samples for analysis, facilitate correlation of 
 results with 
clinical data, allow regulatory audit, and permit tracing of samples for destruction in the 
case of withdrawal of consent. 
 
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Ethical and Regulatory Requirements 
• 
The principles for ethical and regulatory requirements for the study, including this 
 research component, are outlined in Appendix A. 
 
Informed Consent 
• 
The 
 components of this study are optional, and the participant 
may participate in other components of the main study without participating in this 
 component. To participate in the 
 component of the study 
the participant must sign and date both the consent form for the main study and the 
 Information and Consent Form. Copies of both 
signed and dated consent forms must be given to the participant and the originals filed at 
the study site. The Principal Investigator(s) is responsible for ensuring that consent is 
given freely, and that the participant understands that they may freely withdraw from the 
 aspect of the study at any time. 
 
Participant Data Protection 
• 
AstraZeneca will not provide 
 results to 
participants, any insurance company, any employer, their family members, or general 
physician unless required to do so by law. Extra precautions are taken to preserve 
confidentiality and prevent 
 data being linked to the identity of 
the participant. In exceptional circumstances, however, certain individuals might see both 
the 
 data and the personal identifiers of a participant. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a 
participant’s identity and also have access to his or her 
 data. Regulatory 
Authorities may require access to the relevant files, though the participant’s medical 
information and the 
 files would remain physically separate. 
 
Data Management 
• 
Any 
 data generated in this study will be stored at a secure system 
at AstraZeneca and/or designated organisations to analyse the samples. 
• 
AstraZeneca and its designated organisations may share summary results (such as 
 
differences from groups of individuals with a disease) from this 
 
 research with other researchers, such as hospitals, academic organisations, or 
drug- or health-related companies. This can be done by placing the results in scientific 
databases, where they can be combined with the results of similar studies to learn even 
more about health and disease. The researchers can only use this information for health-
related research purposes. Researchers may see summary results, but they will not be able 
to see individual participant data or any personal identifiers. 
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• 
Some or all of the clinical datasets from the main study may be merged with the 
 data in a suitable secure environment separate from the clinical database. 
 
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Appendix E Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law  
E 1 
Introduction  
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law cases and Hy’s Law cases. It is not intended to be a comprehensive 
guide to the management of elevated liver biochemistries.  
During the study the Investigator will remain vigilant for increases in liver biochemistry. The 
Investigator is responsible for determining whether a participant meets potential Hy’s Law 
criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of potential Hy’s Law and 
Hy’s Law events; this includes samples taken at scheduled study visits and other visits 
including central and all local laboratory evaluations even if collected outside of the study 
visits; for example, potential Hy’s Law criteria could be met by an elevated ALT from a 
central laboratory and/or elevated TBL from a local laboratory.  
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible potential Hy’s Law events. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than DILI caused by the IMP.  
The Investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law 
cases and for reporting SAEs and AEs according to the outcome of the review and assessment 
in line with standard safety reporting processes. 
E 2 
Definitions  
Potential Hy’s Law  
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point 
during the study following the start of study intervention irrespective of an increase in ALP. 
Hy’s Law  
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other 
reason, other than the IMP, can be found to explain the combination of increases, eg, elevated 
ALP indicating cholestasis, viral hepatitis, another drug. 

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For potential Hy’s Law and Hy’s Law the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur. 
E 3 
Identification of Potential Hy’s Law Cases  
In order to identify cases of potential Hy’s Law it is important to perform a comprehensive 
review of laboratory data for any participant who meets any of the following identification 
criteria in isolation or in combination: 
• 
ALT ≥ 3 × ULN 
• 
AST ≥ 3 × ULN 
• 
TBL ≥ 2 × ULN 
 
Central Laboratories Being Used: 
When a participant meets any of the potential Hy’s Law identification criteria, in isolation or 
in combination, the central laboratory will immediately send an alert to the Investigator (also 
sent to AstraZeneca representative). 
The Investigator will also remain vigilant for any local laboratory reports where the potential 
Hy’s Law identification criteria are met, where this is the case, the Investigator will: 
• 
Notify the AstraZeneca representative. 
• 
Request a repeat of the test (new blood draw) by the central laboratory without delay. 
• 
Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result. 
 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
• 
Determine whether the participant meets potential Hy’s Law criteria (see Appendix E 2 
for definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results). 
 
Local Laboratories Being Used: 
The Investigator will without delay review each new laboratory report and, if the 
identification criteria are met, will: 
• 
Notify the AstraZeneca representative. 

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• 
Determine whether the participant meets potential Hy’s Law criteria (see Appendix E 2 
for definition) by reviewing laboratory reports from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory eCRF. 
 
E 4 
Follow-up  
E 4.1 
Potential Hy’s Law Criteria not met  
If the participant does not meet potential Hy’s Law criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the participant has not met potential Hy’s Law 
criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the protocol. 
 
E 4.2 
Potential Hy’s Law Criteria met  
If the participant does meet potential Hy’s Law criteria the Investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team. 
• 
Within one day of potential Hy’s Law criteria being met, the Investigator will report the 
case as an SAE of Potential Hy’s Law; serious criteria ‘Important Medical Event’ and 
causality assessment ‘yes/related’ according to the protocol process for SAE reporting. 
• 
For participants who met potential Hy’s Law criteria prior to starting IMP, the 
Investigator is not required to submit a potential Hy’s Law SAE unless there is a 
significant change# in the participant’s condition. 
• 
The Study Clinical Lead will contact the Investigator, to provide guidance, discuss, and 
agree an approach for the study participant’s follow-up (including any further laboratory 
testing) and the continuous review of data. 
• 
Subsequent to this contact, the Investigator will: 
− 
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Complete follow-up SAE Form as required. 
− 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Clinical Lead. For central laboratories, this includes 
deciding which of the tests available in the Hy’s Law laboratory kit should be used. 
− 
Complete the 3 Liver eCRF Modules as information becomes available. 
 

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A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Clinical Lead if there is any uncertainty. 
E 5 
Review and Assessment of Potential Hy’s Law Cases  
The instructions in this appendix should be followed for all cases where potential Hy’s Law 
criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the Study Clinical 
Lead will contact the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting potential Hy’s Law criteria other than DILI caused by 
the IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date potential Hy’s Law criteria was met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
• 
If the alternative explanation is an AE/SAE: Update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term, causality, and seriousness criteria) following the AstraZeneca standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply. 
− 
As there is no alternative explanation for the Hy’s Law case, a causality 
assessment of ‘related’ should be assigned. 

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If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether the case meets the criteria for Hy’s Law, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to protocol process for SAE 
reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are still met. Update the previously submitted potential Hy’s 
Law SAE report following protocol process for SAE reporting, according to the outcome 
of the review and amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined. 
 

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E 6 
Laboratory Tests  
Please see table for Hy’s Law Laboratory Kit for Central Laboratories below. 
Hy’s Law Laboratory Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
HBsAg 
IgM and IgG anti-HBc 
HBV DNA a 
IgG anti-HCV 
HCV RNA b 
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM and IgG anti-CMV 
IgG anti-HSV, and HSV-1 and HSV-2 IgM 
testing, OR HSV-1 and HSV-2 PCR testing d 
IgM and IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin 
(CD-transferrin) c 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin c 
Transferrin saturation 
a 
HBV DNA is only recommended when IgG anti-HBc is positive. 
b 
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive.  
c 
CD-transferrin and transferrin are not available in China. Study teams should amend this list accordingly. 
d 
HSV-1 and HSV-2 IgM testing or HSV-1 and HSV-2 PCR testing depending on the region. 

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Appendix F Protocol Version History  
The Summary of Changes Table for the current revision is located directly before the Table of 
Contents. 
CSP Version 2.0 (Amendment 1.0), 05 June 2024 
Overall Rationale for the Modification: 
The primary rationale for this amendment is 
 
 and to correct and/or clarify 
details related to some procedures, tests, and participant-related evaluation and management 
aspects of the study. Additionally, this amendment incorporated corrections and clarifications 
not impacting the study design, as listed below. 
Summary of Changes: 
List of Non-Substantial Modifications 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis; 
Section 1.3, Schedule 
of Activities; 
Section 8.2.1, ACTH 
Stimulation Test and 
Cortisol Level 
Measurement; 
Section 9.4.2.1, 
Primary and Secondary 
Endpoints 
Addition of a “±
 minute” window to the 
“
 minutes” post-ACTH stimulation 
timepoint for the collection of ACTH 
stimulation blood samples within Table 1 
footnote “g”, and throughout the 
document.  
To provide flexibility in study 
conduct without affecting study 
integrity. 
Section 1.3, Schedule 
of Activities 
Updating Table 1 footnote “a” to read “If 
the EoT Visit is conducted > 10 days after 
the last administered dose, all assessments 
(except the PK sampling) required at EoT 
and SFU Visits are to be conducted within 
the same visit (inclusive of the ACTH 
stimulation testing, serum cortisol 
measurement and K+ only testing) and a 
complete physical examination will be 
performed”, also adding footnote “g” to 
Table 2 to align with this change. 
To provide clarification on how to 
handle the assessments at the EoT 
when it comes close to the timing of 
the SFU. 
Section 1.3, Schedule 
of Activities; 
Section 8.3.4, Clinical 
Safety Laboratory Tests 
Removal of “urinalysis” from whole safety 
panel assessments within Table 2 footnote 
“a” and adding urinalysis is only 
performed “locally” in Table 6 footnote 
“e”. 
To clarify that dipstick urinalysis is 
done locally and not centrally and 
only at Visit 2. 
CCI
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.3, Schedule 
of Activities; 
Section 8.3.4, Clinical 
Safety Laboratory Tests 
Addition of pregnancy testing at 
Double-blind Period (Visit 5), EoT 
(Visit 6, Week 8), and Safety 
Follow-up (SFU Visit) within Table 2 and 
mentioning pregnancy timepoints in 
Table 6 footnote “d”. 
To clarify pregnancy assessment 
timepoints during the study in line 
with CIRB request. 
Section 7.1.3, 
Temporary Interruption 
of Study Intervention; 
Section 7.2, Participant 
Discontinuation/Withdr
awal from the Study; 
Section 8.4.5.1, 
 
 
 
Addition of the subsection “Differential 
Diagnosis for 
” and 
text that “
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, and insertion of the 
cross-references made to this topic. 
To provide clarification regarding 
diagnostic assessment required for 
participants with unexplained signs 
and symptoms that may indicate 
  
ACTH = Adrenocorticotropic hormone; CIRB = Central institutional review board; EoT = End of treatment; 
K+ = Potassium; PK = Pharmacokinetic(s); SFU = Safety follow-up. 
CCI
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11 
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