Conditions: Diabetes Mellitus, Type 2
Keywords: Type 2 Diabetes Mellitus Glucose Homeostasis Pharmacodynamic AZD9567 Prednisolone
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 46
Healthy volunteers: no

Brief summary:
The study is intended to assess the effect on glycaemic control of AZD9567, as measured by the glucose AUC(0-4) versus baseline following a standardised mixed meal tolerance test (MMTT), compared to prednisolone in adults with type 2 diabetes mellitus (T2DM). The study will also evaluate the safety, tolerability, and pharmacokinetics (PK) of AZD9567.

Detailed description:
This is a randomised, double blind, multi-centre, double dummy, and two-way cross-over study.

There will be a total of three cohorts. Each cohort will be treated for two 72-hour periods in a cross-over design, with a 3-week washout period between treatment periods. The total length of participant engagement (from screening to follow-up) is 79 days.

Arms:
arm 1: Participants will be randomised in a ratio of 1:1 to receive AZD9567 and prednisolone over two 72 hour periods in a cross over design (72 mg AZD9567 followed by 40 mg prednisolone \[AB sequence group\] or 40 mg prednisolone followed by 72 mg AZD9567 \[BA sequence group\]). arm 2: Participants will be randomised in a ratio of 1:1 to receive AZD9567 and prednisolone over two 72 hour periods in a cross over design (40 mg AZD9567 followed by 20 mg prednisolone \[AB sequence group\] or 20 mg prednisolone followed by 40 mg AZD9567 \[BA sequence group\]). arm 3: Participants will be randomised in a ratio of 1:1 to receive placebo and prednisolone over two 72 hour periods in a cross over design (placebo followed by 5 mg prednisolone \[AB sequence group\] or 5 mg prednisolone followed by placebo \[BA sequence group\]).

Interventions: intervention 1: AZD9567 intervention 2: Prednisolone intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive 72 mg/day (oral suspension) of AZD9567 for 3 consecutive days of each treatment period in Cohort 1 and 40 mg/day for 3 consecutive days of each treatment period in Cohort 2. intervention 2: Participants will receive 40 mg/day of prednisolone for 3 consecutive days of each treatment period in Cohort 1, 20 mg/day of prednisolone for 3 consecutive days of each treatment period in Cohort 2, and 5 mg/day prednisolone for 3 consecutive days of each treatment period in Cohort 3. intervention 3: Participants will receive placebo for 3 consecutive days of each treatment period in Cohort 3.

Protocol document:
Prot_000.pdf: 
A Phase 2a Randomised, Double Blind, Multi-centre Study to 
Assess the Effect on Glucose Homeostasis of Two Dose Levels of 
AZD9567, Compared to Prednisolone, in Adults with Type 2 
Diabetes 
ClinicalTrials.gov Identifier: NCT04556760 
Protocol Amendment No. 2: Final 3.0, 03 Mar 2021  


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Clinical Study Protocol
Study Intervention
AZD9567
Study Code
D6470C00005
Version
3.0
Date
03 March 2021
A Phase 2a Randomised, Double Blind, Multi-centre Study to 
Assess the Effect on Glucose Homeostasis of Two Dose Levels of 
AZD9567, Compared to Prednisolone, in Adults with Type 2 
Diabetes
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, SE-15185 Södertälje, Sweden
Regulatory Agency Identifier Number(s) EudraCT 2020-000931-35
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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Protocol Number: D6470C00005
Amendment Number: 2
Study Intervention: AZD9567 and prednisolone
Study Phase: 2a
Short Title: Phase 2a, Randomised, Double Blind, Multi-centre Study to Assess the Effect on 
Glucose Homeostasis of Two Dose Levels of AZD9567, Compared to Prednisolone, in Adults 
with Type 2 Diabetes 
Medical Monitor Name and Contact Information will be provided separately
National co-ordinating Investigator


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
03-Mar-2021
Amendment 1
14-Sep-2020
Original Protocol
01-Jul-2020
Amendment 2 (03-Mar-2021)
Overall Rationale for the Amendment:
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Section # 
and Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 1.1 Synopsis 
(Number of Participants)
Latest estimated date of last participant 
completed changed from Feb 2021 to May 
2021
Revised to 
reflect latest 
estimated date
Non-
substantial
Section 1.1 Synopsis 
(Statistical methods)
Section 9.4.1 General 
Considerations
Section 9.4.2.1 Primary 
Endpoint(s)
Section 9.4.2.2 
Secondary Endpoint(s)
Section 9.4.2.3 
Tertiary/Exploratory 
Endpoints
Mixed model repeated measures analysis 
changed to linear
Following text deleted: Normality 
assumptions will be tested and if warranted 
log-transformations will be done prior to 
performing the analysis
Addition of text as follows: and the ratio 
between them
Addition of ‘and placebo versus 5 mg 
prednisolone’ to the following text: The 
treatment comparisons of interest are the 
different doses of AZD9567 versus the 
different doses of prednisolone
Text regarding exploratory endpoints revised
For clarity
Non-
substantial
Section 1.1 Synopsis and 
9.5 Interim Analysis
Addition of second interim analysis and 
corresponding text revision
Progress 
decision
Non-
substantial


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Section # 
and Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 1.3 Schedule of 
Activities
Timepoint of serum cortisol, 
 
and ACTH samples clarified: For the 
MMTT a standardized mixed meal is to be 
provided around 07:00 on Day -1 and Day 4 
(in each period). Serum cortisol, 
 
 and ACTH are to be collected from the 
fasting MMTT blood samples, which is -15 
minutes prior to the mixed meal on Days -1 
and 4 (in each period)
To address 
discrepancy
Non-
substantial
Text in footnote m revised for clarity as 
follows: CGM will be performed during 
baseline (72h) and treatment period (72h), 
CGM/FGM will be fitted on Day -4 and 
removed on Day 4 (in each period) after 
assessments on Day 3 (in each period) are 
completed to ensure 2 continuous 72h 
monitoring periods covering baseline and 
treatment
Revision to clarify that all adverse events will 
be collected from time of signature of 
informed consent
Text revised to clarify that COVID-19 
symptom telephone screening should be done 
prior to each visit, including Visit 6
Text included to clarify that fasting is not 
required for haematology and clinical 
chemistry on Day -2 (in each period)
To clarify 
fasting 
requirement on 
Day -2 (in each 
period)
Text revised that COVID-19 phone call will 
be done one day prior to visit
To clarify 
timepoint of 
COVID-19 
phone call
Section 1.3 Schedule of 
Activities and Section 
8.3.4 Clinical Safety 
Laboratory Assessments 
(Table 6)
Footnote added to SoA for cortisol, 
 and ACTH to match 
footnote in Table 6 and included cortisol in 
footnote c in Table 6
To address 
discrepancy
Non-
substantial
CCI
CCI
CCI


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Section # 
and Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 1.3 Schedule of 
Activities and Section 
9.4.3.1 Adverse Events
Text revised to clarify that adverse events 
after dosing and up to 21 days will be included 
in tables and that the adverse events occurring 
after 21 days will be listed separately
Other minor revisions to this section
Consistency in 
AE follow-up 
for the 2 study 
periods
Non-
substantial
Section 1.3.1 Blood 
Sampling Schedule for 
Mixed Meal Tolerance 
Tests (MMTTs)
Removed '(minutes)' in body of first column 
and add to heading of second column and 
abbreviation for FFAs added to footnote
Administrative 
change
Non-
substantial
Section 1.1 Synopsis 
(Objectives and 
Endpoints Table) and 
Section 3 Objectives and 
Endpoints
 
Aligning with 
the sampling 
points
Non-
substantial
Definition provided for ΔI10/ΔG10, ΔI30/ΔG30, 
ΔC10/ΔG10, ΔC30/ΔG30, HOMA-IR, and 
HOMA-S
Section 4.1.1 Order of 
Assessments
Text revised as follows: Safety ECG and vital 
signs (systolic and diastolic BP, pulse rate) 
should be taken pre-dose and approximately 
1.5 hours after IMP dosing on Days 1 and 28 
and corresponding time on Days 4 and 31
To address 
discrepancy
Non-
substantial
Text revised to clarify aural body temperature 
should be taken and timing of ECG 
assessments
Section 5.1 Inclusion 
Criteria
Text for contraception requirement revised
To address 
discrepancy
Non-
substantial
Clarification that Inclusion Number 2 refers to 
fasting plasma glucose
To correct error
Section 5.2 Exclusion 
Criteria
Text revised to clarify that one rescreening per 
participant is allowed
Addition of following: COVID-19 vaccine 
(regardless of vaccine delivery platform, eg,
vector, lipid nanoparticle) 30 days prior to the 
date of randomisation (from last vaccination 
or booster dose)
To clarify 
rescreening and 
addition of 
COVID-19 
vaccination 
criterion
Non-
substantial
Section 5.3.1 Meals and 
Dietary Restrictions
Text revised to clarify that overnight fasting is 
required prior to each dosing, ie, 12 hours 
prior and 30 minutes after dosing
To clarify 
fasting 
requirement for 
study 
intervention 
dosing
Non-
substantial
CCI


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Section # 
and Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Fasting requirement added for ACTH
To clarify 
fasting 
requirement for 
ACTH
Section 6.2 Preparation/
Handling/
Storage/
Accountability of 
Interventions
Text included to clarify that participants 
should receive the oral suspension first, 
followed by the capsules
To clarify order 
of IMP intake
Non-
substantial
Section 6.5 Concomitant 
Therapy
Following text added: If a patient is being 
considered for enrolment into the study and 
also being considered for COVID-19 
vaccination, the patient must not be 
randomised until at least 30 days after the last 
dose of vaccine or booster.
To clarify 
COVID-19 
vaccination in 
relation to study 
randomisation.
Non-
substantial
Section 7.1 
Discontinuation of Study 
Intervention
Text corrected as follows: FPG > 12 mmol/l 
(216mg/dL)
To correct 
conversion error
Non-
substantial
COVID-19 vaccination related discontinuation 
requirement added
To clarify 
COVID-19 
vaccination 
related 
participant 
discontinuation
Section 8 Study 
Assessments and 
Procedures
Blood volume collected from each participant 
during the study changed from 500 mL to 
600 mL and the following text deleted: 
including any extra assessments that may be 
required
For consistency 
with the blood 
volume noted in 
consent form
Non-
substantial
Section 8.2.2 Mixed 
Meal Tolerance Test 
(MMTT)
Text added to clarify that the solid mixed meal 
should be consumed as fast as the participant 
can, within 30 minutes
To clarify 
requirement for 
completing 
mixed meal
Non-
substantial
 
 
 
Aligning with 
the sampling 
points
Non-
substantial
Section 9.1 Statistical 
Hypotheses
Bullet points added for inclusion of Cohort 2 
and Cohort 3
For better clarity
Non-
substantial
Addition of following text: Cohorts 2 and 3 
are not powered, thus all significance testing 
should be considered exploratory
CCI
CCI


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Section # 
and Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 9.2 Sample Size 
Determination
Text regarding significance testing and 
presentation of Cohorts 2 and 3 results revised
For better clarity
Non-
substantial
Section 9.3 Populations 
for Analyses
Definition of analysis sets updated
To reflect latest 
definitions as 
per the 
statistical 
analysis plan
Non-
substantial
Section 9.4 Statistical 
Analyses
The following text deleted: be finalised prior 
to first participant in and it will
For better clarity
Non-
substantial
Section 9.4.2.1 Primary 
Endpoint(s)
Addition of following: The following 
comparison will be performed:

72 mg AZD9567 versus 40 mg 
prednisolone (Cohort 1).

40 mg AZD9567 versus 20 mg 
prednisolone (Cohort 2).

Placebo versus 5 mg prednisolone 
(Cohort 3).
Deletion of following: Normality assumptions 
will be tested and, if warranted, log 
transformations will be done prior to 
performing the analysis. Further details will be 
provided in the SAP.
Text revised from “Should there be more than 
10% of participants erroneously treated, a 
sensitivity analysis will be performed using 
the actual treatment received.” To “Should 
there be more than 10% of participants 
erroneously treated, a sensitivity analysis will 
be performed on the per protocol set.”
For better clarity
Non-
substantial
Section 9.4.2.2 
Secondary Endpoint(s)
Text regarding analysis methods updated
For better clarity
Non-
substantial
Appendix F
Addition of COVID-19 related restriction
To clarify 
COVID-19 
vaccination 
related 
restriction
Non-
substantial
Appendix H Protocol 
Amendment History
Amendment history for previous version 
moved to Appendix H
For consistency 
with latest 
template
Non-
substantial


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Section # 
and Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Global
Minor editorial corrections (typos, formatting, 
etc)
Document 
quality
Non-
substantial


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 9
1
PROTOCOL SUMMARY ................................................................................ 13
1.1
Synopsis ........................................................................................................... 13
1.2
Schema............................................................................................................. 19
1.3
Schedule of Activities ....................................................................................... 20
1.3.1
Blood Sampling Schedule for Mixed Meal Tolerance Tests (MMTTs)............... 26
2
INTRODUCTION............................................................................................ 27
2.1
Study Rationale ................................................................................................ 27
2.2
Background ...................................................................................................... 27
2.3
Benefit/Risk Assessment................................................................................... 28
2.3.1
Risk Assessment ............................................................................................... 28
2.3.2
Benefit Assessment........................................................................................... 29
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 30
3
OBJECTIVES AND ENDPOINTS................................................................... 31
4
STUDY DESIGN ............................................................................................. 33
4.1
Overall Design.................................................................................................. 33
4.1.1
Order of Assessments........................................................................................ 34
4.2
Scientific Rationale for Study Design and Population ....................................... 34
4.3
Justification for Dose........................................................................................ 35
4.4
End of Study Definition.................................................................................... 36
5
STUDY POPULATION.................................................................................... 36
5.1
Inclusion Criteria .............................................................................................. 36
5.2
Exclusion Criteria ............................................................................................. 38
5.3
Lifestyle Considerations ................................................................................... 40
5.3.1
Meals and Dietary Restrictions ......................................................................... 41
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 43
5.3.3
Activity............................................................................................................. 43
5.4
Screen Failures ................................................................................................. 43
6
STUDY INTERVENTION ............................................................................... 44
6.1
Study Intervention(s) Administered................................................................... 44
6.1.1
Investigational Products.................................................................................... 44
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 45
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 45
6.4
Study Intervention Compliance......................................................................... 47
6.5
Concomitant Therapy........................................................................................ 47




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8.7
Human Biological Sample Biomarkers ............................................................. 62
8.7.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 62
8.8
Optional Genomics Initiative Sample................................................................ 62
8.9
Health Economics/Medical Resource Utilisation and Health Economics (Not 
Applicable)....................................................................................................... 63
9
STATISTICAL CONSIDERATIONS................................................................ 63
9.1
Statistical Hypotheses....................................................................................... 63
9.2
Sample Size Determination............................................................................... 63
9.3
Populations for Analyses................................................................................... 64
9.4
Statistical Analyses ........................................................................................... 64
9.4.1
General Considerations..................................................................................... 65
9.4.2
Pharmacodynamic Effects................................................................................. 66
9.4.2.1
Primary Endpoint(s).......................................................................................... 66
9.4.2.2
Secondary Endpoint(s)...................................................................................... 66
9.4.2.3
Tertiary/Exploratory Endpoint(s) ...................................................................... 67
9.4.3
Safety ............................................................................................................... 67
9.4.3.1
Adverse Events................................................................................................. 67
9.4.3.2
Deaths .............................................................................................................. 67
9.4.3.3
Exposure........................................................................................................... 68
9.4.3.4
Other Safety Parameters.................................................................................... 68
9.4.4
Pharmacokinetics.............................................................................................. 68
9.4.5
Other Analyses.................................................................................................. 69
9.5
Interim Analysis................................................................................................ 69
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 69
11
REFERENCES................................................................................................. 99
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 19
LIST OF TABLES
Table 1
Risk Assessment...................................................................................... 28
Table 2
Objectives and Endpoints......................................................................... 31
Table 3
Mixed Meal Tolerance Test – Solid Meal (Breakfast).............................. 41
Table 4
Mixed Meal Tolerance Test – Solid Meal (Breakfast) Vegetarian Option. 42
Table 5
Investigational Products........................................................................... 44
Table 6
Laboratory Variables ............................................................................... 55


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Table 7
Drugs of Abuse and Alcohol.................................................................... 56
Table 8
Populations for Analysis .......................................................................... 64
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 70
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 75
Appendix C
Handling of Human Biological Samples .................................................. 80
Appendix D
Optional Genomics Initiative Sample....................................................... 82
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 85
Appendix F
Guidance for Restricted Medication......................................................... 91
Appendix G
Abbreviations .......................................................................................... 94
Appendix H
Protocol Amendment History................................................................... 97


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2a Randomised, Double Blind, Multi-centre Study to Assess the 
Effect on Glucose Homeostasis of Two Dose Levels of AZD9567, Compared to 
Prednisolone, in Adults with Type 2 Diabetes 
Short Title: Phase 2a, Randomised, Double Blind, Multi-centre Study to Assess the Effect on 
Glucose Homeostasis of Two Dose Levels of AZD9567, Compared to Prednisolone, in Adults 
with Type 2 Diabetes 
Rationale:
AZD9567 is a glucocorticoid receptor (GR) modulator that shows promising separation 
between anti-inflammatory and dysglycaemic effects in preclinical studies and in two dose 
escalation studies in healthy volunteers (D6470C00001 and D6470C00002). In addition, in a 
study in patients with active rheumatoid arthritis (RA) (D6470C00003), 40 mg AZD9567 
resulted in a similar profile in term of efficacy effects to prednisolone 20 mg following 
14 days of once daily dosing. The aim of this study is to assess the effect on glycaemic control 
of AZD9567 as compared to prednisolone in a more relevant patient population. 
The doses used (40 mg AZD9567 [equipotent to 20 mg prednisolone] and 72 mg AZD9567 
[equipotent to 40 mg prednisolone]) were chosen based on studies D6470C00001 and 
D6470C00002 (equipotency was based on ex-vivo lipopolysaccharide [LPS] stimulated 
tumour necrosis factor alpha [TNFα] release in whole blood). In study D6470C00002, the 
effect of several doses of AZD9567 up to 80 mg (equipotent to 45 mg prednisolone) on 
plasma glucose was investigated and compared with prednisolone. After an oral glucose 
tolerance test (OGTT) the area under the concentration-time curve from 0 to 4 hours post-
dose, AUC(0-4), was measured. The result showed that the effect of AZD9567 80 mg on 
glucose was similar to the lower dose of 5 mg prednisolone despite being equipotent to 45 mg 
prednisolone.
This is a randomised, double blind, multi-centre, double dummy, two-way cross-over study to 
assess the effect on glycaemic control of AZD9567, as measured by the glucose AUC(0-4) 
versus baseline following a standardised mixed meal tolerance test (MMTT), compared to 
prednisolone in adults with type 2 diabetes mellitus (T2DM). This study will also evaluate the 
safety, tolerability, and pharmacokinetics (PK) of AZD9567.






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AZD9567 will be administered once daily as an oral suspension at two dose levels (40 mg/day 
and 72 mg/day). Prednisolone capsules will be administered orally at three different dose 
levels (5 mg/day, 20 mg/day, and 40 mg/day). There will be three separate, two-way 
cross-over cohorts, with three different dose combinations (72 mg AZD9567/40 mg 
prednisolone, 40 mg AZD9567/20 mg prednisolone, and placebo/5 mg prednisolone). Since 
the investigational medicinal product (IMP) has different formulations, it will be administered 
in a double dummy fashion, with each participant taking both oral suspension and capsules of 
prednisolone/placebo.
Participants who meet all eligibility criteria will be randomised in a ratio of 1:1 to a cohort and 
sequence group as shown in the Cohorts and Duration section below.
Disclosure Statement: This is a cross-over study with three separate two-way cross-over 
sequence groups that is participant and investigator blinded.
Number of Participants:
Approximately 46 participants will be randomly assigned to study intervention with a view to 
achieve 40 evaluable participants completing the study.
Study period
Phase of development
Estimated date of first participant enrolled
Sep 2020
Phase 2a
Estimated date of last participant completed
May 2021
Phase 2a
Cohorts and Duration:
There will be three dose comparisons, each in a separate two-way cross-over:

Cohort 1: participants will be randomised in a ratio of 1:1 to receive AZD9567 and 
prednisolone over two 72-hour periods in a cross-over design (72 mg AZD9567 followed 
by 40 mg prednisolone [AB sequence group] or 40 mg prednisolone followed by 72 mg 
AZD9567 [BA sequence group]). There will be a 3-week washout period between 
treatment periods. (N=24 completed [12 in each sequence group].)

Cohort 2: participants will be randomised in a ratio of 1:1 to receive AZD9567 and 
prednisolone over two 72-hour periods in a cross-over design (40 mg AZD9567 followed 
by 20 mg prednisolone [AB sequence group] or 20 mg prednisolone followed by 40 mg 
AZD9567 [BA sequence group]). There will be a 3-week washout period between 
treatment periods. (N=8 completed [4 in each sequence group].)

Cohort 3: participants will be randomised in a ratio of 1:1 to receive placebo and 
prednisolone over two 72-hour periods in a cross-over design (placebo followed by 5 mg 
prednisolone [AB sequence group] or 5 mg prednisolone followed by placebo [BA 


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sequence group]). There will be a 3-week washout period between treatment periods.
(N=8 completed [4 in each sequence group].)
Participants will be expected to take part in the study (from screening to follow-up) for 
79 days; the study duration may be extended for screening and washout (see Schedule of 
Assessments [SoA] in Section 1.3).
Statistical methods
For Cohort 1, with a total sample size of 24 participants we can detect an absolute difference 
of 10% change from baseline in glucose AUC(0-4) (mmol/L 4h), ie, a difference of ~134 
mmol/L 4h between prednisolone and AZD9567, with a power of 80% and significance level 
of 0.05, 1-sided test. Withdrawn participants should be replaced to ensure that 24 participants 
are evaluable (12 in each sequence group).
The primary PD variable, change from baseline in glucose AUC(0-4) following a standardised 
MMTT, will be analysed using a linear mixed model with baseline included as covariate. 
Treatment, period and sequence will be included as fixed effects with participant within 
sequence as random effect. Models will be run separately for each cohort. Should there be 
more than 10% of participants erroneously treated, a sensitivity analysis will be performed 
using the actual treatment received instead. Descriptive statistics and graphical presentations 
will be presented.
Mean daily glucose measured by continuous glucose monitoring (CGM) is a secondary 
endpoint and will be analysed using a MMRM analysis with baseline as covariate. Treatment, 
period and sequence will be included as fixed effects, participant within sequence as random 
effect and day as repeated measure. Models will be run separately for each cohort. Similar 
analyses will be performed for the rise in mean daily glucose over 24-hour periods. Fasting 
glucose as derived from the baseline measure in the MMTT, change in hormones related to 
glucose homeostasis in response to MMTT (insulin, glucagon, GLP-1, glucose-dependent 
insulin releasing polypeptide [GIP]), changes in FFAs during MMTT, HOMA-IR, HOMA-S, 
and 24-hour U-Na and U-K excretion and the ratio between them will be analysed in a similar 
way to the primary PD endpoint.
Safety will be assessed by descriptive analysis of adverse events (AEs)/serious AEs (SAEs), 
vital signs, ECGs, clinical laboratory assessments (clinical chemistry/haematology), morning 
serum cortisol, and adrenocorticotropic hormone (ACTH).
Continuous data will be summarised using descriptive statistics (number of observations, 
mean, standard deviation, median, 25th and 75th percentiles [where appropriate], minimum 
and maximum). For log-transformed data it is more appropriate to present geometric mean, 
geometric coefficient of variation, median, minimum, and maximum. Frequencies and 
percentages will be used for summarising categorical (discrete) data. Time parameters (tmax, 


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tlast, etc) will be presented as minimum, median, and maximum only. Confidence intervals 
and p-values, when presented, will generally be constructed at the 2-sided 95% level. Unless 
otherwise stated, summaries will be presented by cohort and treatment. The treatment 
comparisons of interest are the different doses of AZD9567 versus the different doses of 
prednisolone and placebo versus 5 mg prednisolone. No formal comparisons between the 
different AZD9567 doses will be conducted. Similarly, no formal comparisons between the 
different prednisolone doses will be conducted.
The primary analysis population for pharmacodynamics will be the full analysis set. The 
primary analysis population for safety will be the safety analysis set. The PK analysis set will 
include all participants who received at least one dose of study intervention and for whom 
there is at least one reportable PK concentration, no important protocol deviations, or AEs 
considered to have an effect upon PK.
Two interim analyses are planned to evaluate the feasibility of the assumptions and conduct 
sample size re-estimation if required (see Section 9.5).


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1.2
Schema
Figure 1
Study Flow Diagram
n: number of participants.














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Note: Interim telephone visits may occur at any time during the outpatient periods, as determined by the investigator, to review the safety and well-being of the 
participant.
Abbreviations: ACTH: adrenocorticotropic hormone; aPTT: activated partial thrombin time; CGM: continuous glucose monitoring; CRU: clinical research unit; 
DPP4i: Dipeptidyl peptidase-4 inhibitor; ECG: electrocardiogram; ET: end of treatment; FFA: free fatty acid; FGM: flash glucose monitoring; GIP: glucose-
dependent insulin releasing polypeptide; GLP-1: glucagon-like peptide-1; HAV: Hepatitis A virus; HbA1c: haemoglobin 1Ac; HbsAg: Hepatitis B surface 
antigen; hCG: human chorionic gonadotropin; HCV: Hepatitis C virus; HDL-C: high-density lipoprotein-cholesterol; HIV: human immunodeficiency virus;
IMP: investigational medicinal product; INR: International normalized ratio; IVRS/IWRS: Interactive Voice/Web Response System; MMTT: mixed meal 
tolerance test; PCR: polymerase chain reaction; PK: pharmacokinetics; PT: prothrombin time; SGLT2i: sodium-glucose co-transporter-2 inhibitor; 
T2DM: type 2 diabetes mellitus; TNFα: tumour necrosis factor alpha; U-K: urinary potassium; U-Na: urinary sodium.
1.3.1
Blood Sampling Schedule for Mixed Meal Tolerance Tests (MMTTs)
Day -1, Day 4, Day 27, and Day 31 (minutes)
Comments
Plasma glucose, insulin,
C-peptide GLP-1, GIP, 
glucagon, and FFAs
-15, 10, 20, 30, 60, 75, 120, 180, 240
Time point in relation to the start of the meal
Abbreviations:  FFA: free fatty acid; GLP-1: glucagon-like peptide-1; GIP: glucose-dependent insulin releasing polypeptide


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2
INTRODUCTION
2.1
Study Rationale
AZD9567 is a glucocorticoid receptor (GR) modulator that shows promising separation 
between anti-inflammatory and dysglycaemic effects in preclinical studies and in two dose 
escalation studies in healthy volunteers (D6470C00001 and D6470C00002). In addition, in a 
study in patients with active RA (D6470C00003), 40 mg AZD9567 resulted in a similar 
profile in term of efficacy effects to prednisolone 20 mg following 14 days of once daily 
dosing. The aim of this study is to assess the effect on glycaemic control of AZD9567 as 
compared to prednisolone in a more relevant patient population.
The doses used (40 mg AZD9567 [equipotent to 20 mg prednisolone] and 72 mg AZD9567 
[equipotent to 40 mg prednisolone]) were chosen based on studies D6470C00001 and 
D6470C00002 (equipotency was based on ex-vivo lipopolysaccharide [LPS] stimulated 
tumour necrosis factor alpha [TNFα] release in whole blood). In study D6470C00002, the 
effect of several doses of AZD9567 up to 80 mg (equipotent to 45 mg prednisolone) on 
plasma glucose was investigated and compared with prednisolone. After an OGTT the 
AUC(0-4) was measured. The result showed that the effect of AZD9567 80 mg on glucose 
was similar to the lower dose of 5 mg prednisolone despite being equipotent to 45 mg 
prednisolone.
2.2
Background
For more than 60 years, glucocorticoids (GC) have been among the most commonly 
prescribed drugs, used in treatment protocols of a wide variety of inflammatory and 
autoimmune diseases. Prednisolone, for example, is used to treat more than 55 indications 
spanning across several therapeutic areas including but not limited to rheumatology, 
endocrinology, dermatology, ophthalmology, respiratory, haematology, and gastroenterology. 
The therapeutic success of GCs originates from their ability to modulate the expression of a 
wide range of pro-inflammatory mediators. While GCs remain central to anti-inflammatory 
protocols, it is clear that their prolonged administration influences a diverse set of key 
biological functions and causes concerning side effects such as developing or worsening of 
type 2 diabetes mellitus (T2DM), bone loss, increasing risk of infections, cataracts, oedema, 
weight gain, etc. Glucocorticoids are known to result in whole-body insulin resistance and 
obesity. Such unwanted effects are the reason that most GCs standard regimens are often short 
and tapered for the treatment of chronic inflammations. A new agent with a wider therapeutic 
margin would be expected to be dosed at higher levels for a longer period of time, thus 
leading to improved efficacy with fewer adverse events (AEs).
AZD9567 is an oral, non-steroidal selective glucocorticoid receptor modulator (SGRM), with 
potential use as an oral anti-inflammatory treatment for diseases in which GCs are indicated. It 
is differentiated through a unique binding mode that selectively confers anti-inflammatory 






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with diabetes.
2.3.3 Overall Benefit: Risk Conclusion
AZD9567 is an oral, non-steroidal, potent SGRM under development for the treatment of 
patients requiring oral corticosteroid therapy for acute and chronic inflammatory condition in 
patients at risk of diabetes (or with pre-existing diabetes).
Experience has been gathered from nonclinical safety pharmacology, toxicology studies, 
previous clinical experience with GR agonists and data from the first in man single ascending 
dose study (D6470C00001), the MAD study (D6470C00002) and a Phase 2 study in RA 
patients (D6470C00003, SEMRA). In preclinical testing, AZD9567 displayed features 
consistent with a potent GR agonist and expected findings in humans will be monitorable and 
reversible.
In clinical studies of AZD9567, single doses of AZD9567 up to 155 mg, and multiple doses of 
AZD9567 up to 125 mg have been well tolerated in healthy volunteers. The result of the MAD
study (D6470C0002), also showed a good differentiation in plasma glucose compared to 
prednisolone at doses with similar anti-inflammatory activity. Study D6470C00003, in 
patients with RA, showed a similar safety profile, good tolerability and similar profile in terms 
of efficacy. Based on this experience, it is expected that AZD9567 will be well tolerated in 
participants with diabetes.
In the planned study, participants with T2DM are at risk of complications associated with 
COVID-19 infection and the effect of short-term treatment with corticosteroids or AZD0567 
is unknown on outcomes of COVID-19. 
Participants will be contacted by phone before admission to the CRU for evidence of infection 
and will be advised to socially isolate where possible. Individuals that cannot be enrolled in 
the study due to ongoing infections may be rescreened if the infections resolve within 4 to 
6 weeks. Clinical checks and polymerase chain reaction (PCR) for COVID-19 at screening 
(see Exclusion Criterion 7) ensures they are free of virus at entry to the study. A telephone call 
from the site prior to each visit for enrolled patients, plus screening for evidence of infection, 
have been added to the assessments to minimise the risk of spreading infection. Therefore, 
with current measures the benefit risk balance is very likely to be similar to that expected 
before the COVID-19 pandemic.
More detailed information about the known and expected benefits and potential risks of 
AZD9567 may be found in the IB.






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4
STUDY DESIGN
4.1
Overall Design
This is a randomised, double blind, multi-centre, double dummy, two-way cross-over study 
with the primary objective of determining the effect of AZD9567 on glucose homeostasis (ie,
glycaemic control) versus a dose of prednisolone expected to deliver similar 
anti-inflammatory effects, as assessed by the change in glucose AUC following the 
standardised MMTT compared to baseline. Approximately 46 participants with T2DM will be 
randomised into the study, with a view to achieve 40 evaluable participants completing the 
study. The study will be conducted in Germany.
AZD9567 will be administered once daily as an oral suspension at two dose levels (40 mg/day 
and 72 mg/day). Prednisolone capsules will be administered orally at three different dose 
levels (5 mg/day, 20 mg/day, and 40 mg/day). Since the IMP has different formulations, it will 
be administered in a double dummy fashion, with each participant taking both oral suspension 
and capsules of prednisolone/placebo.
Each cohort will be treated for two 72-hour periods in a cross-over design, with a 3-week 
washout period between treatment periods. The total length of participant engagement (from 
screening to follow-up) is 79 days; the study duration may be extended for screening and 
washout (see SoA in Section 1.3).
Participants with T2DM who meet all eligibility criteria will be randomised in a ratio of 1:1 to 
a cohort and sequence group as shown below.
There will be three separate, two-way cross-over cohorts, with three different dose 
combinations (72 mg AZD9567/40 mg prednisolone, 40 mg AZD9567/20 mg prednisolone 
and placebo/5 mg prednisolone); see Figure 1:

Cohort 1: participants will be randomised in a ratio of 1:1 to receive AZD9567 and 
prednisolone over two 72-hour periods in a cross-over design (72 mg AZD9567 followed 
by 40 mg prednisolone [AB sequence group] or 40 mg prednisolone followed by 72 mg 
AZD9567 [BA sequence group]). There will be a 3-week washout period between 
treatment periods. (N = 24 completed [12 in each sequence group].)

Cohort 2: participants will be randomised in a ratio of 1:1 to receive AZD9567 and 
prednisolone over two 72-hour periods in a cross-over design (40 mg AZD9567 followed 
by 20 mg prednisolone [AB sequence group] or 20 mg prednisolone followed by 40 mg 
AZD9567 [BA sequence group]). There will be a 3-week washout period between 
treatment periods. (N = 8 completed [4 in each sequence group].)

Cohort 3: participants will be randomised in a ratio of 1:1 to receive placebo and 
prednisolone over two 72-hour periods in a cross-over design (placebo followed by 5 mg 


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prednisolone [AB sequence group] or 5 mg prednisolone followed by placebo [BA
sequence group]). There will be a 3-week washout period between treatment periods.
(N = 8 completed [4 in each sequence group].)
In treatment period 1, participants will be fitted with a CGM/Flash Glucose Monitoring 
(FGM) device on Day -4 on an outpatient basis. Participants will then be admitted to the CRU 
on Day -2. On Day -1, they will have a baseline MMTT. Dosing of IMP will occur on Days 1 
to 3. The CGM/FGM device will be removed on Day 4. Participants will have an MMTT in 
the morning of Day 4, before being discharged from the CRU in the afternoon of Day 4. This 
sequence of events will be repeated in the second period (Day 24 to Day 31) (see Section 1.3).
4.1.1 Order of Assessments 
It is important that PK and PD sampling occurs as close as possible to scheduled time. In 
order to achieve this, other assessments scheduled at the same time may be initiated prior to 
the time point. The sequence at a particular time point is:
1
Safety ECG
2
Vital signs (systolic and diastolic BP, pulse rate, and aural body temperature)
3
Pharmacokinetic blood sampling (will be drawn at the specified time point)
4
Pharmacodynamic blood sampling (will be drawn at the specified time point)
5
Safety blood sampling
6
Urine collections for safety assessments
Safety ECG and vital signs (systolic and diastolic BP, pulse rate) should be taken pre-dose and 
approximately 1.5 hours after IMP dosing on Days 1 and 28 and corresponding time on 
Days 4 and 31. 
4.2
Scientific Rationale for Study Design and Population
This is a Phase 2a, two-way, cross-over study designed to assess the PD, PK, and safety of 
AZD9567 in male and female adults with T2DM. The study aims to compare the effects of 
two different doses of AZD9567 (40 mg/day and 72 mg/day) on glucose homeostasis with 
prednisolone (5 mg/day, 20 mg/day, and 40 mg/day) and placebo.
Oral GCs are commonly prescribed to treat various inflammatory and autoimmune disorders, 
including RA. However, GC treatment is associated with several metabolic effects, such as 
insulin resistance and hyperglycaemia. Patients with type 1 diabetes mellitus and T2DM, or 
with increased insulin resistance, require a closer monitoring of their glucose levels while on 
systemic steroids and frequently need increase or modification of their diabetic treatments
(Spanakis et al 2014). Therefore, the availability of a GR agonist with less, or devoid of,
steroid-related unwanted metabolic effects would provide a valuable health benefit to these 
patients. From preclinical studies, AZD9567 at equipotent anti-inflammatory doses to 


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prednisolone is expected to have less effect on the glucose metabolism. Further, the MAD 
study (D6470C00002) indicated that subjects who were on AZD9567 kept their glycemic 
control better than subjects on prednisolone.
In order to assess the effect on glucose homeostasis, the populations selected for this study
will be male and female adults aged 18 – 75 years with T2DM diagnosis of ≥6 months, on 
stable metformin for ≥4 weeks and an HbA1c 6% – 9.5%. These participants, unlike healthy 
volunteers with normal weights and medical history, show an increased glycemic response to 
oral steroids (Yuen et al 2012). The population chosen for this study, therefore, will be the 
most appropriate to assess the effect of AZD9567 on glycemic levels and to compare it to that 
of prednisolone. The cross-over design of the study is designed to maximise data available on 
the clinical effect of AZD9567 versus prednisolone, while limiting the number of patients 
exposed to prednisolone during the study.
4.3
Justification for Dose
The most common prednisolone dosage to treat chronic inflammation is 5 – 60 mg/day, 
tapered to the minimally effective dose in order to impact disease activity while avoiding 
systemic adverse effects, including loss of glycemic control (British National Formulary 
(BNF)).
In this study, prednisolone doses of 5 mg, 20 mg, and 40 mg are selected as low to moderate 
clinically relevant doses spanning the range of therapeutic doses to relatively situate AZD9567 
in terms of effects on glycemic control.
For meaningful assessment of differentiation, it is necessary to compare AZD9567 and 
prednisolone at doses with equal anti-inflammatory effect. In two recent dose escalation 
studies in healthy volunteers (D6470C00001 and D6470C00002), AZD9567 and prednisolone 
were evaluated with respect to anti-inflammatory biomarker effect, using inhibition of the 
cytokine TNFα from the immune cells, over 24 hours, following LPS stimulation in whole 
blood.
TNFα was inhibited by both AZD9567 and prednisolone in an exposure-dependent manner. A 
PK-PD modelling approach was used to establish dose–exposure–response relationships of 
TNFα for both compounds. Using these relationships, the dose AZD9567 that would produce 
the same level of TNFα inhibition as a given dose of prednisolone was predicted. A 
comparison of the dose-response curves enabled estimation of an equipotency relationship. 
Specifically, 20 mg prednisolone was estimated to be equipotent to 40 mg AZD9567 (95% CI:
29 – 54 mg), and 40 mg prednisolone was predicted to be equipotent to 72 mg AZD9567 
(95% CI: 52 – 99) (Almquist et al 2020).
The validity of the equipotency analysis is supported by study D6470C00003 in patients with 
active RA despite stable treatment with conventional disease-modifying anti-rheumatic drugs, 


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where 40 mg AZD9567 resulted in a similar profile in term of efficacy effects to prednisolone 
20 mg following 14 days of once daily dosing.
When comparing the effect of AZD9567 and prednisolone on glycemic control in healthy 
volunteers, it was evident that the effect of AZD9567 at doses up to 80 mg on plasma glucose 
AUC(0–4h) after an OGTT were similar to those observed with 5 mg prednisolone.
Thus, for the assessment of safety differentiation versus prednisolone related to glycemic 
control in relevant populations such as patients with T2DM, 40 mg AZD9567 (equipotent to 
20 mg prednisolone) and 72 mg AZD9567 (equipotent to 40 mg prednisolone) was chosen. 
The highest dose comparison provides enough power to detect a significant difference in 
glucose control between treatments, while lower doses will be evaluated on an exploratory 
basis. This minimises the number of participants and duration of steroid exposure.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed both periods
of the study including the last safety follow-up visit (Visit 6) shown in the SoA.
For a participant, the end of study is defined as the date reported in the ‘End of Study’ 
electronic Case Report Form (eCRF) for that participant. For all participants, the end of study 
is defined as the last date reported in the ‘End of Study’ eCRF for all participants.
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
Participant must be aged 18 to 75 years of age inclusive, at the time of Visit 1.
Type of Participant and Disease Characteristics
2
Participants with diagnosis of T2DM for 6 months prior to screening:  HbA1c in the 
diabetes range or fasting plasma glucose 126 -220 mg/dL.
3
On stable metformin therapy for at least 4 weeks, where no significant dose change 
(increase or decrease ≥500 mg/day) has occurred prior to screening and HbA1c 
6% – 9.5%, or on dual therapy with metformin in combination with SGLT2i or DPP4i 
and HbA1c 6% – 8%. Participants on dual therapy will require 2 weeks washout of 
SGLT2i or DPP4i.
4
Venous access suitable for multiple cannulations.


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Sex
5
Males and females.
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
(a) Male participants: All male participants must be willing to avoid fathering a child by 
either true abstinence1 or use (together with their female partner/spouse) a highly 
effective contraception form of birth control in combination with a barrier method, 
starting from the time of study intervention administration until 3 months after the 
Final/ET visit. Acceptable methods of preventing pregnancy are provided below.
Reproduction
6
Female participants must be not lactating and not of childbearing potential, defined as 
those who are surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or 
complete hysterectomy) or are postmenopausal (defined as at least 1 year since last 
menses and having an elevated [> 40 mIU/mL] follicle-stimulating hormone [FSH]
laboratory value at screening).
If sexually active, nonsterilized males who have a female partner of childbearing potential 
must practice two effective contraceptive measures from screening through at least 
3 months after the last dose of IMP has been administered. Note: Male condom plus 
spermicide is only considered an effective contraceptive measure when used together with 
another method based on following list (none of the listed methods are intended to be 
used alone). Highly Effective Methods of Contraception include:
(a) Tubal occlusion
(b) Copper T intrauterine device
(c) Levonorgestrel-releasing intrauterine system (eg, Mirena®)
(d) Medroxyprogesterone injections (eg, Depo-Provera®)
(e) Etonogestrel implants (eg, Implanon®, Norplan®)
                                               
1 Sexual abstinence is defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. It is only acceptable if preferred and usual lifestyle of the participant.


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(f) Combined pills
(g) Norelgestromin/ethinyl estradiol transdermal system (eg, Ortho Evra®)
(h) Intravaginal device (eg, NuvaRing®)
(i)
Desogestrel (Cerazette®).
Informed Consent
7
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 Clinical 
Study Protocol (CSP).
8
Provision of informed consent prior to any study specific procedures.
9
Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports Genomic 
Initiative (see Appendix D).
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History or presence of type 1 diabetes.
2
History of severe hypoglycaemia or hypoglycaemia unawareness within the last 
6 months.
3
History or presence of diabetic foot ulcers.
4
Participants with advanced diabetic complications (eg, symptomatic nephropathy, 
gastroparesis, proliferative retinopathy, significant atherosclerotic disease, congestive, 
heart failure etc).
5
History of clinically significant lactic acidosis or ketoacidosis following diagnosis with 
T2DM.
6
History of, or known significant infection or positivity at Visit 1, including hepatitis A, B, 
or C, human immunodeficiency virus, tuberculosis (ie, positive result for interferon-γ 
release assay, QuantiFERON® TB-Gold), that may put the participant at risk during 
participation in the study.
7
History and / or presence of COVID-19:
(a) Participants who have had a severe course of COVID-19 (ie, hospitalisation, 
extracorporeal membrane oxygenation [ECMO], mechanically ventilated)
(b) Participants with clinical signs and symptoms consistent with COVID-19, eg, fever, 
dry cough, dyspnoea, sore throat, fatigue, or confirmed current infection by 


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appropriate laboratory test within the last 4 weeks prior to screening or on admission 
to the CRU
(c) Participants with confirmed COVID-19 infection by PCR test before randomisation
8
Donation of blood (≥450 mL) within 3 months or donation of plasma within 14 days 
before Visit 1.
9
History of or current alcohol or drug abuse (including marijuana), as judged by the 
investigator.
10 Previous psychiatric disorders, including but not limited to:
(a) Participants have been committed to an institution by way of official or judicial order
(b) Any active psychiatric illness associated with unstable weight control or which would 
result in inability to comply with study requirements
(c) History of severe affective disorder including major depressive or maniac-depressive 
illness
(d) History of previous steroid psychosis
11 Any latent, acute, or chronic infections or at risk of infection, or history of skin abscesses 
within 90 days prior to the first administration of IMP at the discretion of the investigator.
12 History of adrenal insufficiency.
13 History or current inflammatory disorder.
14 Any other condition that, in the opinion of the investigator, would interfere with 
evaluations of the IMP or interpretation of participant safety or study results, including, 
but not limited to:
(a) History of previous gastric/duodenal ulcers or surgery affecting the upper GI tract
likely to affect the interpretation of safety and tolerability data
(b) History of cholelithiasis leading to episodes of acute cholecystitis not treated by 
cholecystectomy, or known biliary disease
(c) History or presence of dyspepsia or oral intolerance to steroids
(d) History of cancer, with the exception of non-melanoma skin cancer which is 
considered cured based on investigator assessment
(e) History or presence of any other condition known to interfere with absorption, 
distribution, metabolism, or excretion of drugs
15 History of severe allergy/hypersensitivity to AZD9567 or any of the excipients of the 
product, or ongoing clinically important allergy/hypersensitivity as judged by the 
investigator.
Prior/Concomitant Therapy
16 Oral or parenteral steroids 8 weeks prior to randomisation and during the study. Topical 
and inhaled steroids 4 weeks prior to randomisation are acceptable.


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17 Use of any prohibited medication during the study or if the required washout time of such 
medication was not adhered to (see Section 6.5 for details).
18 Receipt of:

Live or live attenuated vaccine within 4 weeks prior to the first administration of 
IMP.

COVID-19 vaccine (regardless of vaccine delivery platform, eg, vector, lipid 
nanoparticle) 30 days prior to the date of randomisation (from last vaccination or 
booster dose).
19 Planned in-patient surgery, major dental procedure, or hospitalisation during the study.
Prior/Concurrent Clinical Study Experience
20 Previous participation or participation in any other research study within 1 month prior to 
Visit 1.
21 Patient treated with any investigational drug within 30 days (or 5 half-lives, whichever is 
longer) prior to Visit 1.
Diagnostic Assessments
22 Uncontrolled hypertension (BP > 160 mmHg systolic or > 95 mmHg diastolic).
23 Diagnosis of heart failure and current symptoms regardless of definition, ie, HfpEF, 
HfrEF.
24 Acute coronary syndrome / unstable angina, coronary intervention procedures 
(percutaneous coronary intervention or coronary artery bypass graft) within the past 
6 months.
25 Stroke within the past 3 months.
26 QTcF > 470 ms or family history of long QT-syndrome.
27 AV-block II-III or sinus node dysfunction with significant pause, not treated with 
pacemaker.
Other Exclusions
28 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
29 Judgment 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.
30 Previous randomisation in the present study. 
31 Vulnerable persons (eg, persons kept in detention).
5.3
Lifestyle Considerations
1
Participants who are blood donors should not donate blood for the duration of the study 
and for 3 months following their last dose of AZD9567.


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2
Unusual meal habits and special diet requirements or unwillingness to eat the food 
provided in the study.
3
Abstain from drugs of abuse for the duration of the study.
5.3.1
Meals and Dietary Restrictions
Standardised meals will be provided to all participants while at the CRU. The exact times of 
the standardised meals relative to dosing of IMP are shown in the SoA (Section 1.3). No 
additional food or beverages must be consumed while in the clinical unit.
1
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice,
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 72 hours before the 
start of study intervention until after the final dose in each treatment period.
2
At screening, participants will be required to fast 12 hours prior to blood sampling for 
adrenocorticotropic hormone (ACTH) collection.
3
During clinic visits, prior to the MMTT, participants will be given a standardised evening 
meal and then be required to fast overnight for a minimum of 12 hours. No fluids will be 
allowed apart from water and participants will need to finish the meal.
4
Participants will be given a standardised mixed meal in the morning prior to the MMTT
(see Table 3 and Table 4 below).
5
Participants will be required to fast overnight before each IMP dosing, ie, 12 hours prior 
and 30 minutes after dosing.
Table 3
Mixed Meal Tolerance Test – Solid Meal (Breakfast)
Amount
Ingredients
Calories
kcal
Protein
g
Fat
g
Carbs
g
Fibre
g
45 g
Wholemeal bread roll (oat, wheat)
100
4.1
1.2
17.7
2.4
50 g
Wheat bread roll
124
4.1
0.4
25.1
1.5
11 g
Butter
82
0.1
9.2
0.1
0.0
29 g
Cheese 30% fat
77
7.8
4.9
0.0
0.0
20 g
Turkey breast
23
4.6
0.4
0.2
0.0
20 g
Strawberry jam
49
0.1
0.1
12.0
0.0
30 g
Curd cheese 20% fat
33
3.7
1.5
0.8
0.0
Fruit with yoghurt:
100 g
Plain yoghurt 1.5% fat 
61
5.3
1.5
6.5
0.0
50 g
Pear
31
0.2
0.1
6.2
1.6
56 g
Apple
32
0.2
0.3
6.4
1.1


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Amount
Ingredients
Calories
kcal
Protein
g
Fat
g
Carbs
g
Fibre
g
To rinse:
100 g
Still mineral water
0
0.0
0.0
0.0
0.0
Total
612
30.2
19.6
75.0
6.6
Nutrient relation:
Energy
612 cal
2555 kJ
Amount
Relation
Fibre
6.6 g
2%
Protein
30.2 g
20%
Fat
19.6 g
29%
Carbohydrate
75.0 g
49%
Table 4
Mixed Meal Tolerance Test – Solid Meal (Breakfast) Vegetarian Option
Amount
Ingredients
Calories
kcal
Protein
g
Fat 
g
Carbs 
g
Fibre
g
45 g
Wholemeal bread roll (oat, wheat)
100
4.1
1.2
17.7
2.4
50 g
Wheat bread roll
124
4.1
0.4
25.1
1.5
10 g
Butter
74
0.1
8.3
0.1
0.0
30 g
Cheese 30% fat 
79
8.1
5.1
0.0
0.0
25 g
Herb curd 20% fat
24
2.5
1.0
1.0
1.0
18 g
Strawberry jam
44
0.1
0.1
10.8
0.0
30 g
Curd cheese 20% 
33
3.7
1.5
0.8
0.0
Fruit with yoghurt:
120 g
Plain yoghurt 1,5 % 
73
6.4
1.8
7.8
0.0
50 g
Pear
31
0.2
0.1
6.2
1.6
50 g
Apple
29
0.2
0.3
5.7
1.0
To rinse:
100 g
Still mineral water
0
0.0
0.0
0.0
0.0
Total
611
29.5
19.8
75.2
6.5
Nutrient relation:
Energy
611 cal
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Amount
Ingredients
Calories
kcal
Protein
g
Fat 
g
Carbs 
g
Fibre
g
Amount
Relation
Fibre
6.5 g
2%
Protein
29.5 g
19%
Fat
19.8 g
29%
Carbohydrate
75.2 g
50%
5.3.2
Caffeine, Alcohol, and Tobacco
1
During each dosing session, participants will abstain from ingesting caffeine- or xanthine-
containing products (eg, coffee, tea, cola drinks, and chocolate) for 24 hours before the 
start of dosing until after collection of the final PK and/or PD sample.
2
During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK and/or PD sample.
3
Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical 
unit.
5.3.3
Activity
1
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during studies (eg, watching television, reading).
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
who have failed to meet one or more of the inclusion/exclusion criteria. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) due to 
ongoing infections that resolve within 4 to 6 weeks may be rescreened. Only one rescreening 
is allowed in the study. Rescreened participants should be assigned the same participant 
number as for the initial screening. Such participants should not be rescreened for at least 14 
days (and on a case by case basis) following full resolution of the infection.


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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the CSP.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
Table 5
Investigational Products
AZD9567
Prednisolone
Placebo
Placebo 
Intervention 
Name
AZD9567 oral 
suspension
Prednisolone 
(modified comparator)
Placebo for 
AZD9567 oral 
suspension
Placebo for 
prednisolone
Type
Drug
Drug
Drug
Drug
Dose 
Formulation
Oral suspension
Capsule
Oral suspension
Capsule
Unit Dose 
Strength(s)
4 mg/mL
5 mg
-
Dosage 
Level(s)
72 mg/day for 
3 consecutive days 
of each treatment 
period (Cohort 1)
40 mg/day for 
3 consecutive days 
of each treatment 
period (Cohort 2)
40 mg/day for 
3 consecutive days of 
each treatment period 
(Cohort 1)
20 mg/day for 
3 consecutive days of 
each treatment period 
(Cohort 2)
5 mg/day for 
3 consecutive days of 
each treatment period 
(Cohort 3)
Placebo for 
3 consecutive days
of each treatment 
period (Cohort 3)
Placebo for 
3 consecutive 
days of each 
treatment period 
(Cohort 3)
Route of 
Administration
Oral
Oral
Oral
Oral
Use
Experimental
Active comparator
Placebo
Placebo
IMP and 
NIMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally 
by the sponsor
Provided centrally by 
the sponsor
Provided centrally 
by the sponsor
Provided 
centrally by the 
sponsor
Packaging and 
Labelling
Oral suspension in 
bulk vials with a 
study specific label
Oral capsules in bulk 
bottles with a study 
specific label
Oral suspension in 
bulk vials with a 
study specific label
Oral capsules in 
bulk bottles with 


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AZD9567
Prednisolone
Placebo
Placebo 
a study specific 
label
(N)IMP: (non)investigational medicinal product
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply 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.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
All used and unused supply of AZD9567 and placebo will be destroyed by the site at the 
end of the study. The certificate of delivery and destruction must be signed in accordance 
with instructions by AstraZeneca. Destruction must not take place unless the responsible 
person at AstraZeneca has approved it.
Labels will be prepared in accordance with GMP and local regulatory requirement. The labels 
will fulfil GMP Annex 13 requirements and will be translated to local language. Details of 
storage conditions will be provided on the label of the IMP.
The IMP will be manufactured in accordance with GMP and will be supplied by the sponsor
as bulk. AstraZeneca will be responsible for the packaging, labelling and final release in 
accordance with GMP.
AZD9567 will be delivered in clear glass vials while prednisolone will be provided in bulk 
bottles. Placebo will be provided in matching vials and bottles in a double dummy fashion.
Participants should receive the oral suspension first, followed by the capsules.
Separate handling instructions for the AZD9567 suspension will be provided for the study by 
the sponsor.
6.3
Measures to Minimise Bias: Randomisation and Blinding
Participants in Cohort 1 who meet all eligibility criteria will be randomised in a ratio of 1:1 to 


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receive either 72 mg AZD9567 followed by 40 mg prednisolone (AB sequence group) or 
40 mg prednisolone followed by 72 mg AZD9567 (BA sequence group) so that 24 participants 
(12 in each sequence group) complete. For Cohort 2, participants will be randomised in a ratio 
of 1:1, 40 mg AZD9567 followed by 20 mg prednisolone (AB sequence group) or 20 mg 
prednisolone followed by 40 mg AZD9567 (BA sequence group) so that eight participants 
(four in each cohort) complete. For Cohort 3, participants will be randomised in a ratio of 1:1, 
to placebo followed by 5 mg prednisolone (AB sequence group) or 5 mg prednisolone 
followed by placebo (BA sequence group) so that eight participants (four in each cohort) 
complete.
All participants will be centrally assigned to randomised study intervention using an 
Interactive Voice Response System (IVRS)/Interactive Web Response System (IWRS). Before 
the study is initiated, the telephone number and call-in directions for the IVRS and/or the log 
in information & directions for the IWRS will be provided to each site.
Study intervention will be dispensed at the study visits summarised in SoA (Section 1.3). 
Returned study intervention should not be re-dispensed to the participants.
The IVRS/IWRS will provide to the investigator(s) or pharmacists the kit identification 
number to be allocated to the participant at the dispensing visit. Routines for this will be 
described in the IVRS/IWRS user manual that will be provided to each centre.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to participant to the AstraZeneca staff.
The following personnel will have access to the randomisation list:

The Covance bioanalytical laboratory

Clinical Supply Study Lead.
With the exception of personnel authorised to access to the randomisation code, the 
randomisation code should not be broken except in medical emergencies when the appropriate 
management of the participant requires knowledge of the treatment randomisation. The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product 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 


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participant have been made and documented.
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the participant’s condition (eg, antidote available), the investigator 
has the sole responsibility for determining if unblinding of a participants’ intervention 
assignment is warranted. Participant safety must always be the first consideration in making 
such a determination. If a participant’s intervention assignment is unblinded, the sponsor must 
be notified within 24 hours after breaking the blind. The investigator documents and reports 
the action to AstraZeneca, without revealing the treatment given to participant to the 
AstraZeneca staff.
Investigators will remain blinded to each participant’s assigned study intervention throughout 
the course of the study. In order to maintain this blind, an otherwise uninvolved third party 
will be responsible for the reconstitution and dispensation of all study intervention and will 
endeavour to ensure that there are no differences in time taken to dispense following 
randomisation. Participants randomised to placebo will receive the corresponding dose 
volume of solution as participants receiving AZD9567 within the same cohort. All dosing will 
be performed at the study site.
This third party will instruct the participant to avoid discussing the taste, dosing frequency, or 
packaging of the study intervention with the investigator.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomisation/dispensing has been done 
accurately.
6.4
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
When participants are dosed at the site, they will receive study intervention 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.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest) that the participant is 


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receiving at the time of enrolment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Preclinical in vitro data indicate that AZD9567 can inhibit drug transporters such as 
P-glycoprotein and breast cancer receptor protein. Therefore, digoxin should not be given 
together with the study intervention due to the risk for elevated plasma levels of digoxin. To 
avoid drug-drug interaction risks for statins (simvastatin, atorvastatin, rosuvastatin and 
fluvastatin) dose administration should be separated in time such as the AZD9567 is taken in 
the morning and the statin in the evening.
AZD9567 is metabolised via CYP3A4 and hence moderate and strong inhibitors or inducers 
of CYP3A should not be administered during this study since that will affect the plasma 
concentration of AZD9567. Participants should not have taken any of these medications 
within 3 days of IMP intake or 5 x t1/2, whichever is longer. Guidance is provided in 
Appendix F. However, the list in Appendix F is not a complete list, ie, it should be treated with 
caution.
Systemic corticosteroids should not be administered during this study.
If a patient is being considered for enrolment into the study and also being considered for 
COVID-19 vaccination, the patient must not be randomised until at least 30 days after the last 
dose of vaccine or booster.
Other medication considered necessary for the participant’s safety and well-being may be 
given at the discretion of the Investigator and recorded in the appropriate sections of the 
eCRF.
6.6
Intervention After the End of the Study
There will be no study intervention provided after the end of the study.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 


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study intervention. If study intervention is permanently discontinued, the participant will have 
the same assessments as at the Final visit and will be discharged with follow-up for any 
ongoing AEs or evaluations that need to be completed. See the SoA in Section 1.3 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. Note that discontinuation from study 
intervention is NOT the same thing as a withdrawal from the study.
If a participant tests COVID-positive during the washout period, they may delay entry into the 
next dosing period while they recover from COVID-19, and may enter the next treatment 
period if they are symptom free and PCR-negative.
There is limited data on potential interaction between COVID-19 vaccines and IMP. If 
COVID-19 vaccination is in the best interest of the participant and the participant is 
vaccinated during the study then the participant should be discontinued from study 
intervention and followed as part of the safety analysis population. No COVID-19 
vaccinations are allowed during the study treatment and within 7 days from treatment 
completion (last study dose of study treatment).
A participant will cease to receive any further investigational product if any of the following 
occur in the participant in question:
1
Withdrawal of consent from further treatment with study intervention or lost to follow-up
2
An AE or SAE that, in the opinion of the investigator or the sponsor, requires treatment 
withdrawal due to its nature, severity, or required treatment, regardless of the causal 
relationship to treatment
3
More than one episode of severe hypoglycaemia
4
Persistent symptomatic hyperglycaemia with FPG > 12 mmol/l (216 mg/dL)
5
Dose-limiting symptoms with respect to GI tolerability, even after measures are taken to 
reduce the risk of vomiting, after discussion with the Medical Monitor
6
QTcF > 500 ms
7
Participant noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
8
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately and 
the pregnancy reported to the sponsor
Participants who have not received study intervention, regardless of the reason, will not be 
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7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural,
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, an ET visit should be conducted, as 
shown in the SoA (Section 1.3). See SoA for data to be collected at the time of study 
withdrawal and follow-up and for any further evaluations that need to be completed.

The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she is still agrees 
for existing samples to be used in line with the original consent. If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken and not tested
should be carried in line with what was stated in the informed consent and local 
regulation The investigator must document the decision on use of existing samples in the 
site study records and inform the Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she 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 clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should 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 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 
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
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented and 
the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor 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 meet the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of the 
study will be approximately 600 mL. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
8.1
Enrolment and Screening Procedures
Enrolment and screening assessments are summarised in the SoA (Section 1.3). The 14-day 
screening period may be extended up to a maximum of 28 days to allow time for re-tests or 
washout of SGLT2i/DDP4i to be completed. Medical history, COVID-19 PCR, serology and 
symptoms, full physical examination, serology, urine drugs of abuse (see Table 7), alcohol 
(breath), safety ECG and laboratory tests, vital signs, FSH (females only), and pregnancy 
testing (females only) will be assessed for eligibility. Baseline ACTH, height, weight, 


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demography and use of concomitant medication will also be recorded.
There is a 20-day washout period between treatment periods. Inclusion/exclusion criteria will 
be checked before each treatment period. In addition, the site staff will call participants 
24 hours before each admission to the CRU to check for any COVID-19 symptoms. 
Participants should also be advised to call the site at any time if they experience any 
symptoms that could indicate COVID-19.
8.2
Pharmacodynamic Assessments
8.2.1
Continuous Glucose Monitoring (CGM)/Flash Glucose Monitoring 
(FGM)
CGM/FGM will be fitted on an outpatient basis on Day -4 and removed on Day 4 of treatment 
period 1 (Day 24 and Day 31, respectively for treatment period 2). Mean daily glucose will be 
determined from multiple measures using a CGM device at the time points specified in the 
SoA in Section 1.3.
8.2.2
Mixed Meal Tolerance Test (MMTT)
On Days -1, 4, 27, and 31, a standardised mixed meal (meal should be consumed as fast as the 
participant can, within 30 minutes) will be administered in the morning, around 0700, after an 
overnight fast of 12 hours. Blood samples will be taken according to the schedule in 
Section 1.3.1 for analysis of glucose, insulin, C-peptide, GLP-1, glucose-dependent insulin 
releasing polypeptide (GIP), glucagon and FFAs.
8.2.3
24-hour Urinary Sodium (U-Na) and Urinary Potassium (U-K)
On Days -1 and 3 and Days 27 and 30, the concentration of sodium and potassium in urine 
will be measured over 24 hours.
8.2.4
TNFα Concentrations 
On Day 3 and Day 30, blood samples will be obtained from Cohort 1 and Cohort 2 for the 
determination of TNFα according to the schedule in the SoA (Section 1.3). Samples will be 
collected according to instructions in the Laboratory Manual. The actual date and time of 
collection of each sample will be recorded. Samples for determination of TNFα concentrations 
with and without stimulation with LPS, using TrueCulture Lab System will be analysed by a 
designated laboratory on behalf of AstraZeneca.
 
 
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On Day 1 and Day 28, the following blood pressure and pulse rate variables will be collected 
before IMP dosing and approximately 1.5 hours after IMP dosing:
!
Systolic BP (mmHg)
!
Diastolic BP (mmHg)
!
Pulse (bpm)
Blood pressure will be measured in triplicate, with all readings averaged to give the 
measurement to be recorded in the eCRF.
The following temperature variable will be collected: 
!
Aural body temperature (ºC)
8.3.3
Electrocardiograms
A 10-second 12-lead safety ECG will be performed at timelines as specified in the SoA 
(Section 1.3), after 10 minutes’ supine rest. On Day 1 and Day 28, the safety ECG will be 
obtained before IMP dosing and approximately 1.5 hours after IMP dosing. The investigator 
will judge the overall interpretation as normal or abnormal and this evaluation will be reported 
in the eCRF. If abnormal, it will be further documented as to whether or not the abnormality is 
clinically significant by the investigator. For all abnormalities (regardless of clinical 
significance) the specific type and nature of the abnormality will be documented in the eCRF. 
Clinically significant findings should also be documented on the AE page of the eCRF if 
applicable. The investigator may add extra 12-lead resting ECG safety assessments if there are 
any abnormal findings or if the investigator considers it is required for any other safety reason. 
These assessments should be entered as an unscheduled assessment. All ECG readings will be 
digitally stored as source documents.
8.3.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry (including triglycerides and 
HDL-C), haematology, coagulation, urinalysis, and additional laboratory variables (HbA1c
[screening only], serum cortisol, ACTH,
 hCG, 24-hour U-Na and U-K, and 
FFAs) will be taken at the visits indicated in the SoA (Section 1.3).
AEs based on examinations and tests should be reported as described in Section 8.4.5.
The following laboratory variables will be measured.
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Table 6
Laboratory Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
White blood cell (WBC) total and differential count
Creatinine
Red blood cell (RBC) count
Bilirubin, total and direct
Platelet count
Alkaline phosphatase (ALP)
Haemoglobin (Hb)
Aspartate transaminase (AST)
Haematocrit (HCT)
Alanine transaminase (ALT)
Mean corpuscular volume (MCV)
Gamma glutamyl transpeptidase (GGT)
Mean corpuscular haemoglobin (MCH)
Potassium
Mean corpuscular haemoglobin concentration 
(MCHC)
Calcium, total
Neutrophils (absolute)
Sodium
Lymphocytes (absolute)
Uric acid
Monocytes (absolute)
Urea
Eosinophils (absolute)
Phosphate
Basophils (absolute)
Bicarbonate
Reticulocytes absolute count
High sensitivity C-reactive protein (hsCRP)
Urinalysis
Triglycerides
Blood
High-density lipoprotein-cholesterol (HDL-C)
Protein
TSH a
24-hour sodium and potassium
Serology
Glucose
Human immunodeficiency virus (HIV) I and II a
Creatinine
Hepatitis A virus (HAV) antibody a
Microscopy (if positive for protein or blood)
Hepatitis B surface antigen (HbsAg) a
Other
Hepatitis C virus (HCV) antibody a
COVID-19 polymerase chain reaction (PCR)
Tuberculosis a
HbA1C a
COVID-19
Glucose (fasting)
Pregnancy testing
Insulin
Human-beta chorionic gonadotrophin (hCG)
(blood and urine dipstick)
C-peptide
Follicle-stimulating hormone (FSH) (serum) a, b
Serum cortisolc
Coagulation
Adrenocorticotropic hormone (ACTH) c
International normalized ratio (INR)
Free fatty acids (FFAs)
Prothrombin time (PT)
Activated partial thrombin time (aPTT)
a
Screening only.
b
Females only. FSH assessment is for menopausal status.
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c
Collected from the fasting MMTT blood samples (-15 min) when MMTT is assessed at the same visit. For 
the MMTT a standardized mixed meal is to be provided around 07:00 on Day -1 and Day 4 (in each period). 
Serum cortisol, 
 and ACTH are to be collected from the fasting MMTT blood samples, 
which is -15 minutes prior to the mixed meal on Days -1 and 4 (in each period).
NB. In case a participant shows an AST or ALT ≥3xULN together with total bilirubin (TBL) 
≥2xULN please refer to Appendix E. Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law’, for further instructions.
8.3.5
Other Safety Assessments
8.3.5.1
Additional Screening Variables
Drugs of abuse and alcohol will be measured at screening and before each treatment period as 
shown in Table 7.
Table 7
Drugs of Abuse and Alcohol
Alcohol
Methamphetamine
Amphetamine
Opiates
Barbiturates
Propoxyphene
Benzodiazepines
Phencyclidine (PCP)
Cocaine
Cannabinoids
Methadone
Tricyclic anti-depressants (TCA)
Drugs of abuse screen will be done via a urine dipstick. Alcohol screen will be done via a breath sample.
8.4
Adverse Events and Serious Adverse Events
The 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.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.4.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse Events will be collected from time of signature of informed consent form throughout 
the treatment period, including the follow-up period, to the Final/ET visit (Visit 6).
SAEs will be recorded from the time of signing of the ICF.
If the investigator becomes aware of an SAE with a suspected causal relationship to the IMP
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that occurs after the end of the clinical study in a participant treated by him or her, the 
investigator shall, without undue delay, report the SAE to the sponsor.
8.4.2
Follow-up of Adverse Event and Serious Adverse Event
Any AEs that are unresolved at the participant’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further 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.
Adverse event variables
The following variables will be collected for each AE:

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity of the AE:

Intensity rating scale:
1 Mild (awareness of sign or symptom, but easily tolerated)
2 Moderate (discomfort sufficient to cause interference with normal activities)
3 Severe (incapacitating, with inability to perform normal activities)

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

AE caused participant’s withdrawal from 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 is serious due to (reason)

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)


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
Causality assessment to other medication
8.4.3 Causality Collection
The investigator should assess causal relationship between Investigational Product 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 investigational product?’
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 to the CSP.
8.4.4 Adverse Events Based on Signs and Symptoms
All AEs 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 visit/you were 
last asked?’, 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 Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
CSR.
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs 
ECGs, and other safety assessments should therefore only be reported as AEs if they fulfil any 
of the SAE criteria, are the reason for discontinuation of treatment with the investigational 
product or are considered to be clinically relevant as judged by the investigator (which may 
include but not limited to consideration as to whether treatment or non-planned visits were 
required or other action was taken with the study treatment, 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-
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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.4.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3xULN together with TBL ≥ 2xULN 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.
8.4.7
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel 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 works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 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 adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel 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 (or delegate).
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
8.4.8
Pregnancy
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
If the pregnancy is discovered before the study participant has received any study drug
8.4.8.1
Maternal Exposure
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately and the 
pregnancy reported to AstraZeneca.
8.4.8.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
3 months following the last dose.
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of the first dose until 3 months after 
the last dose and as indicated by previous studies (preclinical and clinical) should, if possible, 
be followed up and documented in the Pregnancy Report Form. Consent from the partner must 
be obtained before the Pregnancy Report Form is completed. 
8.4.9
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, 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 completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.4.7) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B.
8.5
Overdose
For this study, any dose of IMP greater than the dose intended to be given will be considered 
an overdose.

An overdose with associated AEs is recorded as the AE diagnosis/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
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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 data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see section 8.4.7) and within 30 days 
for all other overdoses.
8.6
Human Biological Samples
Instructions for the collection and handling of biological samples 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 Human Biological 
Sample see Appendix C.
8.6.1
Pharmacokinetics
Venous blood samples will be collected for measurement of plasma concentrations of 
AZD9567 and prednisolone as specified in the SoA in Section 1.3.
Plasma samples for evaluation of the PK of prednisolone will be collected in this study; these 
will be reported outside the CSR.
Samples may be collected at additional time points during the study if warranted and agreed 
upon between the investigator and the sponsor, eg, for safety reasons. The timing of sampling
may be altered during the course of 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. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. Pharmacokinetic samples may be disposed of or anonymised by 
pooling. Additional analyses may be conducted on the anonymised, pooled pharmacokinetic 
samples to further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the CSR.
8.6.1.1
Determination of Drug Concentration
Blood samples for determination of drug concentration of AZD9567 and prednisolone will be 
assayed 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 would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded (ie, at database 


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lock).
Incurred sample reproducibility analysis or additional assay development work, 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.
8.6.2
Immunogenicity Assessments (Not Applicable)
Immunogenicity will not be evaluated in this study.
8.6.3
Pharmacodynamics
8.6.3.1
Collection of Samples
Blood samples will be collected for measurement of TNFα (Section 8.2.4). Urine samples will 
be collected for measurement of 24-hour U-Na and U-K (Section 8.2.3).
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
For storage, re-use, and destruction of PD samples see Appendix C.
8.7
Human Biological Sample Biomarkers
8.7.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to participate in the study the participant consents to participate in the 
mandatory research components of the study. Samples for biomarker research are required and 
will be collected from all participants in this study as specified in the SoA (Section 1.3).
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 
For storage, re-use and destruction of biomarker samples see Appendix C. 
8.8
Optional Genomics Initiative Sample
Collection of optional samples for genomics initiative research is also part of this study as 
specified in the SoA and is subject to agreement in the ICF addendum. 
Blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study.
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual.


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For storage and destruction of genetic samples see Appendix D.
8.9
Health Economics/Medical Resource Utilisation and Health 
Economics (Not Applicable)
Health Economics/Medical Resource Utilisation and Health Economics parameters are not 
evaluated in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
This study aims to demonstrate that AZD9567 improves glucose homeostasis compared to 
oral prednisolone.
The null hypothesis for the primary analysis is that there is no difference in the change in 
glucose AUC(0-4) versus baseline in AZD9567 compared to prednisolone following a 
standardised MMTT. The following comparison will be performed:
!
72 mg AZD9567 versus 40 mg prednisolone in participants with T2DM (Cohort 1)
!
40 mg AZD9567 versus 20 mg prednisolone in participants with T2DM (Cohort 2)
!
Placebo versus 5 mg prednisolone in participants with T2DM (Cohort 3)
As this is a Phase 2a study, no adjustments for multiple testing will be performed. Cohorts 2 
and 3 are not powered, thus all significance testing should be considered exploratory.
 
 
 
 
 
 
 
 
 
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9.3
Populations for Analyses
The following populations are defined in Table 8.
Table 8
Populations for Analysis
Population/Analysis set
Description
All Enrolled Participants 
(ENR)
All participants who sign the ICF prior to any study-related procedures.
All Randomised Participants 
(RND)
All participants in the ENR randomised to one of the two sequence groups 
within a cohort. The ENR will be analysed according to the planned 
sequence or treatment.
Full Analysis Set (FAS)
All participants in the RND who received at least one dose of study 
intervention.
The FAS will be analysed according to the planned treatment and will be 
used as the primary population for reporting pharmacodynamic data and to 
summarize baseline characteristics. Any important deviations from 
randomised treatment will be listed and considered when interpreting the 
pharmacodynamic data.
Safety Analysis Set (SAF)
All participants in the RND who received at least one dose of study 
intervention.
The SAF will be analysed according to actual treatment.
Per Protocol Analysis Set (PP)
All participants in the FAS who did not have an important protocol 
deviation considered to have an impact on the analysis of the primary 
endpoint and who completed the study. The PP will be analysed according 
to the actual treatment received.
PK Analysis Set (PKAS)
All participants in the FAS with at least one quantifiable AZD9567 
concentration and no important protocol deviations, or AEs considered to 
have an effect upon PK. Participants may be excluded from the PK 
population if they have an AE of vomiting before 2x the median tmax of the 
group. Participants in the PKAS will be analysed according to the actual 
treatment.
This population will be defined by the Study Team Physician, 
Pharmacokineticist and Statistician prior to any analysis.
9.4
Statistical Analyses
The SAP will include a more technical and detailed description of the statistical analyses 
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described in this section. This section is a summary of the planned statistical analyses of the 
most important endpoints including primary and key secondary endpoints.
9.4.1
General Considerations
Analyses will be performed by Parexel, except for the derivation of PK parameters, which will 
be performed by Covance Clinical Pharmacokinetic Alliance.
Continuous data will be summarised using descriptive statistics (number of observations, 
mean, SD, median, 25th and 75th percentiles [where appropriate], minimum and maximum). 
For log-transformed data it is more appropriate to present geometric mean, geometric 
coefficient of variation, median, minimum and maximum. Frequencies and percentages will 
be used for summarising categorical (discrete) data. Time parameters (tmax, tlast, etc) will be 
presented as minimum, median, and maximum only.
Confidence intervals and p-values, when presented, will generally be constructed at the 
2-sided 95% level.
Unless otherwise stated, summaries will be presented by cohort and treatment. The treatment 
comparisons of interest are the different doses of AZD9567 versus the different doses of 
prednisolone and placebo versus 5 mg prednisolone. No formal comparisons between the 
different AZD9567 doses will be conducted. Similarly, no formal comparisons between the 
different prednisolone doses will be conducted.
In general, baseline will be defined as the last observation prior to study intervention in each 
period. The baseline for CGM/FGM will be the mean of all daily results prior to study 
intervention. Further details will be described in the SAP.
All statistical analyses will be conducted using SAS® version 9.4.
A complete set of raw data listings will be appended to the final CSR. All tables, figures and 
listings will be presented as PDF documents without any manual editing (ie, they will appear 
unmodified as programmed by means of the statistical package).
In general, there will be no imputation of missing data for the safety analyses. Additional 
details on missing data handling conventions will be provided in the SAP.
Deviations from the protocol will be assessed as “important” or “not-important”. Important 
deviations from the protocol may lead to the exclusion of participants from any of the study 
analysis sets. Deviations will be defined before database hard lock. Important deviations will 
include the following:

Violation of inclusion and/or exclusion criteria


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
Administration of prohibited concomitant medications that are expected to influence the 
measurement of the primary endpoint.

Receiving incorrect study intervention than randomised to.
All protocol deviations will be discussed at a data review meeting prior to database hard lock 
in order to define the analysis sets for the study. All important protocol deviations will be 
listed by participant. Further details will be provided in the SAP.
9.4.2
Pharmacodynamic Effects
9.4.2.1
Primary Endpoint(s)
The primary pharmacodynamic variable is the change from baseline in glucose AUC(0-4)
following a standardised MMTT.
The change from baseline in glucose AUC(0-4) will be analysed using a linear mixed model 
with baseline included as covariate. Treatment, period, and sequence will be included as fixed 
effects, with participant within sequence as random effect. Models will be run separately for 
each cohort.
The following comparisons will be performed:

72 mg AZD9567 versus 40 mg prednisolone (Cohort 1).

40 mg AZD9567 versus 20 mg prednisolone (Cohort 2).

Placebo versus 5 mg prednisolone (Cohort 3).
Should there be more than 10% of participants erroneously treated, a sensitivity analysis will 
be performed on the PP set.
Descriptive statistics and graphical presentations will be presented.
9.4.2.2
Secondary Endpoint(s)
Mean daily glucose as measured by CGM will be evaluated as a secondary endpoint.
The mean daily glucose will be analysed using an MMRM analysis with baseline as covariate.
Treatment, period, and sequence will be included as fixed effects, participant within sequence 
as random effect, and day as repeated measure. Models will be run separately for each cohort.
Similar analyses will be performed for the rise in mean daily glucose over 24-hour periods.
The secondary endpoints (insulin, glucagon, GLP-1, GIP), changes in FFAs during MMTT, 
C-peptide, 24-hour U-Na and U-K excretion and the ratio between them, ΔI10/ΔG10, ΔI30/ΔG30, 
ΔC10/ΔG10, ΔC30/ΔG30 and C-peptide will be summarised and analysed by means of a linear 
model or a mixed model for repeated measurements.


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LPS-stimulated whole blood TNFα levels will be evaluated as a secondary endpoint for 
participants in Cohort 1 and Cohort 2 (high and low dose comparison). For TNFα profiles, the 
AUC will be estimated and the measurements at the sampling points will be summarised. 
Descriptive statistics will be tabulated both for the AUC and individual measurement points
and treatments comparison will be conducted with ANOVA. Models will be run separately for 
each cohort.
Further details on statistical analyses will be provided in the SAP.
Descriptive statistics and graphical presentations will be presented as appropriate.
9.4.2.3
Tertiary/Exploratory Endpoint(s)
 
9.4.3
Safety
Safety will be assessed by descriptive analysis of AEs/SAEs, vital signs, ECGs and clinical 
laboratory assessments.
Serum cortisol and ACTH will be analysed in a similar manner to the TNFα secondary 
endpoint. Further details on statistical analyses will be provided in the SAP.
9.4.3.1
Adverse Events
The MedDRA will be used to code AEs.
The number of participants experiencing each AE will be summarised by the MedDRA system 
organ class and preferred term. The number and percentage of participants with AEs in each 
different category (eg, causally related, severe, etc) will be summarised, and events in each 
category will be further summarised by MedDRA system organ class and preferred term.
SAEs will be summarised separately if a sufficient number occur.
Any AE occurring before first study intervention will be included in the data listings but will 
not be included in the summary tables of AEs. AE summary tables will include only AEs 
occurring after start of study intervention (first dose).
Any AE occurring after last dosing and up to 21 days after discontinuation of study 
intervention, within each period, will be included in AE summaries. AEs occurring after 
21 days will be listed separately, but not included in summaries.
9.4.3.2
Deaths
Details of any deaths will be listed for all participants.
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9.4.3.3
Exposure
Details on study intervention administration will be provided in listings.
9.4.3.4
Other Safety Parameters
Physical examination findings, laboratory tests results (blood glucose, haematology, clinical 
chemistry and urinalysis), ECG findings and vital signs will be summarised using appropriate 
descriptive statistics, including observed results and changes from baseline as appropriate.
Time course of laboratory test results, vital signs and ECG data may be summarised 
graphically.
All analyses of safety outcomes will be performed on the SAF.
9.4.4
Pharmacokinetics
Pharmacokinetic analysis for AZD9567 will be performed by Covance Clinical 
Pharmacokinetic Alliance on behalf of AstraZeneca Research and Development. 
Pharmacokinetic parameters will be derived using standard non-compartmental methods using 
WinNonLin version 8.1 or higher (Certara). All descriptive and inferential statistics will be 
performed using SAS®, version 9.4.
Where possible the following PK parameters will be assessed for.
AUClast
Area under the plasma concentration versus time curve from zero to the last 
quantifiable concentration
AUC(0-24) Area under the plasma concentration versus time curve from zero to 24 hours 
post-dose
AUC(0-6)
Area under the plasma concentration versus time curve from zero to 6 hours 
post-dose
Cmax
Maximum observed drug concentration
tmax
Time to reach maximum observed drug concentration
t½λz
Terminal elimination half-life
CL/F
Apparent total body clearance of drug from plasma after extravascular 
administration
Vz/F
Apparent volume of distribution following extravascular administration
Additional PK parameters may be determined where appropriate.


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Further details regarding the calculation and descriptive statistics of the PK parameters will be 
detailed in the SAP.
9.4.5
Other Analyses 
Not applicable.
9.5
Interim Analysis
Two interim analyses are planned, conditional on the recruitment rate. A first interim analysis 
will be conducted when 50% of the participants of Cohort 1 have completed the study. A
second interim analysis is planned after completion of Cohort 1.
The purpose of the first interim analyses is to evaluate the feasibility of the assumptions and 
conduct sample size re-estimation if required. The second interim analysis serves as main 
statistical analysis for Cohort 1 and facilitates timely readout prior to finalisation of the 
exploratory cohorts 2 & 3.
Further details regarding the interim analyses will be provided in the SAP.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the clinical study protocol (CSP) and 
with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The CSP, CSP amendments, ICF, Investigator’s Brochure (IB), and other relevant 
documents (eg, advertisements) must be submitted to an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the CSP 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.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a 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.

The sponsor 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. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing 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.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
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A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant 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 will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study centre.

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.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the 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 human biological samples. 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 the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.


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
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
A 6
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the 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.

Monitoring details describing strategy (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 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organizations).

Study monitors will perform ongoing source data verification 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 CSP and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.


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
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 7
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 reported on the eCRF or 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 can be found in the source data agreement and 
computerised data check list for electronic source data.
A 8
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.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 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 the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the CSP, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development


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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(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 9
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 the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multi-centre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating 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
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a participant 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 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality 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 Serious AEs. 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-Serious AE. 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 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 serious AE, 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.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
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 


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intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a 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 


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information to make an informed judgment. 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 disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were 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, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS – including those which lead 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)


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
Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the medication 
error.


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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 study site keeps full traceability of collected biological samples from 
the participants while in storage at the centre until shipment or disposal (where appropriate) 
and records relevant processing information related to the samples while at 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 during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for donated biological samples 
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.
The investigator:

Ensures 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 organization(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 documented and study site notified.


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C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation 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 UN3373 and IATA 650
Exempt – 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.

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/whatwedo/cargo/dgr/Documents/DGR-60-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
Optional Genomics Initiative Sample
D 1
Use/analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic 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 blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained no longer than 15 years, or other period as per local 
requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population

All participants will be asked to participate in this genetic 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 genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and: Provide informed consent for the Genomics 
Initiative sampling and analyses.
Exclusion criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection

Healthy Volunteers and paediatric patient samples will not be collected for the 
Genomics Initiative.


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Withdrawal of consent for genetic research:  

Participants may withdraw from this genetic 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 Clinical Study Protocol.
Collection of samples for genetic research

The blood sample for this genetic research will be obtained from the participants at 
Visit 3, Day -2. Although DNA 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 Visit 3, Day -2, it may be taken at any visit until the 
last study visit. Only one sample should be collected per participant for genetics during 
the study.
Coding and storage of DNA samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is 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 sample either before or at the time of 
DNA extraction 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 genetics 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 DNA).

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 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and regulatory requirements

The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A.


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Informed consent

The genetic component of this study is optional and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study centre. The Principal investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time.
Participant data protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic 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 genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.

AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
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. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
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 (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug-Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, 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 PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified 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 PHL 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 ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
When a participant meets any of the PHL 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 PHL 
identification criteria are met, where this is the case the investigator will:

Notify the AstraZeneca representative 

Request a repeat of the test (new blood draw) by the central laboratory without 
delay

Complete the appropriate unscheduled 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 PHL criteria (see Section E 2 for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:


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
Inform the AstraZeneca representative that the participant has not met PHL 
criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP.
E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change# in the participant’s condition

The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ 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. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the Hy’s law lab kit should be used 

Complete the three Liver eCRF Modules as information becomes available 
#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 total bilirubin) 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 Physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.


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As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL 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 a 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 HL case, a causality assessment of
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides 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 CSP 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 


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whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP 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.
E 6
Laboratory tests
Hy’s Law lab kit for central laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HbsAg
HBV DNA a
HCV RNA a
IgG anti-HCV
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin) b
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 b
Transferrin saturation
a
HBV DNA is only tested when IgG anti-HBc is positive ; HCV RNA is only tested when IgG anti-HCV is 
positive or equivocal.
b
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
E 7
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.


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FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.


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Appendix F
Guidance for Restricted Medication
Tables below extracted from FDA webpage.
F 1
Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers
Table 5. Classification of In Vivo Inducers of CYP Enzymes (1) (7/28/2011)
CYP 
Enzymes 
Strong Inducers
≥ 80% decrease in 
AUC
Moderate Inducers
50-80% decrease in AUC
Weak Inducers
20-50% decrease in AUC
CYP3A
Avasimibe,(5) 
carbamazepine, 
phenytoin, rifampin, St. 
John’s wort(3)
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin
Amprenavir, aprepitant, 
armodafinil, echinacea,(4) 
pioglitazone, prednisolone, 
rufinamide
(1) Please note the following: This is not an exhaustive list. For an updated list, see the 
following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInt
eractionsLabeling/ucm080499.htm3. 
(2) For a drug that is a substrate of CYP1A2, the evaluation of the effect of induction of 
CYP1A2 can be carried out by comparative PK studies in smokers vs. non-smokers.
(3) The effect of St. John’s wort varies widely and is preparation-dependent.
(4) Herbal product.
(5) Not a marketed drug.
Classification of Inhibitors
Table 6. Classification of In Vivo Inhibitors of CYP Enzymes (1) (7/28/2011) 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm080499.htm2.
CYP 
Enzymes
Strong Inhibitors(2) 
≥ 5-fold increase in 
AUC or > 80% 
decrease in CL
Moderate inhibitors(3) 
≥ 2 but < 5-fold increase 
in AUC or 50-80% 
decrease in CL
Weak inhibitors(4) 
≥ 1.25 but < 2-fold increase 
in AUC or 20-50% 
decrease in CL
CYP3A
Boceprevir,
clarithromycin, 
conivaptan,
grapefruit juice,(11) 
Amprenavir, aprepitant,
atazanavir, ciprofloxacin,
darunavir/ritonavir, 
diltiazem, erythromycin, 
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine,


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CYP 
Enzymes
Strong Inhibitors(2) 
≥ 5-fold increase in 
AUC or > 80% 
decrease in CL
Moderate inhibitors(3) 
≥ 2 but < 5-fold increase 
in AUC or 50-80% 
decrease in CL
Weak inhibitors(4) 
≥ 1.25 but < 2-fold increase 
in AUC or 20-50% 
decrease in CL
indinavir, itraconazole, 
ketoconazole, 
lopinavir/ritonavir,
mibefradil, (12)
nefazodone, nelfinavir,
posaconazole, ritonavir, 
saquinavir, 
telaprevir,
telithromycin,
voriconazole
fluconazole, fosamprenavir, 
grapefruit juice,(11)
imatinib, verapamil
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo,(5) 
goldenseal,(5)
isoniazid, nilotinib,
oral contraceptives, 
ranitidine, ranolazine,
tipranavir/ritonavir, zileuton
1. Please note the following: This is not an exhaustive list. For an updated list, see the 
following link 
2. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a 
substrate for that CYP by equal or more than 5-fold. 
3. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC 
of a sensitive substrate for that CYP by less than 5-fold but equal to or more than 2-fold. 
4. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a 
sensitive substrate for that CYP by less than 2-fold but equal to or more than 5-fold. 
5. Herbal product. 
6. Gemfibrozil also inhibits OATP1B1. 
7. Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of 
omeprazole, which is also metabolised by CYP3A; fluconazole is a moderate CYP3A 
inhibitor. 
8. Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and 
CYP3A; 
9. Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2. 
10. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. 
11. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A 
inhibitor” when a certain preparation was used (eg, high dose, double strength) or as a 
“moderate CYP3A inhibitor” when another preparation was used (eg, low dose, single 
strength). 
12. Withdrawn from the United States market because of safety reasons.


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13. If a participant is being considered for enrollment into the study and also being considered 
for COVID-19 vaccination, the participant must not be randomised until at least 30 days 
after the last dose of vaccine or booster.
F 2
QT Prolonging Drugs Associated with Torsade de Pointes
Guidance regarding QT prolonging drugs associated with Torsade de Pointes can be found in: 
www.crediblemeds.org. 


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Appendix G
Abbreviations
Abbreviation or special 
term
Explanation
ACTH
Adrenocorticotropic hormone
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC(0-6)
Area under the plasma concentration versus time curve from zero to 6 hours 
post-dose
AUC(0-24)
Area under the plasma concentration versus time curve from zero to 24 hours 
post-dose
AUClast
Area under the plasma concentration versus time curve from zero to the last 
quantifiable concentration
BP
Blood pressure
CGM
Continuous glucose monitoring
CI
Confidence interval
CL/F
Apparent total body clearance of drug from plasma after extravascular 
administration
Cmax
Maximum observed drug concentration
CRO
Contract Research Organisation
CRP
C-reactive protein
CRU
Clinical Research Unit
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CYP3A4
Cytochrome P450 3A4
DAS
Disease Activity Score
DNA
Deoxyribonucleic acid 
DPP4i
Dipeptidyl peptidase 4 inhibitor
ECG
Electrocardiogram 
eCRF
Electronic Case Report Form
EDC
Electronic data capture
ET
End of treatment
FDA
U.S. Food and Drug Administration
FFA
Free fatty acid
FGM
Flash glucose monitoring
CCI


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Abbreviation or special 
term
Explanation
FPG
Fasting plasma glucose
FSH
Follicle-stimulating hormone
GC
Glucocorticoid
GCP
Good Clinical Practice
GI
Gastrointestinal
GIP
Glucose-dependent insulin releasing polypeptide
GLP-1
Glucagon-like peptide-1
glucose AUC(0-4)
Change in glucose area under the concentration-time curve over 4 hours
GMP
Good Manufacturing Practice
GR
Glucocorticoid receptor
HbA1c
Haemoglobin A1c
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HOMA-IR
Homeostatic model assessment-insulin resistance
HOMA-S
Homeostatic model assessment-insulin sensitivity
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICF
Informed consent form
IMP
Investigational medicinal product
IVRS/IWRS
Interactive Voice/Web Response System
LPS
Lipopolysaccharide 
MAD
Multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model repeated measures
MMTT
Mixed meal tolerance test
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
RA
Rheumatoid arthritis
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SGLT2i
Sodium-glucose co-transporter-2 inhibitor
SGRM
Selective glucocorticoid receptor modulator
SoA
Schedule of Activities


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Abbreviation or special 
term
Explanation
T2DM
Type 2 diabetes mellitus
TNFα
Tumour necrosis factor alpha
t½λz
Terminal elimination half-life
tmax
Time to reach maximum observed drug concentration
ULN
Upper limit of normal
U-K
Urinary potassium
U-Na
Urinary sodium
Vz/F
Apparent volume of distribution following extravascular administration


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Appendix H
Protocol Amendment History
Amendment 1 (14-Sep-2020)
Overall Rationale for the Amendment:
The protocol was amended following a request from the German regulatory authority to 
clarify the definition of end of study. In addition, corrections were made for the 
inconsistencies detailed in the protocol clarification letter dated 20 July 2020 and the schema 
was updated to better exemplify the double dummy study design.
Section # 
and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 4.4 
End of Study 
Definition
End of study was defined 
for individual participants 
and all participants
Definition for the end of study 
was requested by the German 
regulatory authority
Non-substantial
Section 1.2 
Schema 
Figure 1 updated to include 
placebos for active study 
intervention
To clarify the study design by 
including the placebos required 
to ensure the double-dummy 
design
Non-substantial
Section 1.1 
and Section 3 
Objectives 
and 
Endpoints
The endpoint relating to the 
pharmacodynamic (PD) 
objective determining the 
effect of AZD9567 
following a mixed meal 
tolerance text (MMTT) 
versus prednisolone was 
corrected as below 
(revision in bold):
Change from baseline 
AUC(0 4) on hormones 
related to glucose 
homeostasis (insulin, 
glucagon, glucagon-like 
peptide-1 [GLP-1], 
glucose-dependent insulin 
releasing polypeptide 
[GIP]) and free fatty acids 
(FFAs)
Free fatty acids (FFAs) are not 
hormones
Non-substantial
Section 1.1 
and Section 3 
Objectives 
and 
Endpoints
The endpoint relating to the 
PD objective to determine 
the effect of AZD9567 on 
glucose homeostasis 
through an MMTT versus 
prednisolone was corrected 
to remove change from 
Change in glucose AUC(0 4) 
versus baseline compared to 
prednisolone following a 
standardised MMTT is already 
included in the primary 
endpoint.
Non-substantial


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Section # 
and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
baseline in AUC(0-4) on 
plasma glucose.
Section 1.3 
Schedule of 
Activities 
and Section 
8.1 
Enrolment 
and 
Screening 
Procedures
Text relating to the 
extension of the screening 
period up to 28 days was 
clarified to include the text 
in bold below
[Screening may be 
extended]…to allow for 
re-tests or washout of 
SGLT2i/DDP4i to be 
completed.
The extension of the screening 
period is intended for both 
re-tests and washout of 
SGLT2i/DDP4i
Non-substantial
Appendix E6 
Laboratory 
Tests
HCV RNA added to Hy’s 
Law kit table and footnote a 
(HCV RNA is only tested 
when IgG anti-HCV is 
positive or equivocal). The 
footnote was also clarified 
to state HBV DNA is only 
tested when IgG anti-HBc 
is positive only (previously 
also stated inconclusive).
Hy’s Law kit for viral hepatitis 
includes HCV RNA
Non-substantial
Global
Minor editorial corrections 
(typos, formatting, etc).
Document quality
Non-substantial




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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase 2a Randomised, Double Blind, Multi-centre Study to 
Assess the Effect on Glucose Homeostasis of Two Dose Levels of 
AZD9567, Compared to Prednisolone, in Adults with Type 2 
Diabetes 
 
 
 
ClinicalTrials.gov Identifier: NCT04556760 
 
 
 
 
 
Statistical Analysis Plan: Final 3.0, 28 Oct 2021 


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Project Document Version No. Final 2.0
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Parexel International
AstraZeneca
D6470C00005
A Phase 2a Randomised, Double Blind, Multi-centre Study to Assess the Effect on Glucose 
Homeostasis of Two Dose Levels of AZD9567, Compared to Prednisolone, in Adults with 
Type 2 Diabetes
Statistical Analysis Plan
Version: Final 3.0
Parexel Project Number: 
CCI
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SPONSOR SIGNATURE PAGE
Approved by:
_________________________
_______________
Date
Global Product Statistician
AstraZeneca
PPD
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TABLE OF CONTENTS
1
INTRODUCTION ................................................................................................................. 9
2
OBJECTIVES AND ENDPOINTS...................................................................................... 10
3
INVESTIGATIONAL PLAN .............................................................................................. 12
3.1
Overall Study Design and Plan.................................................................................... 12
3.2
Variables associated to the different endpoints............................................................ 14
3.2.1
Pharmacodynamic Variables .................................................................................. 14
3.2.2
Safety and Tolerability Variables............................................................................ 15
3.2.3
Pharmacokinetic Variables ..................................................................................... 20
4
STATISTICAL METHODS ................................................................................................ 21
4.1
Data Quality Assurance............................................................................................... 21
4.2
General Presentation Considerations ........................................................................... 21
4.3
General Variables ....................................................................................................... 23
4.3.1
Study Day Definitions ............................................................................................ 23
4.3.2
Handling of Missing Data....................................................................................... 23
4.3.2.1 Imputations of Partial Medication and AEs Dates................................................... 23
4.3.3
Imputation Rules for Laboratory Values Outside of Quantification Range.............. 24
4.4
Software Programs...................................................................................................... 24
4.5
Study Patients ............................................................................................................. 24
4.5.1
Disposition of Patients............................................................................................ 24
4.5.2
Protocol Deviations ................................................................................................ 25
4.6
Analysis Sets .............................................................................................................. 26
4.7
Demographics and Baseline Characteristics ................................................................ 26
4.8
Baseline, change from baseline and percentage change from baseline definitions........ 27
4.9
Medical History .......................................................................................................... 29
4.10 Prior and Concomitant Medications, and other treatments........................................... 29
4.11 Safety and Tolerability Evaluation .............................................................................. 30
4.11.1
Adverse Events....................................................................................................... 30
4.11.2
Deaths and Serious Adverse Events........................................................................ 31
4.11.3
Clinical Laboratory Evaluation............................................................................... 31
4.11.4
Vital Signs, ECGs .................................................................................................. 32
4.11.5
Morning serum cortisol and ACTH......................................................................... 32
4.12 Pharmacodynamics and Pharmacokinetics .................................................................. 33
4.12.1
Analysis and Data Conventions .............................................................................. 33
4.12.1.1 Multi-center Studies ............................................................................................... 33
4.12.1.2 Handling of Dropouts or Missing Data ................................................................... 33
4.12.1.3 Interim Analyses .................................................................................................... 33
4.12.2
Pharmacodynamics................................................................................................. 34
4.12.3
Pharmacokinetics ................................................................................................... 44
4.12.3.1 Concentrations ....................................................................................................... 44
4.12.3.2 Pharmacokinetic Parameters................................................................................... 45
4.13 Other Analyses ........................................................................................................... 47
4.14 Determination of Sample Size..................................................................................... 47
4.15 Changes in the Conduct of the Study or Planned Analysis........................................... 48
5
REFERENCES .................................................................................................................... 49
6
APPENDICES..................................................................................................................... 50
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6.1
Schedule of Activities ................................................................................................. 50
6.2
Blood Sampling Schedule for Mixed Meal Tolerance Tests (MMTTs)........................ 56
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REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
Draft 0.1
Dec 08, 2020
New document
Draft 0.2
Jan 26, 2021
Analysis sets redefined, certain sections updated
Draft 0.3
Feb 14, 2021
Updates based on version 3.0 of the draft Protocol Amendment 
2 (dated 10 Feb 2021)
Draft 0.4
March 04, 2021
Updates based on AZ comments
Draft 0.5
March 12, 2021
Updates based on AZ comments
Final 1.0
April 28, 2021
Updated based on PXL and AZ comments
Final 1.0
May 24,2021
Updated based on PXL and AZ comments during interim 
analysis n 1.
Final 2.0
Aug 16, 2021
Removal of figures that are not require for CSR.
Removed requirement that each cohort should be presented as 
a separate output.
Final 3.0
Oct 28, 2021
Update the Statistical Analysis Plan (SAP) to v3.0 in order to 
re-insert texts which had been included in SAP v1.0 but 
erroneously had been deleted in SAP v2.0.
Note: This does not mean a change to the planned analysis but 
the correction of an error.
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LIST OF ABBREVIATIONS
Abbreviation
Explanation
ACTH
Adrenocorticotropic hormone
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ANOVA 
Analysis of variance
AST
Aspartate transaminase
AUC(0-4)
Area under the curve from zero to 4 hours post-dose
AUC(0-6)
Area under the plasma concentration versus time curve from zero to 6 hours post-dose
AUC(0-24)
Area under the plasma concentration versus time curve from zero to 24 hours post-dose
AUClast
Area under the plasma concentration versus time curve from zero to the last quantifiable 
concentration
BLQ
Below the lower limit of quantification
BP
Blood pressure
CfB
Change from baseline
CGM
Continuous glucose monitoring
CI
Confidence interval
CL/F
Apparent total body clearance of drug from plasma after extravascular administration
Cmax
Maximum observed drug concentration
CRO
Contract Research Organization
CRP
C-reactive protein
CRU
Clinical Research Unit
CSP
Clinical Study Protocol
gCSR
Clinical Study Report
CSRHLD
Standards for reporting clinical data in a Clinical Study Report or Higher Level Document
CV
Coefficient of variation
CYP3A4
Cytochrome P450 3A4
DAS
Disease Activity Score
DBP
Diastolic blood pressure
DNA
Deoxyribonucleic acid
DPP4i
Dipeptidyl peptidase 4 inhibitor
ECF
Extracellular fluid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic data capture
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ENR 
All enrolled subjects
ET
End of treatment
FAS 
Full Analysis Set
FDA
U.S. Food and Drug Administration
FFA
Free fatty acid
FGM
Flash glucose monitoring
FPG
Fasting plasma glucose
FSH
Follicle-stimulating hormone
GC
Glucocorticoid
GCP
Good Clinical Practice
GI
Gastrointestinal
GIP
Glucose-dependent insulin releasing polypeptide
GLP-1
Glucagon-like peptide-1
glucose AUC(0-4)
Change in glucose area under the concentration-time curve over 4 hours
GMP
Good Manufacturing Practice
GR
Glucocorticoid receptor
HbA1c
Haemoglobin A1c
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HOMA-IR
Homeostatic model assessment-insulin resistance
HOMA-S
Homeostatic model assessment-insulin sensitivity
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICF
Informed consent form/Intercellular fluid
IMP
Investigational medicinal product
IPD
Important Protocol Deviation
IVRS/IWRS
Interactive Voice/Web Response System
LMM
Linear mixed model
LPS
Lipopolysaccharide
MAD
Multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measures
MMTT
Mixed meal tolerance test
NC
Not calculable
PD
Pharmacodynamic(s)
PP
Per Protocol Analysis Set
PK
Pharmacokinetic(s)
PKAS
PK Analysis Set
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RA
Rheumatoid arthritis
RND
All randomised subjects
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SGLT2i
Sodium-glucose co-transporter-2 inhibitor
SGRM
Selective glucocorticoid receptor modulator
SoA
Schedule of Activities
T2DM
Type 2 diabetes mellitus
TBW
Total body water
TLFs
Tables, listings and figures
TNFα
Tumour necrosis factor alpha
t1/2λz
Terminal elimination half-life
tmax
Time to reach maximum observed drug concentration
ULN
Upper limit of normal
U-K
Urinary potassium
U-Na
Urinary sodium
Vz/F
Apparent volume of distribution following extravascular administration
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1
INTRODUCTION
AZD9567 is a glucocorticoid receptor (GR) modulator that shows promising separation between 
anti-inflammatory and dysglycaemic effects in preclinical studies and in two dose escalation studies 
in healthy volunteers (D6470C00001 and D6470C00002). In addition, in a study in patients with 
active RA (rheumatoid arthritis) (D6470C00003), 40 mg AZD9567 resulted in a similar profile in 
term of efficacy effects to prednisolone 20 mg following 14 days of once daily dosing. The aim of 
this study is to assess the effect on glycaemic control of AZD9567 as compared to prednisolone in a 
more relevant patient population.
The doses used (40 mg AZD9567 [equipotent to 20 mg prednisolone] and 72 mg AZD9567 
[equipotent to 40 mg prednisolone]) were chosen based on studies D6470C00001 and D6470C00002 
(equipotency was based on ex-vivo lipopolysaccharide [LPS] stimulated tumor necrosis factor alpha 
[TNFα] release in whole blood). In study D6470C00002, the effect of several doses of AZD9567 up 
to 80 mg (equipotent to 45 mg prednisolone) on plasma glucose was investigated and compared with 
prednisolone. After an OGTT (oral glucose tolerance test), the AUC(0-4) (area under the curve) was 
measured. The result showed that the effect of AZD9567 80 mg on glucose was similar to the lower 
dose of 5 mg prednisolone despite being equipotent to 45 mg prednisolone.
The analyses described in this SAP (Statistical analysis plan) are based upon the following study 
documents:
!
Clinical Study Protocol Amendment 2 (v3.0), dated 03 March 2021
!
Electronic Case Report Form (eCRF), Version 1.0 (October 27, 2020)
!
AZ Corporate CSRHLD Reporting Standards v3.3
!
The following AZ templates:
o
AZ Corporate CSRHLD Tables Templates v3.5
o
AZ Corporate CSRHLD Figures Templates v3.2
o
AZ Corporate CSRHLD Listings Templates v1.4
o
AZ Corporate CSRHLD Reporting Standards v3.3.
o
AZ Respiratory CSR/HLD Figure Template
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to follow-up) is 79 days; the study duration may be extended for screening and Wash-out (see the 
Schedule of Activities -SoA-).
There will be three two-way cross-over cohorts, with three different dose combinations (72 mg 
AZD9567/40 mg prednisolone, 40 mg AZD9567/20 mg prednisolone and placebo/5 mg 
prednisolone):
!
Cohort 1: participants will be randomised in a ratio of 1:1 to receive AZD9567 and prednisolone 
over two 72-hour periods in a cross-over design (72 mg AZD9567 followed by 40 mg 
prednisolone [AB sequence group] or 40 mg prednisolone followed by 72 mg AZD9567 [BA 
sequence group]). There will be a 3-week Wash-out period between treatment periods. (N = 24 
completed [12 in each sequence group].)
!
Cohort 2: participants will be randomised in a ratio of 1:1 to receive AZD9567 and prednisolone 
over two 72-hour periods in a cross-over design (40 mg AZD9567 followed by 20 mg 
prednisolone [AB sequence group] or 20 mg prednisolone followed by 40 mg AZD9567 [BA 
sequence group]). There will be a 3-week Wash-out period between treatment periods. (N = 8 
completed [4 in each sequence group].)
!
Cohort 3: participants will be randomised in a ratio of 1:1 to receive placebo and prednisolone 
over two 72-hour periods in a cross-over design (placebo followed by 5 mg prednisolone [AB 
sequence group] or 5 mg prednisolone followed by placebo [BA sequence group]). There will 
be a 3-week Wash-out period between treatment periods. (N = 8 completed [4 in each sequence 
group].)
With the exception of the SoA, where the headings of visits 4 and 5 include both the day within the 
study and within each period (such as 26 and -2 for the same day), all days in this document refer 
to days within each period. As an illustration, Day 28 in the study is only referred to as Day 1 in 
this document. 
In treatment period 1, participants will be fitted with a continuous glucose monitoring/flash glucose 
monitoring (CGM/FGM) device on Day -4 on an Out-patient’ basis. Within each treatment period, 
participants will be admitted to the CRU on Day -2. On Day -1, they will have a baseline MMTT. 
Dosing of IMP will occur on Days 1 to 3. The CGM/FGM device will be removed on Day 4. 
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Participants will have an MMTT in the morning of Day 4, before being discharged from the CRU 
in the afternoon of Day 4. 
3.2
Variables associated to the different endpoints.
As stated in section 3.1, Days refer to those within each treatment period (eg, Days 24, 26, 
27, 28, 39, 30, 31 in the study referred to as Day -4, -2, -1, 1, 2, 3 and 4). 
3.2.1
Pharmacodynamic Variables
Continuous Glucose Monitoring (CGM)/Flash Glucose Monitoring (FGM)
A CGM/FGM device will be fitted on an Out-patient’ basis on Day -4 and removed on Day 4. 
Mean daily glucose will be determined from multiple measures.
Mixed Meal Tolerance Test (MMTT)
On Days -1 and 4, a standardised mixed meal (meal should be consumed as fast as the 
participant can, within 30 minutes) will be administered around 07:00 a.m., after an overnight 
fast of 12 hours. Blood samples will be taken according to the schedule in section 6.2 for 
analysis of glucose, insulin, C-peptide, Glucagon-like peptide-1 (GLP-1), Glucose-dependent 
insulin releasing polypeptide (GIP), glucagon and free fatty acids (FFAs).
24-hour Urinary Sodium (U-Na) and Urinary Potassium (U-K)
On Days -1 and 3, sodium and potassium concentrations in urine will be measured over 24 
hours.
TNFα Concentrations 
On Day 3, TNFα concentrations in blood will be measured and analysed with and without 
stimulation with LPS in Cohorts 1 and 2.
 
 
 
 
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3.2.2
Safety and Tolerability Variables
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant or by a caregiver, surrogate, or the 
participant’s legally authorised representative.
Time Period and Frequency for Collecting AE and SAE Information
Adverse Events will be collected from time of signature of the informed consent form 
throughout the treatment period, including the follow-up period, to the Final/ET visit.
Serious adverse events will be recorded from the time of signing of the ICF.
Adverse event variables
The following variables will be collected:
!
AE (verbatim)
!
The date and time when the AE started and stopped
!
Maximum intensity of the AE:
o 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)
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!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product(s) 
(yes or no)
!
Action taken with regard to Investigational Product(s)
!
AE caused participant’s withdrawal from 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 is serious due to (reason)
!
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.
Causality Collection
The investigator should assess causal relationship between Investigational Product 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 investigational product?’.
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’.
Adverse Events Based on Signs and Symptoms
All AEs 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 visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
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collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
Adverse Events Based on Examinations and Tests
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs 
ECGs, and other safety assessments should therefore only be reported as AEs if they fulfil any 
of the SAE criteria, are the reason for discontinuation of treatment with the investigational 
product or are considered to be clinically relevant as judged by the investigator (which may 
include but not limited to consideration as to whether treatment or non-planned visits were 
required or other action was taken with the study treatment, 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 assessment will be reported as an AE unless unequivocally 
related to the disease under study.
Physical Examinations
A complete examination will include: general appearance, respiratory, cardiovascular, 
abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 
muscular-skeletal (including spine and extremities), and neurological systems.
A brief examination will include, at a minimum, assessments of the skin, lungs, cardiovascular 
system, and abdomen (liver and spleen).
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Height and weight
Height and weight will be assessed at the times specified in the SoA. In addition, as detailed 
in section 3.2.1, weight will be assessed Each time the 
 device is used.
Vital Signs
Vital signs will be assessed after the participant has rested in the supine position for ≥10 
minutes at the times specified in the Schedule of Activities:
!
Systolic BP (mmHg)
!
Diastolic BP (mmHg)
!
Pulse (bpm).
Blood pressure will be measured in triplicate, with all readings averaged to give the 
measurement to be recorded in the eCRF.
Aural body temperature (ºC) will also be measured.
Electrocardiograms
A 12-lead ECG will be performed after 10 minutes’ supine rest at the times specified in the 
Schedule of Activities. The investigator will interpret the overall results as normal or 
abnormal and, if abnormal, whether or not it is clinically significant.
The type and nature of abnormalities will be documented whereas clinically significant 
findings will be recorded as AEs, if applicable. 
Additional ECG unscheduled assessments may be performed by the investigator.
As detailed in the eCRF, the following parameters will be assessed in 12-lead ECGs:
RR-interval (msec)
QRS-interval (msec) 
QT-interval (msec)
QT-interval corrected using the Fridericia correction formula (QTcF) (msec)
Heart rate (beats per minute [bpm]).
The ECG will be evaluated by the Investigator as ‘Normal’ or ‘Abnormal’.
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Clinical Safety Laboratory Assessments
Blood and urine samples for the determination of clinical chemistry (including triglycerides 
and HDL-C), haematology, coagulation, urinalysis, and additional laboratory variables 
(HbA1c [screening only], serum cortisol, ACTH, 
 hCG, 24-hour U-Na and 
U-K, and FFAs) will be taken.
AEs based on examinations and tests should be reported as described in Section 8.4.5 of the 
CSP.
Laboratory Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
White blood cell (WBC) total and differential count
Creatinine
Red blood cell (RBC) count
Bilirubin, total and direct
Platelet count
Alkaline phosphatase (ALP)
Haemoglobin (Hb)
Aspartate transaminase (AST)
Haematocrit (HCT)
Alanine transaminase (ALT)
Mean corpuscular volume (MCV)
Gamma glutamyl transpeptidase (GGT)
Mean corpuscular haemoglobin (MCH)
Potassium
Mean corpuscular haemoglobin concentration (MCHC)
Calcium, total
Neutrophils (absolute)
Sodium
Lymphocytes (absolute)
Uric acid
Monocytes (absolute)
Urea
Eosinophils (absolute)
Phosphate
Basophils (absolute)
Bicarbonate
Reticulocytes absolute count
High sensitivity C-reactive protein (hsCRP)
Urinalysis
Triglycerides
Blood
High-density lipoprotein-cholesterol (HDL-C)
Protein
TSH a
24-hour sodium and potassium
Serology
Glucose
Human immunodeficiency virus (HIV) I and II a
Creatinine
Hepatitis A virus (HAV) antibody a
Microscopy (if positive for protein or blood)
Hepatitis B surface antigen (HbsAg) a
Other
Hepatitis C virus (HCV) antibody a
COVID-19 polymerase chain reaction (PCR)
Tuberculosis a
HbA1C a
COVID-19
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Laboratory Variables
Glucose (fasting)
Pregnancy testing
Insulin
Human-beta chorionic gonadotrophin (hCG) (blood and 
urine dipstick)
C-peptide
Follicle-stimulating hormone (FSH) (serum) a, b
Serum cortisolc
Coagulation
Adrenocorticotropic hormone (ACTH) c
International normalized ratio (INR)
Free fatty acids (FFAs)
Prothrombin time (PT)
Activated partial thrombin time (aPTT)
 
a
Screening only.
b
Females only. FSH assessment is for menopausal status.
c
Collected from the fasting MMTT blood samples (-15 min) when MMTT is assessed at the same visit. For the 
MMTT a standardised mixed meal is to be provided around 07:00 on Day -1 and Day 4 (in each period). Serum 
cortisol, 
 and ACTH are to be collected from the fasting MMTT blood samples, which is -15 
minutes prior to the mixed meal on Days -1 and 4 (in each period).
3.2.3
Pharmacokinetic Variables
Pharmacokinetic analysis for AZD9567 will be performed by Covance Clinical Pharmacokinetic 
Alliance. Pharmacokinetic parameters will be derived using standard non-compartmental methods 
using WinNonLin version 8.1 or higher (Certara).
The following PK parameters will be calculated:
!
AUClast
Area under the plasma concentration versus time curve from zero to the last 
quantifiable concentration
!
AUC(0-24)
Area under the plasma concentration versus time curve from zero to 24 hours 
post-dose
!
AUC(0-6)
Area under the plasma concentration versus time curve from zero to 6 hours 
post-dose
!
Cmax Maximum observed drug concentration
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!
tmax
Time to reach maximum observed drug concentration
!
t½λz
Terminal elimination half-life
!
CL/F
Apparent total body clearance of drug from plasma after extravascular administration
!
Vz/F
Apparent volume of distribution following extravascular administration.
Additional PK parameters may be determined.
The following diagnostic parameters will be listed but not summarised:
!
λz lower
Lower (earlier) t used for λz determination
!
λz upper
Upper (later) t used for λz determination
!
λzN
Number of data points used for λz determination
!
λz span ratio
Time period over which λz was determined as ratio of t½
!
Rsq_adj  
Statistical measure of fit for the regression used for λz determination 
adjusted for the number of used data points (n obs).
4
STATISTICAL METHODS
4.1
Data Quality Assurance
TLFs in the report will be checked for consistency, integrity and in accordance with standard Parexel
procedures.
4.2
General Presentation Considerations
Summary tables will include the results of each planned sequence in the case of the all randomised 
subjects set (RND), planned treatment in the case of the Full Analysis Set (FAS) or actual treatment 
in the case of the Safety Analysis Set (SAF), Per Protocol Analysis Set (PP) and the PK Analysis Set 
(PKAS).
Non-PK continuous data will be summarised in terms of number of observations, the mean, standard 
deviation (SD), median, 25th and 75th percentiles (where appropriate), minimum, maximum. In the 
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case of PK data, the Pharmacokinetics section of this SAP lists the statistics included in the summary 
tables.
For continuous data, the mean, median and geometric mean will be rounded to one additional decimal 
place compared to the original data. The SD and geometric coefficient of variation (CV) will be 
rounded to two additional decimal places compared to the original data. Minimum and maximum will 
be displayed with the same accuracy as the original data. The maximum number of decimal places 
reported will be four for any summary statistic.
One decimal will be presented for the geometric CV % included in the PK summary tables.
Categorical data will be summarised in terms of the number of participants, frequency counts and 
percentages.
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts. 
Percentages will be calculated using n as the denominator (participants included in the analysis sets
or number of non-missing values).
Confidence intervals (CIs) will be presented to one additional place than the original data. P-values 
greater than or equal to 0.001, in general, will be presented to three decimal places. P-values less than 
0.001 will be presented as “<0.001”.
Unless otherwise noted, for the calculation of a change from baseline, the last reliable assessment (in 
the case of blood pressure, the average of triplicate assessments) prior to the first dose of each study 
treatment will be considered the baseline measurement.
In the case of assessments at scheduled timepoints, the post-baseline scheduled or non-scheduled 
reliable assessment closest to the timepoint will be used. If two post-dose assessments are equidistant 
from a timepoint, the earlier of the two will be used. 
All glucose values will be presented in mmol/L. The following formula will be used for the 
conversion of glucose concentrations from mg/dL to mmol/L:
Glucose (mmol/L) = Glucose (mg/dL) x 0.0555
All analyses of pharmacodynamics endpoints involving a linear mixed model will be run separately 
for each cohort.
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Change from baseline and percent change from baseline
The change from baseline at each visit will be calculated as:
Change from baseline at visit X = absolute value at visit X-baseline value
The percent change from baseline will be calculated as:
Percent change from baseline = (change from baseline/baseline value) ×100%
If either a visit value or the baseline visit value is missing, the change from baseline value and the 
percent change from baseline will be set to missing.
4.3
General Variables
4.3.1
Study Day Definitions
Study day 1 is defined as the date of first dose of study treatment within each treatment period. Within 
each treatment period, for visits (or events) prior to first dose, study day is defined as ‘date of visit 
[event] – date of first dose of study treatment’. For visits (or events) that occur on or after first dose 
of study treatment, study day is defined as ‘date of visit [event] – date of first dose of study treatment 
+ 1’.
“Days since last dose” is defined as ‘date of visit [event]– date of last dose of study treatment’ where 
“date of last dose” is defined as the date of dosing immediately preceding the event occurrence.
4.3.2
Handling of Missing Data
Unless otherwise stated, missing data will not be imputed.
4.3.2.1
Imputations of Partial Medication and AEs Dates
There will be no imputation of any incomplete dates.
The following rules will be used to determine whether or not an AE has taken place on-treatment:
1. An AE starting from last dose plus 21 days will be considered on-treatment.
2. An AE with an incomplete start date and whose end date is not prior to the time of dosing on 
Day 1 will be considered to have taken place on-treatment unless the non-missing components 
of the incomplete start date indicate that the start date falls outside the time from dosing on 
Day 1 to last dose plus 21 days.
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The following rules will be used to assign concomitance to a medication:
1. Exclusively prior medications are those that started and stopped prior to the first dose of the 
investigational medicinal product (IMP) in the first treatment period and those that started 
and stopped after 21 days after the last dose in the first period and before the first dose of 
IMP in the second period. Medications taken between the first dose and up to 21 days after 
the last dose in any period are concomitant (including medications that started prior to dosing 
and continued after) 
2. A medication with incomplete start and/or end dates will be considered concomitant unless 
the non-missing components of the incomplete dates indicate that the intake of the medication 
did not take place between Day 1 and the last dose plus 21 days.
AEs and medications with completely missing end dates will be assumed to be ongoing.
4.3.3
Imputation Rules for Laboratory Values Outside of Quantification Range
Values of the form “< x” (i.e., below the lower limit of quantification [LLoQ]) or “> x” (i.e., above
the upper limit of quantification [ULoQ]) will be imputed as “x” in the calculation of summary
statistics but displayed as “< x” or “> x” in the listings.
4.4
Software Programs
All report outputs will be produced using SAS® version 9.4 in a secure and validated environment.
PK analyses will be produced using Phoenix® WinNonLin (WNL) version 8.1 or later in a secure 
and validated environment.
All report outputs will be provided to the Sponsor. Tables and figures will be combined in one PDF 
document and listings in another.
4.5
Study Patients
4.5.1
Disposition of Patients
A listing will be created for subjects discontinued from the study using the ENR. An additional 
listing will be created for subjects completing the study using the RND. Both listings will include 
the standardised disposition term and the date of disposition event.
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A summary table will be created and will include, in addition to the number of patients enrolled, the 
number and percentage of patients who:
!
were randomised
!
were not randomised
!
received at least a dose of the first treatment
!
completed the first treatment
!
discontinued the first treatment
!
received at least a dose of the second treatment
!
completed the second treatment
!
discontinued the second treatment
!
completed study
!
were withdrawn from the study for any reason (one row in the table for all reasons)
!
were withdrawn from the study for each reason (one row in the table for each reason).
4.5.2
Protocol Deviations
Important protocol deviations (IPD) may lead to the exclusion of participants from the PP and the 
PKAS. Deviations will be defined before database lock. Important deviations will include the 
following:
!
Violation of inclusion and/or exclusion criteria
!
Administration of prohibited concomitant medications expected to influence the primary 
endpoint
!
Receiving incorrect study intervention than randomised to.
All protocol deviations will be discussed at a data review meeting prior to database lock in order to 
define the analysis sets for the study. All IPDs will be listed by participant.
The Protocol Deviation Specifications will be followed to assess which protocol deviations are 
important in a Data Review Meeting (DRM) shortly before database lock/unblinding. A DRM report 
detailing the assessment of protocol deviations, AEs, the assignment of participants to analysis sets
and the exclusion of data from specific analyses will be signed by all scientific experts.
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The number and percentage of patients in the FAS meeting each IPD criterion will be summarised 
by cohort. Patients deviating from an IPD more than once will be counted once for that criterion. 
Any patients who have more than one IPD will be counted once in the overall summary. 
The number of enrolled patients included/excluded from each of the analysis sets will be
summarised. Patients and data excluded from each analysis set will be listed with the reason (such 
as the specific IPDs or AEs) for exclusion.
4.6
Analysis Sets
The following sets are defined:
Population/Analysis set
Description
All enrolled subjects (ENR)
All participants who signed informed consent prior to any study-related procedures.
All randomised subjects (RND)
All participants in the ENR randomised to one of the two sequence groups within a
cohort. The ENR will be analysed according to the planned sequence or treatment.
Full Analysis Set (FAS)
All participants in the RND who received at least one dose of study intervention.
The FAS will be analysed according to the planned treatment and will be used as 
the primary population for reporting pharmacodynamic data and to summarize 
baseline characteristics. Any important deviations from randomised treatment will 
be listed and considered when interpreting the pharmacodynamic data.
Safety Analysis Set (SAF)
All participants in the RND who received at least one dose of study intervention. The 
SAF will be analysed according to the actual treatment.
Per Protocol Analysis Set (PP) 
All participants in the FAS who did not have an important protocol deviation 
considered to have an impact on the analysis of the primary endpoint and who 
completed the study. The PP will be analysed according to the actual treatment
received.
PK Analysis Set (PKAS)
All participants in the FAS with at least one quantifiable AZD9567 concentration and 
no important protocol deviations, or AEs considered to have an effect upon PK. 
Participants may be excluded from the PK population if they have an AE of vomiting 
before 2x the median tmax of the group. The PKAS will be analysed according to the 
actual treatment.
4.7
Demographics and Baseline Characteristics
Demographic characteristics (age, sex, race, ethnicity, country) and baseline patient characteristics 
(height, weight and BMI) will be listed and will be summarised by cohort in the SAF and FAS. In 
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addition to presenting descriptive statistics for age, the summary table will present the number and 
percentage of patients per age group (18-44, 45-64 and 65-75 years).
4.8
Baseline, change from baseline and percentage change from baseline definitions
Demography and baseline characteristics
For demography and baseline characteristics other than weight, the baseline will be the assessment 
at screening. For weight, the baseline will be the assessment at Day -1 performed by means of the 
 device. If the weight at Day -1 is missing, the weight at Day -2 (or at Screening, in the case of 
period 1 if the value at Day -2 is also missing) will be the baseline for such a period.
Pharmacodynamics
Change in AUC(0-4) 
In the case of the linear mixed models for the change from baseline in glucose AUC(0-4) (primary 
endpoint), hormones related to glucose homeostasis (insulin, glucagon, GLP-1, GIP), FFAs and C-
peptide (secondary endpoints), the baseline measurement will be the AUC(0-4) on Day -1 (i.e., prior 
to first dosing) of each period.
Glucose concentrations assessed by CGM
For the calculation of the rise in mean glucose and the mean daily glucose, the baseline will be the 
average of the values from -24 hours to first dosing on Day 1 (values from -72 to -24 hours will be 
excluded from the baseline) of each period.
For the MMRM for the rise in mean glucose and the mean glucose, the baseline included as a 
covariate in the model will be the value -24 hours to first dosing on Day 1 of each period.
MMTT derived first phase insulin response
For the calculation of the change from baseline of insulin, glucose and C-peptide included in the 
calculation of ΔI10/ΔG10, ΔI30/ΔG30, ΔC10/ΔG10 and ΔC30/ΔG30, the baseline will be value at 
Day -1 of each period.
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24-hour U-Na and U-K
For Na and K and the Na/K ratio, the baseline will be the value at Day -1 in each period. 
 
 
 
 
 
Safety
ECG and vital signs
For ECG and vital signs, the baseline will be the pre-dose assessment at Day 1 in each period. If 
this value is missing the value closest in time prior to Day 1 within the same visit (or at Screening, 
in the case of period 1) will be the baseline for such a period.
Clinical chemistry/haematology/urinalysis
For the safety laboratory assessments, the baseline for the calculation of the change from baseline 
will be the pre-dose assessment at Day 1 in each period. If this value is missing, the value closest 
in time prior to Day 1 within the same visit (or at Screening, in the case of period 1) will be the 
baseline for such a period.
For the linear mixed models for Na, K and Na/K, the baseline included as covariate will be the 
same as that used to calculate the change from baseline.  
 
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Serum cortisol and ACTH
For the calculation of the difference in the concentration of each of these hormones between Days -1 
and 4 of each period, the baseline will be value on Day -1. If the concentration of ACTH at Day -1 in 
period 1 is missing, the concentration at the Screening visit will be the baseline for such a period.
4.9
Medical History
The Full Analysis Set will be used for the presentation of the data.
Medical history data will be listed by patient.
A summary of the number and percentage of patients with any relevant medical history will be 
presented by SOC and PT, by treatment sequence.
Relevant surgical history will be listed in the same manner.
Medical history data of diabetes will be listed by patient including start date and end date or on
going.
4.10 Prior and Concomitant Medications, and other treatments
All listings and tables will be based on the Safety Analysis Set.
Medications will be coded using the World Health Organisation-Drug Dictionary (WHODRUG) 
and will be classified by Anatomical Therapeutic Chemical (ATC) categories. 
Exclusively prior medications are those that started and stopped prior to the first dose of the 
investigational medicinal product (IMP) in the first treatment period and those that started and 
stopped after 21 days after the last dose in the first period and before the first dose of IMP in the 
second period. Medications taken between the first dose and up to 21 days after the last dose in any 
period are concomitant (including medications that started prior to dosing and continued after). 
Concomitant medication will be listed by participant and will include the reported name, anatomical 
therapeutic chemical (ATC), route of administration, total dose, frequency, start date/time, duration,
whether or not ongoing and indication and will be summarised by ATC and PT.
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Medications ongoing during both the periods will be counted under both Period 1 and Period 2.
Prior and concomitant use of Metformin will be listed by participant and will include the total dose, 
frequency, start date/time, duration and whether or not ongoing and will be summarised by ATC 
and PT.
The number of subjects taking concomitant medications under each treatment will be summarised
by ATC classification/ Generic term.
The duration will be calculated as:
Duration (in days) = (end date – start date) + 1, if only date is known.
4.11 Safety and Tolerability Evaluation
The actual treatment will be used for all safety and tolerability analyses. All listings and tables will 
be based on the Safety Analysis Set.
The listings of the safety data (AEs, laboratory data, vital signs, and ECG) will include scheduled 
and unscheduled assessments.
4.11.1 Adverse Events
Within each cohort, AEs will be assigned as having taken place after each of the two treatments if 
the start of the AE is after the first dose of the treatment but before the end of 21 days after the last 
dose (i.e., the end of Day 24, in the case of subjects whose last dose was on Day 3). AEs on Day 1 
with a missing start time will be assumed to have started after the first dose.
In order to assign the corresponding SOC and preferred term to each AE, AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 or higher.
AEs occurring prior to the time of dosing on Day 1 and after 21 days after the last dose will not be 
included in summaries.
An AE listing for the Safety analysis set will cover details for each individual AE. A summary table 
with the number of AEs, by SOC and PT will be created. 
The following summaries for the number and percentage of participants will be created:
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!
Number of subjects with adverse events in any of these categories:

Any AE

Any AE with outcome = death

Any SAE (including events with outcome = death)

Any AE leading to discontinuation of IP

Any AE leading to drug interruption

Any AE leading to withdrawal from study
!
Number of subjects with adverse events, by SOC and PT
!
Number of subjects with adverse events, by PT
!
Number of subjects with adverse events leading to discontinuation of investigational 
product, by system organ class and preferred term.
In summaries including SOC or PT, the summaries will first be sorted by decreasing percentage of 
participants in each SOC and PT within SOC, and then alphabetically by SOC, and PT within SOC.
The following summaries for the number and percentage of adverse will be created:
!
Number of adverse events by system organ class and preferred term.
4.11.2 Deaths and Serious Adverse Events
The number of SAEs, by SOC and PT will be summarised.
These summaries will be created for the number of subjects and adverse events, by SOC and PT.
4.11.3 Clinical Laboratory Evaluation
All values will be classified as low (below range), normal (within range), or high (above range) based 
on central laboratory reference ranges. 
The Na/K ratio will be calculated at each timepoint and this ratio will be included in clinical chemistry 
listings and tables. All clinical laboratory results will be listed. 
The comparison of the effect of treatment on changes in Na, K and Na/K will be analysed by means 
of the same statistical model as that used for the analysis of the primary endpoint.
For haematology, clinical chemistry and coagulation a table with descriptive statistics of absolute 
values and changes from baseline for each laboratory variable over time. Only planned tests will be 
summarized. In the case of the urinalysis, individual measurements will be listed and a summary table 
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of the baseline versus maximum value on-treatment (ie, a shift table) will be created.
The on-treatment definition will be based on the on-treatment definition used for AE.
4.11.4 Vital Signs, ECGs
Vital Signs
Vital signs data will be listed by participant including changes from baseline. Flags for a clinically 
significant assessment will be provided in the listing. 
Descriptive statistics for absolute values and changes from baseline will be presented by treatment 
and by cohort.
ECGs
All ECG parameters will be listed by participant including changes from baseline for numeric ECG 
parameters. Abnormalities in ECG will also be listed.
Descriptive statistics for absolute values and changes from baseline will be presented by treatment
and cohort. The on-treatment definition will be based on the on-treatment definition used for AE.
The number and percentage of participants under each treatment exceeding the following ICH 
boundaries of QTcF will be tabulated:
!
Absolute value > 450 msec and > 480 msec
!
Increase from baseline > 30 msec and > 60 msec.
This summary table will also include the number and percentage of participants under each treatment
exceeding the following values:
!
Absolute value >450 msec and Increase from baseline >30 msec
!
Absolute value >500 msec and Increase from baseline >60 msec.
The following figure will be provided for each ECG parameter:
-
Box-plot by treatment and day
4.11.5 Morning serum cortisol and ACTH
The morning serum cortisol and ACTH will be listed and tables with descriptive statistics for the 
value -15 minutes prior to the mixed meal on Days -1 and 4 (in each period) and change from baseline 
will be created. 
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4.12 Pharmacodynamics and Pharmacokinetics
4.12.1 Analysis and Data Conventions
This study aims to demonstrate that AZD9567 improves glucose homeostasis compared to oral 
prednisolone.
The null hypothesis for the primary analysis is:
H0: there is no difference in the change in glucose AUC(0-4) versus baseline in AZD9567 
compared to prednisolone following a standardised MMTT. 
The alternative hypothesis for the primary analysis is:
Ha: there is a difference in the change in glucose AUC(0-4) versus baseline in AZD9567 
compared to prednisolone following a standardised MMTT. 
In order to test the null hypothesis, a main analysis involving the FAS will be conducted. If more 
than 10% of participants receive the wrong treatment, a sensitivity analysis involving the PP will 
be conducted. 
The following comparison will be performed:
!
72 mg AZD9567 versus 40 mg prednisolone (Cohort 1)
!
40 mg AZD9567 versus 20 mg prednisolone (Cohort 2)
!
Placebo versus 5 mg prednisolone (Cohort 3)
As this is a Phase 2a study, no adjustments for multiple testing will be performed.
4.12.1.1
Multi-center Studies
No adjustments for center will be performed.
4.12.1.2
Handling of Dropouts or Missing Data
Summary statistics will be based on non-missing values. 
4.12.1.3
Interim Analyses
Two interim analyses are planned.
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The first interim analysis will be conducted when 50% of the participants in Cohort 1 have completed 
the study. The purpose of the first interim analysis is to evaluate the feasibility of the assumptions 
and conduct sample size re-estimation if required.
The main objective of the first interim analysis is to report the statistical analyses involving the first 
endpoint, the secondary endpoints related to glucose (mean daily glucose at 48-72 hours treatment 
and rise in mean daily glucose over 24-hour periods from start of IMP dosing) and the safety 
endpoints (AEs/SAEs) for 50% of the subjects in Cohort 1.
The second interim analysis will be conducted when all the participants in Cohort 1 have completed 
the study. The main objective of the second interim analysis is to report the statistical analyses 
involving all subjects in Cohort 1.
The second interim analyses will not include PK data.
4.12.2 Pharmacodynamics
All the models presented in this section will be analysed with unstructured covariance structure used 
for the within-participant errors. In the case of a model which does not converge, the analysis will be 
performed with a Toeplitz covariance structure and, in case of non-convergence, it will be performed 
with a compound symmetry structure.
Primary endpoint
The primary endpoint is the change in glucose AUC(0-4) and will be summarised by timepoint 
(baseline and Day 4) and by each cohort. The comparison of the change in glucose AUC(0-4) (where 
change from baseline in glucose AUC is assumed to be normally distributed) between the two 
treatments administered within each cohort after a standardised MMTT will be performed by means 
of two linear mixed effects models, with an unstructured covariance structure, with treatment, period 
and sequence as fixed effects, participant within sequence as random effect and baseline as covariate.
Two models will be run separately for each cohort:
1. In the first model, the dependent variable will be the change from baseline in AUC(0-4)
whereas the AUC(0-4) on Day -1 will be included as a covariate. The treatment effects will 
be estimated by the Least Square means (LS means) and their 95% CIs and the difference 
between the two treatments by the difference in LS means with its 95% CI. 
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2. The second model will involve the following three steps:
a) Log-transformation of the AUC(0-4):
First, the AUC(0-4) in Day -1 and the AUC(0-4) in Day 4 will be log-transformed. The 
log-transformed AUC(0-4) in Day -1 will then be subtracted from the log-transformed 
AUC(0-4) in Day 4 to calculate the change in AUC (0-4) in log units. 
b) Execution of the model:
The model will include the change in AUC (0-4) in log units as a dependent variable and 
the log-transformed AUC(0-4) in Day -1 as covariate.
c) Back-transformation of the results from the model:
The results from the execution of the model will be back transformed to the original scale 
after an exponentiation of the means and CIs estimated by the model to obtain the
percentage geometric LS means of the treatments and their percentage SEs. The LS mean
difference and its CI between the two treatments will also be back-transformed to yield 
the percentage geometric mean ratio between the two treatments with its 95% CI at Day 4.
The statistics for the percentages geometric LS means, percentage SE, percentage geometric LS mean 
ratio and percentage 95% CI will be calculated as follows: 
i) Percentage geometric LS mean = (exp(estimate)-1)*100 where estimate is the natural log 
of LS mean
ii) Percentage SE = sqrt(exp(2*estimate)*SE^2)*100
iii) Percentage geometric LS mean ratio= (exp(estimate)-1)*100 where estimate= log LS 
mean difference
iv) percentage 95% CI lower and upper: (exp(lower)-1)*100; (exp(upper)-1)*100.
If more than 10% of participants are treated erroneously, a sensitivity analysis will be carried out 
using the actual treatment received instead. Descriptive statistics and graphical presentations will be 
presented.
The following graphs will be provided:
-
Line plot: the Mean glucose levels (MMTT) by sampling time in minutes by treatment -visit 
day; (per cohort) 
-
AUC(0-4) change from baseline (MMTT) for glucose level by visit day of linear mixed model  
(Full Analysis Set) (all cohorts in a single plot) 
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-
AUC(0-4) percentage change from baseline (MMTT) for glucose level by visit day linear 
mixed model  (Full Analysis Set) (all cohorts in a single plot).
The following comparison will be performed by the execution of a linear mixed effects model in 
each case:
-
72 mg AZD9567 versus 40 mg prednisolone (Cohort 1)
-
40 mg AZD9567 versus 20 mg prednisolone (Cohort 2)
-
placebo versus 5 mg prednisolone (Cohort 3).
Secondary endpoints
Mean daily glucose at 48-72 hours (CGM)
The Mean daily glucose (CGM) as well as the change from baseline will be summarize by timepoint
(baseline, 00-24 h, 24-48 h and 48-72 h) and by treatment group.
The comparison of the effect of the two treatments on the mean daily glucose at 48-72 measured by 
CGM will be analysed by means of repeated measures mixed model (MMRM) with treatment + time
(0-24h, 24-48h, 48-72h), treatment*time, period and sequence as fixed effects with baseline (mean 
glucose at -24-0 hours) as covariate and participants within sequence as random effect. Two models 
will be run separately for each cohort and will be:
1. In the first model, the dependent variable will be the mean daily glucose whereas the mean 
glucose at -24-0 hours will be included as covariates. The treatment effects will be estimated 
as described in the first model for the primary endpoint.
2. The second model will involve a log-transformation of both the mean glucose at 0-24, 24-
48 and 48-72 hours and the mean glucose at -24-0 hours will be included as a covariate. The
treatment effects will be estimated as described in the second model for the primary endpoint.
The following graphs will be provided:
-
Glucose mean levels (CGM) at 0-72 h by treatment (per cohort) 
-
Glucose mean levels (CGM) at 0-72 h by treatment (all cohorts in a single plot).
Rise in mean glucose at 00-24 h, 24-48h and 48-72 h (CGM) 
The comparison of the effect of the two treatments on the rise in mean glucose at 0-24, 24-48 and 
48-72 hours will be performed following two different approaches:
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1) In the first approach three different models will be performed:
i)
Change at 00-24 h from baseline (24 hours of CGM prior to dosing) performed by means of 
mixed models with treatment, period and sequence as fixed effects, participants within 
sequence as random effect and baseline mean glucose
ii) Change at 24-48 h from baseline (24 hours of CGM prior to dosing) performed by means of 
mixed models with treatment, period and sequence as fixed effects, participants within 
sequence as random effect and baseline mean glucose
iii) Change at 48-72 h from baseline (24 hours of CGM prior to dosing) performed by means of 
mixed models with treatment, period and sequence as fixed effects, participants within 
sequence as random effect and baseline mean glucose.
2) In the second approach three different models will be performed:
i)
Change at 00-24 h from baseline (24 hours of CGM prior to dosing) performed by means of 
mixed models with treatment, period and sequence as fixed effects, participants within 
sequence as random effect and baseline mean glucose
ii)
Change at 24-48 h from baseline (00-24 h) performed by means of mixed models with 
treatment, period and sequence as fixed effects, participants within sequence as random 
effect and baseline mean glucose
iii) Change at 48-72 h from baseline (24-48h) performed by means of mixed models with 
treatment, period and sequence as fixed effects, participants within sequence as random 
effect and baseline mean glucose.
The three models for each of the approaches were repeated considering the log-transformation of the 
dependent variable to obtain the Geometric LS means and the Geometric LSMean Ratio (%).
The following comparison will be performed for the change and the percent change from baseline
at 0-24, 24-48 and 48-72 hours:
-
72 mg AZD9567 versus 40 mg prednisolone (Cohort 1) 
-
40 mg AZD9567 versus 20 mg prednisolone (Cohort 2)
-
placebo versus 5 mg prednisolone (Cohort 3).
The following graphs will be provided:
-
Rise in mean change from baseline (CGM) for glucose by Days (Day -1 (24 h prior to 
dosing), Day 1 (00-24 h), Day 2(24-48 h), Day 3(48-72 h)) 1st approach (per cohort)
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-
Rise in mean change from baseline (CGM) for glucose by Days (Day -1 (24 h prior to 
dosing), Day 1 (00-24 h), Day 2(24-48 h), Day 3(48-72 h)) 2nd approach (all cohorts in a 
single plot)
-
Rise in mean percentage change from baseline (CGM) for glucose by Days (Day -1 (24 h 
prior to dosing), Day 1 (00-24 h), Day 2(24-48 h), Day 3(48-72 h)) 2nd approach (all cohorts 
in a single plot).
Change from baseline in fasting glucose
The comparison of the effect of the two treatments on the change from baseline in fasting glucose
(-15 minutes) between Days -1 and 4 will be performed by the same model as that for the comparison 
of the primary endpoint.
The following comparison will be performed for the change and the percent change from baseline
at Day 4:
-
72 mg AZD9567 versus 40 mg prednisolone (Cohort 1) 
-
40 mg AZD9567 versus 20 mg prednisolone (Cohort 2) placebo versus 5 mg 
prednisolone (Cohort 3).
Changes in in AUC(0-4) in hormones, FFAs and C-peptide in response to a MMTT
The comparison of the effect of treatment on changes in insulin, glucagon, GLP-1, GIP, FFAs and 
C-peptide will be analysed as the primary endpoint.
The following graphs will be provided for each of the variable with the exception of C-peptide:
-
The changes from baseline at different timepoints by treatment (all cohorts in a single plot) 
-
The percentage changes from baseline at different timepoints by treatment (all cohorts in a 
single plot).
MMTT derived first phase insulin response
The ratio between variables will be calculated based on the following steps:
i)
Calculate ΔI10= difference in I (insulin) values between 10 and 0 minutes at Day -1 and Day 
4 of each period
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ii)
Calculate ΔG10= difference in G (glucose) values between 10 and 0 minutes at Day-1 and
Day 4 of each period
iii) Calculate the ratio ΔI10/ ΔG10 at Day-1 and Day 4 of each period.
The same steps i) to iii) accordingly to timepoints 10 and 30, will be performed for ΔC10/ΔG10, 
ΔI30/ΔG30, and ΔC30/ΔG30.
The comparison of the effect of the two treatments on the change in ΔI10/ΔG10 and ΔI30/ΔG30, 
between Days -1 and 4 will be performed by the same model as that for the comparison of the primary 
endpoint.
The following comparison will be performed for the change from baseline and the percent change 
from changes from baseline at Day 4 at 10 and 30 minutes:
-
72 mg AZD9567 versus 40 mg prednisolone (Cohort 1) 
-
40 mg AZD9567 versus 20 mg prednisolone (Cohort 2)
-
placebo versus 5 mg prednisolone (Cohort 3).
The previous analyses will be repeated for the comparison of the effect of the two treatments on the 
change in ΔC10/ΔG10, ΔC30/ΔG30 using C-peptide instead of insulin in the calculation of these 
ratios.
HOMA-IR and HOMA-S
A summary of the baseline HOMA-IR and HOMA-S and at Day 4 as well as change from baseline, 
will be provided by treatment. 
24-hour U-Na and U-K
The 24-hour Na and K concentration and its ratio (Na/K) in urine will be analysed as the primary 
endpoint.
The following comparisons will be performed for the change and percentage change from baseline at 
0-24 hours on Day 3:
-
72 mg AZD9567 versus 40 mg prednisolone (Cohort 1)
-
40 mg AZD9567 versus 20 mg prednisolone (Cohort 2)
-
placebo versus 5 mg prednisolone (Cohort 3).
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TNFα concentrations
Descriptive statistics will be tabulated for the individual measurement points of the LPS-stimulated 
TNFα levels. 
An ANOVA model with treatment, sequence and subject as random effect will be run separately for 
each cohort (Cohort 1 and Cohort 2) for the comparisons of the treatments at Day 3.
A scatter plot of individual plasma concentrations of AZD9567 (nmol/L) in a log scale on the X axis 
versus individual LPS-Stimulated TNFα Levels (ng/L) in log scale on the Y axis will be created.
 
 
 
 
 
 
 
 
 
 
 
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!
C1 and C2 are the concentrations at times 1 (t1) and 2 (t2).the first time interval 
(t1 – t2) is equal to t1 (ie, the concentration at -15 minutes is assumed to be the 
same as if it had been made at 0 minutes),
!
for assessments at 10, 20, 30, 60, 75, 120 and 180 minutes, t1 and t2 are actual 
times,
!
for the planned assessment at 240 minutes, the planned time (240) will be used 
if such an assessment has been performed within the allowed time window (±5
minutes).
The total AUC between 0 and 240 minutes will be calculated as the sum of the AUC for each 
of the intervals described in i) and ii).
The total AUC between two time points will be calculated as the sum of the AUCs calculated 
for each of the intervals between the two time points. 
2. The change in AUC(0-4) will be calculated as:
Δ AUC(0-4) =AUC(0-4) at Day 4 - AUC(0-4) at Day -1
For the calculation of MMTT AUC0-4hr, the pre-meal measurement (at -15 min) value will be treated 
as the value at the meal time (0 minutes). The actual time span for each post-meal measure will be 
calculated starting from the meal time (0 minutes). If any actual sample collection times are missing, 
use the scheduled nominal times with reference to the actual meal time to impute.
If the actual sampling times differ from the nominal times more or equal to | 5| min, this will be 
deemed on case-by-case basis if should be considered protocol deviation.
If greater than 50% of scheduled measures are missing, the AUC will be set as missing; if the first 
two or last two scheduled measures are both missing, then the AUC will also be set as missing; 
otherwise:
For all the MMTT endpoints (glucose, insulin, glucagon, GLP-1, GIP, FFAs and C-peptide):
If any interior measures are missing, the trapezoid rule can be used to calculate the AUC 
by ignoring the missing time point: i.e. The missing timepoint X will be imputed with the 
value obtained considering the linear interpolation between the last actual assessment 
taken prior to point X, and the first actual assessment taken after point X.
For glucose MMTT endpoint:
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!
If the pre-meal value is missing, set the missing value = 92% of the value for next 
scheduled time point. 
!
If the last value is missing, set the missing value = 87% of the value for the time point that 
is scheduled immediately prior to the last time point. 
For the rest of MMTT endpoints (insulin, glucagon, GLP-1, GIP, FFAs and C-peptide):
!
If the pre-meal value is missing, set AUC = missing
!
If the last value is missing, set AUC = missing
AUC(0 -4h) calculation assumes that measurements are available at 240 min exactly. Deviation from 
240 min will induce a systematic overestimation of the actual value of the sampling time is used 
exceeds 240 min and underestimation of the actual time is under 240 min. If the deviation is within 
the allowance window (± 5 min) the sampling time will be equated to 240 min. If the sampling time 
for the 240 min measurement is out of the sampling window (± 5 min) a linear interpolation will be 
considered to assess the value at 240 min using the actual sampling times for the 180 min and the 240 
min measurements. 
Actual time point (at 180 min) and the time point for last sampling will be defined with t180 and with 
tlast respectively, and the values of the endpoint (glucose, insulin etc) at the actual measured timepoint 
and at time point for the last sampling will be defined with y180 and ylast. From the available 
information (t180, y180), (tlast, ylast) the value at t240 , i.e. the value that the endpoint would have if we 
would have taken the sample at exactly 240 min form start will be interpolated. Interpolation assumes 
a linear equation with slope 
m = (ylast-y180)/(tlast-t180)
and intercept 
b = mean(ylast;y180)- m*mean(tlast;t180)
giving the value at 240 minutes of:
y240 = b + m*240.
The 92 % and 87 % correction factors were based on the MEDI0382 (D5670C00007) study. 
Calculation of HOMA-IR
The HOMA-IR will be calculated as follows based on glucose and insulin measured prior to MMTT 
(-15 min):
HOMA −IR =
 !"#$% &''# 
(
) x Insulin (mU/L)
22.5
HOMA-S will be calculated as the reciprocal of HOMA-IR. 
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Statistical Analysis Plan
CONFIDENTIAL
Project Document Version No. Final 2.0
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Page 44 of 56
4.12.3 Pharmacokinetics
4.12.3.1 Concentrations
Plasma concentrations of AZD9567 will be listed by actual and relative (to dose administration) 
sampling time. The following summary statistics will be presented for these concentrations at each 
time point by treatment and cohort:
!
n below the lower limit of quantification (LLOQ) (only for concentrations)
!
Geometric Mean
!
Geometric CV%
!
Geometric Mean - SD
!
Geometric Mean + SD
!
Arithmetic Mean
!
Arithmetic SD
!
Median
!
Minimum
!
Maximum
In listings, concentrations less than the lower limit of quantification (LLOQ) will be presented as 
below the lower limit of quantification (BLQ). In listings and tables where the terms BLQ or LLOQ 
are included, the LLOQ (numerical value) will be included in a footnote.
For the calculation of statistics, concentrations that are BLQ will be handled as follows at each time 
point:
!
If ≤50% of the concentrations are BLQ, all BLQ values will be set to the LLOQ, and all 
descriptive statistics will be calculated.
!
If >50%, but not all, of the concentrations are BLQ, the arithmetic mean, arithmetic CV, 
arithmetic mean, and arithmetic SD will be reported as ‘NC’ (not calculable). The maximum 
value will be reported from the individual data, and the minimum and median will be set as 
‘BLQ’.
!
If all concentrations are BLQ, no descriptive statistics will be calculated. ‘NA’ (not 
applicable) will be presented for geometric CV, and arithmetic SD, and ‘BLQ’ will be 
presented for geometric mean, arithmetic mean, median, minimum, and maximum.
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Parexel International
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Statistical Analysis Plan
CONFIDENTIAL
Project Document Version No. Final 2.0
Project Document Effective Date: <Date of last signature>
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For PK concentration and parameter data, if there are <3 values available at a time point, only the 
maximum, minimum, and n will be reported; the remaining descriptive statistics will be reported as 
‘NC’. Concentrations that are BLQ are considered a value.
Post-dose concentrations where the actual time deviation deviates more than 10% from the scheduled 
time will be excluded from summaries by planned time point.
Missing samples will be reported as no sample ("NS") and excluded from analysis. 
Source data shall be used in all derived PK concentrations without prior rounding 
The following figures, will be generated for each IMP by Cohort:
!
Individual Subject Profiles, Plasma Concentration-time Data - Linear Scale: both days on 1 
plot 
!
Individual Subject Profiles, Plasma Concentration-time Data - Semi-Logarithmic Scale : 
both days on 1 plot
!
GMean, Plasma Concentration-time Data - Linear Scale: both days on 1 plot
!
GMean, Plasma Concentration-time Data - Semi-Logarithmic Scale: both days on 1 plot.
In combined figures displaying subject profiles, all subjects will be included in the same figure and 
concentrations will be displayed by actual sampling time. In figures displaying mean concentrations, 
mean concentrations will be displayed by time point.
4.12.3.2 Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated following these guidelines:
Pharmacokinetic analysis will, where possible, be calculated using times recorded in the raw data. If 
actual times are missing, nominal times may be used.
The concentrations reported by the analytical laboratory for PK analysis will be used in all the 
analyses. The units of concentration and resulting PK parameters, with amount or concentration in 
the unit, will be presented as they are received from the analytical laboratory.
Cmax and tmax will be obtained directly from the plasma concentration-time profiles. For multiple 
peaks, the highest post-dose concentration will be reported as Cmax. In the case that multiple peaks 
are of equal magnitude, the earliest tmax will be reported.
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Parexel International
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Statistical Analysis Plan
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Project Document Version No. Final 2.0
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Concentrations BLQ from the time of pre-dose sampling (t=0) up to the time of the first quantifiable 
concentration will be set to zero with the following exceptions:
!
Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values following 
the last quantifiable concentration in a profile will be set to missing for the purposes of PK 
analysis.
!
If there are late positive concentration values following 2 BLQ concentration values in the 
apparent terminal phase, these values will be set to missing, unless there is a scientific 
rationale not to do so, which will be documented by the pharmacokineticist.
!
If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis.
!
If a pre-dose concentration is missing, these values may be set to zero by default.
The terminal elimination rate constant (∀z) will be calculated by log-linear regression of the terminal 
portion of the concentration-time profile. The following will be considered:
!
If more than one phase is present only data points from the terminal phase will be used.
!
A minimum of 3 data points after Cmax, including the last measurable concentration, will be 
used for calculating ∀z.
!
Where the elimination half-life is estimated over less than 3 times the subsequently estimated 
terminal half-life the robustness of the t½∀estimate will be discussed in the CSR.
!
Rsq adjusted should be greater than 0.8. Where Rsq adjusted < 0.8, half-life and half-life 
dependent parameters may be excluded from summary statistics and statistical analysis with 
sponsor agreement.
The AUCs will be calculated using the linear trapezoidal method when concentrations are increasing 
and the logarithmic trapezoidal rule when concentrations are decreasing (linear up log down). The 
minimum requirement for the calculation of AUC will be the inclusion of at least 3 consecutive 
plasma concentrations above the LLOQ.
Generally, data should not be excluded from analysis. However, where this is scientifically merited a 
sensitivity analysis may be performed and the data will be discussed in the CSR.
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Parexel International
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Statistical Analysis Plan
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Project Document Version No. Final 2.0
Project Document Effective Date: <Date of last signature>
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Pharmacokinetic summaries will be based upon the PKAS.
Pharmacokinetic parameters will be listed by subject and summarised by treatment. Descriptive 
statistics for calculated PK parameters will include: n, arithmetic mean, SD, CV%, geometric mean, 
geometric CV%, median, minimum and maximum values. For tmax, only median, minimum and 
maximum values will be presented. No descriptive statistics will be determined when fewer than three 
individual PK parameters are available.
The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings for PK parameters: 
!
Individual PK parameters will be presented to four significant digits, with the exception of 
tmax, which will be presented to two decimal places. 
!
Parameters derived directly from source data (e.g. Cmax,) shall be reported with the same 
precision as the source data (if this is not four significant digits). 
!
The mean, geometric mean, median and SD values will be reported to four significant digits, 
all other descriptive statistics will be reported to three significant digits except for CV% which 
will be presented to one decimal place. 
!
For tmax the minimum and maximum will be presented to two decimals places and all other 
descriptive statistics will be presented to three decimal places. 
4.13 Other Analyses
Not applicable.
4.14 Determination of Sample Size
 
 
 
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Statistical Analysis Plan
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Project Document Version No. Final 2.0
Project Document Effective Date: <Date of last signature>
Page 48 of 56
 
 
 
 
 
4.15 Changes in the Conduct of the Study or Planned Analysis
The following changes to the statistical methodology planned in Study Protocol will be applied:
!
The repeated measures mixed model will also include the time term.
CCI
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Parexel International
D6470C00005
Statistical Analysis Plan
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Project Document Version No. Final 2.0
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Page 49 of 56
5
REFERENCES
van Genugten RE, van Raalte DH, Muskiet MH, Heymans MW, Pouwels PJW, Ouwens DM, et al. 
Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with 
the metabolic syndrome? A randomised controlled trial. Eur J Endocrinol. 2014 Feb 4;170(3):429-
39.
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample 
size, median, range and/or interquartile range. BMC Med Res Methodol 2014 Dec 19;14:135.
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Parexel International
D6470C00005                                                                                                                                                                                                                                Statistical Analysis Plan
                                                                                    CONFIDENTIAL                                                        Project Document Version No. Final 2.0
                                                                                                                                            Project Document Effective Date: <Date of last signature>
                                                                                       Page 55 of 56
Note: Interim telephone visits may occur at any time during the Out-patient’ periods, as determined by the investigator, to review the safety and well-being of the participant.
Abbreviations: ACTH: adrenocorticotropic hormone; aPTT: activated partial thrombin time; CGM: continuous glucose monitoring; CRU: clinical research unit; DPP4i: Dipeptidyl 
peptidase-4 inhibitor; ECG: electrocardiogram; ET: end of treatment; FFA: free fatty acid; FGM: flash glucose monitoring; GIP: glucose-dependent insulin releasing polypeptide; 
GLP-1: glucagon-like peptide-1; HAV: Hepatitis A virus; HbA1c: haemoglobin 1Ac; HbsAg: Hepatitis B surface antigen; hCG: human chorionic gonadotropin; 
HCV: Hepatitis C virus; HDL-C: High-density lipoprotein-cholesterol; HIV: human immunodeficiency virus; IMP: investigational medicinal product; INR: International 
normalised ratio; IVRS: Interactive Voice Response System; MMTT: mixed meal tolerance test; PCR: polymerase chain reaction; PK: pharmacokinetics; PT: prothrombin time; 
SGLT2i: sodium-glucose co-transporter-2 inhibitor; T2DM: type 2 diabetes mellitus; TNFα: tumor necrosis factor alpha; U-K: urinary potassium; U-Na: urinary sodium.
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Parexel International
D6470C00005                                                                                                                                                                                                                                Statistical Analysis Plan
                                                                                    CONFIDENTIAL                                                        Project Document Version No. Final 2.0
                                                                                                                                            Project Document Effective Date: <Date of last signature>
                                                                                       Page 56 of 56
6.2
Blood Sampling Schedule for Mixed Meal Tolerance Tests (MMTTs)
Day -1, Day 4, Day 27, and Day 31
Comments
Plasma glucose, insulin, 
C-peptide GLP-1, GIP, 
glucagon (minutes), and FFAs
-15, 10, 20, 30, 60, 75, 120, 180, 240
Time point in relation to the start of the meal
GLP-1: glucagon-like peptide-1; GIP: glucose-dependent insulin releasing polypeptide.
CCI


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