Conditions: Rheumatoid Arthritis
Keywords: rheumatoid arthritis, swollen joints, tender joints, autoimmunity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
This is a phase 2a study to be run in 2-3 countries in European Union involving 5-6 sites. It will enroll approximately 80 patients to ensure 40 randomized with active rheumatoid arthritis. The treatment period is 2 weeks and total study duration per patient is approximately 1 month. The study drugs are AZD9567 40 mg (an oral SGRM) and the comparator is prednisolone 20mg. The primary endpoint is DAS28 including evaluation of 28 joints and C-reactive protein. Safety parameters will also be evaluated and a biomarker program is included for future research.

Detailed description:
This randomized double blind with double dummy technique phase 2a study will be run in 2-3 EU countries, most likely Sweden, Denmark and The Netherlands involving 5-6 sites. It is estimated that 80-100 patients have to be enrolled to ensure the randomization target of 40. The study population is patients with rheumatoid arthritis on stable treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs) with an active flare. It is a two-arm parallel study and the randomization ratio is 1:1 to the two weeks of once daily treatment of 40 mg of AZD9567 and 20 mg prednisolone.

The primary objective is to assess the efficacy of AZD9567 40 mg, compared to prednisolone 20 mg in patients with active rheumatoid arthritis in spite of stable treatment with conventional and/or s.c/i.v. biological DMARDs and the primary variable is change from baseline in 28 joint Disease Activity Score using CRP (DAS28 - CRP). As secondary variables swollen and tenderness of 66-68 joints and safety variables are also included. For exploratively purposes there is also a biomarker program, collecting blood samples for future research.

Arms:
arm 1: oral suspension of 40 mg AZD9567 once daily (OD) for two weeks arm 2: oral OD treatment of 20 mg prednisolone administered as capsules

Interventions: intervention 1: AZD9567 intervention 2: Prednisolone
Intervention descriptions: intervention 1: oral OD SGRM administered as suspension intervention 2: oral capsules of 20 mg prednisolone administered OD for two weeks

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
AZD9567
Study Code
D6470C00003
Version
3
19 March 2019
A Phase 2a, Randomised, Double-blind, Parallel Study to Assess 
the Efficacy, Safety and Tolerability of AZD9567 compared to 
Prednisolone 20 mg in patients with active Rheumatoid Arthritis 
(RA)
Sponsor: AstraZeneca AB, S-151 85 Södertälje, Sweden


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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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CLINICAL STUDY PROTOCOL SYNOPSIS
A Phase 2a, Randomised, Double-blind, Parallel Study to Assess the 
Efficacy, Safety and Tolerability of AZD9567 compared to Prednisolone 
20 mg in patients with active Rheumatoid Arthritis (RA)
International Co-ordinating Investigator
Division Internal Medicine and Dermatology, Rheumatology & Clinical Immunology
University Medical Center Utrecht
P.O. Box 85500 
3508 GA UTRECHT
The Netherlands
Study site(s) and number of subjects planned
This Phase 2a Proof of Principle study will be conducted in a maximum of 10 sites in 
2-3 countries. Approximately 80-100 patients will be enrolled to achieve 40 randomised. 
Study design
This is a Phase 2a, double-blind, double dummy, parallel arm study in patients with active 
rheumatoid arthritis (RA). It comprises 5 clinic visits and one telephone visit during 
approximately 5 weeks.
At Visit 1 (screening visit) patients will be consented and screened for eligibility. 
At Visit 2, which can occur 1-6 days after Visit 1, pre-dose/baseline assessments will be 
made. Thereafter, patients will be randomised in the ratio 1:1 to take either 40 mg AZD9567 
or 20 mg prednisolone for 14 days once daily. Since this study is double-blind and AZD9567 
and prednisolone are different formulations (oral suspension and capsules respectively), all 
patients will have to take both formulations every day (active AZD9567 + placebo to 
prednisolone or placebo to AZD9567 + active prednisolone). 
A telephone call on study Day 5 to check on patient well-being will be termed Visit 3. 
Clinic Visit 4 will occur 7 days into the treatment and Visit 5 will be the end of treatment visit 
occurring approximately 14 days after Visit 2. 
PPD


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A follow-up visit, Visit 6, will be performed approximately 14 days after last IMP 
administration on Visit 5, in order to ensure the safety and well-being of patients.
Objectives
Primary Objective:
Outcome Measure:
To assess the efficacy of AZD9567, 40 mg, 
compared to prednisolone 20 mg in patients with 
active rheumatoid arthritis in spite of stable 
treatment with conventional and/or s.c/i.v. biological 
DMARDs
Change from baseline in 28 joint Disease Activity Score 
using CRP (DAS 28 - CRP)
Secondary Objective:
Outcome Measure:
To further assess the efficacy of AZD9567, 40 mg, 
compared to prednisolone 20 mg in patients with 
active rheumatoid arthritis in spite of stable 
treatment with conventional and/or s.c/i.v. biological 
DMARDs
Proportion of subjects reaching ACR (American College of 
Rheumatology) 20, 50 and 70 responses 
Change from baseline in Swollen Joint Count 66 (SJC 66)
Change from baseline in Tender Joint Count 68 (TJC 68)
Change from baseline in individual components of DAS28 
and ACR response criteria (number of swollen and tender 
joints, patients assessments of global disease activity, pain, 
physician´s global assessment of disease activity, and CRP)
To evaluate the pharmacokinetic profile of 
AZD9567 in patients with active rheumatoid 
arthritis in spite of stable treatment with 
conventional and/or s.c/i.v. biological DMARDs
E g but not limited to plasma AUC(0-24), AUC(0-last), Cmax and 
tmax.
Safety Objective:
Outcome Measure:
To assess the safety and tolerability of AZD9567 in 
patients with active rheumatoid arthritis in spite of 
stable treatment with conventional and/or s.c/i.v. 
biological DMARDs
Adverse events, vital signs, ECG and laboratory parameters 
(haematology, clinical chemistry and urine)
Exploratory Objective:
Outcome Measure:
To evaluate the pharmacokinetic profile of 
prednisolone in patients with active rheumatoid 
arthritis in spite of stable treatment with 
conventional and/or s.c/i.v. biological DMARDs
E g but not limited to plasma AUC(0-24), AUC(0-last), Cmax and 
tmax.


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Exploratory Objective:
Outcome Measure:
To assess the responses to AZD9567 of relevant 
biomarkers. Whole blood and serum/plasma will be 
collected to enable relevant analyses such as, but not 
limited to, effects on bone, metabolism and HPA 
axis.
Exploratory variables will be reported in a separate 
biomarker report and will not be included in the 
clinical study report (CSR), unless something 
clinically important is observed.
Exploratory blood biomarkers (e g LPS stimulated TNFα, 
cortisol and other possible exploratory markers including 
RNA)
To obtain optional blood samples for future 
pharmacogenetic (PGx) research aiming to 
identify/explore pharmacodynamic biomarkers or 
genetic variations that may affect the efficacy, 
pharmacodynamics, safety and tolerability profile 
related to AZD9567 treatment. 
Data from the PGx research will not be included in 
the CSR.
DNA from whole blood
Target subject population
The study population will comprise adult patients with active rheumatoid arthritis in spite of 
stable treatment with conventional Disease-modifying anti-rheumatic drugs.
Duration of treatment
The total duration of the study for each patient is approximately 5 weeks, which includes a 
2 week treatment period and up to 2 week follow up period. The screening period can be up to 
one week or as short as 1-2 days.
Investigational product, dosage and mode of administration
AZD 9567 is a non-steroidal selective glucocorticoid receptor modulator. In the study the aim 
is to investigate the safety, efficacy and tolerability of AZD9567 compared to prednisolone in 
patients with active Rheumatoid Arthritis.
The drug substance is presented as a drug powder and formulated as a suspension for oral 
administration, using standard excipients. A placebo formulation, an oral suspension, using 
inactive standard excipients is included in the study. A comparator product, prednisolone 
capsules and placebo for prednisolone capsules, will also be used. The dose of AZD9567 will 
be 40 mg once daily (OD) and the dose of prednisolone is 20 mg OD.


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Statistical methods
The main objective of this study is to demonstrate that the efficacy of AZD9567 is equivalent 
to the efficacy of prednisolone 20 mg, where the efficacy endpoint used is change from 
baseline (CFBL) in DAS28. More precisely, we will use the difference in DAS28 units, XT-
XP, between, XT, the average CFBL of the chosen dose of AZD9567 and, XP, the mean CFBL 
of prednisolone 20 mg to estimate the average difference in DAS28 between the two arms. 
This difference will be calculated using a mixed model.
The primary analysis population for efficacy will be the intention to treat (ITT) population. 
This will include all patients who were randomised and received at least one dose of study 
medication. Patients will thus be analyzed according to the treatment to which they were 
intended to be randomised to. 


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TABLE OF CONTENTS
1.
INTRODUCTION............................................................................................ 15
1.1
Background and rationale for conducting this study .......................................... 15
1.2
Rationale for study design, doses and control groups ........................................ 15
1.3
Benefit/risk and ethical assessment ................................................................... 16
1.4
Study Design .................................................................................................... 17
1.5
Study governance and oversight (Not Applicable)............................................. 19
2.
STUDY OBJECTIVES..................................................................................... 19
2.1
Primary objective.............................................................................................. 19
2.2
Secondary objectives ........................................................................................ 19
2.3
Safety objectives............................................................................................... 19
2.4
Exploratory objectives ...................................................................................... 20
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ................... 20
3.1
Inclusion criteria............................................................................................... 20
3.1.1
Acceptable birth control methods...................................................................... 21
3.2
Exclusion criteria.............................................................................................. 22
3.3
Subject enrolment and randomisation................................................................ 23
3.4
Procedures for handling incorrectly enrolled or randomised subjects................. 23
3.5
Methods for assigning treatment groups............................................................ 23
3.6
Methods for ensuring blinding .......................................................................... 24
3.7
Methods for unblinding..................................................................................... 24
3.8
Restrictions....................................................................................................... 25
3.9
Discontinuation of investigational product........................................................ 25
3.9.1
Procedures for discontinuation of a subject from investigational product .......... 25
3.10
Criteria for withdrawal...................................................................................... 26
3.10.1
Screen failures .................................................................................................. 26
3.10.2
Rescreening ...................................................................................................... 26
3.10.3
Withdrawal of the informed consent ................................................................. 26
3.11
Discontinuation of the study ............................................................................. 26
4.
STUDY PLAN AND TIMING OF PROCEDURES ......................................... 28
4.1
Screening/Enrolment period.............................................................................. 30
4.2
Treatment period............................................................................................... 30
4.3
Follow-up period .............................................................................................. 30
5.
STUDY ASSESSMENTS................................................................................. 30
5.1
Efficacy assessments......................................................................................... 31
5.1.1
DAS 28............................................................................................................. 31
5.1.2
Swollen and Tender Joint Count 66/68.............................................................. 31


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5.2
Safety assessments............................................................................................ 32
5.2.1
Laboratory safety assessments .......................................................................... 32
5.2.2
Physical examination ........................................................................................ 34
5.2.3
ECG ................................................................................................................. 34
5.2.3.1
Resting 12-lead ECG ........................................................................................ 34
5.2.4
Vital signs......................................................................................................... 34
5.2.4.1
Pulse and blood pressure................................................................................... 34
5.2.4.2
Body temperature ............................................................................................. 34
5.3
Pharmacokinetics.............................................................................................. 34
5.3.1
Collection of samples........................................................................................ 34
5.3.2
Determination of drug concentration................................................................. 35
5.3.3
Storage and destruction of pharmacokinetic samples......................................... 35
5.4
Pharmacodynamics........................................................................................... 35
5.4.1
Collection of samples........................................................................................ 35
5.5
Genetics............................................................................................................ 35
5.5.1
Collection of optional genetic samples.............................................................. 35
5.5.2
Storage and destruction of genetic samples ....................................................... 36
5.6
Biomarker analysis ........................................................................................... 36
5.6.1
Storage, re-use and destruction of biological samples........................................ 36
5.6.2
Labelling and shipment of biological samples................................................... 36
5.6.3
Chain of custody of biological samples............................................................. 36
5.6.4
Withdrawal of Informed Consent for donated biological samples...................... 37
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................ 37
6.1
Definition of adverse events.............................................................................. 37
6.2
Definitions of serious adverse event.................................................................. 38
6.3
Recording of adverse events ............................................................................. 38
6.3.1
Time period for collection of adverse events..................................................... 38
6.3.2
Follow-up of unresolved adverse events............................................................ 38
6.3.3
Variables .......................................................................................................... 38
6.3.4
Causality collection........................................................................................... 39
6.3.5
Adverse events based on signs and symptoms................................................... 40
6.3.6
Adverse events based on examinations and tests ............................................... 40
6.3.7
Hy’s Law.......................................................................................................... 40
6.3.8
Disease under Study (DUS) .............................................................................. 40
6.4
Reporting of serious adverse events .................................................................. 41
6.5
Overdose .......................................................................................................... 41
6.6
Pregnancy......................................................................................................... 42
6.6.1
Maternal exposure ............................................................................................ 42
6.6.2
Paternal exposure.............................................................................................. 43
6.7
Medication Error............................................................................................... 43
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS.................. 44
7.1
Identity of investigational product(s)................................................................. 44
7.2
Dose and treatment regimens ............................................................................ 44


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7.3
Labelling .......................................................................................................... 45
7.4
Storage ............................................................................................................. 45
7.5
Compliance....................................................................................................... 45
7.6
Accountability .................................................................................................. 45
7.7
Concomitant and other treatments..................................................................... 45
7.7.1
Other concomitant treatment............................................................................. 45
8.
STATISTICAL ANALYSES BY ASTRAZENECA......................................... 46
8.1
Statistical considerations................................................................................... 46
8.2
Sample size estimate......................................................................................... 47
8.3
Definitions of analysis sets................................................................................ 47
8.3.1
Efficacy analysis set.......................................................................................... 47
8.3.2
Safety analysis set............................................................................................. 48
8.3.3
PK analysis set.................................................................................................. 48
8.3.4
Other analysis sets ............................................................................................ 48
8.4
Outcome measures for analyses ........................................................................ 48
8.5
Methods for statistical analyses......................................................................... 48
8.5.1
Analysis of the primary variable(s) ................................................................... 48
8.5.2
Analysis of the secondary variable(s)................................................................ 48
8.5.2.1
Pharmacokinetic analyses ................................................................................. 49
8.5.3
Subgroup analysis (if applicable) ...................................................................... 49
8.5.4
Sensitivity analysis (if applicable)..................................................................... 49
8.5.5
Exploratory analysis (if applicable)................................................................... 49
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA........................ 50
9.1
Training of study site staff ................................................................................ 50
9.2
Monitoring of the study..................................................................................... 50
9.2.1
Source data....................................................................................................... 50
9.2.2
Study agreements.............................................................................................. 51
9.2.3
Archiving of study documents .......................................................................... 51
9.3
Study timetable and end of study ...................................................................... 51
9.4
Data management by AstraZeneca or delegate .................................................. 51
10.
ETHICAL AND REGULATORY REQUIREMENTS...................................... 52
10.1
Ethical conduct of the study.............................................................................. 52
10.2
Subject data protection...................................................................................... 52
10.3
Ethics and regulatory review............................................................................. 53
10.4
Informed consent .............................................................................................. 53
10.5
Changes to the Clinical Study Protocol and Informed Consent Form................. 54
10.6
Audits and inspections ...................................................................................... 54
11.
LIST OF REFERENCES.................................................................................. 55


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LIST OF TABLES
Table 1
Study Plan detailing the procedures ......................................................... 28
Table 2
Laboratory Safety Variables..................................................................... 32
Table 3
Volume of blood to be drawn from each patient....................................... 33
LIST OF FIGURES
Figure 1
Study flow chart ..................................................................................... 18
LIST OF APPENDICES
Appendix A
Additional Safety Information.................................................................. 57
Appendix B
International Airline Transportation Association (IATA) 6.2 Guidance 
Document ................................................................................................ 59
Appendix C
Genetic Research..................................................................................... 60
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 63
Appendix E
Guidance for restricted medication........................................................... 69


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special 
term
Explanation
AE
ACR20
ACR50
ACR70
AUC
Cmax
CFBL
Adverse Event
American College of Rheumatology 20% improvement criteria 
American College of Rheumatology 50% improvement criteria 
American College of Rheumatology 70% improvement criteria
Area under the concentration curve - a pharmacokinetic variable
Maximal Concentration of a drug in the blood, ie peak of the plasma 
concentration curve - a pharmacokinetic variable
Change from baseline
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
DAE
DAS28
DAS28(CRP) 
DHEA-S
DMARD
Discontinuation of Investigational Product due to Adverse Event
Disease Activity Score in 28 joints 
Disease Activity Score in 28 joints using C-reactive protein 
Dehydroepiandrosterone Sulfate
Disease-modifying anti-rheumatic drug
DNA
Deoxyribonucleic acid 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and Independent 
Ethics Committee (IEC)
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating Investigator 
is the Investigator co-ordinating the investigators and/or activities internationally. 
IMP
Investigational Medicinal Product 
IxRS (IWRS/IVRS)
Interactive Web/Voice Response System
ITT
LIMS
LPS
Intention to treat
Laboratory Information Management System
Lipopolysaccharide (used as challenging agent in e g blood cell biomarker analyses)
LSLV
Last Subject Last Visit
OAE
OC
Other Significant Adverse Event
Overencapsulated


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Abbreviation or special 
term
Explanation
Gx
OGTT
Genetic research
Oral glucose tolerance test
PI
PK
PRO
Principal Investigator 
Pharmacokinetics
Patient Reported Outcome
SAE
Serious Adverse Event 
SAP
SGRM
SJC66/68
TJC
Tmax
Statistical Analysis Plan
Selective glucocorticoid receptor modulator
Swollen Joint Count, assessing 66 or 68 joint
Tender Joint Count
Time point of the maximal plasma concentration of a drug
WBDC
WOCBP
Web Based Data Capture
Women of Child Bearing Potential


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that is associated with 
significant morbidity and mortality. The disease is characterized by inflammation of the 
synovial joints that can result in pain, swelling, and joint damage with secondary deformity 
and progressive disability. Worldwide, the prevalence of RA is estimated to be between 0.6% 
and 1.1% with variations across geographical regions (Pincus et al, 1987, Harris, 1997, 
Symmons, 2002). Uncontrolled active RA causes joint damage, disability and decreased 
quality of life, comorbidities including cardiovascular disease and osteoporosis, and reduced 
life expectancy (Wong et al, 2001, Pincus et al, 1989, Harris, 1997).
Oral glucocorticoids (GC), such as prednisolone, have been used for the treatment of signs 
and symptoms of RA since before the 1950’s (Hench et al, 1949) and remain an important 
component of the treatment paradigm for both early and established RA [ACR 
guidelines 2015]. GC modulate the activities of a variety of inflammatory cells and mediators 
in the synovium of RA patients contributing its therapeutic efficacy (Gerlag et al, 2004). The 
challenge of GC treatment for the clinicians has been the safety/tolerability of GC especially 
after long-term use particularly with respect to effects on osteoporosis (Siu et al, 2015), risk of 
diabetes (Gulliford et al, 2006) cardiovascular disease (del Rincon et al, 2014) and mortality 
(del Rincon et al, 2014).
AZD9567 is a non-steroidal selective glucocorticoid receptor modulator (SGRM) that has 
potential to be used as an oral treatment for RA. Pre-clinical studies have been able to show 
significant anti-inflammatory effect with a differentiation between desired efficacy and the 
unwanted effects (eg, glucose metabolism, bone effects and mineralocorticoid effect) in 
nonclinical models and systems. AZD9567 has also been safe and well tolerated thus far in 
clinical studies of healthy volunteers. Therefore, there is strong pre-clinical evidence 
supporting the use of an oral SGRM in the therapy of RA. 
This is a first-in-patients, Phase 2a, randomised, double-blinded, parallel arm study designed 
to assess the efficacy of one dose level of AZD9567 compared to prednisolone 20mg once 
daily in rheumatoid arthritis patients as evaluated by change from baseline of DAS28-CRP. 
This study will also evaluate the safety, tolerability and PK of AZD9567.
1.2
Rationale for study design, doses and control groups
This is a Phase 2a, randomised, double-blind, parallel arm study to assess the efficacy, safety 
and tolerability of 40 mg AZD9567 compared to prednisolone 20 mg in patients with active 
RA. According to the American College of Rheumatology Guidelines, short-term 
glucocorticoid treatment is indicated to control disease in RA patients with moderate to high 
disease activity. The current study randomizes eligible patients with established RA and 


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moderate to high disease activity as defined by ACR Guidelines (DAS28>3.2) to prednisolone 
20 mg or AZD9567 40 mg for 14 days. 
Prednisolone 20 mg is chosen as a moderate dose of prednisolone that falls within the ACR 
recommendations for treatment of active disease as moderate doses have been shown to be as
effective as higher doses in active early RA (ter Wee et al, 2015). A two weeks duration of 
therapy was chosen on the basis that prior study has suggested that this duration can 
significantly impact disease activity as measured by DAS28 score (Gerlag et al, 2004). 
A dose AZD9567 of 40 mg has been selected based on review of available safety, PK, and PD 
data from the first studies in humans in which AZD9567 was administered to healthy 
volunteers as single doses 2, 10, 20, 40, 80, 100, 125 and 155 mg (D6470C00001) and, in a 
multiple dose setting, once daily for 5 days using 10, 20, 40 and 80 mg. (D6470C00002). 
AZD9567 was well tolerated in all studied dose levels. 
The selected AZD9567 dose 40 mg showed effects on inflammatory activity (reduced 
lipopolysaccharide (LPS) stimulated TNFα response) and on the HPA axis (plasma cortisol 
reduction) similar to what was observed for 20 mg prednisolone.
Although the selected comparator dose of 20 mg prednisolone is known to be efficacious in 
RA and considered safe and tolerable for 14 days administration, it also has significant effect 
on glucose homeostasis. The 40 mg dose of AZD9567 showed a significantly better side effect 
profile with respect to glucose levels after an oral glucose tolerance test (OGTT) compared to 
prednisolone 20 mg in the ongoing MAD study (D6470C00002).
1.3
Benefit/risk and ethical assessment 
AZD9567 is an oral, non-steroidal, potent and selective glucocorticoid receptor modulator 
(SGRM) under development for the treatment of rheumatoid arthritis. Experience has been 
gathered from non-clinical safety pharmacology, toxicology studies, previous clinical 
experience with GR agonists and preliminary data from the first in man single ascending dose 
study (D6470C00001) and the ongoing multiple ascending dose study (D6470C0002).
In preclinical testing AZD9567 displays 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 80
mg have been well tolerated in healthy volunteers. Based upon this experience, it is expected 
that the dose of 40 mg will be well tolerated in RA patients.
Potential adverse effects are discussed in the Investigator’s Brochures (Section 6.1). They 
include potential effects on glucose and lipid metabolism, bone metabolism, and 
inflammation. The occurrence of any AE, abnormality in laboratory variables or any other 
safety variables will be closely monitored and evaluated on an ongoing basis during the 


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clinical studies. Potential benefit for patients taking part in the current study include 
improvement of their symptoms and decrease in RA disease activity. Using the described 
measures to avoid exposing the subjects participating in studies to unacceptable risks, it is thus 
concluded that the potential benefits compared to risks of evaluating AZD9567 justify its 
further evaluation in this Phase 2a Study.
1.4
Study Design 
This is a Phase 2a, double-blind, double dummy, parallel study in patients with active 
rheumatoid arthritis (RA) in spite of stable treatment with conventional disease-modifying 
anti-rheumatic drugs (DMARDs). A total of 40 patients will be randomised in the study.
At Visit 1 (screening visit) eligible patients will be identified. Patients will be asked to provide 
informed consent after which screening assessments will be performed.
At Visit 2, patients will be randomised in a ratio 1:1 to take either AZD9567 40 mg or 
prednisolone 20 mg for 14 days once daily. Since this study is double-blind and AZD9567 and 
prednisolone are different formulations (oral suspension and capsules respectively), all 
patients will have to take both formulations every day (active AZD9567 + placebo to 
prednisolone or placebo to AZD9567 + active prednisolone). A telephone call to check patient 
well-being will be termed Visit 3. Visit 4 will occur approximately 7 days after Visit 2, and 
Visit 5, which is the end-of-treatment visit, will occur approximately 14 days after Visit 2.
A follow-up visit (Visit 6) will be performed approximately 14 days after last IMP 
administration (at Visit 5) in order to ensure the safety and well-being of patients.
For more information regarding the visits and time windows please refer to the study 
flowchart, Figure 1.
For details of the study assessments, please see Table 1 in Section 4.


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Figure 1
Study flow chart 


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1.5
Study governance and oversight (Not Applicable)
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the efficacy of AZD9567, 40 mg, 
compared to prednisolone 20 mg in patients with 
active rheumatoid arthritis in spite of stable 
treatment with conventional and/or s.c/i.v. biological 
DMARDs
Change from baseline in 28 joint Disease Activity Score 
using CRP (DAS 28 - CRP)
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To further assess the efficacy of AZD9567, 40 mg, 
compared to prednisolone 20 mg in patients with 
active rheumatoid arthritis in spite of stable 
treatment with conventional and/or s.c/i.v. biological 
DMARDs
Proportion of subjects reaching ACR (American College of 
Rheumatology) 20, 50 and 70 responses 
Change from baseline in Swollen Joint Count 66 (SJC 66)
Change from baseline in Tender Joint Count 68 (TJC 68)
Change from baseline in individual components of DAS28 
and ACR response criteria (number of swollen and tender 
joints, patients assessments of global disease activity, pain, 
physician´s global assessment of disease activity, and CRP)
To evaluate the pharmacokinetic profile of 
AZD9567 in patients with active rheumatoid 
arthritis in spite of stable treatment with 
conventional and/or s.c/i.v. biological DMARDs
E g but not limited to plasma AUC(0-24), AUC(0-last), Cmax and 
tmax.
2.3
Safety objectives
Safety Objective:
Outcome Measure :
To assess the safety and tolerability of AZD9567 in 
patients with active rheumatoid arthritis in spite of 
stable treatment with conventional and/or s.c/i.v. 
biological DMARDs
Adverse events, vital signs, ECG and laboratory parameters 
(haematology, clinical chemistry and urine)


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2.4
Exploratory objectives 
Exploratory Objective:
Outcome Measure :
To evaluate the pharmacokinetic profile of 
prednisolone in patients with active rheumatoid 
arthritis in spite of stable treatment with 
conventional and/or s.c/i.v. biological DMARDs
E g but not limited to plasma AUC(0-24), AUC(0-last), Cmax and 
tmax.
To assess the responses to AZD9567 of relevant 
biomarkers. Whole blood and serum/plasma will be 
collected to enable relevant analyses such as, but not 
limited to, effects on bone, metabolism and HPA 
axis.
Exploratory variables will be reported in a separate 
biomarker report and will not be included in the 
clinical study report (CSR), unless something 
clinically important is observed.
Exploratory blood biomarkers (e g LPS stimulated TNFα, 
cortisol and other possible exploratory markers including 
RNA)
To obtain optional blood samples for future 
pharmacogenetic (PGx) research aiming to 
identify/explore pharmacodynamic biomarkers or 
genetic variations that may affect the efficacy, 
pharmacodynamics, safety and tolerability profile 
related to AZD9567 treatment. 
Data from the PGx research will not be included in 
the CSR.
DNA from whole blood
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1
Provision of informed consent prior to any study specific procedures 
2
Male and female patients aged 18 through 80 years at screening 
3
Established RA diagnosis according to the 2010 American College of Rheumatology 
(ACR)/EULAR classification or the 1987 criteria
4
Active RA (DAS28-CRP score ≥ 3.2) with at least 3 swollen joints and 3 tender joints 
using the DAS28 joint count 


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5
Patients must have be on stable dosing of conventional and/or s.c./i.v biological 
DMARDs for the last 8 weeks prior to Visit 1
6
CRP levels >5mg/L at screening if seronegative for RF and anti-CCP Ab, or >2mg/L if 
seropositive for either marker 
7
BMI between 18 and 35 (inclusive)
8
Negative pregnancy test (serum) for female subjects of childbearing potential.
9
Female subjects must be 1 year post-menopausal, surgically sterile, or using an acceptable
method of contraception (defined as a barrier method in conjunction with a spermicide) 
for the duration of the study, for details refer to Section 3.1.1
10 Male subjects must be surgically sterile or using an acceptable method of contraception 
(defined as barrier methods in conjunction with spermicides) for the duration of the study 
(from the time they sign consent) and for 1 month after the last dose of IMP to prevent 
pregnancy in a partner.
11 Subjects who are blood donors should not donate blood during the study and for 3 months 
following their last dose of IMP.
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
above and:
12 Provide informed consent for the genetic sampling and analyses.
3.1.1
Acceptable birth control methods
Female patients are not pregnant and do not plan to become pregnant during the study, are not 
lactating, or are of non-childbearing potential. Females of childbearing potential must provide 
a negative serum pregnancy test at screening, have a date of last menstruation consistent with 
non-pregnancy, negative urine pregnancy tests at the follow-up visit, and must be using at 
least one highly effective method of contraception.
Women not of childbearing potential are defined as women who are either permanently 
sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but excludes 
bilateral tubal occlusion), or who are postmenopausal. 
Women will be considered postmenopausal if they have been amenorrheic for 12 months or 
more following cessation of exogenous hormonal treatment prior to the planned date of 
randomisation without an alternative medical cause and have follicle stimulating hormone 
(FSH) levels in the postmenopausal range.
Acceptable methods of contraception are tubal occlusion, intrauterine device (provided coils 
are copper-banded), levonorgestrel intrauterine system (e.g., Mirena™), medroxyprogesterone 
injections (e.g., Depo-Provera™), etonogestrel implants (e.g., Implanon™, Norplan™), 
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intravaginal device (e.g., ethinylestradiol and etonogestrel ), desogestrel (e.g., Cerazette™), 
total sexual abstinence and vasectomized sexual partner (with participant assurance that 
partner received post-vasectomy confirmation of azoospermia). Women should have been 
stable on their chosen method of contraception for a minimum of 3 months before entering the 
trial and should continue with contraception for 1 month after the last dose of IMP. In addition 
to the acceptable method of contraception (except for the practice of total sexual abstinence), 
condom should be used by male partner for sexual intercourse from randomisation and for 
1 month after the last dose of IMP to prevent pregnancy.
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1
History or current inflammatory rheumatic disease other than RA (secondary Sjogren’s 
syndrome excluded)
2
History or current clinically important disease which may either put the subject at risk 
because of participation in the study, or influence the results or the subject’s ability to 
participate in the study
3
Any clinical contraindications to treatment with steroids
4
Oral or parenteral steroids (beyond study medication) 8 weeks prior to study start and 
during the study. Stable use and dose of topical and inhaled steroids for longer than 4 w 
prior to randomisation is acceptable
5
Use of any prohibited medication during the study or if the required washout time of such 
medication was not adhered to (for details see Section 7.7.1)
6
History of severe allergy/hypersensitivity or ongoing clinically important 
allergy/hypersensitivity to drugs with a similar class to study drugs
7
Any concomitant medications that are known to be associated with Torsades de Pointes, 
for additional information see Section 7.7.1)
8
Any clinically significant ECG; vital signs or laboratory abnormalities identified at 
screening or prior to randomisation 
9
Known history of drug or alcohol abuse within 1 year of screening
10 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)
11 Previous randomisation in the present study 
12 Participation in another clinical study with an investigational product during the last 3 
months
In addition, any of the following is regarded as criteria for exclusion from the genetic
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13 Previous bone marrow transplant
14 Whole blood transfusion within 120 days of the date of genetic sample collection
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4.
3.3
Subject enrolment and randomisation
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening.
The Investigator(s) will:
1
Obtain signed informed consent from the potential subject before any study specific 
procedures are performed.
2
Assign potential subject a unique enrolment number, beginning with ‘E#’.
3
Determine subject eligibility. See Section 3.1 and 3.2.
4
Assign eligible subject unique randomisation code (obtained via IWRS).
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
Randomisation codes will be assigned strictly sequentially as subjects become eligible for 
randomisation.
3.4
Procedures for handling incorrectly enrolled or randomised 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Subjects who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomised 
or initiated on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the subject from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
The randomisation scheme for this study will be generated by the biostatistics group at 
AstraZeneca or designee. This will be done using the AZRand system. Randomisation will be 


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done through a centralized interactive voice and web response system (IxRS). Patients will be 
block randomised 1:1 to either AZD9567 or prednisolone.
3.6
Methods for ensuring blinding
The study is double-blind; patients, study site personnel and AZ personnel involved in the 
evaluation of the data must be kept blinded.
Packaging and labelling of study drug will be performed in a way that ensures blinding. The 
following personnel will have access to the randomisation list:

AstraZeneca Supply Chain

IxRS vendor

CRO for drug distribution (Fisher)

Personnel performing the PK sample analysis (Covance BioA)
Randomisation will occur after eligibility has been confirmed based on all study inclusion and 
exclusion criteria.
If all eligibility criteria are met, blinded personnel will contact the centralized interactive 
voice and web response system (IxRS) to receive a randomisation number and treatment 
assignment.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
subject, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS. Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to subject 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. Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
subject have been made and documented.


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3.8
Restrictions
The following restrictions are applied during the trial or as indicated below:

Patients should abstain from donating blood and plasma during the study

No change or addition of non-steroidal anti-inflammatory drugs (NSAIDs) (including 
topical administration) less than 24 hours before joint evaluation or paracetamol and other 
painkillers less than 12 hours before joint evaluation

Due to the risk for drug-drug interactions certain drugs should be excluded, for details see 
Section 7.7.1

Male patients should refrain from fathering a child or donating sperm during the treatment 
and until 1 month following the last dose

WOCBP using hormonal contraceptives must abstain from use of any medication with 
CYP3A4 enzyme inducing properties from three months before Visit 1 until 1 month after 
last dose of IP, for details see Section 7.7.1
3.9
Discontinuation of investigational product
Subjects may be discontinued from investigational product (IP) in the following situations:

Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse Event: An AE or SAE that, in the judgment of the Investigator, requires 
treatment withdrawal due to its nature, severity, or required treatment, regardless of the 
causal relationship to treatment.

Pregnancy

Severe non-compliance with the Clinical Study Protocol 

Subject Lost to follow-up: Non-attendance to visits. In these cases, every effort should be 
made by the Investigator to ascertain the reason and to assure subject´s attendance as soon 
as possible. Every effort (at least three documented attempts) should be made to contact 
the subject and documented in the medical records. If subject could not be reached after 
that, a registered mail letter will be sent to the subject and documented in the medical 
records.

Others: At the Investigator´s or Sponsor’s request, study cancellation or any other reason 
not described above
3.9.1
Procedures for discontinuation of a subject from investigational 
product 
At any time, subjects are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments - see Section 3.10), without prejudice to 
further treatment. A subject that decides to discontinue investigational product will always be 
asked about the reason(s) and the presence of any adverse events. If possible, they will be seen 


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and assessed by an Investigator(s). Adverse events will be followed up (See Section 6); and all 
study drugs should be returned by the subject.
If a subject is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are subjects who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised. These subjects should have the reason for study withdrawal 
recorded as ‘Screen failure’(the potential subject who does not meet one or more criteria 
required for participation in a trial, this reason for study withdrawal is only valid for not 
randomised subjects). ‘Failure to meet randomisation criteria’ should be selected for an 
indication that the subject has been unable to fulfil/satisfy the criteria required for assignment 
into a randomised group (it is only applicable for randomised studies and should be used for 
subject withdrawal post-screening).
3.10.2
Rescreening 
Possible re screening may be allowed, but will be decided on an ad hoc basis depending on the 
reason. If re screening will take place, the patient will keep the same E-number.
3.10.3
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE). The Investigator will follow up AEs outside of the clinical study. 
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced. 
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that:

meet individual stopping criteria or are otherwise considered significant 

are assessed as causally related to study drug, 

are not considered to be consistent with continuation of the study


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Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.


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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Study Plan detailing the procedures
Study procedures
Screening
Visit 1
Day 1
Visit 2
(within 1 week of V1)
Day 5 
Phone call
Visit 3 
Day 8 +/- 1
Visit 4
Day 15 +/- 1
EOTa
Visit 5
Day 28 +/- 2
Follow-up
Visit 6
Inclusion/exclusion criteria
X
Demographic data
X
Medical history (incl. RA history and oral 
health)
X
Concomitant medication
X
X
X
X
X
X
Informed consent
X
Informed consent for genetic sample
X
Randomisation
X
Study drug dispensation
Xb
X
Study drug administration:
Xb
→
→
NB: at site
X 
NB: at site
Study drug return
X
Adverse events
X
→
→
→
X
Serious adverse events
X
→
→
→
→
X
Vital signs (BP/P and body temperature)
X
Xd
X
X
X
12-lead ECG
X
Xd, f
X
X
Clinical laboratory evaluations (Haematology, 
serum biochemistry, endocrinologye, and urinee
analysis)
Xc
Xd
Xd
Xd
X
Pregnancy test (serum)
X
X
Erythrocyte sedimentation rate, ESR (at site)
X
Xd
Xd
Xd
X
Physical examination, 
X
X
X
X
X
Body weight & heighte
X
X
X
DAS28-CRP
X
Xd
X
X
X
ACR20, 50, and 70
X
Xd
X
X
X
SJC and TJC 66/68
X
Xd
X
X
X
Blood sampling for exploratory biomarkers 
(cortisol, serum)
Xd,g
Profile: 0, 1, 2, 3, 4 and 6 h
Pre doseg &1, 2, 3, 4 
and 6 h post dose
Blood sampling for exploratory biomarkers 
(LPS stimulated TNFα, whole blood)
Xd
Profile: 0, 1, 2, 3, 4 and 6 h
Pre dose &1, 2, 3, 4 
and 6 h post dose
Blood sample (whole blood) for mRNAi
Xd
Xh


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Table 1
Study Plan detailing the procedures
Study procedures
Screening
Visit 1
Day 1
Visit 2
(within 1 week of V1)
Day 5 
Phone call
Visit 3 
Day 8 +/- 1
Visit 4
Day 15 +/- 1
EOTa
Visit 5
Day 28 +/- 2
Follow-up
Visit 6
Blood sample for other potential biomarkers 
(serum)
Xd
Xd
X
Blood sample for DNA (future exploratory 
research)
Xb
Blood sampling for PK of AZD9567/ 
prednisolone
Pre-dose, 0.25, 0.5, 
1, 1.5, 2, 3, 4 and 6 h
a
End of treatment
b
After randomisation
c
Local lab
d
Pre-dose 
e
Only at Visit 1
f
Only performed if Visit 1 was >3 days ago
g
Preferably starting as close to 08.00 as possible
h
At 1h post dose (Cmax)
i
A peripheral blood mononuclear cell method may be used at selective site/s


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4.1
Screening/Enrolment period
Procedures will be performed according to the Study Plan, Table 1. 
At screening, Visit 1, consenting subjects are assessed to ensure that they meet eligibility 
criteria. Subjects who do not meet these criteria must not be enrolled in the study.
Because recruited subjects will have active disease, and require treatment, the screening will 
be short allowing patients to be randomised 1-6 days after Visit 1, as along as all screening 
assessments to verify eligibility are available.
4.2
Treatment period
At Visit 2, the pre-dose/baseline assessments will be performed. Thereafter the patients will be 
randomised 1:1 to receive either 40 mg AZD9567 or 20 mg prednisolone. The treatment 
period is 2 weeks. Patients will receive IMP to bring home sufficient for one week treatment. 
They will also receive handling instructions in local language detailing how to take the IMP. 
Double dummy technique is applied as the IMP has different formulations, see Section 0. The 
site staff will call the patients 5 days after start of treatment and ask for possible adverse 
events. This phone call will be called Visit 3 in the eCRF. This precaution is taken to ensure 
the safety of the patients as 5 days is the longest treatment regimen so far in a clinical study 
with AZD9567. Patients will then come back to the clinic after one week, Visit 4, to receive 
medication for the last week and to perform study assessments. After two weeks of treatment 
the end of treatment visit, Visit 5, will be performed. For details, see Table 1.
4.3
Follow-up period
Approximately 2 weeks after Visit 5, a follow up visit will be scheduled, Visit 6. For details of 
the study procedures, see Table 1.
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded on the electronic Case 
Report Forms as specified in the Clinical Study Protocol and in accordance with the 
instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed electronic Case Report Forms. A copy of the completed 
electronic Case Report Forms will be archived at the study site.


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5.1
Efficacy assessments
5.1.1
DAS 28
The DAS28 is a composite, validated index for measuring disease activity in RA and is 
calculated at timepoints indicated in Table 1. The DAS28 (CRP) has been validated against 
radiographic progression and physical function (HAQ-DI), and the validation profile is similar 
to the DAS28 (ESR; Wells et al, 2009). 
The DAS28 (CRP/ESR) considers 28 of the 68 TJC and 28 of the 66 SJC and subject’s global 
health (GH) using PGA of disease activity using the VAS of 0 (= best), 100 (= worst) plus 
levels of CRP (mg/L) or ESR (mm/Hour).                                
DAS28(CRP) values will be calculated as follows (Wells et al, 2009): 
DAS28(CRP) = 0.56 × square root (sqrt) (TJC28) + 0.28 × sqrt(SJC28) + 0.014 × GH 
+ 0.36 × ln(CRP+1) + 0.96 
DAS28(CRP) values will be calculated at screening for eligibility assessment using an online 
calculator (ref link http://www.4s-dawn.com/DAS28/)
DAS28(CRP/ESR) IDAS 28 (CRP/ESR) Improvement 
Background DAS28(CRP/ESR) Score at 
Time of DAS28 Improvement Assessment 
Level of Improvement from Baseline 
> 1.2 
≥ 0.6 to ≤ 1.2 
< 0.6 
< 3.2 
Good response 
Moderate response 
No response 
≥ 3.2 to ≤ 5.1 
Moderate response 
Moderate response 
No response 
> 5.1 
Moderate response 
No response 
No response 
DAS28(CRP/ESR) = Disease Activity Score in 28 joints using C-reactive protein/erythrocyte sedimentation rate. 
Note: DAS28(CRP/ESR)-defined remission is DAS28 (CRP/ESR) of < 2.6. Low disease activity is < 3.2 and 
high disease activity is > 5.1.
5.1.2
Swollen and Tender Joint Count 66/68
The TJC assesses the following 68 joints for tenderness: temporomandibular (n = 2), 
sternoclavicular (n = 2), acromioclavicular (n = 2), the 8 proximal interphalangeal joints of the 
fingers, the interphalangeal joints of the thumbs (n = 2), the 8 distal interphalangeal joints, the 
10 metatarsophalangeal, the 10 metacarpo-phalangeal joints plus the wrists (n = 2), elbows 
(n = 2), shoulders (n = 2), hips (n = 2), ankle mortise and tarsus (n = 4), knees (n = 2), and 
toes (n = 10; Felson et al, 2011). 


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The SJC assesses 66 joints, which includes all of the joints in the TJC excluding the hip joints 
(n = 2). 
Swollen and tender joint counts will be assessed by a qualified, independent Joints Counts 
Assessor who is a skilled arthritis assessor who will be responsible for completing the joint 
counts. 
In order to calculate the ACR20, ACR50, ACR70, and DAS28 (CRP) responses, each of the 
66 joints will be evaluated for swelling and each of the 68 joints will be evaluated for 
tenderness. Standardized metrology training will be provided if necessary.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Section 4).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
A central laboratory will be used in this study (Covance Central Laboratory Services) but for the 
safety lab panel at Visit 1 also local labs will be used. The clinical chemistry, haematology 
and urinalysis can therefore be analyzed at a local laboratory at or near to the Investigator site 
both at Visit 1 and if needed on ad hoc basis if deemed necessary by the investigator. Sample 
tubes and sample sizes may vary depending on laboratory method used and routine practice at 
the site. Reference values from all labs used in the study will be included in the eCRF.
The following laboratory variables will be measured:
Table 2
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (neutrophils, lymphocytes,
S/P-Alkaline phosphatise (ALP)
monocytes, eosinophils and basophils)
S/P-Aspartate transaminase (AST)
B-Platelet count
S/P-Alanine transaminase (ALT)
Erythrocyte sedimentation rate, ESR
S/P-Albumin
S/P-Potassium
Urinalysis (dipstick)
S/P-Calcium, total
U-Hb/Erythrocytes/Blood 
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U-Protein/Albumin 
U-Glucose
Endocrinology
FSHa
S/P-Creatine kinase (CK)
S/P-C-reactive protein (CRP)
S/P-Low density lipoprotein (LDL)
S/P-High density lipoprotein (HDL)
S/P-Free fatty acids (FFA)
S/P-fasting glucoseb
S/P-insulin
a
Only at Visit 1 for women under the age of 50 considered to be post-menopausal to determine that the 
hormones are in the post-menopausal range
b
Fasting glucose on Visit 2, Visit 4 and Visit 5.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
NB. In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer 
to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin - Hy’s Law’, for further instructions.
Table 3
Volume of blood to be drawn from each patient
Assessment
No of 
samplesb
Sample 
volume (mL)
Total volume 
(mL)b
Safety - Clinical Chemistry
5
5
25
Safety - Haematology
5
2
10
Endocrinology (FSH)a
1
2.5
2.5
Exploratory Biomarkers (whole blood mRNA)
2
5
10
Other Potential Biomarkers (serum)
3
2 x 8.5
2 x 25.5 
Exploratory Biomarkers (whole blood for TNFα)
12
2
24
Exploratory Biomarkers (serum for cortisol)
12
8
96
PK samples for AZD9567/prednisolone
9
3
27
Pharmacogenetics
1
10
10
TOTAL
53
255.5
a
only females
b
The number of samples may be changed due to additional sampling at unscheduled visits and the blood 
volume required may be altered to fit the assay requirements. 


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5.2.2
Physical examination
A complete physical examination will be performed as indicated in Table 1 and include an 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen skin, 
head and neck (including ears, eyes, nose, mouth - including teeth and gums - and throat), 
lymph nodes, thyroid, abdomen, musculo-skeletal (including spine and extremities) and 
neurological systems.
The outcome of the examination is to be recorded as normal/abnormal in the eCRF. Any new 
or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline measurement will be reported as an AE (see Section 6.1).
5.2.3
ECG
5.2.3.1
Resting 12-lead ECG
12-lead pECG recordings will be collected as detailed in Table 1. The investigator will make 
an overall evaluation of the pECG as normal or abnormal. If abnormal, it will be decided 
whether or not the abnormality is clinically significant or not clinically significant and the reason 
for the abnormality will be recorded on the eCRF.
5.2.4
Vital signs
Vital signs will include pulse, and systolic and diastolic blood pressure as well as body 
temperature. Vital signs will be obtained at timepoints indicated in see Table 1 (and ad-hoc as 
medically indicated).
5.2.4.1
Pulse and blood pressure
Pulse (beats/minute, radial artery, during 30 seconds) will be measured before blood pressure 
and in a lying or sitting position after 5 minutes of rest. Thereafter, systolic and diastolic blood 
pressure (mmHg) will be measured using the same cuff, appropriate for arm circumference, 
and in the same position, throughout the study. 
5.2.4.2
Body temperature 
Body temperature (Celcius) will be collected at timepoints indicated in Table 1 and according 
to standard procedures at the clinics.
5.3
Pharmacokinetics
5.3.1
Collection of samples
Blood samples for determination of AZD9567 in plasma will be taken at the times presented 
in the study plan Table 1.
Blood samples for determination of prednisolone in plasma will also be taken at the times 
presented in the study plan Table 1.


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Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual. 
5.3.2
Determination of drug concentration
Samples for determination of drug concentration in plasma will be analysed by Covance 
Laboratory Services on behalf of AstraZeneca, using an appropriate bioanalytical method. Full 
details of the analytical method used will be described in a separate bioanalytical report.
5.3.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalization 
or six months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and 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 Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report.
5.4
Pharmacodynamics 
5.4.1
Collection of samples 
The pharmacodynamics (PD) of oral AZD9567 will be assessed by effects on CRP levels as 
part of the primary endpoint DAS28-CRP. CRP is collected as part of the lab screen at time 
points indicated in Table 1. ESR is also collected as an exploratory biomarker and is also part 
of the lab screen at time points indicated in Table 1. In addition, there will be samples 
collected for exploratory biomarkers for future exploratory research, see Section 5.6.
5.5
Genetics
5.5.1
Collection of optional genetic samples
The subject’s consent to participate in the genetic research components of the study is 
optional. 
The blood sample for genetic research will be obtained from the subjects after or at Visit 2, ie 
after randomisation. Although DNA variants are stable parameter, early sample collection is 
preferred to avoid introducing bias through excluding subjects who may withdraw due to an 
adverse event (AE), such subjects would be important to include in any genetic analysis. If for 
any reason the sample is not drawn at Visit 2, it may be taken at any visit until the last study 
visit. Only one sample should be collected per subject for genetics during the study. 


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Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
5.5.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 
15 years or as per local regulations from the date of the Last Subject’s Last Visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. The 
results of any possible future analyses will not be reported in the CSR, but separately in a 
scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA
5.6
Biomarker analysis 
The subject’s consent to the use of donated biological samples is mandatory. 
 
 
 
5.6.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed.
 
 
5.6.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual.
5.6.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival.
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 documentation of receipt of arrival.
CCI
CCI


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AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank during the entire 
life cycle.
5.6.4
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Principal Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
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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.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject 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 subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from randomisation, Visit 2 throughout the treatment period 
and including the follow-up period Visit 6.
SAEs will be recorded from the time of informed consent.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at study Visit 6 are followed up by the Investigator for as long as 
medically indicated, but without further recording in the CRF. AstraZeneca retains the right to 
request additional information for any subject with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity, 

Intensity rating scale:

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
moderate (discomfort sufficient to cause interference with normal activities)

severe (incapacitating, with inability to perform normal activities)

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to investigational product

AE caused subject’s withdrawal from study (yes or no)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalization

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, 

Description of AE.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2. 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 Section 6.2. 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 Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, 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 will also be assessed for other medication and study procedures 
and additional study drug. Note that for SAEs that could be associated with any study 
procedure the causal relationship is implied as ‘yes’.


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A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you/the child had any health problems since the previous 
visit?’, or revealed by observation will be collected and recorded in the CRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
6.3.6
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR. Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs should therefore only be reported as AEs if they fulfil any of the
SAE criteria or are the reason for discontinuation of treatment with the investigational 
product.
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 (e.g., 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).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
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
6.3.7
Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs. Please refer to Appendix D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.3.8
Disease under Study (DUS) 
Symptoms of DUS are those which might be expected to occur as a direct result of active RA. 
Events, which are unequivocally due to disease under study should not be reported as an AE


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during the study unless they meet SAE criteria or lead to discontinuation of the investigational 
product.
6.4
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 CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., 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 i.e., 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 WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC 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 and the EU Summary of Product Characteristics (SPC) for the active comparator 
product.
6.5
Overdose
To date there is no experience of overdose and no antidote to AZD9567. In cases of known or 
suspected overdose, symptomatic treatment and monitoring of vital functions and e.g. blood
parameters should be performed according to routine clinical practice based on the judgment 
of the investigator. In addition, should an overdose occur the following procedures should be 
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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or 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.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4. 
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study subject has received any study drug
6.6.1
Maternal exposure
If a subject becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., 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 SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.


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The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and 
1 month following the last dose.
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality), 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.
6.7
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 subject or 
has the potential to cause harm to the subject. 
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 subject.
Medication error includes situations where an error. 

occurred

was identified and intercepted before the subject received the drug

did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to 
the subject

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature 

Wrong subject received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to subject (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:


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
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 

Subject accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
If an medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., 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 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1
Identity of investigational product(s)
AZD9567 is a differentiated selective-Glucocorticoid-Receptor-Modulator. In the study the 
aim is to investigate the safety, efficacy and tolerability of AZD9567 compared to 
prednisolone in patients with active Rheumatoid Arthritis.
The drug substance is presented as a drug powder and formulated as a suspension for oral 
administration, using standard excipients. A placebo formulation, an oral suspension, using 
inactive standard excipients is included in the study. A comparator product, Prednisolone 
capsules and placebo for prednisolone capsules, will also be used.
Investigational product
Dosage form and strength
Manufacturer
AZD9567 Oral suspension
AZD9567 Oral suspension 
OC Prednisolone capsules 
OC Prednisolone capsules
0.5 mg/ml - 10 mg/ml 
Placebo
5 mg 
Placebo
AstraZeneca R&D Gothenburg
AstraZeneca R&D Gothenburg
AstraZeneca R&D Gothenburg
AstraZeneca R&D Gothenburg
7.2
Dose and treatment regimens
A total of 40 eligible patients will be randomly assigned 1:1 to the study treatment. This will 
be managed via IWRS. The dose of IP, AZD9567 40 mg and prednisolone 20 mg, will be 


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taken once daily (in the morning) for 14 days. Detailed instructions are provided in the 
Handling instructions each patient will be provided with in local language. The first dose of 
IMP will be taken at the clinic after the baseline assessments have been performed on Visit 2. 
Also at the end of treatment visit, Visit 5, the IMP should be taken at the site to allow for a pre 
dose blood sample to be drawn for PK analyses. As the IMP has different formulations, 
double dummy technique is applied. Each patient will therefore take both oral suspension and 
4 capsules of prednisolone/placebo on a daily basis for 14 days. The oral suspensions of 
AZD9567 and placebo are not taste neutral. This information will be included in the Patient 
Informed Consent form. Opening aids for the IMP bottles will be supplied by AstraZeneca 
and will be described in the Handling instructions.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. Details 
of storage condition will be provided on the label of the IMP. The IMP storage area must be 
temperature monitored and the site will maintain documentation of the temperature 
monitoring. Handling instructions for the patients will be provided separately by AstraZeneca.
7.5
Compliance
The administration of all study drugs should be recorded in the appropriate sections of the 
Case Report Form.
7.6
Accountability
The study drug provided for this study will be used only as directed in the Clinical Study 
Protocol.
The study site staff will account for all study drugs dispensed to and returned from the subject.
The study drug should be destructed locally. Study site staff, if applicable, or the AZ monitor
will account for all study drugs received at the site, unused study drugs and for appropriate 
destruction. Certificates of delivery and destruction should be signed. 
7.7
Concomitant and other treatments 
7.7.1
Other concomitant treatment
Pre-clinical 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 


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together with the IMP 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. Patients should not have taken any of these medications within 
3 days of IMP intake (ref exclusion criteria 5). Guidance is provided in Appendix E. However, 
the list in Appendix E is not a complete list, ie it should be treated with caution.
Guidance for avoiding QT-prolonging medications can also be found in a link provided in
Appendix E.
Other medication, which is considered necessary for the subject’s safety and wellbeing, may 
be given at the discretion of the Investigator and recorded in the appropriate sections of the 
Case Report Form.
8.
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1
Statistical considerations
The purpose of this section is to provide a brief outline of the statistical methods to be 
employed in this Phase IIa, Randomised Multi-Center, Double- Blind, comparator-Controlled 
Study of AZD9567 xx mg in patients with Rheumatoid Arthritis (RA) and prednisolone 
20 mg. A more detailed description of all statistical matters as well as data derivations and 
data summaries will be included in separate statistical analysis plan (SAP) based on the 
current protocol and in accordance to the International Conference on Harmonization (ICH) 
E3 and E9 Guidelines. 
All efficacy and safety variables will be summarized by treatment groups using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum, and maximum for continuous 
data and absolute and relative frequencies for categorical data). Data will be summarized for 
baseline, endpoint and by visit (if applicable).
Descriptive statistics will be presented to assess the distribution of the baseline variables 
across treatment groups. Assessment of efficacy will be made using the decision framework 
(cf. 8.2) used to determine the necessary sample size. Formal statistical tests for differences 
between treatment groups will be applied for exploratory purposes only. Moreover

All personnel involved with the analysis of the study will remain blinded until database 
lock and Clinical Study Protocol violators identified.

Analyses will be performed by AstraZeneca or its representatives. 


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
Refer to Statistical Analysis Plan (SAP) for details.
8.2
Sample size estimate 
This study, is a Phase IIa study, where the aim is to show that the efficacy of AZD9567 is 
equivalent to the efficacy of prednisolone 20 mg. The design is a two arm design, one arm 
receiving prednisolone 20 mg and the other receiving AZD9567. 
The endpoint proposed is the change from baseline (CFBL) in DAS28 units for each patient. 
The main analysis will be based on the difference XT-XP, between XT, the average change 
from base line of the chosen dose of AZD9567 and, XP, the mean CFBL of prednisolone 
20 mg. Therefore, this difference quantifies the treatment effect i.e. how much better 
AZD9567 is compared to prednisolone 20 mg in terms of average CFBL in DAS28 units. 
The details of the sample size calculation are based on internal decision criteria as explained 
in Frewer et al, 2016. In these calculations we use the reliability threshold of the DAS28 index 
known to be 0.6 (Siemons et al, 2014). 
Using a sample size of 18 per arm, results in good decision criteria. In comparison with 
traditional hypothesis testing this corresponds to a test with significance level alpha=0.09 and 
beta=0.10.
The above results have been evaluated using simulations. Further details of the statistical 
methodology will be outlined in the SAP.
8.3
Definitions of analysis sets
8.3.1
Efficacy analysis set
The primary analysis population for efficacy will be analyzed using the intention to treat (ITT) 
population. This is in accordance to the ICH E9 guideline suggesting that the analysis of the 
primary endpoint should be analyzed according to the treatment to which patients were 
actually randomised. The ITT population will include all patients who were randomised and 
received at least one dose of study medication. Patients will be analyzed according to the 
treatment to which they were intended to be randomised to. ITT is sometimes referred to as 
Full Analysis Set.
Moreover, the primary analysis population for efficacy will also be analyzed using the Per 
Protocol (PP) population which includes all patients who were randomised, treated with study 
medication and did not have a major protocol deviation. Major protocol deviations leading to 
exclusion from the PP population will be finalized prior to un-blinding during the blind data 
review meeting. Full criteria for exclusion from the analysis set will be detailed in the 
Statistical Analysis Plan (SAP).


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8.3.2
Safety analysis set
The Safety Population will include all patients who were randomised and received at least one 
dose of study medication. Patients will be analyzed according to the treatment which they 
actually received.
8.3.3
PK analysis set
The PK analysis set will include all subjects with at least one quantifiable AZD9567 
concentration with a documented related dosing history.
8.3.4
Other analysis sets
Pharmacodynamic (PD) analysis set will include all subjects who received at least one dose of 
study treatment and have available pharmacodynamic data.
8.4
Outcome measures for analyses 
The primary efficacy endpoint is the difference in change from baseline in DAS28, XT-XP, 
between, XT, the average CFBL of the chosen dose of AZD9567 and, XP, the mean CFBL of 
prednisolone 20 mg. 
Secondary efficacy variables are the change from baseline in ACR and the percentage of 
patients with ACR20, 50 and 70.
8.5
Methods for statistical analyses
8.5.1
Analysis of the primary variable(s)
To show that the efficacy of AZD9567 is equivalent to the efficacy of p20 mg in terms of 
change from baseline in DAS28, we will use the difference in DAS28 units, XT-XP, between, 
XT, the average CFBL of the chosen dose of AZD9567 and, XP, the mean CFBL of 
prednisolone 20 mg. This difference will be calculated using a mixed model. It will be 
concluded that the data support better efficacy of AZD9567 whenever the observed difference 
is positive (larger than 0). Similarly, it will be concluded that the AZD9567 is less efficacious
than prednisolone 20 mg if the difference is negative (less than -0.4). Formal statistical 
testsing will be performed for exploratory purposes only.
8.5.2
Analysis of the secondary variable(s)
Secondary efficacy variables;
The change from baseline in core set measures of ACR and DAS28 will be analyzed with an 
ANCOVA model approach using PROC MIXED in SAS with baseline value as covariate.


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8.5.2.1
Pharmacokinetic analyses
The derivation of the PK parameters will performed at Covance (Clinical Pharmacokinetic 
Alliance).The PK parameters will be derived using non-compartmental methods with 
Phoenix® WinNonlin® Version 6.3, or higher (Pharsight Corp., Mountain View, California), 
in accordance with “Best Practice Reference Guidelines Pharmacokinetic Evaluations in 
Clinical Studies”. All descriptive statistical computations will be performed using SAS 
Version 9.2, or higher.
Where possible, the following PK parameters will be assessed for AZD9567 and 
prednisolone.
AUC(0-24)
Area under the plasma concentration-time curve from time zero to 24 hours 
after administration (using the pre-dose value as the 24 h time point)
AUC(0-last)
Area under the plasma concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(0-6)
Area under the plasma concentration-time curve from time zero to 6 h after 
administration
tmax
Time to reach maximum plasma concentration 
Cmin
Predose concentration
Additional PK parameters may be determined where appropriate. 
Further details regarding the calculation and descriptive statistics of the PK parameters will be 
described in the SAP.
8.5.3
Subgroup analysis (if applicable)
Exploratory analyses may be performed where subgroups of interest have been identified and 
depending on the numbers of subjects within each subgroup.
8.5.4
Sensitivity analysis (if applicable)
To be confident in the results of the study, we need to check that the assumptions of the 
performed analyses are compatible the data at hand. Therefore, sensitivity analysis is required. 
This can concern (but is not restricted to) issues related to choice of the method of analysis, 
handling of missing data, simplifying assumptions such as ignoring correlations and 
interaction terms or handling of outliers. A more detailed description of sensitivity analysis 
will be included in the SAP. 
8.5.5
Exploratory analysis (if applicable)
Exploratory and post hoc analyses may be performed to answer additional questions.


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9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site staff
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC
system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the Clinical Study Protocol, that data 
are being accurately and timely recorded in the CRFs, that biological samples are handled 
in accordance with the Laboratory Manual and that study drug accountability checks are 
being performed

Perform source data verification (a comparison of the data in the CRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (e.g., clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.


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9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with AZD9567.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by IQVIA, according to the Data Management Plan.
The data collected through third party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA). Medications 
will be classified according to the WHO Drug Dictionary. All coding will be performed by the 
Medical Coding Team at IQVIA.
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.


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When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data Management of genotype data
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or any other organization 
contracted to work with AstraZeneca to analyse samples. The results from this genetic 
research may be reported in the CSR for the main study, or in a separate report as appropriate.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory (ies) internal or 
external to AstraZeneca.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Subject data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician, unless required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a subject’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.


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10.3
Ethics and regulatory review
An Ethics Committee should approve the final Clinical Study Protocol, including the final 
version of the Informed Consent Form and any other written information and/or materials to 
be provided to the subjects. The Investigator will ensure the distribution of these documents to 
the applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any subject into the study. 
The Ethics Committee should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
Ethics Committee annually.
Before enrolment of any subject into the study, the final Clinical Study Protocol, including the 
final version of the Informed Consent Form, is approved by the national regulatory authority 
or a notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study

Ensure each subject is notified that they are free to discontinue from the study at any time

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the Investigator’s 
Study File

Ensure a copy of the signed Informed Consent Form is given to the subject


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
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an Ethics Committee.
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, National Co-ordinating Investigator and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee and if applicable, also the national regulatory authority approval, before 
implementation. Local requirements are to be followed for new versions of Clinical Study 
Protocols.
AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator(s). For distribution to Ethics Committee see Section 10.3.
If a change to a Clinical Study Protocol requires a change to a centre’s Informed Consent 
Form, AstraZeneca and the centre’s Ethics Committee are to approve the revised Informed 
Consent Form before the revised form is used. 
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the Clinical Study 
Protocol, Good Clinical Practice (GCP), guidelines of the International Conference on 
Harmonisation (ICH), and any applicable regulatory requirements. The Investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre.


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11.
LIST OF REFERENCES 
del Rincon et al, 2014
del Rincon I, Battafarano DF, Restrepo JF, Erikson JM, Escalante A. Glucocorticoid dose 
thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. 
Arthritis & rheumatology (Hoboken, NJ) 2014;66(2):264-72.
Felson et al, 2011
Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College 
of Rheumatology/European League Against Rheumatism provisional definition of remission 
in rheumatoid arthritis for clinical trials. Arthritis and rheumatism 2011;63(3):573-86.
Frewer et al, 2016
Frewer P, Mitchell P, Watkins C, Matcham J. Decision-making in early clinical drug 
development. Pharmaceutical statistics. 2016;15(3):255-63
Gerlag et al, 2004
Gerlag DM, Haringman JJ, Smeets TJ, Zwinderman AH, Kraan MC, Laud PJ, et al. Effects of 
oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid 
arthritis. Arthritis Rheum 2004;50(12):3783-91.
Gulliford et al, 2006
Gulliford MC, Charlton J, Latinovic R. Risk of diabetes associated with prescribed 
glucocorticoids in a large population. Diabetes Cre 2006;29(12):2728-9.
Harris, 1997
Harris ED Jr. Rheumatoid Arthritis. Philadelphia: WB Saunders; 1997.
Hench et al, 1949
Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal 
cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocortical 
hormone in arthritis: preliminary report. Ann Rheum Dis 1949;8(2):97-104.
Pincus et al, 1987
Pincus T, Callahan LF, Burkhauser RV. Most chronic diseases are reported more frequently 
by individuals with fewer than 12 years of formal education in the age 18-64 United States 
population. J Chronic Dis 1987;40(9):865-74.
Pincus et al, 1989
Pincus T, Callahan LF. Reassessment of twelve traditional paradigms concerning the 
diagnosis, prevalence, morbidity and mortality of rheumatoid arthritis. 
Scand J Rheumatol Suppl 1989;79:67-96.


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Shacham, 1983
Shacham S. A shortened version of the Profile of Mood States. 
J Pers Assess 1983;47(3):305-6.
Siemons et al, 2014
Siemons L, ten Klooster PM, Vonkeman HE, van de Laar MA, Glas CA. Further optimization 
of the reliability of the 28-joint disease activity score in patients with early rheumatoid 
arthritis. PloS one 2014;9(6):e100544.
Siu et al, 2015
Siu S, Haraoui B, Bissonnette R, Bessette L, Roubille C, Richer V, et al. Meta-analysis of 
tumor necrosis factor inhibitors and glucocorticoids on bone density in rheumatoid arthritis 
and ankylosing spondylitis trials. Arthritis Care Res (Hoboken) 2015;67(6):754-64.
Symmons, 2002
Symmons DP. Epidemiology of rheumatoid arthritis: determinants of onset, persistence and 
outcome. Best Pract Res Clin Rheumatol 2002;16(5):707-22.
ter Wee et al, 2015
ter Wee MM, den Uyl D, Boers M, Kerstens P, Nurmohamed M, van Schaardenburg D, et al. 
Intensive combination treatment regimens, including prednisolone, are effective in treating 
patients with early rheumatoid arthritis regardless of additional etanercept: 1-year results of 
the COBRA-light open-label, randomised, non-inferiority trial. 
Ann Rheum Dis 2015;74(6):1233-40.
Wells et al, 2009
Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 28-
joint Disease Activity Score (DAS28) and European League Against Rheumatism response 
criteria based on C-reactive protein against disease progression in patients with rheumatoid 
arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. 
Ann Rheum Dis 2009;68(6):954-60.
Wong et al, 2001
Wong JB, Ramey DR, Singh G. Long-term morbidity, mortality, and economics of 
rheumatoid arthritis. Arthritis Rheum 2001;44(12):2746-9.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d6470c00003-csp-v3
Document Title:
D6470C00003 Clinical Study Protocol version 3
Document ID:
Doc ID-003377555
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
04-Apr-2019 06:21 UTC
Evelina Björnsson
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
 
Statistical Analysis Plan 
Study Code 
D6470C00003 
Edition Number 
2 
Date 
28 Nov 2019 
A Phase 2a, Randomised, Double-blind, Parallel Study to Assess the 
Efficacy, Safety and Tolerability of AZD9567 compared to Prednisolone 
20 mg in patients with active Rheumatoid Arthritis (RA) 
 
 
 
 


Statistical Analysis Plan  
Study Code D6470C00003 
Edition Number 2  
Date 28 Nov 2019 
2 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................. 5 
AMENDMENT HISTORY ..................................................................................... 8 
1. 
STUDY DETAILS ................................................................................................... 9 
1.1 
Study objectives ....................................................................................................... 9 
1.1.1 
Primary objective ..................................................................................................... 9 
1.1.2 
Secondary objectives ............................................................................................... 9 
1.1.3 
Safety objective ...................................................................................................... 10 
1.1.4 
Exploratory objectives ........................................................................................... 10 
1.2 
Study design ........................................................................................................... 11 
1.3 
Number of subjects ................................................................................................ 12 
2. 
ANALYSIS SETS ................................................................................................. 13 
2.1 
Definition of analysis sets ...................................................................................... 13 
2.1.1 
All subjects enrolled (ENR) analysis set................................................................ 13 
2.1.2 
All subjects randomised (RND) analysis set ......................................................... 13 
2.1.3 
Safety analysis set (SAF) ....................................................................................... 13 
2.1.4 
Full analysis set (FAS) ........................................................................................... 13 
2.1.5 
Per protocol (PP) analysis set ................................................................................ 13 
2.1.6 
Pharmacokinetics (PK) analysis set ....................................................................... 14 
2.2 
Violations and deviations ....................................................................................... 14 
2.2.1 
Protocol deviation monitoring ............................................................................... 14 
2.2.2 
Protocol deviation reporting .................................................................................. 14 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 15 
3.1 
Primary Variable .................................................................................................... 15 
3.1.1 
Tender Joint Count 28 ............................................................................................ 15 
3.1.2 
Swollen Joint Count 28 .......................................................................................... 16 
3.1.3 
Global Health ......................................................................................................... 16 
3.1.4 
C-reactive protein (CRP) ....................................................................................... 16 
3.2 
Secondary Variables .............................................................................................. 17 
3.2.1 
ACR20, ACR50 or ACR70 .................................................................................... 17 
3.2.2 
Swollen Joint count 66 ........................................................................................... 18 
3.2.3 
Tender Joint count 68 ............................................................................................. 18 
3.2.4 
Change from baseline in individual components of DAS28.................................. 19 
3.2.5 
Change from baseline in individual components of ACR ..................................... 19 


Statistical Analysis Plan  
Study Code D6470C00003 
Edition Number 2  
Date 28 Nov 2019 
3 
3.3 
Pharmacokinetics ................................................................................................... 19 
3.4 
Safety outcomes ..................................................................................................... 21 
3.4.1 
Adverse events ....................................................................................................... 21 
3.4.2 
Vital signs .............................................................................................................. 22 
3.4.3 
ECG ........................................................................................................................ 22 
3.4.4 
Laboratory data ...................................................................................................... 22 
3.5 
Exploratory outcomes ............................................................................................ 23 
3.5.1 
Biomarkers ............................................................................................................. 23 
3.5.2 
Other exploratory outcomes ................................................................................... 23 
4. 
ANALYSIS METHODS ....................................................................................... 24 
4.1 
General principles .................................................................................................. 25 
4.1.1 
Reference start date ................................................................................................ 25 
4.1.2 
Baseline measurements .......................................................................................... 25 
4.1.3 
Visit windowing ..................................................................................................... 25 
4.1.4 
Table outputs .......................................................................................................... 26 
4.1.5 
Statistical modelling ............................................................................................... 26 
4.2 
Analysis methods for efficacy variables ................................................................ 26 
4.2.1 
Primary efficacy variable analysis method ............................................................ 26 
4.2.2 
Secondary efficacy variable analysis methods....................................................... 26 
4.3 
Statistical models ................................................................................................... 27 
4.3.1 
Primary efficacy statistical model .......................................................................... 27 
4.3.2 
Secondary efficacy statistical models .................................................................... 28 
4.3.3 
Exploratory outcomes statistical models ............................................................... 29 
4.3.3.1 
TNFα ...................................................................................................................... 29 
4.3.3.2 
Plasma cortisol (nmol/L) AUEC(0-6) biomarkers ................................................. 29 
4.3.3.3 
Morning plasma cortisol (nmol/L) biomarkers ...................................................... 30 
4.3.3.4 
Pharmacokinetics ................................................................................................... 31 
4.3.3.5 
Other exploratory outcomes ................................................................................... 33 
4.4 
Missing primary and secondary variables .............................................................. 33 
4.4.1 
Missing DAS28 (CRP) components ...................................................................... 33 
4.4.2 
Missing tender or swollen joints ............................................................................ 33 
4.4.3 
Missing ACRxx components ................................................................................. 33 
4.5 
Multiple Comparisons/Multiplicity ....................................................................... 34 
4.6 
Subgroups .............................................................................................................. 34 
4.7 
Sensitivity analysis ................................................................................................. 34 
4.8 
Demographic, Dosing, and Safety and Tolerability data ....................................... 34 
4.8.1 
Subject disposition, important protocol deviations and analysis set ...................... 34 
4.8.2 
Demographic and baseline characteristics ............................................................. 35 
4.8.3 
Prior, concomitant, and post-discontinuation medications and therapies .............. 36 
4.8.4 
Medical history ...................................................................................................... 37 
4.8.5 
Exposure ................................................................................................................ 37 


Statistical Analysis Plan  
Study Code D6470C00003 
Edition Number 2  
Date 28 Nov 2019 
4 
4.8.6 
Safety ..................................................................................................................... 37 
4.8.6.1 
Adverse events ....................................................................................................... 38 
4.8.6.2 
Overdose ................................................................................................................ 39 
4.8.6.3 
Laboratory variables .............................................................................................. 39 
4.8.6.4 
Vital signs .............................................................................................................. 40 
4.8.6.5 
ECG variables ........................................................................................................ 41 
4.8.6.6 
Physical examinations ............................................................................................ 41 
5. 
INTERIM ANALYSES ......................................................................................... 41 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 42 
7. 
REFERENCES ...................................................................................................... 43 
8. 
APPENDIX ............................................................................................................ 44 
8.1 
Appendix A Health assessment questionnaire score derivation ............................ 45 
8.2 
Appendix B AstraZeneca defined reference ranges for vital signs ........................ 50 
8.3 
Appendix C Laboratory Parameters ....................................................................... 51 
8.4 
Appendix D Partial and missing date conventions ................................................ 52 
 


Statistical Analysis Plan  
Study Code D6470C00003 
Edition Number 2  
Date 28 Nov 2019 
5 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
ACR 
American College of Rheumatology 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomic therapeutic chemical 
AUC 
Area under the concentration curve 
AUC(0-6) 
Area under the concentration curve from time 0 to 6 hours 
AUC(0-24) 
Area under the concentration curve from time 0 to 24 hours 
AUC(0-last) 
Area under the concentration curve from time 0 to last measurable 
concentration 
AUEC(0-6) 
Area under the effect curve from time 0 to 6 hours 
BMI 
Body mass index 
CFB 
Change from baseline 
CL/F 
Apparent total body clearance for drug following extravascular 
administration 
Cmax 
Maximum  observed drug concentration 
Covance 
Clinical Pharmacokinetic Alliance 
Ctrough 
Observed trough plasma concentration 
CRP 
C-reactive protein 
CSR 
Clinical study report 
DAS28 
Disease Activity Score in 28 joints 
DAS28 (CRP) 
Disease Activity Score in 28 joints using C-reactive protein 
DMARD 
Disease-modifying anti-rheumatic drug 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ENR 
All subjects enrolled analysis set 
EULAR 
European League Against Rheumatism 
FAS 
Full analysis set 
HAQ 
Health Assessment Questionnaire 
HAQ-DI 
Health Assessment Questionnaire - Disability Index 


Statistical Analysis Plan  
Study Code D6470C00003 
Edition Number 2  
Date 28 Nov 2019 
6 
Abbreviation or 
special term 
Explanation 
GCV 
Geometric coefficient of variation 
GH 
Global health 
GSD 
Geometric standard deviation 
HPA 
Hypothalamic–pituitary–adrenal 
IARA 
Investigator's Global Assessment of RA 
ICH 
International Committee on Harmonisation 
ITT 
Intent-to-treat 
i.v. 
Intravenous 
LLOQ 
Lower limit of quantification 
LPS 
Lipopolysaccharide 
MCP 
Metacarpophalangeal joints 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 
NQ 
Non-quantifiable 
PD 
Pharmacodynamic analysis set 
PGx 
Pharmacogenetics 
PIP 
Proximal interphalangeal 
PK 
Pharmacokinetic 
PP 
Per protocol analysis set 
PT 
Preferred term 
RA 
Rheumatoid arthritis 
RNA 
Ribonucleic acid  
RND 
All subjects randomised analysis set 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SARA 
Subject's Assessment of Rheumatoid Arthritis 
REML 
Residual/restricted maximum likelihood 
s.c 
Subcutaneous 
SJC 66 
Swollen joint count 66 
SOC 
System organ class 


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Abbreviation or 
special term 
Explanation 
t1/2z 
Half-life associated with the terminal slope (λz) of the semi-logarithmic 
concentration time curve 
TEAE 
Treatment emergent adverse event 
TJC 68 
Tender joint count 68 
tmax 
Time point of the maximal plasma concentration of a drug 
TNFα 
Tumour necrosis factor alpha 
VAS 
Visual Analogue Scale 


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Edition Number 2  
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1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective of this study is to assess the efficacy of AZD9567 40 mg, compared to 
Prednisolone 20 mg in subjects with active rheumatoid arthritis (RA) in spite of stable 
treatment with conventional and/or subcutaneous (s.c)/ intravenous (i.v.) biological 
disease-modifying anti-rheumatic drugs (DMARDs) by assessment of: 
− Change from baseline (CFB) in 28 joints Disease Activity Score (DAS28) using C-
reactive protein (DAS28 - CRP) after 14 days of treatment at Day 15. 
1.1.2 
Secondary objectives 
The secondary objectives of this study after approximately two weeks treatment period are: 
− To further assess the efficacy of AZD9567 40 mg, compared to Prednisolone 20 mg in 
subjects with active RA in spite of stable treatment with conventional and/or s.c/i.v. 
biological DMARDs by assessment of: 
• Proportion of subjects achieving American College of Rheumatology (ACR) 
20, 50 and 70 responses. 
• Change from baseline in Swollen Joint Count 66 (SJC 66). 
• Change from baseline in Tender Joint Count 68 (TJC 68). 
• Change from baseline in individual components of: 
− DAS28 (number of swollen and tender joints 28, subject's assessments 
of global disease activity (GH) and CRP). 
− ACR response criteria (number of swollen joints 66 and tender joints 
68, subject's assessments of global disease activity (GH), physician´s 
global assessment of disease activity, subject's assessments of pain, 
subject's assessments of physical function and CRP). 
− To evaluate the pharmacokinetic (PK) profile of AZD9567 in subjects with active RA 
in spite of stable treatment with conventional and/or s.c/i.v. biological DMARDs by 
assessment of: 
• PK parameters including area under the plasma concentration-time curve until 
the last quantifiable concentration AUC(last), area under the concentration-
time curve from time zero to 24 hours after dose AUC(0-24), area under the 
concentration-time curve from time zero to 6 hours after dose AUC(0-6), 
maximum plasma concentration during a dosing interval (Cmax), time to reach 


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maximal plasma concentration (tmax) the last plasma concentration measured 
before the last dose (Ctrough) and apparent plasma clearance (CL/F). 
1.1.3 
Safety objective 
To assess the safety and tolerability of AZD9567 in subjects with active RA in spite of stable 
treatment with conventional and/or s.c/i.v. biological DMARDs by assessment of: 
• Adverse events (AEs). 
• Vital signs. 
• Electrocardiogram (ECG). 
• Laboratory parameters (haematology, clinical chemistry and urine). 
1.1.4 
Exploratory objectives 
The exploratory objectives of this study after approximately two weeks treatment period are: 
• To assess the responses to AZD9567 of relevant biomarkers. Whole blood and 
serum/plasma will be collected to enable relevant analyses such as, effects on bone, 
metabolism and hypothalamic–pituitary–adrenal (HPA) axis by assessment of 
exploratory blood biomarkers: 
o Lipopolysaccharide (LPS) stimulated tumour necrosis factor alpha (TNFα). 
o Plasma cortisol. 
o Other possible exploratory biomarkers including RNA. 
• Exploratory biomarker variables will be reported in a separate biomarker report and will 
not be included in the clinical study report (CSR) unless something clinically important is 
observed, with the exception of plasma cortisol which will be analysed and reported in the 


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CSR. TNFα planned analyses will be described in this SAP but will be reported separate to 
the CSR. 
• European League Against Rheumatism (EULAR) response criteria. 
• DAS28 remission. 
• Clinically important change in DAS28 score. 
• Low disease activity based on DAS28 score. 
The following exploratory objective is outside the scope of this SAP and will be presented in a 
separate report: 
• To evaluate the PK profile of Prednisolone in subjects with active RA in spite of stable 
treatment with conventional and/or s.c/i.v. biological DMARDs. 
The following exploratory objective is outside the scope of this SAP and will not be included 
in the clinical study report (CSR), unless something clinically important is observed: 
• To obtain optional blood samples for future pharmacogenetic (PGx) research aiming to 
identify/explore pharmacodynamic biomarkers or genetic variations that may affect the 
efficacy, pharmacodynamics, safety and tolerability profile related to AZD9567 treatment 
by assessment of: 
o Deoxyribonucleic acid (DNA) from whole blood. 
1.2 
Study design 
This is a Phase 2a, randomised, double-blind, double dummy, parallel study to assess the 
efficacy, safety and tolerability of AZD9567 40mg compared to Prednisolone 20 mg in 
subjects with active RA in spite of stable treatment with conventional or biological DMARDs.  
At Visit 1 (screening visit) eligible subjects will be identified. Subjects will be asked to 
provide informed consent after which screening assessments will be performed. 
At Visit 2, eligible subjects with established RA and moderate to high disease activity as 
defined by ACR Guidelines (DAS28 > 3.2) will be randomised in a ratio 1:1 to take either 
AZD9567 40 mg or Prednisolone 20 mg for 14 days once daily. Since this study is double-
blind and AZD9567 and Prednisolone are different formulations (oral suspension and capsules 
respectively), all subjects will have to take both formulations every day (active AZD9567 + 
placebo to Prednisolone or placebo to AZD9567 + active Prednisolone). 
A telephone call to check subject well-being will be termed Visit 3.  
Visit 4 will occur approximately 7 days after Visit 2, and Visit 5, which is the 
end-of-treatment visit, will occur approximately 14 days after Visit 2. 


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A follow-up visit (Visit 6) will be performed approximately 14 days after last study treatment 
dose (at Visit 5) to ensure the safety and well-being of subjects. 
For more information regarding the visits and time windows refer to the study flowchart, 
Figure 1. 
Figure 1 
Study flow Chart 
 
R: Randomised to study treatment 
1.3 
Number of subjects 
It is planned to randomise approximately 40 subjects in total, 20 subjects to each treatment 
group. It is anticipated that approximately 80-100 subjects will need to be screened in order to 
achieve randomisation total. Planned recruitment of subjects will take place across 7 sites in 2 
countries (Sweden and Netherlands). 
The main analysis will be based on the difference in the mean CFB for AZD9567 and the 
mean CFB of prednisolone.  
The details of the sample size calculation are based on internal decision criteria as explained 
in Frewer et al, 2016. In these calculations we use the reliability threshold of the DAS28 index 
known to be 0.6 (Siemons et al, 2014). 
A sample size of n=10 per group was agreed on however is not sufficiently powered to 
support hypothesis testing. 


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Edition Number 2  
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2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
The following analysis sets will be used in this study: 
2.1.1 
All subjects enrolled (ENR) analysis set 
The all subjects enrolled (ENR) set will contain all subjects who signed informed consent 
prior to performing any specific study-related procedures. 
2.1.2 
All subjects randomised (RND) analysis set 
The all subjects randomised (RND) analysis set will contain all subjects in the ENR analysis 
set and who were randomised to one of the two treatment groups. The all subjects randomised 
analysis set will be analysed according to their planned treatment arm, regardless of the actual 
treatment received. 
2.1.3 
Safety analysis set (SAF) 
The safety analysis set (SAF) will include all subjects randomised and received at least one 
dose of study treatment. The SAF will be analysed according to the actual treatment received, 
regardless of the randomised treatment assigned. 
2.1.4 
Full analysis set (FAS) 
The primary analysis variable for efficacy will be analysed using the full analysis set (FAS). 
The FAS, will include all subjects randomised and received at least one dose of study 
treatment. In accordance with International Committee on Harmonisation (ICH) E9, the FAS 
will be analysed using the Intent-to-treat (ITT) principle, which is the analysis on planned 
treatment arm, regardless of actual treatment received. The SAF and FAS will have the same 
set of subjects but will be analysed differently according to actual vs. planned.   
2.1.5 
Per protocol (PP) analysis set 
The PP analysis set will include subjects from the FAS who: 
• Did not have an important protocol deviation that are considered to have an impact on 
the analysis of the primary endpoints; 
• Completed the study. 
The PP analysis set will be analysed according to the actual treatment received, regardless of 
the planned treatment. 
Criteria for exclusion from the PP analysis set will be documented in a separate analysis sets 
and PDs plan. 


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2.1.6 
Pharmacokinetics (PK) analysis set 
The PK analysis set will include all subjects with at least one quantifiable AZD9567 
concentration with a documented related dosing history. Subjects in the PK analysis set will 
be analysed according to their planned treatment arm, regardless of actual treatment received. 
Subjects may be excluded from the PK analysis set if they have an adverse event (AE) of 
vomiting that occurs within approximately 2 times the median time of maximum observed 
drug concentration (tmax) or an important protocol deviation considered to affect PK. All 
decisions to exclude subjects from the PK analysis set will be made prior to the unblinding of 
the study. 
2.2 
Violations and deviations 
2.2.1 
Protocol deviation monitoring 
During study conduct, protocol deviations will be closely monitored by the clinical team via 
the IMPACT report.  A decision will be made prior to unblinding the study to determine 
which protocol deviations may significantly affect the study outcome and should result in a 
subject’s exclusion from the PP or PK analysis sets. 
The following categorisations of the protocol deviations will be used to identify important 
protocol deviations: 
• Did not fulfil eligibility criteria. 
• Received incorrect study treatment/dose. 
• Received prohibited concomitant medication. 
• Protocol-required procedure not adhered to. 
• Developed discontinuation criteria but continued. 
2.2.2 
Protocol deviation reporting 
Protocol deviations that may affect the study outcome significantly and the interpretability of 
the study results are defined as important protocol deviations (IPD).  
The criteria for all important protocol deviations will be provided in a separate protocol 
deviation document from the SAP. Protocol deviations that the study team considers to be 
important will be tabulated or listed in CSR. 


Statistical Analysis Plan  
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Edition Number 2  
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3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Primary Variable 
The difference in DAS28 units will be used to show that the efficacy of AZD9567 40 mg is 
equivalent to the efficacy of Prednisolone 20 mg at Day 15: 
Diff = XT - XP 
where XT is the mean change from baseline in DAS28 of AZD9567 and XP is the mean 
change from baseline in DAS28 of Prednisolone. 
DAS28 scores will be derived at baseline and each post-baseline assessments using the 
following formula: 
𝐷𝐴𝑆28 (𝐶𝑅𝑃) =  0.56 ∗√𝑇𝐽𝐶28 +  0.28 ∗√𝑆𝐽𝐶28 +  0.014 ∗𝐺𝐻 +  0.36 ∗ln(𝐶𝑅𝑃+ 1)
+  0.96 
Where: 
TJC28 = 28 joint count for tenderness (Section 3.1.1Tender Joint Counts). 
SJC28 = 28 joint count for swelling (Section 3.1.2 Swollen Joint Counts). 
Global health (GH) = subject's global assessment on Visual Analogue Scale (VAS) of 100 mm 
(Section 3.1.3 Global Health). 
ln (CRP) = natural logarithm of CRP (mg/L) (Section 3.1.4 CRP). 
Refer to Section 4.4.1 Missing DAS28 (CRP) for handling of missing DAS28 (CRP) 
components. 
The following supplementary variables will be used to calculate the primary variable DAS28: 
3.1.1 
Tender Joint Count 28 
The following 28 joints (14 left, 14 right) will be evaluated for tenderness as obtained from 
the Joint Count Right or Left electronic case report form (eCRF): 
• 2 each: Interphalangeal joints of the thumbs, wrist joints, elbow joints, shoulder joints, 
knee joints. 
• 8 Proximal interphalangeal (PIP) joints of the fingers. 
• 10 Metacarpophalangeal joints (MCP) joints. 
The tender joint count represents the number of joints in which pain is reported after either 
manoeuvre. 
TJC28 = Sum of tender joints with present status on the eCRF. Maximum TJC28 = 28. 


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Refer to Section 4.4.2 Missing tender or swollen joints for missing joint counts. 
3.1.2 
Swollen Joint Count 28 
The same joints mentioned in Section 3.1.1 will be evaluated for swelling. 
The swollen joint count represents the number of joints in which there is synovial fluid and or 
soft tissue swelling, but not if bony overgrowth is found. 
SJC28 = Sum of swollen joints with present status on the eCRF. Maximum SJC28 = 28. 
Refer to Section 4.4.2 Missing tender or swollen joints for missing joint counts. 
3.1.3 
Global Health 
Subject's GH using patient's global assessment (PGA) of disease activity by means of the 
VAS. 
The PGA VAS consists of a 100 mm long scale ranging for 0 (very well) to 100 (very poor). 
This VAS score is located on the subject's assessment of RA (SARA) eCRF. 
3.1.4 
C-reactive protein (CRP) 
CRP (mg/L) is collected at the local laboratory for Visit 1. Central laboratory will be used for 
Visit 2, 4, 5 and 6. Visit 3 will be a phone call only, therefore no laboratory testing will take 
place on that visit. 


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3.2 
Secondary Variables 
There are 12 secondary efficacy variables in this study: 
• Percentage of subjects achieving ACR20, ACR50 and ACR70 responses. 
• Change from baseline in individual components of DAS28 and ACR response criteria: 
o SJC 66. 
o TJC 68. 
o SJC 28. 
o TJC28. 
o Subject's assessment of pain (VAS). 
o Subject's assessment of global disease activity (GH VAS). 
o Physician's assessment of global disease activity (VAS). 
o Subject's assessment of physical function. 
o CRP. 
3.2.1 
ACR20, ACR50 or ACR70  
Subjects will be considered to have an ACR20, ACR50 or ACR70 response if a 20%, 50% or 
70% improvement from baseline (respectively) occurred. The ACR20, ACR50 or ACR70 
responses will be derived at each of the following post-baseline scheduled assessments: 
• Day 8, Visit 4. 
• Day 15, Visit 5. 
• Day 28, Visit 6. 
As Day 28, Visit 6 is a follow-up visit and two week off-treatment, a possible decrease in 
efficacy is expected. 
A subject will have an ACR20 response if all of the following occur:  
• A ≥20% improvement in the SJC 66 (Section 3.2.2 Swollen Joint count). 
• A ≥20% improvement in the TJC 68 (Section 3.2.3 Tender Joint count). 
• A ≥20% improvement in at least 3 of the following 5 assessments: 
o Subject’s assessment of pain: 
Obtained from the VAS score on the Health Assessment Questionnaire (HAQ) 
eCRF. 


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o Subject’s global assessment of disease activity (GH): 
Obtained from the VAS score on the SARA eCRF. 
o Physician’s global assessment of disease activity: 
Derived from the VAS score on the Investigator's Global Assessment of RA 
(IARA). 
o Subject’s assessment of physical function: 
As derived by the Total score on the HAQ eCRF. See Appendix A Health 
assessment questionnaire score derivation for more information. 
o Acute phase reactant (CRP measure in mg/L). 
A subject will have ACR50 or ACR70 response if a 50% or 70% improvement from baseline 
(respectively) rather than 20% was observed in the criteria specified above for ACR20. 
Refer to Section 4.4.3 Missing ACRxx components for missing ACR components. 
3.2.2 
Swollen Joint count 66 
The following 66 joints (33 left, 33 right) will be evaluated for swelling: 
• 2 each: Temporomandibular, sternoclavicular, acromioclavicular, interphalangeal 
joints of the thumbs, wrist joints, elbow joints, shoulder joints, knee joints, ankle 
mortise and tarsus. 
• 8 each: PIP joints of the fingers, distal interphalangeal joints. 
• 10 each: Metatarsophalangeal, MCP joints, toe joints. 
The swollen joint count represents the number of joints in which there is synovial fluid and or 
soft tissue swelling, but not if bony overgrowth is found. 
SJC = Sum of swollen joints with present status on eCRF. Maximum SJC = 66. 
Refer to Section 4.4.2 Missing tender or swollen joints for missing joint counts. 
3.2.3 
Tender Joint count 68 
The following 68 joints (34 left, 34 right) will be evaluated for swelling: 
• 2 each: Temporomandibular, sternoclavicular, acromioclavicular, interphalangeal 
joints of the thumbs, wrist joints, elbow joints, shoulder joints, knee joints, hip joints, 
ankle mortise and tarsus. 


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• 8 each: PIP joints of the fingers, distal interphalangeal joints. 
• 10 each: Metatarsophalangeal, MCP joints, toe joints. 
TJC = Sum of tender joints with present status on eCRF. Maximum TJC = 68. 
Refer to Section 4.4.2 Missing tender or swollen joints for missing joint counts. 
3.2.4 
Change from baseline in individual components of DAS28 
The four individual components of DAS28 (as discussed in Primary Variables Section 3.1: 
TJC 28, SJC 28, subject’s global assessment of disease activity [GH], CRP) will be used in 
order to calculate change from baseline. 
3.2.5 
Change from baseline in individual components of ACR 
The seven individual components of ACR (as discussed in Section 3.2.1: SJC 66, TJC 68, 
subject’s assessment of pain, subject’s global assessment of disease activity [GH], physician’s 
global assessment of disease activity, subject’s assessment of physical function, CRP) will be 
used in order to calculate change from baseline.Appendix A 
Health assessment 
questionnaire score derivation 
3.3 
Pharmacokinetics 
The derivation of the PK parameters for AZD9567 will be performed at Covance (Clinical 
Pharmacology Alliance).  The PK parameters will be derived using non-compartmental 
methods with Phoenix WinNonlin (Version 8.1 or higher). 
The PK profile of AZD9567 in subjects with active RA in spite of stable treatment with 
conventional and/or s.c/i.v. biological DMARDs will be assessed by calculating the following 
parameters where possible: 
AUC(0-24): 
Area under the plasma concentration-time curve from time zero to 24 hours 
after study treatment dose. 
 
AUC(last): 
Area under the plasma concentration-time curve until the last quantifiable 
concentration 
 
AUC(0-6): 
Area under the plasma concentration-time curve from time zero to 6 hours after 
study treatment dose. 
 
tmax:  
Time point of the maximal plasma concentration of a drug. 
 
Cmax:  
Maximum observed drug concentration. 
 
Ctrough: 
The last plasma concentration measured before the last dose. 
 
CL/F:  
Apparent plasma clearance following an extravascular dose. 


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Vz/F:  
Apparent volume of distribution following an extravascular dose. 
Other pharmacokinetic parameters may be calculated if appropriate. 
The following diagnostic parameters for plasma PK analysis may be listed but will not 
summarised: 
z: 
Terminal elimination rate constant 
zN: Number of data points included in the log-linear regression analysis 
Rsq_adj: 
Regression coefficient adjusted for n obs, Goodness of fit statistic for the 
calculation of z 
AUCextr(0-24): Percentage of AUC(0-24) obtained by extrapolating the area under the 
plasma concentration-time curve from the time of the last quantifiable concentration to 24h.  
Pharmacokinetic analysis will, where possible times recorded in the raw data. If actual times 
are missing, nominal times may be used. 
Concentrations are used as supplied by the analytical laboratory for PK analysis. 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. 
Concentrations below the limit of quantification (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 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. 


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The terminal elimination half-life, calculated as (ln2/z) will be estimated by log-linear least 
squares regression of the terminal phase of the concentration-time curve.  The choice of data 
points used to estimate z should follow the general guidelines: 
• The start of the terminal elimination phase for each subject will be defined by visual 
inspection and will be the first point at which there is no systemic deviation from the 
log-linear decline in plasma concentrations. 
• A minimum of 3 data points will be used in calculating z and the duration of time 
over which z is recommended to be at least 3 times the subsequently estimated 
terminal half-life.  Where the elimination half-life is estimated over less than 3 times 
the subsequently estimated terminal half-life it will be flagged in the data listings and 
discussed in the study report. 
• Should include the last measurable concentration 
• Include only observations after Cmax 
• The λz may not be assigned if the R2 adjusted value of the regression line is less than 
0.8. In cases where the λz is not assigned all regression-based parameters (including R2 
adjusted) will not be calculated 
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. 
AUC(0-24) values where the percentage extrapolation is <20% will be reported. AUC(0-24) 
values where the percentage extrapolation is ≥20% will be flagged.   
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data and 
the CSR.  
PK parameter data associated with quantifiable pre-dose values >5% of Cmax may be 
excluded from the summary statistics and statistical analysis at the discretion of the 
Pharmacokineticist. 
3.4 
Safety outcomes 
3.4.1 
Adverse events 
Adverse events will be collected throughout the treatment period and including the follow-up 
period (Visit 6). 


Statistical Analysis Plan  
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Serious AEs (SAEs) will be collected from the time of informed consent (Visit 1) whereas 
AEs will be collected from randomisation (Visit 2), throughout the treatment period and 
including the follow-up period (Visit 6). 
The latest version of the Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
will be used to code the AEs. The investigator’s verbatim term for each AE will be mapped to 
a system organ class (SOC) and preferred term (PT) from MedDRA. All coding will be 
performed by the Medical Coding Team. 
Treatment emergent adverse event (TEAE) is defined as an AE that started on or after 
treatment start date and within 14 days after treatment stop date. 
3.4.2 
Vital signs 
Vital signs (systolic and diastolic blood pressure, pulse rate and body temperature, all three in 
a lying or sitting position after 5 minutes of rest) will be taken at the times indicated in the 
Study Plan and Timing of Procedures (refer to protocol Table 1).  
Change from baseline in vital signs to each post-baseline assessment will be calculated.  There 
will be no imputation for missing values. 
Observed values and change from baseline for all assessments will be compared to the 
relevant AstraZeneca defined reference ranges (see Appendix B 
AstraZeneca defined 
reference ranges for vital signs) and all values (observed and change) falling outside the 
reference ranges will be flagged. The minimum and maximum values post-baseline will be 
derived for SBP, DBP, pulse rate and temperature based on pre-defined criteria provided by 
AZ in Appendix B (low, normal, high). 
3.4.3 
ECG 
Twelve-lead ECGs will be obtained at the times indicated in the Study Plan and Timing of 
Procedures (refer to protocol Table 1).  An overall evaluation (normal, abnormal not clinically 
significant, and abnormal clinically significant) with a reason for abnormality will also be 
recorded. 
3.4.4 
Laboratory data 
Blood and urine samples for determination of clinical chemistry, haematology, endocrinology, 
and urinalysis will be taken at the times indicated in the Study Plan and Timing of Procedures 
(refer to protocol Table 1). 
The parameters to be determined are presented in Appendix C 
Laboratory Parameters. 
Changes from baseline in continuous laboratory variables to each post-baseline assessments 
will be calculated. 
Observed values will be compared to the central laboratory reference ranges and all observed 
values falling outside these reference ranges will be flagged. 


Statistical Analysis Plan  
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For laboratory results below or above the limit of quantification: 
• Assign as equal to the limit of quantification, for example < 100 mL will be assigned 
as 100 mL. 
The minimum and maximum values post-baseline will be derived based on reference ranges 
provided in the most recent Covance lab manual available at database lock (low, normal, 
high). A listing of normal ranges will be provided. 
3.5 
Exploratory outcomes 
3.5.1 
Biomarkers 
Whole blood and serum/plasma will be collected to enable relevant analyses such as, effects 
on bone, metabolism and HPA axis by assessment of: 
• Individual LPS-stimulated WB TNFα levels (pg/mL). 
• Individual plasma cortisol (nmol/L) AUEC(0-6). 
• Change from baseline for morning plasma cortisol (nmol/L) at Day 15 and follow-up 
visit. 
For each subject, the total AUEC at Day 1 and Day 15 will be calculated for plasma cortisol. 
Plasma cortisol is collected pre-dose only on Day 1 at 0, 1, 2, 3, 4 and 6 hours, and then pre-
dose and post-dose at 1, 2, 3, 4 and 6 hours on Day 15. Each AUEC will be calculated using 
trapezoids as 
𝐴𝑈𝐸𝐶= ∑(𝑡𝑖+1 −𝑡𝑖)
𝑦𝑡𝑖+1 + 𝑦𝑡𝑖
2
6
𝑖=1
 
The summation is over all available time points. The yt are the concentration measurements. If 
any two consecutive measurements are missing, or if one or both of the measurements at time 
0 for Day 1, pre-dose for Day 15 or 6 hours on either day are missing, then the AUEC for that 
day is missing. However, if the measurement at any single intermediate number of hours is 
missing, the AUEC will be calculated using linear interpolation.  
For example, if measurements are available at only 0, 1, 2, 3 and 6 hours for Day 1, then  
𝐴𝑈𝐸𝐶= (1 −0) 𝑦1 + 𝑦0
2
+ (2 −1) 𝑦2 + 𝑦1
2
+ (3 −2) 𝑦3 + 𝑦2
2
+ (6 −3) 𝑦6 + 𝑦3
2
 
3.5.2 
Other exploratory outcomes 
DAS28 will be used for additional comparison between AZD9567 and Prednisolone 20mg, by 
means of: 
• European League Against Rheumatism (EULAR) response criteria. 
• DAS28 remission. 


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• Clinically important change in DAS28 score. 
• Low disease activity based on DAS28 score. 
Improvement (can be either positive or negative and is defined as post-baseline minus 
baseline) in DAS28 score will be calculated at each post-baseline scheduled assessment and 
categorised using the EULAR response criteria in Table 1. Good, moderate or no response 
will be determined by the DAS28 score at Day 8, 15 and 28 against the level of improvement 
(mean change from baseline in DAS28 at Day 8, 15 and 28). 
Table 1 
DAS28 EULAR Response 
DAS28 improvement 
Background DAS28(CRP) 
Score at 
Time of DAS28 Improvement 
Assessment 
Level of Improvement from Baseline 
> 1.2 
 ≥ 0.6 to ≤ 1.2 
< 0.6 
< 3.2 
Good response 
Moderate response 
No response 
≥ 3.2 to ≤ 5.1 
Moderate 
response 
Moderate response 
No response 
> 5.1 
Moderate 
response 
No response 
No response 
DAS28: Disease Activity Score in 28 joints. DAS28(CRP): Disease Activity Score in 28 joints using C-reactive 
protein/erythrocyte sedimentation rate. 
DAS28 remission: 
• DAS28 score < 2.6 
Clinically important change: 
• Improvement from baseline in DAS28 score > 1.2 
Low disease activity: 
• DAS28 score ≤ 3.2 
4. 
ANALYSIS METHODS 
Statistical analysis will be performed by IQVIA™ using SAS® Version 9.4 or higher. 
The derivation of the PK parameters will be performed at Clinical Pharmacokinetic Alliance 
(Covance). The PK parameters will be derived using non-compartmental methods with 
Phoenix® WinNonlin® (Version 8.1 or higher), in accordance with “Best Practice Reference 
Guidelines Pharmacokinetic Evaluations in Clinical Studies”. 


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4.1 
General principles 
4.1.1 
Reference start date 
Study day will be calculated from the reference start date and will be used to show start/stop 
day of assessments and events. 
Reference start date is defined as the date of the first dose of study treatment. 
Relative date will be calculated according to the aforementioned reference date as follows: 
• If the date of the event is on or after the reference date, then: 
o Study Day = (date of event – reference date) + 1. 
• If the date of the event is prior to the reference date, then: 
o Study Day = (date of event – reference date). 
Revere to Appendix D 
Partial and missing date conventions for partial dates for 
calculating relative day. 
4.1.2 
Baseline measurements 
Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior 
to reference start date. 
In the case where the last non-missing assessment and the reference start date and time 
coincide, that assessment is considered as occurring before the start of the study treatment 
dose and the assessment is considered as baseline. However, AEs and medications 
commencing on the start date and time of first dose will be considered as post-baseline and 
flagged as treatment-emergent AEs and concomitant medications. 
For by visit tables, the screening visit will be presented along with baseline as applicable. 
In the case where the assessment time is missing, but reference start date and assessment date 
coincide, that assessment is considered as occurring before the start of the study treatment 
dose and the assessment is considered as baseline. 
In the case where two assessments exist on the same date on or prior to the reference start 
date, the assessment with more complete data should be used as baseline, i.e. if time is 
missing on the one assessment, the assessment with time included should be used as baseline. 
There will be no baseline record where the first non-missing assessment is after the reference 
start date. 
4.1.3 
Visit windowing 
No visit windowing will be implemented. Scheduled visits will be used for analysis purposes. 


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4.1.4 
Table outputs 
In general, all summaries will be split by treatment and occasionally added total as follows: 
Number (%) of subjects 
AZD9567 
Prednisolone 
Total 
Continuous data will be summarised by descriptive statistics including number of subjects (n), 
mean, standard deviation (SD), median and range (i.e. minimum value and maximum value). 
Additionally, the first and third quartiles will be presented for continuous data summaries of 
exposure data, laboratory parameters and vital signs parameters. For log transformed data, the 
following descriptive statistics will be presented: number of subjects (n), geometric mean, 
geometric SD, median and range (i.e. minimum value and maximum value).  The mean and 
median will be presented with one more decimal place than the original data.  Standard 
deviation with two more decimal places than the original data.  Minimum and maximum 
values with the same number of decimal places than the original data. 
For categorical data, the variable counts and percentage n (%) per treatment group will be 
presented. Summaries of continuous variables will be based on non-missing observations.  
Unless otherwise stated, percentages will be calculated relative to total number of subjects in 
the analysis set and treatment group. Percentages will be rounded to 1 decimal place. 
4.1.5 
Statistical modelling 
Standard diagnostic approaches will be used to verify that the key statistical assumptions of 
the mixed model repeated measures (MMRM), ANCOVA and logistic regression models 
hold. 
If the distributional assumptions of the MMRM for the primary analysis do not hold, 
alternative models will be explored. 
4.2 
Analysis methods for efficacy variables 
4.2.1 
Primary efficacy variable analysis method 
The difference in change from baseline in DAS28 between AZD9567 and prednisolone 
(AZD9567 – prednisolone) will be calculated using a mixed model.   
4.2.2 
Secondary efficacy variable analysis methods 
Percentage of subjects achieving ACR20, ACR50 and ACR70 will be analysed with a logistic 
regression model using PROC GENMOD.  
The change from baseline (CFB) in core set measures of ACR and DAS28 will be analysed 
with a  MMRM, using PROC MIXED. 


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4.3 
Statistical models 
Prior to unblinding, the difference between countries in DAS28 scores at Day 1 will be tested 
using a two-sample t-test and if the result is non-significant (p-value > 5%), the country term 
may be dropped from the primary and secondary models. 
4.3.1 
Primary efficacy statistical model 
Formal statistical testing will be performed for exploratory purposes only. 
The default significant level will be two-sided 5%, CIs will be 95% and all tests will be 
two-sided, unless otherwise specified in the description of the analyses.  Two-sided p-value ≤ 
0.05 will be considered statistically significant. 
Confidence intervals (CIs) for the true difference in means, µAZD9567 – µPrednisolone, will be 
calculated using the estimated treatment effect and the mean square error.  
A MMRM is to be used to examine the primary efficacy variable, using the PROC MIXED 
procedure in SAS. 
The MMRM model will include the baseline DAS28 score as a covariate. 
The MMRM model will include categorical fixed effects of treatment, visit, treatment-by-visit 
interaction and country: 
• Change from baseline (at Day 15) = Treatment group baseline DAS28 score Treatment 
group*visit 
• Treatment group 
= AZD9567 or Prednisolone. 
• Visit 
 
= Day 8 and Day 15. 
• Country 
= Netherlands or Sweden 
• Change from baseline (at Day 15) 
= Change in DAS28 from baseline at Day 15. 
An unstructured matrix for the within-subject error variance covariance will be used. The 
denominator degrees of freedom will be calculated according to the Kenward-Roger method. 
In case of non-convergence of the preferred model or memory space issues the following 
models will be explored in the order given: 
1. Country may be removed from the model. 
2. The second backup model is the same as the preferred model but the Kenward- Roger 
method will be replaced by Satterthwaite approximation. 
The least squares mean (LSM) change from baseline in DAS28 score and corresponding 
standard error (SE) and 95% confidence interval (CI) by treatment group at Day 8 and Day 15 
will be provided in a table. The least squares mean difference (LSMD) between the two 


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treatment groups at Day 8 and Day 15 and corresponding 95% CI and two-sided p-value will 
also be presented in the table.  
A figure will be provided displaying the LSM change from baseline by treatment group and 
visit, along with the 95% CI. 
The FAS and PP analysis sets will be used for primary efficacy with FAS analysis set as 
primary interest. 
Results for the PP analysis will be tabulated and displayed graphically in the same manner as 
the primary analysis. 
A summary of all continuous efficacy parameters by visit will be provided: DAS28 score, SJC 
66, TJC 68, SJC 28, TJC 28, subject’s assessment of pain, GH, physician’s assessment of 
global disease activity, subject’s assessment of physical function and CRP. DAS28 score will 
also be summarised separately by visit for the FAS using summary statistics. 
4.3.2 
Secondary efficacy statistical models 
The same MMRM approach for primary variables will be repeated on the following secondary 
variables:  
• Change from baseline in SJC 66. 
• Change from baseline in TJC 68. 
• Change from baseline in individual components of DAS28 and ACR response: 
o Change from baseline in TJC28. 
o Change from baseline in SJC28. 
o Change from baseline in subject's assessments of global disease activity (GH). 
o Change from baseline in physician´s global assessment of disease activity. 
o Change from baseline in subject's assessments of pain. 
o Change from baseline in subject's assessments of physical function. 
o Change from baseline in CRP 
The MMRM model for each variable will include the baseline value for the variable of interest 
as a covariate. Categorical fixed effects of treatment, visit, treatment-by-visit interaction and 
country will also be included in the model. 


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A table summarising the results, similar to the primary analysis, will be provided for each 
endpoint. Figures will not be produced for the above secondary endpoints. 
Comparisons between treatment groups regarding the ACR20, ACR50 and ACR70 at Day 8, 
and 15 will be performed using a logistic regression model for both the FAS and PP analysis 
sets. The PROC GENMOD procedure in SAS will be used. The covariates of interest are 
treatment, country and baseline DAS28. 
Should there not be sufficient number of observations per outcome category (< 5 in either 
treatment group) the aforementioned logistic regression will be replaced by a Fisher’s exact 
test. 
The number and percentage of subjects achieving ACRxx in each treatment group at Day 8 
and Day 15, and the odds ratio and corresponding 95% CI and p-value for the comparison 
between treatment groups will be summarised in tables for the FAS and PP analysis sets. The 
proportion of subjects achieving ACRxx at Day 15 will be presented in a bar chart for the FAS 
and PP analysis sets separately. 
No formal statistical hypothesis testing will be carried out on any variables, which will be 
summarised using standard summary statistics. The aforementioned statistical models are only 
applied for exploratory purposes. 
The FAS will be used for both the secondary and exploratory efficacy endpoints unless 
otherwise specified. 
4.3.3 
Exploratory outcomes statistical models 
4.3.3.1 
TNFα 
Individual LPS-stimulated WB TNFα levels (pg/mL), will be listed and summarised by 
treatment, study day and time point using descriptive statistics (n, arithmetic mean, SD, 
geometric mean, geometric SD, geometric CV%, minimum, median, and maximum). 
Arithmetic mean (+/- SE bars) TNF𝛼 levels versus time will be plotted by study day and 
treatment. A panel plot will be used with Day 1 and Day 15 displayed side-by-side. In 
addition, a graphical presentation of individual LPS-stimulated WB TNFα levels (pg/mL) 
following AZD9567 treatment versus individual AZD9567 levels (nmol/L) from the same 
sampling time points will be made, which will include a plot of all timepoints on the final 
page. For this figure, AZD9567 levels with non-quantifiable results will be displayed as the 
lower limit of quantification. 
4.3.3.2 
Plasma cortisol (nmol/L) AUEC(0-6) biomarkers 
Individual plasma cortisol (nmol/L), will be listed and summarised by treatment, study day 
and time point using descriptive statistics (n, arithmetic mean, SD, geometric mean, geometric 
SD, geometric CV%, minimum, median, and maximum).  


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Arithmetic mean (+/- SE bars) plasma cortisol (nmol/L) versus time will be plotted by study 
day and treatment. A panel plot will be used with Day 1 and Day 15 displayed side-by-side. 
AUEC(0-6) plasma cortisol will be analysed on the log scale for change from baseline 
(defined as the Day 1 measurements) to Day 15. Therefore, the change from baseline in 
AUEC(0-6) plasma cortisol, when back-transformed from the log scale, will be a relative 
change from baseline (ratio). 
𝐷𝑎𝑦 15 𝐴𝑈𝐸𝐶(0 −6)
𝐷𝑎𝑦 1 𝐴𝑈𝐸𝐶(0 −6)
 
The relative change from baseline in AUEC(0-6) plasma cortisol (nmol/L) will be analysed as 
follows:  
• The change from baseline to Day 15 in the log-transformed AUEC(0-6) plasma cortisol 
will be analysed using ANCOVA model with log plasma cortisol AUEC(0-6) at baseline 
as covariate and treatment group as factor. 
Where: 
Log transformed AUEC(0-6) = Change from baseline in the log-transformed AUEC(0-6) 
plasma cortisol, i.e. log (AUEC(0-6) at Day 15) – log (AUEC(0-
6) at Day 1) 
• The back-transformed LS-Means and 95% confidence interval will be presented by 
treatment group to present relative change from baseline to Day 15 (ratio). The 
difference relative to prednisolone 20mg (ratio) will be presented along with 95% 
confidence interval and p-value for two-sided comparison. 
LS-Means for each treatment group, LS-mean difference between treatment groups and 
corresponding confidence interval limits will be back-transformed from the log scale by 
exponentiating.  
A figure will be provided displaying the LSM relative change from baseline to Day 15 in plasma 
cortisol AUEC(0-6) by treatment group, along with the 95% CI. Individual values will be 
overlaid on the same figure as scatter points. The treatment groups will be presented side-by-
side on the x-axis.   
4.3.3.3 
Morning plasma cortisol (nmol/L) biomarkers 
Morning plasma cortisol includes 2 measurements per subject, i.e. first pre-dose measurement 
(08:00am) at baseline and pre-dose at Day 15. 
Change from baseline in morning plasma cortisol (nmol/L) will be analysed using an ANCOVA 
model with covariate baseline morning plasma cortisol (nmol/L) and treatment group as a factor. 
LS-Means and 95% confidence interval for the change from baseline in morning plasma cortisol 
(nmol/L) at Day 15 will be presented by treatment group. P-value for the two-sided comparison 


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to baseline will be provided for each treatment group. For this variable no comparison to 
prednisolone 20mg will be done.    
4.3.3.4 
Pharmacokinetics 
Pharmacokinetic summaries will be based on the PK analysis set. 
Post-dose concentrations where actual time deviates more than 10% from scheduled time will 
be excluded from summaries by planned time point. 
Plasma concentrations of AZD9567 will be summarised by planned time point using n, counts 
of the number of subjects with results less than the lower limit of quantification (LLOQ), 
geometric mean, geometric mean +/- geometric standard deviation (GSD), geometric 
coefficient of variation (GCV), arithmetic mean, SD, CV, median, minimum and maximum. 
PK parameters listed in Section 3.3 will be summarised using n, geometric mean, CV (%), 
arithmetic mean, SD, CV, median, minimum and maximum.  For tmax, only median, 
minimum and maximum will be presented. 
Plasma concentrations that are <LLOQ or if there are missing values (e.g. no result [NR]) will 
be handled as follows: 
• Any values reported as no result or no sample will be excluded from descriptive 
statistics, inferential statistics and summary tables.  However, data from subjects 
excluded from the PK analysis set will be included in the data listings. 
• At a time point where less than or equal to 50% of the concentration values are non-
quantifiable (NQ), all NQ values will be substituted with the LLOQ value, and all 
descriptive statistics will be calculated accordingly. 
• At a time point where more than half (but not all) of the values are NQ, the geometric 
mean, geometric mean +/- GSD, GCV (%), SD, and CV (%) will be set to NC.  The 
maximum value was reported from the individual data and the minimum and median 
were set to NQ.  
• If all values are NQ at a time-point, no descriptive statistics will be calculated for that 
time-point.  Not calculated (NC) will be written in the field for SD and CV% and NQ 
will be written in fields for mean, geometric mean, minimum, median and maximum 
Three observations >LLOQ are required as a minimum for a plasma concentration or PK 
parameter to be summarised.  Two values are presented as a minimum and maximum with the 
other summary statistics as NC. 
Concentration data will be presented to the same number of significant figures as the data 
received from the bioanalytical laboratory; for PK parameters, the listings will be presented 
according to the following rules: 


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• Cmax – will be presented to the same number of significant figures as received from the 
bioanalytical laboratory 
• tmax, t lower and t upper time limit – will be presented as received in the data, usually 
to 2 decimal places 
• AUClast, t½z, CL/F, Vz/F, Rsq adj will be presented to 3 significant figures 
• λz – will be presented to 4 significant figures 
• λz, N – will be presented as an integer (no decimals) 
• AUC(0-24)extr– will be presented to 2 decimal places 
For PK concentration data all descriptive statistics will be presented to 4 significant figures with 
the exception of the minimum and maximum which will be presented to 3 significant figures. 
For PK parameters data the descriptive statistics will be presented according to the following 
rules: 
• Cmax, AUClast, t½z, CL/F, Vz/F – all descriptive statistics will be presented to 4 
significant figures with the exception of the minimum and maximum which will be 
presented to 3 significant figures 
• λz – all descriptive statistics will be presented to 5 significant figures with the exception 
of the minimum and maximum which will be presented to 3 significant figures 
• tmax – all descriptive statistics will be presented as received in the data, usually to 
2 decimal places 
Individual plasma concentrations of AZD9567 will be plotted for each subject based on actual 
timepoint the sample was collected in linear and semi-logarithmic scale. NQ results will be 
plotted as the LLOQ for the linear scale and log(LLOQ) for the semi-logarithmic scale. 
The geometric mean (+/-GSD) plasma concentrations of AZD9567 will be plotted by planned 
timepoint in linear and semi-logarithmic scale (no GSD bars). For mean plots, BLQ values 
will be handled as described for the summary tabulations; for individual plots plasma 
concentrations which are <LLOQ prior to the first quantifiable concentration will be set to a 
value of zero (linear plots only).  After the first quantifiable concentration, any <LLOQ 
plasma concentrations will be regarded as missing. 
Pharmacokinetic parameters will be listed. 
A listing of plasma concentrations of AZD9567 including sample collection times as well as 
derived sampling time deviations will be provided. 


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4.3.3.5 
Other exploratory outcomes 
EULAR responses, DAS28 remission, clinically important change in DAS28 and low disease 
activity based on DAS28 score will be summarised separately by treatment group and visit to 
Day 28 using counts and percentages. No formal statistical testing will be done. 
4.4 
Missing primary and secondary variables 
4.4.1 
Missing DAS28 (CRP) components 
DAS28-CRP will be set to be missing if one or more components as defined above are 
missing.  Higher DAS28-CRP scores indicate more severe symptoms and greater functional 
impairment 
4.4.2 
Missing tender or swollen joints 
The number of tender/swollen joints will be calculated by summing all joints checked to have 
tenderness/swelling present.  If at least half but not all of the joints are evaluable, then the 
observed prorated joint count will be calculated instead.  The prorated scores for TJC will be 
adjusted based upon the number of evaluable joints: the counted score will be multiplied by 68 
then divided by the number of joints evaluated (excluding non-evaluable joints and any joints 
with a missing response).  For example:  if only 60 of the 68 joints are assessed to be 
evaluable at a visit, and 32 of those 60 are tender, the prorated joint count is 
(32/60)×68=36.27 (not 32) and it will be used in calculating the percent change from baseline 
in TJC.  The same algorithm will be applied to the calculation of percent change from baseline 
in SJC with the exception that the counted score will be multiplied by 66 then divided by the 
number of joints evaluated.  If less than half of the joints are evaluable, the number of 
tender/swollen joints is missing 
This same algorithm will be used for the calculation of TJC and SJC based on 28 joints, which 
is part of the DAS28-CRP score. 
4.4.3 
Missing ACRxx components 
At any visit, if one or more components are missing, such that a determination of ACR20 
response cannot be made, then ACR20 will be set to missing.  ACR20 will be set to missing 
for all visits for subjects with 0 SJC or 0 TJC at baseline.  However, ACR20 will not be set to 
missing in cases where a determination of ACR20 response can be made based on the non-
missing components. 
In particular, in calculating ACR20: 
• If SJC66 ≥ 20% improvement and TJC68 ≥ 20% improvement and if at least 3 of the 5 
components are present, then: 
o if at least three are ≥ 20% improvement, then ACR20 = 'Responder' 
o if at least 3 are <20% then  ACR20 = 'Nonresponder' 
o else ACR20 is set to missing 


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• If SJC66 < 20% improvement or TJC68 < 20% improvement, then ACR20 = 
'Nonresponder'. 
• If either SJC66 or TJC68 is missing and the nonmissing value < 20% improvement, 
then ACR20 is set to "Nonresponder". 
• If either SJC or TJC is missing and the nonmissing value ≥ 20% improvement, then 
ACR20 is set to missing. 
• If SJC and TJC are both missing, then ACR20 is set to missing. 
The same rules are followed in calculating ACR50 and ACR70, replacing 20% improvement 
with 50% and 70%, respectively.  
Any subject with missing ACRxx, will be defined as “Nonresponder” for that visit. 
4.5 
Multiple Comparisons/Multiplicity  
Not applicable. 
4.6 
Subgroups 
Exploratory analyses may be performed where subgroups of interest have been identified and 
depending on the numbers of subjects within each subgroup. 
4.7 
Sensitivity analysis 
A sensitivity analysis for the MMRM analysis of the primary endpoint will be performed 
using an ANCOVA model of change from baseline to Day 15 in DAS28 score with DAS28 
score at baseline as covariate and country and treatment group as factors. The PROC GLM 
procedure in SAS will be used. 
The LS-Means and 95% confidence interval will be presented by treatment group. The 
difference relative to prednisolone 20mg will be presented along with 95% confidence interval 
and p-value for two-sided comparison 
4.8 
Demographic, Dosing, and Safety and Tolerability data 
There is no formal statistical analysis of safety and tolerability data required for this study.  
Demographic and other baseline disease characteristics, protocol deviations, concomitant 
medication, dosing, exposure, safety and tolerability data will be summarised and listed per 
AZ corporate CSRHLD reporting standard. 
4.8.1 
Subject disposition, important protocol deviations and analysis set 
Subject disposition will be summarised for all subjects using the ENR analysis set. The 
number and percentages of subjects will be presented for the following categories: enrolled, 
randomised to study treatment, not randomised to study treatment (and reason), received study 
treatment, did not receive study treatment, completed study treatment, discontinued from 


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study treatment (either), discontinued from AZD9567/AZD9567 placebo treatment (and 
reason),  discontinued from Prednisolone/Prednisolone placebo treatment (and reason),  
completed study and prematurely withdrawn from study (and reason). A subject will be 
enrolled and randomised into the study once all the inclusion/exclusion criteria are met as 
discussed in Section 3 in the latest version of the protocol. 
Reasons for subjects not randomised will be obtained from the disposition eCRF, where 
randomisation code received is no. 
Subjects who completed treatment are defined as subjects who completed in both 
AZD9567/AZD9567 placebo and Prednisolone/Prednisolone placebo groups. 
Subjects who discontinued treatment are defined as subjects who discontinued treatment in 
either treatment group AZD9567/AZD9567 placebo or Prednisolone/Prednisolone placebo. 
Reasons for discontinuation of study treatment and prematurely withdrawn from study will 
also be listed including the study day of treatment discontinuation. 
Important protocol deviations and analysis sets will be tabulated using the FAS only on 
important protocol deviations. Important protocol deviations will also be summarised and 
listed. 
The number and percentage of subjects included and excluded from each analysis set will also 
be presented, including the reason for exclusion from each analysis set. Listings of subjects 
excluded from each analysis set (SAF, FAS, PP, PK) will be provided. 
4.8.2 
Demographic and baseline characteristics 
Demographic and baseline characteristics will be summarised based on the all subject analysis 
set FAS. 
Demography data such as age (years), age group (years) (<18, 18-40, 41-65, >65), sex, race, 
and ethnicity will be summarised and listed. 
Various baseline characteristics of the subjects will also be summarised and listed.  These 
include weight, height and body mass index (BMI), disease characteristics, and extent of 
disease at baseline. 
Disease characteristics are obtained from the rheumatoid arthritis history eCRF page. The 
following will be summarised using frequencies and percentages: 
• Presence of radiological erosions (Yes, No) 
• Rheumatoid factor positive (Yes, No) 
• Current functional capacity class (Class I, Class II, Class III, Class IV) 
• Previously treated with TNFα antagonist (Yes, No) 
• Reason for TNFα discontinuation (No response, Initial response but subsequent loss of 
response, Adverse effect/Intolerance, Other) 


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Years since onset of RA symptoms will be summarised using summary statistics and is 
calculated relative to informed consent date: 
𝑌𝑒𝑎𝑟𝑠 𝑠𝑖𝑛𝑐𝑒 𝑜𝑛𝑠𝑒𝑡 𝑜𝑓 𝑅𝐴 𝑠𝑦𝑚𝑝𝑡𝑜𝑚𝑠
= (𝑖𝑛𝑓𝑜𝑟𝑚𝑒𝑑 𝑐𝑜𝑛𝑠𝑒𝑛𝑡 𝑑𝑎𝑡𝑒−𝑂𝑛𝑠𝑒𝑡 𝑜𝑓 𝑅𝐴 𝑠𝑦𝑚𝑝𝑡𝑜𝑚𝑠 𝑑𝑎𝑡𝑒+ 1)/365.25 
Years since RA diagnosis will be summarised using summary statistics and is calculated 
relative to start date: 
𝑌𝑒𝑎𝑟𝑠 𝑠𝑖𝑛𝑐𝑒 𝑅𝐴 𝑑𝑖𝑎𝑔𝑛𝑜𝑠𝑖𝑠
= (𝑖𝑛𝑓𝑜𝑟𝑚𝑒𝑑 𝑐𝑜𝑛𝑠𝑒𝑛𝑡 𝑑𝑎𝑡𝑒 𝑅𝐴 𝑓𝑖𝑟𝑠𝑡 𝑑𝑖𝑎𝑔𝑛𝑜𝑠𝑒𝑑 𝑑𝑎𝑡𝑒+ 1)/365.25 
Details on partial date handling for onset of RA symptoms date and RA first diagnosed date 
can be found in Appendix D. 
Age will be summarised as collected on the eCRF and will not be rederived. 
BMI will be calculated as the ratio of the subject’s baseline weight (in kilograms) to the 
square of the subject’s height (in metres): BMI = kg/m². 
4.8.3 
Prior, concomitant, and post-discontinuation medications and therapies 
Concomitant medications and therapies tabulations will be summarised based on the SAF. 
Disease-related and other medications and therapies will be classified by the AstraZeneca 
designee according to the latest version of the World Health Organization (WHO) Drug 
Dictionary and they will be categorised as follows: 
• Prior medications, defined as those medications taken prior to the first 
AZD9567/Prednisolone dose. 
• Concomitant medications, defined as those medications taken during the course of the 
treatment period (i.e., from the day of the first AZD9567/Prednisolone dose up to the 
day of the last AZD9567/Prednisolone dose).  A medication started prior to the first 
AZD9567/Prednisolone dose that is still used during the treatment period will be 
identified as both prior and concomitant. 
• Post-discontinuation medications, defined as those medications started after the last 
AZD9567/Prednisolone dose. 
If a medication has a missing start date then unless the stop date of the medication indicates 
otherwise, this medication will be considered as both prior and concomitant.  Similarly, if a 
medication has a partial start date, then unless the partial start date or the stop date indicate 
otherwise, this medication will be considered as both prior and concomitant.  See Appendix D
 
Partial and missing date conventions for additional details. 


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All concomitant medications will be summarised by WHO Drug anatomic therapeutic 
chemical (ATC) level 4 classification and generic term.  Prior and post-discontinuation 
medications will be listed only. 
4.8.4 
Medical history 
Medical history and relevant surgical history will be coded by the AstraZeneca designee using 
the latest version of the MedDRA and will be summarised and listed. 
4.8.5 
Exposure 
Exposure data will be summarised and listed for the SAF. 
Total treatment duration and compliance will be summarised and listed. In addition, 
interruptions and compliance are not taken into account for duration of exposure.  Reason for 
dose discontinuation will also be summarised and listed. 
• Duration (days): 
(End date - start date) + 1. 
• Total treatment exposure (months): 
[(End date – start date) + 1]/12 
 
• Actual number of study treatment taken: 
Total number of bottle/capsules dispensed - total number of bottle/capsules returned. 
 
Duration for study treatment will summarised cumulatively in the following categories:  
• Treatment received more or equal to 1 day: Treatment duration ≥ 1 
• Treatment received more or equal to 15 days: Treatment duration ≥ 15 
 
Subjects taking ≥75% and ≤125% of planned study treatment are considered compliant. 
The percentage treatment compliance will be calculated as the actual number of study 
treatment taken relative to the expected number of study treatment to be taken.  
 
• Expected number of study treatment taken: 
AZD9567/AZD9567 placebo: 
1 bottle x 15 days = 15 
Prednisolone/Prednisolone placebo: 4 capsules x 15 days = 60 
 
• Percentage treatment compliance: 
(Actual number of study treatment taken) / (Expected number of study treatment 
taken) x 100 
 
4.8.6 
Safety 
Safety and tolerability summaries will be presented using the SAF, unless other specified. 


Statistical Analysis Plan  
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The following tables, required by the AZ corporate standards, will not be provided for this 
study because the relevant data were not planned to be collected on the eCRF. 
Urinalysis, baseline versus maximum value on treatment, shift table (<<analysis set>>) 
Urinalysis, treatment-emergent changes (<<analysis set>>) 
QTcF and QTcF intervals, at <<last>> any observation on treatment (<<analysis set>>) 
Electrocardiogram results exceeding ICH reference range boundaries (<<analysis set>>) 
 
4.8.6.1 
Adverse events 
Summary tables will include TEAEs only, unless otherwise specified.  That is, pre- and post-
treatment AEs will not be included in the summary tables of AEs.  Any AE after 
discontinuation of study treatment and pre-treatment AEs will be flagged in the data listings as 
post-treatment AEs and pre-treatment AEs, respectively. 
Pre-treatment AEs are defined as AEs with start date before the first dose of study treatment. 
TEAEs are defined as AEs with start date and time ≥ the first dose of study treatment and ≤ 
the last dose of study treatment + 14 days.  
Post- treatment AEs are defined as AEs with start date > the last dose of study treatment + 14 
days. 
If an AE has a missing onset date then unless the stop date of the AE indicates otherwise, this 
will be considered treatment emergent. Similarly, if an AE has a partial onset date, then unless 
the partial onset date or the stop date indicates otherwise, this will be considered a TEAE. In 
cases where the AE start time is missing but the AE start date is the same as the first dose of 
study treatment, then that AE will be considered a TEAE. 
An overall summary table will be produced showing the number and percentage of subjects 
with at least 1 AE for each of the following categories: 
• Any AE. 
• Any AE with an outcome = death. 
• Any AE with an outcome = death, causally related to study treatment. 
• Any SAE (including events with outcome = death). 
• Any AE leading to discontinuation of study treatment. 
• Any AE causally related to study treatment. 
• Any AE with intensity = severe. 


Statistical Analysis Plan  
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Edition Number 2  
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AEs will be summarised by MedDRA SOC and MedDRA PT.  For each SOC/PT, the number 
and percentage of subjects reporting at least one occurrence will be presented i.e., for a 
subject, multiple occurrences of an AE will be only counted once.  
Summaries will also be done on AEs with most common frequency (≥ 5%), non-serious AEs 
occurring in ≥5% subjects, causally related to study treatment, outcome of death, serious AEs, 
SAEs causally related to study treatment, leading to discontinuation of the study treatment, 
and leading to discontinuation of study treatment, causally related to study treatment. Number 
and percentage of subjects with AEs by PT and relationship will also be provided. 
A summary of the number and percentage of AEs by SOC and PT will be presented along 
with a separate summary of the number and percentage of SAEs by SOC and PT. 
The number and percentage of subjects with AEs by SOC and PT and maximum reported 
intensity (mild, moderate, severe) will be summarised. 
Key subject information for AEs with outcome of death will be summarised for all subjects. 
Similarly, key subject information for SAEs and AEs leading to discontinuation of 
investigational product will be summarised. 
Separate listings of AEs leading to death and SAEs will be presented. 
AEs with missing relatedness will be considered related and AEs with missing intensity will 
be considered as maximum intensity. 
4.8.6.2 
Overdose 
Details of subjects who overdosed will only be listed with details regarding actual treatment 
group. 
4.8.6.3 
Laboratory variables 
Observed results and changes from baseline at each scheduled visit will be summarised for 
each quantitative haematology and clinical chemistry parameter. The following rules will be 
applied if more than one observation is available for a subject at a single visit: 
• If there are two or more observations at the same scheduled visit, the observation 
closest to the target day will be used in the summary 
• If two observations are equidistant from the target day and the ties are on different 
sides of the target day, the observation with the earlier assessment date will be used in 
the analysis. 
• If two observations are equidistant from the target day and the ties located on the same 
sides of the target day (i.e. more than one observation for the same day but different 
time), the observation with the earlier (if the assessment day is equal or larger than the 
target day) or later (if the assessment day is smaller than the target day) assessment 
time will be used in the analysis. 


Statistical Analysis Plan  
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Edition Number 2  
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A shift table from baseline to minimum value post-baseline will be provided for qualitative 
haematology and chemistry values (low, normal, high). Similarly, a shift table from baseline 
to maximum value post-baseline will be provided for qualitative haematology and chemistry 
values (low, normal, high). Low, normal and high will be defined based on Covance reference 
ranges. 
To identify potential Hy’s Law cases, a listing of subjects who have ALT or AST ≥ 3 x ULN 
and total bilirubin ≥ 2 x ULN will be presented.  This listing will include all visits for this 
subset of subjects. 
A plot will also present maximum post-baseline ALT/AST versus maximum post-baseline 
total bilirubin, expressed as multiples of ULN.  
Line plots of the mean (+/- SE) of the following clinical chemistry and haematology 
parameters will be presented in a figure: CRP, glucose, potassium, ESR, haemoglobin, 
platelets and leukocytes. 
Key subject information for haematology and chemistry results outside the Covance reference 
ranges will be provided, along with an overview of number and percentage of subjects with 
results outside the reference ranges post-baseline. 
Pregnancy test results will only be listed for eligible subjects of childbearing potential. 
4.8.6.4 
Vital signs 
Observed values at baseline and observed and change from baseline values for post-baseline 
visits will be summarised for each vital sign. A figure with line plots of the mean change from 
baseline (+/- SE) of selected vital signs parameters (SBP, DBP and pulse) will be provided. 
Additionally, a qualitative summary over time of vital signs results will be provided for SBP, 
DBP, pulse and temperature with categories low, normal and high assigned per the 
AstraZeneca-defined reference ranges for vital signs (Appendix B). A shift table from baseline 
to minimum value post-baseline for each parameter (SBP, DBP, pulse, temperature) will be 
summarised. Similarly, a shift table from baseline to maximum value post-baseline for each 
parameter will be summarised. 
Observed values will be listed and values outside AstraZeneca defined reference ranges and 
clinically significant change criteria (see Appendix B 
AstraZeneca defined reference 
ranges for vital signs) will be flagged. If both the baseline and post-baseline values of a 
parameter are beyond the same limit for that parameter, then the post-baseline value only will 
be flagged if it is more extreme (farther from the limit) than the baseline value. If the baseline 
value is beyond the low, and the post-baseline value is beyond the high limit (or vice-versa), 
then the post-baseline value will be flagged. If the baseline value is not beyond either limit, 
and the post-baseline value is beyond either limit, then the post-baseline value will be flagged. 
Sitting and supine results for vital signs will not be summarised separately. All results will be 
summarised together regardless of position (e.g. “diastolic blood pressure” could include both 
supine and sitting results). 


Statistical Analysis Plan  
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Edition Number 2  
Date 28 Nov 2019 
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4.8.6.5 
ECG variables 
A shift table from baseline to last observation post-baseline for ECG evaluation (normal, 
abnormal - not clinically significant, abnormal - clinically significant, and not done) will be 
summarised and all results listed for each ECG performed. 
4.8.6.6 
Physical examinations 
As any clinically relevant abnormal medical findings should be recorded on the medical 
history or AE form if the finding was reported during the experimental phase of the study, no 
physical examination data will be listed. 
5. 
INTERIM ANALYSES 
No interim analysis specific to this study will be conducted. 


Statistical Analysis Plan  
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Edition Number 2  
Date 28 Nov 2019 
42 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
Table 2 
Summary of changes from protocol 
Reference 
Protocol 
Change 
Justification 
SAP Section 1.1.4 
Section 2.4. 
The following exploratory 
endpoints will be included: 
• 
European League Against 
Rheumatism (EULAR) 
response criteria. 
• 
DAS28 remission. 
• 
Clinically important 
change. 
• 
Low disease activity. 
 
Additional endpoints 
considered important 
for efficacy 
interpretation by study 
team. 
SAP Section 1.3 
Section 8.2. 
Comparison to traditional 
hypothesis testing has been 
removed and replaced with a 
statement that the study is “not 
sufficiently powered to support 
hypothesis testing”. 
The sample size of “n=18” per 
arm has been updated to 
“n=10” per arm. 
Power of the study 
expected to be lower 
than that stated in the 
protocol, given the 
sample size and 
expected effect size. 
Wording updated to 
remove power 
calculation. 
Update to n reflects 
agreement to close 
recruitment early. 
Hence a reduced n per 
arm was agreed. 
SAP Section 4.2.1 
Section 8.5.1 
Concluded that the difference 
in mean CFB in DAS28 of 
AZD9567 - mean CFB in 
DAS28 of Prednisolone will 
show a better efficacy if the 
observed difference negative 
(less than 0) instead of positive 
(larger than 0).  
Lower DAS28 score is 
better.  
 
 
 
 
 


Statistical Analysis Plan  
Study Code D6470C00003 
Edition Number 2  
Date 28 Nov 2019 
43 
7. 
REFERENCES 
D6470C00003 Clinical Trial Protocol, Version 3.0, dated 19MAR2019. 
D6470C00003 Annotated CRF, Version 11.5, final, dated 22NOV2017. 
RA Endpoint Definitions TA Guidance dated 02JUN2014. 
Felson DT, Smolen JS, Wells G, Zhang B, et al.  American College of 
Rheumatology/European League Against Rheumatism Provisional Definition of Remission in 
Rheumatoid Arthritis for Clinical Trials.  Arthritis Rheum. 2011; 63(3):573-86. 
 Frewer et al, 2016 
Frewer P, Mitchell P, Watkins C, Matcham J. Decision-making in early clinical drug 
development. Pharmaceutical statistics. 2016;15(3):255-63. 
Siemons et al, 2014 
Siemons L, ten Klooster PM, Vonkeman HE, van de Laar MA, Glas CA. Further optimization 
of the reliability of the 28-joint disease activity score in patients with early rheumatoid 
arthritis. PloS one 2014;9(6):e100544