Clinical trial NCT02962960
Conditions: Systemic Lupus Erythematosus
Sponsor: AstraZeneca
Start date: 2017-02-14; Completion date: 2018-12-17
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to characterize pharmacokinetics, pharmacodynamics, safety, and tolerability of anifrolumab given via the subcutaneous (SC) route of administration in adult Systemic Lupus Erythematosus (SLE) subjects with a type I Interferon (IFN) test high result and active skin manifestations while receiving Standard of Care (SOC) treatment. In addition, the efficacy of anifrolumab on SLE skin manifestations will be characterized.

Detailed description:

Arms: arm 1: 1ml, once every second week, one subcutaneous injection as added to stand of care, from week 0 to week 50 arm 2: 1ml, once every second week, one subcutaneous injection added to stand of care, from week 0 to week 50 arm 3: 2×1ml, once every second week, two subcutaneous injections as added to stand of care, from week 0 to week 50 arm 4: 2×1ml , once every second week, two subcutaneous injections as added to stand of care, from week 0 to week 50
Interventions: intervention 1: Anifrolumab intervention 2: Placebo
Intervention descriptions: intervention 1: subcutaneous administration every 2 weeks from week 0 to week 50 intervention 2: subcutaneous administration every two weeks from week 0 to week 50

Protocol documents:
Prot_002.pdf: 
1 (131) 
 
Clinical Study Protocol  
 
Drug Substance 
Anifrolumab (MEDI-546) 
 
Study Code 
D3461C00008 
 
Version 
1.0 
 
Date 
20 Sep 2016 
 
 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 
Study Characterizing the Pharmacokinetics, Pharmacodynamics, and Safety 
of Anifrolumab following subcutaneous administration in Adult Systemic 
Lupus Erythematosus Subjects with Type I Interferon test high result and 
active skin manifestations 
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden 




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This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 


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PROTOCOL SYNOPSIS 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 
Study Characterizing the Pharmacokinetics, Pharmacodynamics, and 
Safety of Anifrolumab following subcutaneous administration in Adult 
Systemic Lupus Erythematosus Subjects with Interferon type I test high 
result and active skin manifestations 
 
 
Study site(s) and number of subjects planned 
Approximately 32 subjects are planned to be randomized from approximately 15 sites in 4-5 
countries.  
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
Q4 2016 
Phase 2  
Estimated date of last subject completed 
Q4 2018 
Phase 2  
Study design 
This is a Phase 2, multicentre, double-blind, randomized, placebo-controlled study 
characterizing the pharmacokinetics, pharmacodynamics, and safety of two fixed doses of 
anifrolumab administered as Subcutaneous (SC) injections in adult type I Interferon (IFN) test 
-high Systemic Lupus Erythematosus (SLE) subjects with active skin manifestations while 
receiving Standard of Care (SOC) treatment.  The study will be double-blind until primary 
analysis performed after all subjects have completed Week 12.  Thereafter, the sponsor will be 
unblinded while investigators and subjects will remain blinded throughout the remainder of 
the study. 
Approximately 32 subjects will be randomized to one of the four treatment groups in a 3:1:3:1 
ratio receiving:  
x
anifrolumab at a fixed dose of 150mg as added to SOC, given Q2W as 
one SC injection in a volume of 1mL (12 subjects);  
x
placebo as added to  SOC, given Q2W as one SC injection in a volume of 
1mL  (4 subjects);  
x
anifrolumab at a fixed dose of 300mg as added to SOC, given Q2W as 
two SC injections in a volume of 1mL each (12 subjects) or  


Clinical Study Protocol Synopsis 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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x
placebo as added to SOC, given Q2W as two SC injections in a volume 
of 1mL each (4 subjects). 
The study is blinded with respect to anifrolumab or placebo but not for dose since treatments 
will be given as one or two SC injections depending on dose level. 
Objectives 
Primary Objective: 
Outcome Measures: 
To characterize the PK and PD of 150 mg 
and 300 mg anifrolumab administered as SC 
injections Q2W as measured by anifrolumab 
concentrations, PK parameters, 
21-gene type I IFN PD signature and 
neutralisation ratio at Week 12 
Anifrolumab concentrations and PK parameters 
including maximum concentration (Cmax) after first 
dose and trough concentration (Ctrough) after subsequent 
dosing 
21-gene type 1 IFN PD signature and neutralization 
ratio (relative to baseline) 
 
Secondary Objectives: 
Outcome Measure : 
To characterize the safety and tolerability of 
anifrolumab when SC administered for a 52 
Week treatment period 
Adverse events (AE); serious adverse events (SAEs); 
adverse events of special interest (AESIs) including 
herpes zoster, influenza, opportunistic infections, 
non-opportunistic serious infections, tuberculosis 
(TB), malignancies, non-SLE related vasculitis, 
anaphylaxis, and major adverse cardiovascular events 
(MACE); laboratory variables; physical 
examinations; vital signs; and ECG 
To characterize the immunogenicity of 
anifrolumab when administered SC for a 52 
Week treatment period 
Anti-drug antibodies (ADA) 
 
Exploratory Objectives: 
Outcome Measure: 
To characterize the efficacy of SC 
administered anifrolumab on SLE skin 
manifestations as measured by the change in 
Cutaneous Lupus erythematosus disease Area 
and Severity Index (CLASI) activity score 
from baseline 
Proportion of subjects achieving 50% improvement 
in CLASI activity score from baseline to Week 12 
and week 52 
To explore the effects of SC administered 
anifrolumab on type I IFN and other pathway-
related gene expression in skin tissue 
(optional part of study) 
 21-gene type I IFN and other pathway-related gene 
expression in skin tissue at baseline and at Week 12 
 




Clinical Study Protocol Synopsis 
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Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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Two data base locks and analyses are planned for the study, i.e., the main analysis after all 
randomized subjects complete Week 12 or discontinue the study prior to Week 12, and the 
“end of extension”-analysis that take place once all subjects have completed Week 60 or 
discontinued the study prior to Week 60. 
The full analysis set will be used as the primary population for reporting PD, efficacy and 
safety data.  This comprises of all subjects randomized into the study who receive at least 1 
dose of IP and did not discontinue IP, and will be analyzed according to randomized treatment 
(modified Intention-To-Treat).  All subjects who received anifrolumab and who had at least 1 
quantifiable serum PK observation post first dose, will be included in the PK analysis dataset. 
All PK summaries will be based on this analysis set.  
Descriptive statistics (number, mean, standard deviation [SD], median, minimum, maximum, 
and coefficient of variance [%CV]) will be provided by dose level for continuous variables, 
and counts and percentages will be presented for categorical variables. 
The primary characterization of the effect of anifrolumab on the 21-gene type I IFN PD 
signature will be carried out through the individual and median 21-gene type 1 IFN signature 
scores and neutralization ratios at Week 12.  The PD gene signature will also be explored over 
time.  The primary characterization of anifrolumab PK will be done by descriptive statistics of 
the derived PK parameters. 
 
 
CCI


Clinical Study Protocol 
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Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1
VERSION HISTORY .............................................................................................. 2
PROTOCOL SYNOPSIS ......................................................................................... 4
TABLE OF CONTENTS ......................................................................................... 8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 15
1.
INTRODUCTION ................................................................................................. 18
1.1
Background ............................................................................................................ 18
1.2
Rationale for study population, study design, and dosing ..................................... 19
1.2.1
Rationale for study population and study design ................................................... 19
1.2.2
Rationale for primary endpoint selection ............................................................... 20
1.2.3
Rationale for dosing and study duration ................................................................ 20
1.2.4
IFN test background ............................................................................................... 21
1.3
Benefit/risk and ethical assessment ....................................................................... 22
1.4
Study Design .......................................................................................................... 27
2.
STUDY OBJECTIVES .......................................................................................... 30
2.1
Primary objective ................................................................................................... 30
2.2
Secondary objectives ............................................................................................. 30
2.3
Safety objectives .................................................................................................... 30
2.4
Exploratory objectives ........................................................................................... 31
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 31
3.1
Inclusion criteria .................................................................................................... 31
3.2
Exclusion criteria ................................................................................................... 34
3.2.1
General exclusion criteria ...................................................................................... 35
3.2.2
Exclusion criteria related to concomitant medications .......................................... 36
3.2.3
Exclusion criteria related to systemic lupus erythematosus and other 
diseases .................................................................................................................. 37
3.2.4
Exclusion criteria related to infection and malignancy risk factors ....................... 38
3.3
Subject enrolment and randomization ................................................................... 39
3.4
Procedures for handling incorrectly enrolled or randomized subjects ................... 39
3.5
Methods for assigning treatment groups ................................................................ 40


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3.6
Methods for ensuring blinding ............................................................................... 40
3.7
Methods for unblinding .......................................................................................... 41
3.8
Restrictions ............................................................................................................ 41
3.8.1
Fasting lipid profile ................................................................................................ 41
3.8.2
Perioperative management of investigational product ........................................... 41
3.9
Discontinuation of investigational product ............................................................ 42
3.9.1
Discontinuation of investigational product due to worsening of SLE ................... 43
3.9.2
Procedures for discontinuation of a subject from investigational product ............. 43
3.10
Criteria for withdrawal ........................................................................................... 43
3.10.1
Screen failures ........................................................................................................ 43
3.10.2
Withdrawal of the informed consent ...................................................................... 44
3.10.3
Lost to follow-up .................................................................................................... 44
3.11
Discontinuation of the study .................................................................................. 44
4.
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 44
4.1
Enrolment/screening period ................................................................................... 52
4.1.1
Re-testing and re-screening .................................................................................... 52
4.1.2
Other considerations for screening ........................................................................ 52
4.1.2.1
Medical history ...................................................................................................... 52
4.1.2.2
SLE medication history .......................................................................................... 52
4.1.2.3
Oral examination .................................................................................................... 53
4.1.2.4
Mammography ....................................................................................................... 53
4.2
Treatment period .................................................................................................... 53
4.2.1
Patient survey at week 12 ...................................................................................... 53
4.2.2
Follow-up visits after premature discontinuation of investigational product ........ 54
4.3
Follow-up period .................................................................................................... 54
4.4
Unscheduled visits ................................................................................................. 54
5.
STUDY ASSESSMENTS ..................................................................................... 55
5.1
Efficacy assessments .............................................................................................. 55
5.1.1
Training and certification for Systemic Lupus Erythematosus assessments ......... 55
5.1.2
Cutaneous Lupus Erythematosus Disease Area and Severity Index ...................... 56
5.1.3
Systemic Lupus Erythematosus Disease Activity Index 2000............................... 56
5.1.4
Physician Global Assessment ................................................................................ 56
5.1.5
Oral corticosteroid tapering ................................................................................... 57
5.2
Safety assessments ................................................................................................. 57
5.2.1
Clinical Laboratory assessments ............................................................................ 57
5.2.1.1
Haematology, clinical chemistry, and urinalysis testing........................................ 59
5.2.1.2
Coagulation Testing ............................................................................................... 59
5.2.1.3
Infectious Disease Panel ........................................................................................ 59
5.2.1.4
Fasting lipid profile ................................................................................................ 59
5.2.1.5
Tuberculosis Testing .............................................................................................. 59


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5.2.1.6
Pregnancy Testing .................................................................................................. 59
5.2.2
Physical examination ............................................................................................. 60
5.2.3
ECG ........................................................................................................................ 60
5.2.4
Vital signs .............................................................................................................. 60
5.2.5
Assessment of Injection Sites ................................................................................ 60
5.2.6
Other safety assessments ........................................................................................ 60
5.2.6.1
Chest x-ray ............................................................................................................. 60
5.2.6.2
Tuberculosis screening and monitoring ................................................................. 61
5.2.6.3
Cervical cancer screening ...................................................................................... 63
5.2.6.4
Colombia-Suicide Severity Rating Scale (C-SSRS) .............................................. 64
5.3
Pharmacokinetics ................................................................................................... 64
5.3.1
Collection of samples ............................................................................................. 64
5.3.2
Determination of drug concentration ..................................................................... 64
5.3.3
Storage and destruction of pharmacokinetic samples ............................................ 65
5.4
Immunogenicity ..................................................................................................... 65
5.4.1
Anti-drug antibodies .............................................................................................. 65
5.4.2
Neutralising antibodies .......................................................................................... 65
5.5
Pharmacodynamics ................................................................................................ 65
5.5.1
21-gene type I IFN PD signature in whole blood (PD marker) ............................. 65
5.5.2
4-gene type I IFN test ............................................................................................ 65
5.5.3
Exploratory Transcriptome Analysis (optional) .................................................... 66
5.6
Pharmacogenetics (Not Applicable) ...................................................................... 66
5.7
Biomarker analysis (Not Applicable) .................................................................... 66
5.8
Storage, re-use and destruction of biological samples ........................................... 66
5.9
Labelling and shipment of biological samples ....................................................... 66
5.10
Chain of custody of biological samples ................................................................. 67
5.11
Withdrawal of Informed Consent for donated biological samples ........................ 67
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 68
6.1
Definition of adverse events .................................................................................. 68
6.2
Definitions of serious adverse event ...................................................................... 68
6.3
Recording of adverse events .................................................................................. 68
6.3.1
Time period for collection of adverse events ......................................................... 68
6.3.2
Follow-up of unresolved adverse events ................................................................ 69
6.3.3
Variables ................................................................................................................ 69
6.3.4
Causality collection ................................................................................................ 70
6.3.5
Adverse events based on signs and symptoms ...................................................... 70
6.3.6
Adverse events based on examinations and tests ................................................... 70
6.3.7
Hy’s Law ................................................................................................................ 71
6.3.8
Disease progression/worsening of SLE ................................................................. 71


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Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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6.4
Reporting of serious adverse events....................................................................... 71
6.5
Overdose ................................................................................................................ 72
6.6
Pregnancy ............................................................................................................... 72
6.6.1
Maternal exposure .................................................................................................. 72
6.6.2
Paternal exposure ................................................................................................... 73
6.7
Adverse Events of Special Interest ........................................................................ 73
6.7.1
Non-opportunistic serious infection ....................................................................... 73
6.7.2
Opportunistic serious infection .............................................................................. 73
6.7.3
Anaphylaxis ........................................................................................................... 74
6.7.4
Malignancy ............................................................................................................ 74
6.7.5
Herpes zoster .......................................................................................................... 74
6.7.6
Tuberculosis ........................................................................................................... 74
6.7.7
Influenza ................................................................................................................ 75
6.7.8
Vasculitis (non-Systemic Lupus Erythematosus) .................................................. 76
6.7.9
Major acute cardiovascular events ......................................................................... 76
6.8
Reporting of adverse events of special interest ...................................................... 76
6.9
Management of IP related toxicities ...................................................................... 77
6.9.1
Anaphylaxis, hypersensitivity, and injection-related reactions ............................. 77
6.9.2
Infections ................................................................................................................ 77
6.10
Study governance and oversight ............................................................................ 78
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 78
7.1
Identity of investigational product(s) ..................................................................... 78
7.2
Dose and treatment regimens ................................................................................. 78
7.2.1
Investigational product administration procedures ................................................ 79
7.2.2
Monitoring of investigational product administration ........................................... 79
7.3
Labelling ................................................................................................................ 79
7.4
Storage ................................................................................................................... 79
7.5
Compliance ............................................................................................................ 80
7.6
Accountability ........................................................................................................ 80
7.7
Concomitant treatment ........................................................................................... 80
7.7.1
Standard of Care treatment for SLE ....................................................................... 80
7.7.2
Corticosteroid treatment ......................................................................................... 81
7.7.2.1
Protocol-specified corticosteroid tapering ............................................................. 81
7.7.2.2
Corticosteroid bursts .............................................................................................. 82
7.7.2.3
Increase in oral corticosteroids for intercurrent disease or to prevent 
adrenal insufficiency .............................................................................................. 83
7.7.2.4
Topical therapy ...................................................................................................... 83
7.7.3
Anti-hypertensive agents and statins ..................................................................... 83
7.7.4
NSAIDs .................................................................................................................. 84


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7.7.5
Acetaminophen or equivalent ................................................................................ 84
7.7.6
Low-dose aspirin .................................................................................................... 84
7.7.7
Narcotic analgesics ................................................................................................ 84
7.7.8
Other concomitant treatment .................................................................................. 84
7.8
Prohibited medications ........................................................................................... 84
7.9
Post Study Access to Study Treatment .................................................................. 86
8.
STATISTICAL ANALYSES BY ASTRAZENECA ............................................ 86
8.1
Statistical considerations ........................................................................................ 86
8.2
Sample size estimate .............................................................................................. 87
8.3
Definitions of analysis sets .................................................................................... 87
8.3.1
All subjects analysis set ......................................................................................... 87
8.3.2
Full analysis set ...................................................................................................... 87
8.3.3
PK analysis set ....................................................................................................... 87
8.4
Outcome measures for analyses ............................................................................. 87
8.4.1
Primary outcome measures .................................................................................... 88
8.4.1.1
Pharmacodynamics (PD) ....................................................................................... 88
8.4.1.2
Pharmacokinetics (PK) .......................................................................................... 88
8.4.2
Secondary outcome measures ................................................................................ 88
8.4.2.1
Immunogenicity ..................................................................................................... 88
8.4.2.2
Safety ..................................................................................................................... 88
8.4.3
Exploratory outcome measures .............................................................................. 89
8.4.3.1
Efficacy .................................................................................................................. 89
8.4.3.2
Oral corticosteroid management ............................................................................ 89
8.4.3.3
Skin tape test (optional) ......................................................................................... 89
8.5
Methods for statistical analyses ............................................................................. 89
8.5.1
Analysis of the primary variable (s) ....................................................................... 90
8.5.2
Analysis of the secondary variables ....................................................................... 90
8.5.2.1
Safety ..................................................................................................................... 90
8.5.2.2
Immunogenicity ..................................................................................................... 91
8.5.3
Interim analysis ...................................................................................................... 91
8.5.4
Sensitivity analysis ................................................................................................. 91
8.5.5
Analysis methods for exploratory outcome measures ........................................... 91
8.5.5.1
Efficacy .................................................................................................................. 91
8.5.5.2
Oral corticosteroid management ............................................................................ 92
8.5.5.3
Skin tape test .......................................................................................................... 92
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA .......................... 92
9.1
Training of study site personnel ............................................................................. 92
9.2
Monitoring of the study ......................................................................................... 93
9.2.1
Source data ............................................................................................................. 93
9.2.2
Study agreements ................................................................................................... 93
9.2.3
Archiving of study documents ............................................................................... 94


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9.3
Study timetable and end of study ........................................................................... 94
9.4
Data management by AstraZeneca or delegate ...................................................... 94
10.
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 95
10.1
Ethical conduct of the study ................................................................................... 95
10.2
Subject data protection ........................................................................................... 95
10.3
Ethics and regulatory review ................................................................................. 95
10.4
Informed consent ................................................................................................... 96
10.5
Changes to the protocol and informed consent form ............................................. 96
10.6
Audits and inspections ........................................................................................... 97
11.
LIST OF REFERENCES ....................................................................................... 97
 
LIST OF TABLES 
Table 1 
Highly effective intrauterine device and hormonal methods and 
effective barrier methods of birth control (2 methods are required, 
one being a barrier method and one being a intrauterine 
device/hormonal method) ......................................................................... 33
Table 2
Study plan detailing the procedures at screening ..................................... 45
Table 3
Study plan detailing the procedures during the Treatment Period ........... 47
Table 4
Study plan detailing the procedures during Follow-up ............................ 51
Table 5
Clinical Laboratory Variables .................................................................. 57
 
LIST OF FIGURES 
Figure 1  
Mean serum concentrations of anifrolumab following single SC 
(300 and 600 mg) and IV (300 mg) dosing in healthy volunteers ............ 20
Figure 2 
Distribution of IFN transcript scores ........................................................ 22
Figure 3 
Study flow chart ....................................................................................... 29
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information ................................................................ 100


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Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ............................................................................... 102
Appendix C 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .......................................................................... 104
Appendix D 
American College of Rheumatology Criteria for Systemic Lupus 
Erythematosus Classification ................................................................. 108
Appendix E 
Systemic Lupus Erythematosus Disease Activity Index 2000 ............... 110
Appendix F 
Cutaneous Lupus Erythematosus Disease Area and Severity Index ...... 112
Appendix G 
Physician global assessment ................................................................... 113
Appendix H 
Oral Corticosteroid Guidance ................................................................. 114
Appendix I 
General guidance for Determination of Major Surgery.......................... 115
Appendix J 
Guidance for abnormal Pap-smear results .............................................. 116
Appendix K 
Anaphylaxis ............................................................................................ 117
Appendix L 
Classification criteria for catastrophic anti-phospholipid syndrome ...... 121
Appendix M 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 122
Appendix N 
Vasculitic syndromes excluded from the study ...................................... 128
Appendix O 
Patient Survey at Week 12...................................................................... 129
 
 
 
 
 
 
 
 
 
 
 


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Version 1.0 
Date 20 Sep 2016 
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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 
ACR 
American College of Rheumatology  
ADA 
Anti-Drug Antibodies  
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest  
AIS 
Adenocarcinoma In Situ  
ALP 
Alkaline Phosphatise  
ALT 
Alanine Aminotransferase  
ANA 
Antinuclear Antibody  
anti-dsDNA 
Anti-Double Stranded Deoxyribonucleic Acid  
AST 
Aspartate Aminotransferase  
AUC 
Area Under the Curve 
BCG 
Bacillus Calmette-Guerin  
BICLA 
British Isles Combined Lupus Assessment 
BP 
Blood Pressure 
C3 
Third Component of Complement 
C4 
Fourth Component of Complement 
CDC 
Centers for Disease Control and Prevention 
CH50 
Total Haemolytic Complement 
CHMP 
Committee for Medicinal Products for Human Use  
CIS 
Carcinoma In Situ  
CK 
Creatine Kinase  
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Index  
Cmax 
Maximum plasma (peak) drug concentration after single dose 
administration 
Ctrough 
Trough concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSA 
Clinical Study Agreement  
CSR 
Clinical Study Report 


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Abbreviation or 
special term 
Explanation 
C-SSRS 
Colombia Suicidality Severity Rating Scale  
CV-EAC 
Cardiovascular Event Adjudication Committee  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EOT 
End of Treatment  
EULAR 
European League Against Rheumatism  
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practice  
GMP 
Good Manufacturing Practice  
HBcAb 
Hepatitis B Core Antibody  
HBsAg 
Hepatitis B Surface Antigen  
HBV 
Hepatitis B Virus  
HDL 
High Density Lipoprotein  
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus  
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation 
IFA 
Immunofluorescent Assay  
IFIGx 
Interferon-Inducible Gene Expression  
IFN 
Interferon  
IFNAR1 
Type I Interferon Receptor 
Ig 
Immunoglobulin 
IP 
Investigational Product  
IRB 
Institutional Review Board  
IV 
Intravenous  
IVIG 
Intravenous Immunoglobulins  
IXRS 
Interactive Voice/Web Response System  
LDL 
Low Density Lipoprotein  
LLOQ 
Lower Limit of Quantitation 
mAb 
Monoclonal Antibody  
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities  


Clinical Study Protocol 
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Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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Abbreviation or 
special term 
Explanation 
mRNA 
Messenger Ribonucleic Acid  
NSAID 
Nonsteroidal anti-Inflammatory Drugs 
OCS 
Oral Corticosteroids  
PA 
Posterior-Anterior 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PGA 
Physician Global Assessment 
PI 
Principal Investigator  
PP 
Per-Protocol  
PT 
Prothrombin Time  
PTT 
Partial Thromboplastin Time  
Q2W 
Every 2 Weeks 
Q4W 
Every 4 Weeks 
QFT-G 
QuantiFERON-TB Gold 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction  
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SC 
Subcutaneous 
SLE 
Systemic Lupus Erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SOC 
Standard of Care  
SRI[4] 
Systemic Lupus Erythematosus Responder Index of 4  
SSc 
Systemic Sclerosis  
TB 
Tuberculosis  
ULN 
Upper Limit of Normal  
WBDC 
Web Based Data Capture  


Clinical Study Protocol 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
18 (131) 
1.
INTRODUCTION
1.1
Background
Systemic Lupus Erythematosus (SLE) is a chronic, multisystemic, disabling autoimmune 
rheumatic disease of unknown aetiology.  The disease predominantly affects women of 
childbearing years (Cooper et al, 1998; Lahita, 1999) with a female-to-male ratio in the 
childbearing years of about 12:1 (Ramsey-Goldman and Manzi, 2000).  There is substantial 
unmet medical need in the treatment of SLE, particularly in subjects with moderate or severe 
disease.  SLE has a broad range of clinical manifestations including constitutional symptoms, 
alopecia, skin rashes, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, 
haemolytic anaemia, cognitive dysfunction and other nervous system involvement.  Skin is the 
second most commonly involved organ and even though the reported prevalence varies among 
different studies more than 80% of SLE patients have skin symptoms at some stage of their 
disease (Rothfield N et al, 2006, Kapadia N et al, 1996, Wysenbeek AJ et al, 1992, Grönhagen 
CM et al, 2010).  Both the disease manifestations as well as the currently used SOC treatment, 
commonly oral corticosteroids (OCS) and other immunosuppressive agents, cause a 
significant disease burden (Doria and Briani, 2008; Petri, 2001; Zonana-Nanach et al, 2000).  
All currently used SLE therapies have well known adverse effects and there is a medical need 
to identify new targeted therapies, particularly agents that may reduce the requirement for 
corticosteroids and cytotoxic agents. 
There is growing evidence that type I IFNs play an important role in autoimmune diseases 
including SLE.  Subjects with high anti-double stranded deoxyribonucleic acid (anti-dsDNA) 
antibody titers, progressive skin rashes, and lupus nephritis (LN), have high serum levels of 
type I IFN (Bengtsson et al, 2000).  Overexpression of type I IFN activated genes, the so 
called “interferon signature”, has been shown in blood and skin biopsies from SLE subjects 
with acute skin involvement (Dall’era et al, 2005, Blomberg S et al, 2001, Farkas et al, 2001, 
Yao et al, 2009). 
Anifrolumab is a human immunoglobulin G1 kappa (IgG1ț) monoclonal antibody (mAb) 
directed against subunit 1 of the type I IFN receptor (IFNAR1).  Anifrolumab inhibits binding 
of type I IFN to IFNAR and inhibits the biologic activity of all type I IFNs.  The growing 
evidence that type I IFNs play an important role in SLE, suggests that inhibition of the 
biological activity of type I IFNs with anifrolumab may be a novel therapy for the treatment of 
SLE patients with significant unmet medical need. 
Anifrolumab as administered as intravenous (IV) infusions is currently being investigated by 
the Sponsor for treatment of moderate to severe active SLE in the following ongoing studies; 
one global open-label extension phase 2 study, one phase 2 study in adult Japanese subjects, 
two global phase 3 studies and a long-term extension study of these, and in proliferative LN 
(one global phase 2 study).  
Development of a SC route of administration for anifrolumab is expected to offer increased 
flexibility in meeting patients’ dosing needs and to improve treatment accessibility and 


Clinical Study Protocol 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
19 (131) 
compliance.  The PK/PD, bioavailability and safety of SC administered anifrolumab in 
healthy volunteers is being evaluated in a phase 1 study (D3461C00006). 
The purpose of this study is to better understand the PK and PD of SC administered 
anifrolumab in SLE with the goal to identify dose and dosing regimen to be further evaluated 
in future development of the SC route of administration. 
1.2
Rationale for study population, study design, and dosing 
1.2.1
Rationale for study population and study design 
The overall aim of this Phase 2, multicentre, double-blind, randomized, placebo-controlled 
study is to provide PK/PD, safety and efficacy data to facilitate identification of dose and 
dosing regimen for future development of the SC route of administration of anifrolumab in 
SLE.  To allow optimal evaluation of the PD marker, i.e., changes of the 21-gene type 1 IFN 
PD signature, only subjects with type I IFN test-high results will be eligible for the study.  In 
addition to evaluate the effects on the 21-gene type I IFN PD signature, anifrolumab efficacy 
on active skin manifestations will be characterized by recruitment of subjects with CLASI 
activity score 10.  
Data from phase 2b study (CD-IA-MEDI-546-1013) shows that anifrolumab administered IV 
Q4W, demonstrated a clinically relevant benefit in patients with moderate to severe SLE when 
added to SOC.  The proportion of patients achieving a SLE responder index (SRI) 4 response 
with a sustained reduction in corticosteroids at Day 169, was greater in both the 300 mg 
(34.3%) and 1000 mg (28.8%) anifrolumab groups than in the placebo group (17.6%).  
Similar response rates were seen in the type I IFN test-high subpopulation (approximately 
75% of the overall population): 13.2% in the placebo group, 36.0% in the 300 mg anifrolumab 
group, and 28.2% in the 1000 mg anifrolumab group. 
Anifrolumab showed efficacy across multiple efficacy measures including improvement of 
skin symptoms.  The proportion of subjects with a CLASI activity score  10 at baseline who 
achieved at least a 50% decrease from baseline was numerically higher for anifrolumab than 
placebo group and the difference was observed from Day 29 and was sustained during the 52 
week treatment period.  Furthermore, data showed that the majority of subjects with active 
skin manifestations exhibited high IFN test scores. 
To ensure adequate treatment, subjects will remain on stable doses of SOC treatment with at 
least one of the following; oral corticosteroids, antimalarials, or immunosuppressants.  This is 
consistent with both the European League Against Rheumatism (EULAR) (Bertsias et al, 
2008) and American College of Rheumatology (ACR) (ACR ad hoc committee, September 
1999) management guidelines of moderate to severe SLE, including treatment of skin 
manifestations. 
The study will be randomized, placebo-controlled, and double-blind until primary analysis 
after all subjects have completed Week 12 to ensure a robust design and minimise bias.  The 
study is blinded with respect to anifrolumab and placebo, but not blinded at dose level.  This is 
the preferred design as outlined in the June 2010 FDA Guidance for Industry Systemic Lupus 


Clinical Study Protocol 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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Erythematosus-Developing Medical Products for Treatment and in the Committee for 
Medicinal Products for Human Use (CHMP) Guideline on clinical investigation of medicinal 
products for the treatment of SLE and LN (CHMP, February 2015).  After Week 12, and 
unblinding of the sponsor, treatment will continue with investigators and subjects kept blinded 
throughout the remainder of the study.  A treatment period of 52 weeks will allow further 
characterization of PK/PD, safety, and efficacy of SC administered anifrolumab. 
1.2.2
Rationale for primary endpoint selection 
The 21-gene type I IFN PD signature was chosen as a PD biomarker as an increase in type I 
IFN inducible mRNAs is a direct molecular consequence of increased expression of type I 
IFN proteins.  Furthermore, measurement of mRNA via reverse transcription-polymerase 
chain reaction (RT-PCR) is a comprehensive and reliable technique.  A robust panel of 21 
type I IFN-inducible genes were selected based on the magnitude of their overexpression in 
whole blood of patients with SLE, providing a sensitive and specific PD marker where mRNA 
expression can be measured quantitatively. 
CCI


Clinical Study Protocol 
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Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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1.2.4
IFN test background 
Type I IFN has long been considered to be important in the pathogenesis of SLE and 
inhibition of this pathway is an attractive goal, targeted by anifrolumab.  To understand the 
relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to 
know if a specific patient’s disease is driven by type I IFN activation.  Direct measurement of 
the IFN is challenging, so a transcript-based marker, measuring the effect of IFN, was 
developed to evaluate the effect of over-expression of the target protein on a specific set of 
messenger ribonucleic acid (mRNA) markers.  The expression of these markers is easily 
detected in whole blood and demonstrates a correlation with expression in diseased tissue, 
such as skin, in SLE.  The bimodal distribution of the transcript scores for SLE patients, as 
shown in the Figure 2 below, supports defining an IFN test-high and IFN test-low 
subpopulation. 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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Figure 2 
Distribution of IFN transcript scores 
 
1.3
Benefit/risk and ethical assessment 
A detailed assessment of the overall benefit/risk of anifrolumab is discussed in the 
Investigator’s Brochure. 
There is significant unmet medical need for the treatment of patients with moderate to severe 
SLE.  Since type I IFNs seem very likely to have a role in SLE, a therapy such as anifrolumab, 
that targets type I IFN receptors, may be beneficial. 
Anifrolumab has been, or is being, investigated in the following MedImmune/AstraZeneca-
sponsored clinical studies in adult subjects with systemic sclerosis (SSc) or SLE: 
x
Study MI-CP180 was a Phase 1, open-label, dose escalation study of 
single and multiple IV doses of anifrolumab in adult subjects with SSc 
(completed study). 
x
Study CD-IA-MEDI-546-1013 was a Phase 2b, randomized, double-
blind, placebo-controlled study of anifrolumab (300 mg and 1000 mg IV 
Q4W) in adult subjects with moderately to severely active SLE 
(completed study). 


Clinical Study Protocol 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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x
Study CD-IA-MEDI-546-1145 is the open-label extension for subjects 
completing Study CD-IA-MEDI-546-1013 (ongoing at the time of 
writing this protocol). 
x
Study D3461C00002 is an open-label study in Japanese adult subjects 
with moderately to severely active SLE (ongoing at the time of writing 
this protocol). 
x
Study D3461C00004 and study D3461C00005 are phase 3 randomized, 
double-blind, placebo-controlled studies evaluating safety and efficacy in 
adult subjects with moderately to severely active SLE (ongoing at the 
time of writing this protocol). 
x
Study D3461C0007 is a Phase 2 randomized, double-blind, placebo-
controlled study characterizing the safety and efficacy of anifrolumab in 
adult subjects with LN (ongoing at the time of writing this protocol). 
x
Study D3461C009 is randomized, double-blind, placebo-controlled phase 
3 extension study characterizing the long-term safety and tolerability of 
anifrolumab in adult subjects with moderately to severely active SLE 
enrolling subjects who have completed studies D3461C00004 and 
D3461C00005 (ongoing at the time of writing this protocol). 
x
Study D3461C00006 is a Phase 1 study evaluating two dose levels (300 
and 600 mg) of SC administered and one dose level (300 mg) of IV 
administered anifrolumab in healthy volunteers. 
Study CD-IA-MEDI-546-1013 
This was a Phase 2b, randomized, double-blind, placebo-controlled, parallel group study to 
characterize the efficacy and safety of anifrolumab in adult subjects with moderately to 
severely active SLE with an inadequate response to SOC treatment.  In total 305 subjects were 
randomized and received placebo (n=102), anifrolumab 300 mg (n=99), or anifrolumab 1000 
mg (n=104) IV Q4W while continuing SOC treatment.  The study has been completed.  
Efficacy findings 
Anifrolumab demonstrated a clinically relevant benefit with the proportion of patients 
achieving the primary endpoint, an SRI (4) response with a sustained reduction in 
corticosteroids at Day 169, being greater in both the 300 mg (34.3%) and 1000 mg (28.8%) 
anifrolumab groups than in the placebo group (17.6%).  The response rates in the IFN test- 
high population (approximately 75% of the overall population) were 13.2% in the placebo 
group, 36.0% in the 300 mg anifrolumab group, and 28.2% in the 1000 mg anifrolumab 
group.  Compared with the placebo group, a numerically higher proportion of patients in the 
anifrolumab groups achieved SRI (4) response with sustained reduction of OCS at Day 365 
(placebo, 25.5%; 300 mg, 51.5%; and 1000 mg, 38.5%).  The 300mg anifrolumab group saw a 
numerically higher proportion of patients have a reduction of background OCS dose to 7.5 




Clinical Study Protocol 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
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Expression of type I IFN-inducible genes in whole blood using the 21-gene type I IFN PD 
signature decreased following anifrolumab administration for all dose groups in subjects with 
a baseline IFN test-high result in whole blood.  For both the 300 mg and 1000 mg anifrolumab 
groups, > 85% median neutralization of the 21-gene type I IFN PD signature was observed 
through Day 365, with numerically greater neutralization observed in the 1000 mg group.  In 
the placebo group (N = 70 at baseline), no neutralization of the 21-gene type I IFN PD 
signature was observed at any time point.  Because subjects who were PD signature negative 
do not have significant type I IFN signature expression at baseline, the level of signature 
neutralization could not be robustly determined in this population. 
Safety findings  
The 300 and 1000 mg doses of anifrolumab were generally safe and well tolerated compared 
to placebo.  After the review of all adverse events (AEs) as well as pre-specified safety topics 
of interest, the review revealed a favourable safety profile for anifrolumab.  The overall 
number of patients with treatment-emergent adverse events (TEAEs), treatment-emergent 
serious adverse events (TESAEs), and AESIs; new or reactivated tuberculosis; malignancy; 
and infusion, hypersensitivity, or anaphylactic reactions, and non SLE related vasculitis) were 
similar between the placebo and anifrolumab groups.  TESAEs classified by the investigator 
as related to the study drug were observed in 5.9% of the patients in the placebo group, 3.0% 
in the 300 mg anifrolumab group, and 1.0% in the 1000 mg anifrolumab group.  AEs leading 
to discontinuation of the study drug were observed in 7.9% in the placebo group, 3.0% in the 
300 mg anifrolumab group, and 9.5% in the 1000 mg anifrolumab group.  There was 1 death 
in the 1000 mg anifrolumab group 
 and none in the other 2 treatment groups. 
There was a higher frequency of patients with infection-related AEs in both the 300 mg 
(63.6%) and 1000 mg (61.9%) anifrolumab groups compared with the placebo group (51.5%).  
An event of special interest, herpes zoster, was reported more frequently in the anifrolumab-
treated patients (300 mg anifrolumab group [5.1%]; 1000-mg anifrolumab group [9.5%]) 
compared with placebo-treated patients (2.0%).  Importantly, patients with herpes zoster 
infection responded well to standard antiviral treatment.  One TESAE of transverse myelitis 
with a positive varicella zoster virus polymerase chain reaction in cerebrospinal fluid was 
reported.  The patient fully recovered following treatment with pulsed steroid and standard 
antiviral medication. 
Herpes zoster reactivation, including cutaneous events, has been confirmed as an identified 
risk associated with administration of anifrolumab. 
There was a higher number of patients with infections reported as influenza in the anifrolumab 
groups (300 mg [6.1%]; 1000 mg [7.6%]) compared with placebo (2.0%); however, the 
protocol did not require objective evidence confirming the aetiology of these infections. 
Infusion-related reactions were observed in 5.9% of placebo-treated patients, 2.0% in the 300 
mg anifrolumab group, and 3.8% in the 1000 mg anifrolumab group.  The characteristics and 
severity of these reactions were similar in all 3 treatment groups. 


Clinical Study Protocol 
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Study Code D3461C00008 
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No clinically important difference was observed in haematology, chemistry, urinalysis, vital 
signs, lipid parameters, or electrocardiograms (ECGs) in any of the treatment groups. 
Overall benefit/risk assessment 
Anifrolumab demonstrated a clinically relevant benefit in subjects with moderate to severe 
SLE receiving SOC treatment.  The efficacy was supported by a broad range of clinical 
measures of global (various levels of SRI responses, BICLA) and organ-specific disease 
activity (CLASI, joint count).  A clinically relevant increase in the proportion of subjects 
achieving pre-specified corticosteroid reduction in the 300 mg group was observed compared 
with placebo.  No apparent difference was observed when comparing the 1000 mg and 
placebo group.  Anifrolumab was generally well tolerated.  A dose ordered increase in the 
proportion of subjects with uncomplicated herpes zoster infections was observed in subjects 
receiving anifrolumab compared with placebo.  Herpes zoster has been determined to be an 
identified risk associated with anifrolumab treatment in SLE patients. 
To date, in clinical studies of anifrolumab, hypersensitivity events or 
anaphylaxis/anaphylactoid events have not occurred more frequently in subjects who were 
treated with anifrolumab IV as compared to placebo, although careful monitoring for such 
events will continue.  The administration of any foreign protein may be associated with acute 
allergic reactions that may be severe, and may result in death.  Reports of infusion-related 
reactions from clinical studies conducted to date suggest that the frequency, severity and 
characteristics of these reactions are similar across all treatment groups after IV 
administration. In the Phase 1 SC study (Study D3461C00006), anifrolumab 300 mg or 
placebo were administered SC to healthy volunteers.  Both anifrolumab and placebo were 
administered as 2 injections into the SC tissue of the anterior thigh or abdomen.  Subjects 
experienced minimal to mild and very transient pain immediately after the injections with no 
difference between the placebo and anifrolumab group.  Similarily, injection-site pruritus was 
minimal and transient and showed no difference between anifrolumab and placebo groups.  
Even though anifrolumab is a human monoclonal antibody, subjects can develop ADA that 
may neutralise the activity of the drug or may be associated with acute or delayed 
hypersensitivity reactions, including anaphylaxis.  Subjects will be monitored for clinical 
manifestations that may be associated with the formation of specific antibodies to anifrolumab 
generated during the study, as well as for the presence of such antibodies. 
In order to minimise the risk associated with anifrolumab treatment, subjects with risk factors 
for serious infections, recurrent herpes zoster, malignancy, or immune deficiency disorders 
are specifically excluded from participation.  Serious infections including non-opportunistic 
serious infections, opportunistic infections, anaphylaxis, malignancy, herpes zoster, TB 
(including latent TB), influenza, and vasculitis (non-SLE) are designated as AESIs in this 
study.  An external independent adjudication committee will assess all deaths and 
cardiovascular SAEs to determine if they meet criteria for MACE (stroke, acute coronary 
syndrome, myocardial infarction, or cardiovascular death).  Specific details will be addressed 
in a cardiovascular event adjudication charter.  There have been no imbalances in reported 
rates of MACE or other non-MACE cardiovascular events observed either with anifrolumab 


Clinical Study Protocol 
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Study Code D3461C00008 
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or other agents sharing a similar mechanism of action compared to controls/placebo to date. 
However, since accelerated coronary artery disease and cerebrovascular accidents are 
recognised complications of SLE, the adjudication process is put in place to support rigorous 
case identification and categorisation for signal detection activity across treatment arms. 
Compared to the general population, patients with lupus have a higher rate of depression and 
suicide.  Therefore, subjects will be screened for suicidality and those who are at high risk as 
assessed at screening and baseline will be excluded from participation in the study.  
In conclusion, AstraZeneca believes that the available non-clinical and clinical data indicate 
an acceptable safety profile for anifrolumab when administered via the IV route.  A similar 
safety and tolerability profile has been seen in a Phase 1 SC study in healthy volunteers.  The 
proposed dosing regimens for this study are adequately justified and the management plan for 
potential risks associated with anifrolumab is appropriate.  The emerging safety profile has not 
identified any risks that would preclude continued investigation of anifrolumab.  AstraZeneca 
believes that anifrolumab continues to demonstrate an overall positive benefit/risk balance to 
support its clinical evaluation in subjects with moderate to severe SLE and development of a 
SC administration route. 
1.4
Study Design
This is a Phase 2, multicentre, double-blind, randomized, placebo-controlled study 
characterizing the PK/PD, and safety of two fixed doses of anifrolumab administered as SC 
injections in adult SLE subjects with type I IFN test-high result and active skin manifestations 
while on stable SOC treatment.  The study will be double-blind until database lock for the 
primary analysis performed after all subjects completed Week 12.  Thereafter, the sponsor will 
be unblinded while the investigators and subjects will remain blinded throughout the 
remainder of the study. 
Approximately 32 subjects will be randomized to one of the four treatment groups in a 3:1:3:1 
ratio receiving:  
x
anifrolumab at a fixed dose of 150mg as added to SOC, given Q2W as 
one SC injection in a volume of 1mL (12 subjects);  
x
placebo as added to  SOC, given Q2W as one SC injection in a volume of 
1mL  (4 subjects);  
x
anifrolumab at a fixed dose of 300mg as added to SOC, given Q2W as 
two SC injections in a volume of 1mL each (12 subjects) or  
x
placebo as added to SOC, given Q2W as two SC injections in a volume 
of 1mL each (4 subjects). 
Subjects must be taking either 1 or any combination of the followings: OCS, antimalarial, or 
immunosuppressants at stable doses.  Specific medication restriction are contained in the 
eligibility criteria as described in Sections 3.1 and 3.2.2.  OCS doses should remain stable 


Clinical Study Protocol 
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Study Code D3461C00008 
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Date 20 Sep 2016 
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through Week 12, unless there is a clinical, safety or ethical reason for not to taper in which 
case reduction of OCS dose may be permitted from Week 4.  Starting at Week 12 a mandatory 
steroid tapering attempt will be required for all subjects with an OCS dose 10.0 mg per day 
of prednisone or equivalent at randomization as described in Section 7.7.2.1.  
See Figure 3 for outline of the study design.  
This study includes:  
A screening period of up to 30 days; 
A treatment period of 52 weeks;  
A follow-up period of 8 weeks. 
IP will be administered at study visits for a total of 26 doses (Week 0 to Week 50) during the 
treatment period and the last follow-up visit will be 10 weeks after the last IP dose.  


Clinical Study Protocol 
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Study Code D3461C00008 
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Figure 3 
Study flow chart 
 
Abbrev: Q2W= once every second week; SOC= standard of care; OCS=oral corticosteroids 


Clinical Study Protocol 
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Study Code D3461C00008 
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2.
STUDY OBJECTIVES 
2.1
Primary objective 
Primary Objective: 
Outcome Measures: 
To characterize the PK and PD of 150 mg 
and 300 mg anifrolumab administered as SC 
injections Q2W as measured by anifrolumab 
concentrations, PK parameters, 21-gene type 
I IFN PD signature score and neutralisation 
ratio at Week 12. 
Anifrolumab concentrations and PK parameters 
including maximum concentration (Cmax) after first 
dose and trough concentration (Ctrough) after subsequent 
dosing 
21-gene type 1 IFN PD signature  and neutralization 
ratio (relative to baseline) 
 
2.2
Secondary objectives 
Secondary Objective: 
Outcome Measure : 
To characterize the safety and tolerability of 
anifrolumab when SC administered for a 52 
Week treatment period  
Adverse events (AE); serious adverse events (SAEs); 
Adverse events of special interest (AESIs) including 
herpes zoster, influenza, opportunistic infections, 
non-opportunistic serious infections, tuberculosis 
(TB), malignancies, non-SLE related vasculitis, 
anaphylaxis, and major adverse cardiovascular events 
(MACE); laboratory variables; physical 
examinations; vital signs; and ECG 
To characterize the immunogenicity of 
anifrolumab when administered SC for a 52 
Week treatment period  
Anti-drug antibodies (ADA) 
 
 
2.3
Safety objectives 
Safety Objective: 
Outcome Measure : 
See above.  
 


Clinical Study Protocol 
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2.4
Exploratory objectives 
Exploratory Objective: 
Outcome Measure : 
To characterize the efficacy of SC 
administered anifrolumab on SLE skin 
manifestations as measured by the change in 
Cutaneous Lupus erythematosus disease Area 
and Severity Index (CLASI) score from 
baseline 
Proportion of subjects achieving 50% improvement 
in CLASI activity score from baseline to Week 12 
and Week 52 
 
To explore the effects of SC administered 
anifrolumab on type I IFN and other pathway-
related gene expression in skin tissue (optional 
part of study) 
21-gene type 1 IFN and other pathway-related gene 
expression in skin tissue at baseline and at Week 12 
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
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 
1.
In the opinion of the investigator, the subject must be able to understand the 
informed consent form (ICF), and all protocol-related assessments 
2.
Written informed consent and any locally required authorisation (e.g., Health 
Insurance Portability and Accountability Act [HIPAA] in the US, Data Privacy 
Directive in the European Union [EU]) obtained from the subject prior to 
performing any protocol-related procedures, including screening evaluations 
3.
Completion of all screening procedures within 30 days of signing the ICF 
4.
Aged 18 through 70 years at the time of screening 
5.
Diagnosis of paediatric or adult SLE for  24 weeks prior to signing the ICF and 
fulfilling at least 4 of the 11 ACR classification criteria for SLE with at least one of 
which  being:  
x
Positive antinuclear antibody (ANA) test at screening by 
immunofluorescent assay (IFA) at the central laboratory with titer 1:40; 
or 
x
anti-dsDNA antibodies at screening elevated to above normal (i.e., 
indeterminate or positive results) as per central laboratory or 


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x
anti-Smith (anti-Sm) antibodies at screening elevated to above normal 
(i.e., positive or equivocal results), as per central laboratory 
Clinical criteria may have been present by history if documented in the medical record. 
Historical laboratory values can be counted for SLE criteria but at least one of the values 
specified above must be met during screening for eligibility. 
6.
Weight 40.0 kg at screening 
7.
Type I IFN test-high result 
8.
Having a CLASI activity score   10 at screening 
9.
Currently receiving at least 1 of the following for treatment of SLE*: 
x
A dose of oral prednisone or equivalent of 40 mg/day for a minimum of 
2 weeks prior to signing the ICF.  The dose of oral prednisone or 
equivalent must be stable for a minimum of 2 weeks prior to 
randomization at Day 1 
x
Any of the following medications administered for a minimum of 12 
weeks prior to signing the ICF, and at a stable dose for a minimum of 8 
weeks prior to randomization at Day 1: 
(i) Azathioprine 200 mg/day 
(ii) Antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine) 
(iii) Mycophenolate mofetil 2 g/day or mycophenolic acid 1.44 g/day 
(iv) Oral, subcutaneous (SC), or intramuscular methotrexate 25 mg/week 
(v) Mizoribine 150 mg/day 
* If receiving oral prednisone (or equivalent) combined with another agent listed above, the 
dose duration for both must be met. If subject´s immunosuppressive treatment consists of oral 
prednisone or other oral corticosteroid alone the minimal dose must be 7.5 mg/day or 
equivalent. 
10.
Negative serum ȕ-human chorionic gonadotropin (ȕ-hCG) test at screening (females 
of childbearing potential only) 
11.
Females of childbearing potential must use effective methods (Table 1) of avoiding 
pregnancy, only one of which is a barrier method and the other is a highly effective 
intrauterine device or hormonal method described in Table 1 below, from Screening 
until 12 weeks after the final dose of IP unless the subject is surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy), has a 


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sterile male partner, is 1 year post-menopausal, or practices sustained abstinence. 
Cessation of birth control after the specified period for IP should be discussed with 
a responsible physician. 
x
Sustained abstinence is an acceptable practice; however, periodic 
abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. 
x
Post-menopausal is defined as at least 1 year since last menses and the 
subject having an elevated follicle-stimulating hormone (FSH) level 
greater than the central laboratory value of post-menopausal at screening 
if  <55 years of age at the time of signing the ICF. 
Effective methods of birth control include those listed in Table 1. 
Table 1 
Highly effective intrauterine device and hormonal methods and 
effective barrier methods of birth control (2 methods are required, one 
being a barrier method and one being a intrauterine device/hormonal 
method) 
Contraceptive methods 
Barrier Methods 
(choose only one) 
Intrauterine Device/Hormonal Methods 
(choose only one) 
 
Intrauterine Device 
Methods 
 Hormonal Methods 
Male condom 
(with spermicide*) 
Progesterone T  
Contraceptive implants 
Cap (with spermicide cream or 
jelly*) 
Copper T 
Hormone shot or injection 
Diaphragm (with spermicide 
cream or jelly*) 
 
Combined pill (progesterone and 
estrogen) 
 
 
Minipill (progesterone only) 
 
 
Contraceptive patch 
*where commercially available 
 
12.
All males (sterilised or non-sterilised) who are sexually active must use condom 
(with spermicide where commercially available for contraception if sexually active 
with a woman of child bearing potential) from Day 1 until at least 12 weeks after 
receipt of the final dose of IP.  It is strongly recommended that  female partners of 
child bearing potential of  male subjects also use a highly effective method of 
contraception from Table 1 (other than a barrier method) throughout this period. 


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13.
Male subjects must not donate sperm during the course of the study and for 12 
weeks after the last dose of the IP. 
14.
Females with an intact cervix must have documentation of a normal Pap smear with 
no documented malignancy (e.g., cervical intraepithelial neoplasia grade III [CIN 
III], carcinoma in situ [CIS], or adenocarcinoma in situ [AIS]) within 2 years prior 
to randomization. (See Appendix J for guidance on abnormal Pap smear results). 
Any abnormal Pap smear result documented within 2 years prior to randomization 
must be repeated to confirm patient eligibility.  
15.
Meets all the following TB criteria: 
(a) No history of latent or active TB prior to screening, with the exception of latent TB with 
documented completion of appropriate treatment or currently receiving prophylactic treatment 
for latent TB and the subject commits to completing the full duration of prophylaxis 
(b) No signs or symptoms suggestive of active TB from medical history or physical 
examination 
(c) No recent close contact with a person with active TB or if there has been such contact, 
referral to a physician specialising in TB to undergo additional evaluation prior to 
randomization (documented appropriately in source), and, if warranted, receipt of appropriate 
treatment for latent TB at or before the first administration of IP 
(d) Meet one of the following criteria: 
x
Negative QuantiFERON-TB Gold [QFT-G] test result for TB obtained from 
central laboratory within 30 days prior to randomization or 
x
Positive QFT-G test result for TB obtained during the screening period from 
central laboratory for which active TB has been ruled out and appropriate 
treatment for latent TB has been initiated prior to the first IP administration and 
the subject commits to completing the full duration of prophylaxis, which may 
mean completing prophylaxis during the study or 
x
Indeterminate (confirmed as indeterminate on retest during screening) QFT-G 
test for TB obtained during the screening period from central laboratory with 
ongoing QFT-G testing for TB to the Study Plan (Table 2) 
x
A chest radiograph with no evidence of current active TB or other infection, or 
old active TB, malignancy, or clinically significant abnormalities (unless due to 
SLE) obtained during the screening period or anytime within 12 weeks prior to 
signing of the ICF 
3.2
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled. 


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3.2.1
General exclusion criteria 
1.
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of the IP or interpretation of subject safety or study results. 
2.
Concurrent enrolment in another clinical study with an IP. 
3.
Individuals involved with the conduct of the study, their employees, or immediate 
family members of such individuals. 
4.
Lactating or pregnant females or females who intend to become pregnant anytime 
from initiation of Screening until the 12-week safety follow-up period following 
last dose of IP.  If serum or urine ȕ-hCG is positive at randomization the subject 
must be excluded. 
5.
Current alcohol, drug or chemical abuse, or a history of such abuse within 1 year 
prior to randomization. 
6.
Major surgery within 8 weeks prior to signing the ICF or elective major surgery 
planned during the study period. 
7.
Spontaneous or induced abortion, still or live birth, or pregnancy 4 weeks prior to 
signing the ICF. 
8.
At Screening (within 4 weeks before Week 0 [Day 1]), any of the following: 
x
Aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN) 
x
Alanine aminotransferase (ALT) >2.0 × ULN 
x
Total bilirubin >ULN (unless due to Gilbert's syndrome) 
x
Serum creatinine >2.0 mg/dL (or >181 ȝmol/L) 
x
Urine protein/creatinine ratio >2.0 mg/mg (or >226.30 mg/mmol) 
x
Neutrophil count <1000/ȝL (or <1.0 × 109/L) 
x
Platelet count <25000/ȝL (or <25 × 109/L) 
x
Haemoglobin <8 g/dL (or <80 g/L), or <7 g/dL (or <70 g/L) if related to 
subject's SLE such as in active haemolytic anaemia 
x
Glycosylated haemoglobin (HbA1c) >8% (or >0.08) at screening 
(diabetes subjects only) 


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Note: Abnormal screening laboratory tests may be repeated once on a separate sample before 
subject is declared a screen failure. 
3.2.2
Exclusion criteria related to concomitant medications 
9.
Receipt of any IP (small molecule or biologic agent) within 4 weeks or 5 half-lives 
prior to signing of the ICF, whichever is greater. 
10.
Prior receipt of anifrolumab 
11.
Receipt of any commercially available biologic agent (as indicated in Section 7.8) 
within 5 half-lives prior to randomization 
12.
Receipt of B cell-depleting therapy (including but not limited to ocrelizumab, 
ofatumumab, obinutuzumab, or rituximab) 26 weeks prior to signing the ICF.  If 
B-cell depleting therapy was administered >26 weeks ago an absolute B cell count 
(CD19+ cells determined during screening by the central laboratory) less than the 
lower limit of normal or baseline value prior to receipt of B cell-depleting therapy 
(whichever is lower) will be exclusionary prior to signing the ICF. 
13.
Receipt of epratuzumab, belimumab, or tabalumab 12 weeks prior to signing the 
ICF or atacicept 40 weeks prior to signing the ICF 
14.
A known history of allergy or reaction to any component of the IP formulation or 
history of anaphylaxis to any human gamma globulin therapy 
15.
Receipt of any of the following: 
x
Intra-articular, intramuscular or IV glucocorticosteroids within 2 weeks 
prior to signing the ICF. 
x
Any live or attenuated vaccine within 8 weeks prior to signing the ICF 
(administration of killed vaccines is acceptable, the Sponsor recommends 
Investigators ensure all subjects are up to date on required vaccinations, 
including influenza [inactivated/recombinant] vaccine prior to study 
entry); 
x
Bacillus Calmette-Guerin (BCG) vaccine within 1 year of signing the 
ICF; 
x
Any prohibited medication listed in Section 7.8, if the washout period is 
not met; 
x
Blood transfusion within 4 weeks prior to signing the ICF 


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3.2.3
Exclusion criteria related to systemic lupus erythematosus and other diseases  
16.
History of, or current diagnosis of, a clinically significant non SLE-related vasculitis 
syndrome.  Vasculitis due to SLE is allowed in the study; 
17.
History or evidence of suicidal ideation (severity of 4 [active: method and intent, but 
no plan] or 5 [active: method, intent, and plan]) within the past 6 months; or any 
suicidal behaviour within the past 12 months based on an assessment with the C-
SSRS at screening or at baseline;  
18.
Active severe or unstable neuropsychiatric SLE including, but not limited to: 
aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes 
(ascending, transverse, acute inflammatory demyelinating polyradiculopathy); 
acute confusional state; impaired level of consciousness; psychosis; acute stroke or 
stroke syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; and 
mononeuritis multiplex:  
x
That would make the subject unable to fully understand the ICF OR  
x
Where, in the opinion of the Principal Investigator (PI), protocolspecified  
SOC is insufficient and utilisation of a more aggressivetherapeutic 
approach, such as adding IV cyclophosphamide and/or high dose IV 
pulse corticosteroid therapy or other treatments not permitted in the 
protocol, is indicated; 
19.
Active severe SLE-driven renal disease where, in the opinion of the investigator, 
protocol specified SOC is insufficient and utilisation of a more aggressive 
therapeutic approach, such as adding IV cyclophosphamide and/or high dose IV 
pulse corticosteroid therapy or other treatments not permitted in the protocol, is 
indicated 
20.
History of or current diagnosis of catastrophic or severe anti-phospholipid syndrome 
within 1 year prior to signing the ICF. Antiphospholipid syndrome adequately 
controlled by anticoagulant therapy for at least 3 months is acceptable 
21.
History of, or current, inflammatory joint or skin disease other than SLE that, in the 
opinion of the Investigator, could interfere with the inflammatory arthritis or skin 
assessments and confound the disease activity assessment 
22.
History of any non-SLE disease that has required treatment with oral or parenteral 
corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to 
signing the ICF 


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3.2.4
Exclusion criteria related to infection and malignancy risk factors  
23.
Known history of a primary immunodeficiency (e.g., common variable 
immunodeficiency syndrome), splenectomy, or any underlying condition that 
predisposes the subject to infection 
24.
Opportunistic infection requiring hospitalisation or parenteral antimicrobial 
treatment within 3 years of randomization 
25.
Any of the following: 
- Clinically significant chronic infection (i.e., osteomyelitis, 
bronchiectasis, etc.) within 8 weeks prior to randomization (chronic nail 
infections  not causing open skin lesions are allowed) 
- Any infection requiring hospitalisation or treatment with IV anti-
infectives not completed at least 4 weeks prior to randomization  
- Any infection requiring IV or oral anti-infectives (including antivirals) 
within 2 weeks prior to randomization 
26.
Confirmed positive HIV test at screening 
27.
Confirmed positive test for hepatitis B serology for 
- Hepatitis B surface antigen, or 
- Hepatitis B core antibody (HBcAb) and hepatitis B virus (HBV) DNA 
with a quantifiable level detected by reflex testing by the central 
laboratory at screening. 
Note: Subjects with HBcAb positivity at screening will be tested every 3 months for HBV 
DNA. To remain eligible in the study, subject HBV DNA levels must remain below the lower 
level of quantitation (LLOQ) as per the central laboratory. 
28.
Positive test for hepatitis C antibody as confirmed by central laboratory 
29.
Any severe herpes zoster infection at any time prior to randomization, including, 
but not limited to, disseminated herpes (ever), herpes encephalitis (ever), recurrent 
herpes zoster (defined as 2 episodes within 2 years) or ophthalmic herpes (ever) 
30.
Any herpes zoster infection that has not completely resolved within 12 weeks prior 
to signing the ICF; 
31.
History of cancer, apart from:  
- Squamous or basal cell carcinoma of the skin treated with documented 
success of curative therapy 3 months prior to randomization 


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- Cervical cancer in situ treated with apparent success with curative 
therapy 1 year prior to randomization 
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4. 
3.3
Subject enrolment and randomization 
If a subject does not meet eligibility criteria on the basis of a laboratory value at screening, 
then the laboratory parameter may be repeated once within the screening period; this will be 
considered as re-testing and re-screening is not required.  Please refer Section 4.1.1 for details 
on re-screening and re-testing. 
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.  The subject is considered enrolled when the ICF is 
signed and the enrolment call is done in the interactive voice/web response system 
(IXRS). 
2.
Assign potential subject a unique enrolment number, beginning with 
. 
3.
Determine subject eligibility.  See Section 3. 
4.
At randomization the IXRS will assign eligible subjects to one of the four treatment 
groups, and assign eligible subjects a unique randomization code and blinded IP kit 
number(s) to the subject.  
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. 
Randomization codes will be assigned strictly sequentially as subjects become eligible for 
randomization. 
IP (anifrolumab or placebo) should, if possible, be administered the same day the IP kit 
number is assigned.  
3.4
Procedures for handling incorrectly enrolled or randomized 
subjects 
Subjects who fail to meet the eligibility criteria, other than laboratory parameter as described 
in section 3.2, should not, under any circumstances, be enrolled or receive IP.  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 randomized or initiated on treatment, and must be 
withdrawn from the study.


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Where a subject does not meet all the eligibility criteria but is randomized 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 patient from 
treatment.  The AstraZeneca study physician must ensure all decisions are appropriately 
documented. 
3.5
Methods for assigning treatment groups 
Block randomization using an IXRS will be used to randomize subjects and the AstraZeneca 
Biometrics and Information Sciences group is responsible for generating the randomization 
scheme for this study using the AZRand. 
All 32 subjects will be randomized to one of the four treatment groups in a 3:1:3:1 ratio 
receiving:  
x
anifrolumab at a fixed dose of 150mg as added to SOC, given Q2W as 
one SC injection in a volume of 1mL (12 subjects);  
x
placebo as added to  SOC, given Q2W as one SC injection in a volume of 
1mL  (4 subjects);  
x
anifrolumab at a fixed dose of 300mg as added to SOC, given Q2W as 
two SC injections in a volume of 1mL each (12 subjects) or  
x
placebo as added to SOC, given Q2W as two SC injections in a volume 
of 1mL each (4 subjects). 
3.6
Methods for ensuring blinding 
This is a double-blind study in which anifrolumab and placebo are distinguishable during 
preparation of the suspension for injection by syringe.  Given that the treatments will be given 
as one or two SC injections depending on dose level, the study is double-blinded with respect 
to anifrolumab or placebo, but not to dose level.  The double-blind period will last up until 
analyses of primary endpoints at Week 12.  Thereafter investigators and subjects will remain 
blinded throughout the remainder of the study.  All packaging and labelling of IP is done in 
such way as to ensure blinding for all Sponsor and investigational site staff other than the 
unblinded person responsible for final preparation steps and for injections of IP and placebo. 
The kits on the shelf look identical.  Preparation of IP and placebo and injections must be 
done by an unblinded, qualified person (e.g., pharmacist or nurse) who is otherwise not 
involved in the study. 
Neither the subject nor any of the Investigator or Sponsor staff/designee who are involved in 
the treatment or clinical evaluation and monitoring of the subjects will be aware of if the 
subjects has received anifrolumab or placebo.  In the event that the treatment allocation for a 
subject becomes known to the Investigator or other study staff involved in the management of 
study subjects, the Sponsor, or designee must be notified immediately by the Investigator. 


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3.7
Methods for unblinding  
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the Investigator(s) or pharmacists from the IXRS.  Routines for 
this will be described in the IXRS 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 randomized treatment allocation.  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 IP 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. 
3.8
Restrictions 
3.8.1
Fasting lipid profile 
Subjects will be required to fast for at least 8 hours prior to assessment of lipid profile at the 
visits described in Study Plan (Table 2 and Table 3).  If the subject has not fasted, he/she 
should fast before the next visit, and the test can be done at that visit. 
3.8.2
Perioperative management of investigational product 
Planned surgeries should be avoided during the study if clinically feasible. 
Pre-operative management of investigational product:  
If a non-urgent major surgery becomes necessary during the study, it should be scheduled at 
least 4 weeks after the last administration of investigational product, if clinically feasible.  The 
determination of whether or not a surgery is “urgent” will be at the discretion of the 
investigator, preferably in consultation with the AstraZeneca study physician.  The decision to 
withhold investigational product administration is at the Investigator’s discretion.  
Post-operative management of investigational product:
Investigational product administration can be resumed at the Investigator’s discretion after all 
of the following criteria are met:
x
External wound healing is complete and 
x
Any post-operative antibiotic course is completed and 
x
All acute surgical complications have resolved 


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Blood donation 
Subjects must not donate blood from date of randomization until 12 weeks after the last dose 
of IP. 
3.9
Discontinuation of investigational product 
At any time, subjects are free to discontinue IP or withdraw from the study without prejudice 
to further treatment.  A subject that decides to discontinue IP will always be asked about the 
reason(s) and the presence of any adverse events.  Discontinuation of IP does not mean 
withdrawal from study participation.  
Subjects may be discontinued from IP in the following situations; 
1.
Subject decision.  The primary reason should be documented as one of the 
following: 
x
Subject is unable to comply with protocol-specified visits and/or 
procedures due to conflicts not related to clinical trial 
x
An AE or laboratory abnormality is of concern to the subject, but not 
clinically significant to physician 
x
The subject perceives the IP to be ineffective 
x
Subject wishes to participate in another clinical trial 
x
Subject is interested in taking a treatment that is not allowed in this study 
x
Subject perceives logistics at the clinical site to be unacceptable 
x
Other reason 
2.
Adverse event that, in the opinion of the Investigator or AstraZeneca Study 
physician contradicts further dosing with IP. 
3.
Severe non-compliance with the study protocol. 
4.
The Investigator or AstraZeneca Study Physician deems withdrawal as being in the 
subject's best interest. 
5.
Pregnancy, positive pregnancy test, or subject expresses an interest to become 
pregnant. 
6.
Isolated HBc positivity with HBV DNA above LLQ confirmed by the central 
laboratory. 
7.
Receipt of any medications identified in Section 7.8. 


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8.
The use of SOC medications listed in Section 7.7.1 in doses exceeding the maximal 
allowed doses, if the AstraZeneca study physician, determines the subject must be 
discontinued. 
9.
A diagnosis of active TB, premature discontinuation of treatment for latent TB, or 
noncompliance with latent TB therapy.  Note: Duration of treatment for latent TB 
should follow the local practice.  If local practice is not defined, then CDC guidance 
for immunocompromised patients should be used. 
10.
Subjects who develop worsening of SLE as described in Section 3.9.1.  
11.
IP is unblinded by the Investigator. 
If a subject is withdrawn from study, see Section 3.10 for details. 
3.9.1
Discontinuation of investigational product due to worsening of SLE 
IP will be discontinued at any time during the study in subjects who develop active severe 
SLE disease manifestations that in the opinion of the Investigator, require treatment with 
cyclophosphamide, high dose corticosteroids, plasmapheresis, or intravenous 
immunoglobulins (IVIG) or other treatments not permitted in the protocol. 
3.9.2
Procedures for discontinuation of a subject from investigational product  
In order to support safety analysis (see Section 8) for anifrolumab subjects who are 
discontinued from the IP should continue to undergo study visits 4, 6, 8, 10, 12, 14, 16, 18, 20, 
22, 24, 26, and 28 (as applicable).  All visit-related procedures except those associated with IP 
administration should be completed, (Table 3).  Protocol-specified OCS tapering will not be 
required for these subjects.  All subjects should complete an observation period of at least 10 
weeks after the last IP received.  In case this does not occur within the time frame of the visits 
specified above, a follow-up visit might be required.  The approach taken and reason for 
premature discontinuation of IP should be registered in the CRF.  If the subject permanently 
discontinues IP prior to their completion of the study and wishes to continue with only 
selected study assessments; prioritised assessments are listed in Section 3.9.  For subjects who 
wish to withdraw from the study completely refer to Section 3.10.2.  
3.10
Criteria for withdrawal  
3.10.1
Screen failures  
Screening failures are subjects who have provided informed consent but who do not fulfil the 
eligibility criteria for the study, and therefore must not be randomized.  These subjects should 
have the reason for study withdrawal recorded as “Screen Failure” (i.e., subject does not meet 
the required eligibility criteria).  This reason for study withdrawal is only valid for screen 
failures (not randomized subjects).  For eligibility for re-screening of a subject refer to Section 
4.1.1.  Rescreening of a subject will be permitted once. 


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3.10.2
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.  A patient 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/randomization code cannot be reused.  
3.10.3
Lost to follow-up 
Subjects will be considered lost to follow-up only if no contact has been established, despite 
several attempts, by the time of study completion.” Lost to follow-up” as a reason for study 
withdrawal must be documented by time and date of last contact and time. 
3.11
Discontinuation of the study 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (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 anifrolumab.  The study may be stopped if, in the judgement of the 
Sponsor, study subjects are placed at undue risk because of clinically significant findings that: 
x
Meet individual stopping criteria (see Section 3.9 for reasons for 
discontinuation of investigational product) or are otherwise considered 
significant 
x
Are assessed as causally related to investigational product 
x
Are not considered to be consistent with continuation of the study 
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. 
4.
STUDY PLAN AND TIMING OF PROCEDURES  
Table 2, Table 3 and Table 4 below show the procedures for the Screening, Treatment, and 
Follow-up visits, respectively.  




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Visit 
 
V1  
Screening
Study Day  
Day -30 to Day -1 
Week / Procedure 
-4 to 0 
TB questionnaire 
X 
Colombia Suicidality Severity Rating Scale (C-SSRS) 
X 
Assessment of AEs/SAEs/AESIs 
X 
Verify eligibility criteria 
X 
aStandard 12-lead ECG 
bPA and lateral chest x-ray will be performed at screening, if not performed within the previous 12 weeks 
cThese assessment must all be completed at same visit (CLASI, SLEDAI-2K, PGA),  if applicable. 
dFemale subjects, unless surgically sterile or 1 year postmenopausal 
eFemales < 55 years of age suspected to be post menopausal. 
fOnly in females with an intact cervix who have not had a Pap smear the last 2 years prior to screening that 
metinclusion criteria 








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gSubjects who are HBcAb positive at screening will be tested every 3 months for HBV DNA. To remain eligible for the study, the subject’s HBV DNA 
levelsmust remain below the LLOQ as per the central laboratory 
hQuantiFERON-TB Gold test will be followed for those subjects with indeterminate levels at screening.




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dQuantiFERON-TB Gold test will be followed for those subjects with indeterminate levels at screening. 
 
4.1
Enrolment/screening period 
At screening, consenting subjects are assessed to ensure that they meet eligibility criteria. 
Once the subject signs the informed consent, they are considered enrolled in the study.  
Subjects who do not meet eligibility criteria must not be randomized in the study. 
Screening assessments will be performed accordingly to the Screening Visit Procedures 
(Table 2), from Day -30 to Day -1.  Screening procedures may take place during more than 1 
visit. 
Once screening assessments are complete and all necessary laboratory results are obtained, a 
subject may be randomized.  The randomization at Week 0 (Day 1) may occur at any time 
point within 30 days after screening visit provided that all required assessment results are 
available. 
Chest x-rays and Pap smears may be completed anytime during the screening period as long 
as all results have been reviewed by the Investigator prior to randomization.  
4.1.1
Re-testing and re-screening 
Re-testing 
If a subject does not meet the eligibility criteria on the basis of a laboratory value for liver 
enzymes, haematological, or disease activity related tests the laboratory parameter may be 
repeated once within the screening period.  This re-testing is allowed without requirement for 
re-screening.  
Re-screening 
Subjects who fail to meet the inclusion/exclusion criteria (i.e., screening failures) may be 
eligible to be re-screened once and AstraZeneca Study Physician can be contacted for 
discussion and decision regarding re-screening.  Subjects who are re-screened will be required 
to re-consent and complete/ repeat all applicable study procedures.   
4.1.2
Other considerations for screening  
4.1.2.1
Medical history 
A complete medical history by body system will be completed during screening.  This will 
also include history of allergies and anaphylaxis, concomitant diseases, viral reactivation 
events, and previous manifestations of SLE.  On Day 1, the medical history will be reviewed 
and any changes since screening will be documented, if applicable. 
4.1.2.2
SLE medication history 
All prescription medications the subject has ever taken for SLE should be documented in the 
subject's file (except for only minor dose adjustments if these were done ޓ3 months prior to 


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the ICF signature date), including prior use of cyclophosphamide, mycophenolate mofetil, 
mycophenolic acid, oral and parenteral corticosteroids; if these were discontinued, then 
reasons for discontinuation must be included.  Any medications ongoing at the time of 
informed consent or received following signing the ICF are considered concomitant 
medications.  Any non-prescription medications, e.g., naturopathic or ayurvedic remedies, 
ever used for SLE or for any other purpose should be documented, as well as continuing use 
of any non-prescription remedies not excluded from use during the study period. 
4.1.2.3
Oral examination 
In several biological programs there have been serious infections and/or death related to 
Ludwig’s angina.  Although this has not been seen in the anifrolumab program, Investigators 
should check a subject’s oral cavity and review their dental health carefully during the 
screening process.  While a dental examination is not required prior to enrolment in this study, 
Investigators are cautioned to consider carefully whether subjects have active caries or a 
dental infection that might impact on subject safety prior to enrolment.  
4.1.2.4
Mammography 
As subjects with SLE have impaired immune response, are treated with immunosuppressants, 
and are at potential risk for malignancy, it is recommended that patients enrolled into the 
study are compliant and up to date with local recommendations for mammography or other 
screening procedures for breast cancer.  
4.2
Treatment period 
Assessments during the Treatment Period will be performed according to the Schedule of 
Treatment Visit procedures (Table 3), from Week 0 (Day 1) to Week 52.   
On Day 1, upon confirmation that the subject continues to meet eligibility criteria, the subject 
will be randomized in to the study via the IXRS system. 
Subjects will have scheduled visits at 2-week intervals to complete protocol-specified 
assessments and IP administration according to the Schedule of Treatment Visit Procedures 
(Table 3). 
The last dose of IP will be administered on Week 50. At Week 52, subjects will have End of 
Treatment (EOT) visit.  For subjects who prematurely discontinue IP and are not willing to 
continue to participate in the study refer to Section 3.9. 
4.2.1
Patient survey at week 12 
After subjects complete all the assessments/procedures required at week 12, subjects will be 
asked to complete patient survey for trial experience.  See Appendix O.  For subjects who are 
premature discontinued, the patient survey will be completed at the early discontinuation visit.  


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4.2.2
Follow-up visits after premature discontinuation of investigational product 
Subjects who discontinue IP should continue to undergo study visits 4, 6, 8, 10, 12, 14, 16, 18, 
20, 22, 24, 26, and 28 (as applicable).  If the subject is unwilling to complete all regularly 
scheduled clinic visits, the subject should complete the Early Discontinuation Visit (Week 52 
procedures) within 2 weeks of the last dose of IP, as well as Follow-up Visits (Week 56 and 
Week 60 procedures) unless consent is withdrawn.  If the subject is unwilling to continue with 
any study visits, including EOT, at the minimum, the following assessment should be 
completed:  
x
PK/PD blood sample 
x
CLASI 
x
SLEDAI-2K 
x
PGA 
In addition the following safety assessments must be performed: 
x
C-SSRS 
x
Assessment of AEs/SAEs (including AESIs) 
x
Concomitant medications 
x
Targeted physical exam 
x
Vital Signs (BP, HR, RR and body temperature) 
x
Weight  
x
Safety lab tests 
x
ADA test 
x
TB questionnaire 
4.3
Follow-up period 
All subjects will be followed for 10 weeks after the last IP dose.  Table 4 shows all procedures 
to be conducted during the follow-up period.  
4.4
Unscheduled visits 
If a subject needs an unscheduled visit the Investigator should decide the assessments needed 
to be completed based on the reason for the visit and for subject´s safety.  Concomitant 


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medications and AEs should be collected at all unscheduled visits.  Efficacy assessments 
should not be completed at unscheduled visit. 
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 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. 
5.1
Efficacy assessments 
Efficacy measurements will be made at the times indicated in the Study Plan (Table 2, Table 3 
and Table 4).  
5.1.1
Training and certification for Systemic Lupus Erythematosus assessments 
In order to maintain consistent evaluation of SLE disease activity across study sites, training 
and certification of Investigator and designated site physicians who will be completing the 
disease evaluation listed below will be conducted.  
x
CLASI 
x
SLEDAI-2K 
x
PGA  
The CLASI, SLEDAI-2K, PGA must be administered by the Investigator or another qualified 
physician, unless prior sponsor approval has been obtained for any other clinically trained site 
personnel with documentation of adequate assessment experience and training.  Training will 
include printed training materials, digital video disks (DVDs) and formal presentations, web-
based training modules, as well as training sessions during investigator’s meeting if 
applicable.   
After attending study presentations (i.e., Investigator Meeting) or after completion of online 
training module, all Investigators and designed site physicians must pass an online 
examination in order to obtain certification for all disease evaluation assessments.  
Investigators and designated site personnel must be trained and certified prior to subjects 
entering screening at their respective sites.  If there is a change in site personnel over the 
course of the study, new Investigators or physicians must be certified prior to perform the 
CLASI, SLEDAI-2K and PGA assessments.  


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Documentation of all training will be maintained in the site’s study file.  
Over the course of the study, Investigator assessments for a given subject should be completed 
by the same trained and/or certified Investigator, designated physician, or qualified site 
personnel (as described above) whenever possible.  
5.1.2
Cutaneous Lupus Erythematosus Disease Area and Severity Index  
The CLASI is a validated index used for assessing the cutaneous lesions of SLE and consists 
of 2 separate scores: the first summarises the inflammatory activity of the disease; the second 
is a measure of the damage done by the disease (see Appendix F).  The activity score takes 
into account erythema, scale/hypertrophy, mucous membrane lesions, recent hair loss and 
non-scarring alopecia.  The damage score represents dyspigmentation, 
scarring/atrophy/panniculitis, and scarring of the scalp.  Subjects are asked if their 
dyspigmentation lasted 12 months or longer, in which case the dyspigmentation score is 
doubled.  Each of the above parameters is measured in 13 different anatomical locations, 
included specifically because they are most often involved in cutaneous lupus erythematosus 
(CLE).  The most severe lesion is each area is measured.  
5.1.3
Systemic Lupus Erythematosus Disease Activity Index 2000 
The SLEDAI-2K disease activity index (See Appendix E) consists of a list of organ 
manifestations, each with a definition.  A certified Investigator or designated physician will 
complete the SLEDAI-2K assessments and decide whether each manifestation is “present” or 
“absent” in the last 2 weeks.  The assessment also include the collection of blood and urine for 
assessment of the laboratory categories of the SLEDAI-2K.  
The SLEDAI-2K assessment consists of 24 lupus-related items.  It is a weighted instrument, 
in which descriptors are multiplied by a particular organ’s “weight”.  For example, renal 
descriptor are multiplied by 4 and central nervous descriptor by 8 and these weighted organ 
manifestations are totalled into the final score.  The SLEDAI-2K score range is 0 to 105 points 
with 0 indicating inactive disease.  The SLEDAI-2K score are valid, reliable and sensitive 
clinical assessments of lupus disease activity.  
5.1.4
Physician Global Assessment 
A trained and certified Investigator will complete the PGA (see Appendix G).  The PGA 
represents the physician’s overall assessment of average SLE disease severity on a VAS scale 
with 0 (no disease) to 3 (severe) disease activity.  The PGA for a given subject should be 
completed by the same physician whenever possible.  
The PGA is a modification of the classic analogue scale in that it is anchored with numbers 
from 0 to 3 demarcating no, mild, moderate and severe disease.  The number 3 indicates 
severe disease and is at the end of the scale.  This refers to the most severe possible disease, 
and does not reflect the most severe seen in a particular subject, but the most severe disease 
ever seen in all SLE subjects.  Therefore, the line made by the physician along this scale 
should virtually never get to this edge.  Any disease rated greater than 2.5 is very severe.  The 


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range of moderate disease covers approximately 1.5 to 2.4. Mild disease falls below 1.5.  The 
instrument is similar to a logarithmic scale, with greater distances or demarcations possible 
among more mild-moderate symptoms.  
When scoring the PGA, the score from the previous visit should be reviewed and the mark 
should be moved relative to the score from the previous visit.  This is global assessment, 
factoring in all aspects of subject’s lupus disease activity.  It should not reflect non-lupus 
medical conditions.  
5.1.5
Oral corticosteroid tapering 
Please refer to Section 7.7.2 for all information regarding steroid tapering.  
5.2
Safety assessments 
5.2.1
Clinical Laboratory assessments 
All clinical laboratory tests will be performed in a central clinical laboratory at the times 
indicated in the Study Plan (Table 2, Table 3 and Table 4).  
A serum pregnancy test (or serum FSH in postmenopausal females of age < 55 years with 
menses absent for  1 year) will be performed at screening at the central laboratory.  Urine 
pregnancy tests will be performed at the site using a dipstick.  
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.   
Every attempt should be made to redraw any missing safety laboratory tests, even if the 
subject has received the investigational product.  
The following laboratory variables will be measured: 
Table 5
Clinical Laboratory Variables 
Haematology (whole blood) 
Clinical Chemistry (serum) 
B-Haemoglobin (Hb) 
Calcium 
B-Leukocyte count 
Chloride 
B-Leukocyte differential count (absolute count) 
Potassium 
B-Platelet count 
Sodium 
B-Haematocrit 
AST* 
B-MCV, MCH, MCHC 
ALT* 
B cell count (only if prior B cell-depleting 
treatment) 
ALP* 
Urinalysis  
GGT 


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Colour 
BUN 
Appearance 
Creatinine 
Specific gravity 
Total bilirubin* (reflexively fractionated if 
elevated) 
pH 
Glucose 
Protein dipstick 
Albumin 
Glucose 
CK 
Ketones 
Fasting lipid profile: 
Blood 
Total Cholesterol 
Bilirubin 
High density lipoprotein (HDL) 
Microscopy including WBC/HPF, RBC/HPF, 
casts 
Low density lipoprotein (LDL)
Urine creatinine and protein, Urine 
protein/creatinine ratio 
Triglycerides 
Inflammatory marker panel  
Infection related test  
ESR, IgM, IgG, IgA 
Human immunodeficiency virus (HIV)  
 
Hepatitis B surface antigen (HbsAg) 
SLEDAI-2K lab tests 
Hepatitis B core antibody (HbcAb) (reflex DNA 
testing if isolated HBc positive) 
C3, C4, CH50, anti-dsDNA, Urine 
protein/creatinine ratio, 
Hepatitis C antibody 
Autoantibody Panel 
Coagulation test 
ANA, anti-dsDNA, anti-Smith, anti-ribonuclear 
protein 
Prothrombin time (PT) 
 
Partial Thromboplastin time (PTT) 
Pregnancy  
Other 
Serum ȕ-HCG pregnancy test 
Type I IFN 4-gee test  
Serum FSH 
Hemoglobin A1c (only diabetics) 
Urine pregnancy test 
QuantiFERON-TB Gold test 
*Note for serum chemistry: Tests for AST, ALT, ALP, and total bilirubin must be conducted 
concurrently and assessed concurrently. 
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. 


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NB. In case a subject shows an AST or ALT 3xULN or total bilirubin  2xULN please refer 
to Appendix C ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
5.2.1.1
Haematology, clinical chemistry, and urinalysis testing 
Haematology, chemistry, and urinalysis, will be taken throughout the study as described in 
Sections 4.1, 4.2 and 4.3.  Table 5 provides a complete list of the tests included in the Safety 
Laboratory Variables.  
5.2.1.2
Coagulation Testing 
Prothrombin time (PT) and partial thromboplastin time (PTT) will be performed as part of the 
screening tests. 
5.2.1.3
Infectious Disease Panel 
All subjects will be required to undergo infectious disease testing as part of the screening 
assessments.  The Infectious Disease panel includes testing for human immunodeficiency 
virus, Hepatitis B and C virus. 
Subjects with a confirmed positive HIV test, Hepatitis B surface antigen, or Hepatitis C 
antibody will not be eligible to participate.  
Subjects with an isolated positive test for Hepatitis B core antibody at enrolment/screening, 
will be tested for Hepatitis B DNA at the central laboratory.  Subjects with HBV DNA test 
above LLQ the will not be eligible to participate and subjects with undetectable HBV DNA, 
defined as below the LLQ, will be eligible to participate and must be tested every 3 months 
for HBV DNA.  If, at any time during the Active Treatment period, HBV DNA is detected, 
the subject must be discontinued according to Section 3.9.2. 
5.2.1.4
Fasting lipid profile 
Subjects will have a fasting lipid profile (total cholesterol, high density lipoprotein 
cholesterol, low density lipoprotein cholesterol, and triglycerides) completed at times 
indicated in Table 2 and Table 3.  Subjects will be required to fast for at least 8 hours prior to 
this assessment (see Section 3.8.1). 
5.2.1.5
Tuberculosis Testing 
Subjects will be tested for TB at screening and at various additional time points throughout the 
study, if required.  Please refer to Section 5.2.6.2 for details of TB screening and monitoring. 
5.2.1.6
Pregnancy Testing 
Females of child-bearing potential will be required to have a negative serum ȕ-hCG test 
during the enrolment/screening period; please refer to Section 4.1  A negative urine dipstick 
pregnancy testing is required prior to administration of IP and pregnancy testing is also 
required at follow-up visits; please refer to Sections 4.2 and 4.3. 


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Follicle-stimulating hormone (FSH) testing is required at screening for all post-menopausal 
female subjects of an age of < 55 years, defined as at least 12 months since last menses.  FSH 
level must be greater than the central laboratory value of post-menopausal.  If the FSH level is 
not above the central laboratory value of post-menopausal, two effective methods of 
contraception (see Table 1) must be used. 
5.2.2
Physical examination 
Complete physical examination 
A complete physical examination will be performed at the visits specified in Table 2, Table 3, 
and Table 4.  The examination includes assessments of;  general appearance, respiratory, 
cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph 
nodes, thyroid, abdomen, musculo-skeletal (including spine and extremities) and neurological 
systems. 
Targeted physical examination 
A targeted physical examination will include an assessment of the organ systems required to 
complete protocol-specified assessment tools (SLEDAI-2K and CLASI).  Additional 
assessment should be done as clinically indicated.  Abnormal findings will be recorded as part 
of AE, SAE, AESI, or SLE activity, as appropriate.  
5.2.3
ECG 
Standard 12-lead ECGs will be performed on all patients at specific time points as described 
in the Study Plan (Table 2, Table 3, and Table 4), as to local routines.  A single ECG will be 
taken after the patient has been resting for 5 minutes in the supine position.  Clinically 
significant abnormalities according to the Investigators´ discretion registered after screening 
visit should be reported as AEs.  
5.2.4
Vital signs 
Vital signs (body temperature, blood pressure [BP], pulse rate and respiratory rate) will be 
obtained at each visit and before and after IP administration as described in Section 7.2.2. 
7.2.2 
5.2.5
Assessment of Injection Sites 
Injection sites will be visually inspected before (except at Day 1) and after IP administration at 
every visit from Week 0 through Week 50.  
5.2.6
Other safety assessments 
5.2.6.1
Chest x-ray 
A posterioranterior (or anteriorposterior) and lateral view chest x-ray will be obtained during 
the screening period or can be substituted with documentation of a previous chest x-ray 
performed anytime within 12 weeks of the expected date of randomization. A chest x-ray that 


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has no evidence of current active infection (e.g., TB) or old active TB, malignancy, or 
clinically significant abnormalities (unless due to SLE) is required to meet inclusion criteria. 
A formal radiologic report of the chest x-ray should be available at the site.  The report should 
allow the assessment of the following: 
x
No evidence of any active infection including TB 
x
No evidence of old active TB 
x
No evidence of malignancy 
x
No evidence of other clinically significant abnormalities unless felt 
secondary to SLE (these should be specified [e.g., pleural effusion]) 
5.2.6.2
Tuberculosis screening and monitoring 
Screening evaluation 
A blood test for TB will be done at screening using QFT-G.  This is an IFN gamma release 
assay (IGRAs) test.  Evaluation of all subjects by QFT-G test will be performed by the central 
clinical laboratory, and chest x-rays within 12 weeks prior to Week 0 (Day 1) will be 
completed.  Compared to culture confirmed TB, overall, 87.6% of patients have a positive 
QFT-G result (Cellestis, 2005).  The false negative rate in this setting appears to be over 12%. 
Further, the performance of the test in the setting of immunosuppressant drugs has not been 
evaluated.  Nor has it been evaluated in individuals with medical conditions other than, or in 
addition to, latent TB or TB disease.  The guide also states that “Medical treatments or 
conditions that impair immune functions can potentially reduce IFN-Ȗ responses and prevent 
detection of a specific response to the (secretory proteins) ESAT-6 and CFP-10 (the test 
stimulators)”.  Given the population to be enrolled in this study, false negative tests are 
possible, so a chest x-ray, both PA and lateral views, is a relevant and warranted technique 
(unless limited by local practice) for detecting active pulmonary disease and minimising 
potential risk to study subjects. 
Tuberculosis results from screening evaluations 
x
If the screening QFT-G test is negative and there is no known history of 
recent exposure to individuals with active TB, and chest radiograph 
shows no evidence of active TB, the subject may be randomized without 
prophylaxis. 
x
If the screening QFT-G test is newly positive (can be preceded by an 
indeterminate or negative result) and chest x-ray shows no evidence of 
active TB, and the subject has no symptoms or medical history consistent 
with active TB, treatment for latent TB must be initiated prior to the first 
investigational product administration and the subject must commit to 


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completing the full duration of prophylaxis, which may mean completing 
prophylaxis during the study. 
x
If the screening QFT-G test is positive at screening but the subject is not 
newly positive, the subject may be randomized if: 
- Previous or current active TB infection was ruled out and 
- The subject was previously diagnosed with latent TB and has 
documentation confirming completion of appropriate latent TB treatment 
or 
- The subject was previously diagnosed with latent TB and is currently 
receiving prophylactic treatment for latent TB and commits to completing 
the full duration of prophylaxis. 
x
If the screening QFT-G test is indeterminate, the test must be repeated at 
least once by the central laboratory as soon as possible.  The subject may 
be randomized if: 
- The QFT-G test result remains indeterminate or becomes negative and 
- There are no signs or symptoms of active TB and 
- There is no known recent close contact with anyone with active TB and 
- There is no history of latent TB (unless diagnosed with documentation 
of completion of appropriate treatment or active TB. 
Additionally, an expert specialising in TB may be consulted prior to randomization, if deemed 
necessary in the opinion of the Investigator, after discussion with AstraZeneca study 
physician.  If the subject is randomized, additional QFT-G testing will be performed according 
to Table 3 and Table 4. 
Tuberculosis monitoring during the study 
If, during the trial a subject who had an indeterminate TB result at screening is determined to 
have a: 
x
Positive QFT-G test result, the subject should be referred to a TB 
specialist.  If a TB specialist is not available, the local country guidelines 
should be followed for further diagnostic work up and anti-TB treatment 
regimens.  If no local guidelines exist for immunocompromised 
individuals, then CDC guidelines may be followed.  This should also be 
reported as an AESI. Once a latent TB is confirmed, treatment must be 
instituted immediately and no investigational product may be 
administered until treatment of latent TB has begun. 


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x
Negative QFT-G test result, then the subject does not need to continue 
TB testing outlined for subjects with indeterminate results at screening. 
x
Indeterminate QFT-G test result, the subject will continue in the study 
and TB testing will be performed as outlined for subjects with 
indeterminate results at screening. 
For subjects with negative QFT-G at baseline and no symptoms of active TB: 
x
Week 52 QFT-G negative: no further testing 
x
Week 52 QFT-G indeterminate: repeat at Week 56. If negative no further 
testing, however if indeterminate repeat again at Week 60. 
x
QFT-G positive at Week 52 or later. Confirm positive QFT-G on another 
blood sample.  If confirmed follow recommendations for positive QFT-G 
results during study.  If repeat test is indeterminate or negative follow 
recommendation for indeterminate results above.  Consider referral to TB 
specialist. 
Tuberculosis questionnaire 
To aid in the early detection of new or reactivated TB, a TB questionnaire will be used to 
evaluate subjects for signs and symptoms of TB prior to receiving investigational product.  If 
the evaluation raises suspicion that a subject may have new or reactivated TB, an immediate 
and thorough investigation should be undertaken including, where possible, consultation with 
experts specialising in TB. 
Investigators should be aware that TB in immunocompromised patients may present as 
disseminated disease or with extrapulmonary features and should be referred for appropriate 
treatment. 
5.2.6.3
Cervical cancer screening 
Most cases of cervical cancer appear to be related to infection with human papilloma virus 
(HPV), usually HPV types 16 and 18.  Because of the potential for viral reactivation due to 
blockade of the IFN pathway, cervical dysplasia is being assessed in this study, although to 
date there has been no signal in the anifrolumab studies.  A Pap smear is required at screening 
in women who have not had their cervix surgically removed.  If a Pap smear was preformed 
within 2 years prior to screening with no documented malignancy (e.g., CIN III, CIS, or AIS), 
it does not need to be repeated.  Subjects with abnormal Pap smear results of atypical 
squamous cells of undetermined significance (ASC-US), atypical squamous cells where high-
grade squamous intraepithelial lesion cannot be ruled out (ASC-H), atypical glandular cells 
(AGC), or CIN grades I and II (CIN I and II) will be allowed to enter the study (please see 
Appendix J for guidance).  The Pap smear will be repeated during the last 4 weeks of the 
study to ensure that there is no evidence of new cervical dysplasia.  Since the access to a Pap 
smear may vary by country, AstraZeneca recommends that local guidelines for obtaining Pap 


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smears in subjects who have received immunomodulators or immunosuppressive treatment be 
followed. 
If the Pap smear performed at Week 52 is not normal but shows no evidence of malignancy 
(e.g., CIN III, CIS, or AIS), it should be repeated as per the subject´s gynecologist´s 
recommendations.  If the subject´s gynaecologist has recommended a specified interval, the 
Pap smear should be obtained as recommended and the report provided in the source 
document.  
5.2.6.4
Colombia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a unique, simple, and short method of assessing both behaviour and ideation 
that tracks all suicidal events, and provides a summary of suicidality (Posner et al, 2007).  It 
assesses the lethality of attempts and other features of ideation (frequency, duration, 
controllability, reasons for ideation, and deterrents), all of which are significantly predictive of 
completed suicide.  The C-SSRS will be administered at study visits by a trained assessor and 
the procedure is described in the Study Reference Manual.  The assessor will record the 
clinical observation on the scale, which will be used as the source document.  If possible, the 
same individual should perform the assessment at each visit to reduce scoring variability.  In 
the event the primary assessor is not available, a designated back-up assessor who meets the 
same qualifications may perform the C-SSRS.  If a subject indicates having a rating of type 4 
or 5 suicidal ideation on the C-SSRS suicidal ideation scale at any time since the previous 
visit when the C-SSRS was administered or indicates having had any suicidal behaviour since 
the previous visit, the subject should be referred to a mental health professional immediately.  
If the C-SSRS is administered by an assessor other than the Investigator, it is recommended 
that the Investigator confirms suicidal ideation before making a referral to mental health 
services; however this should not delay the referral. 
5.3
Pharmacokinetics 
5.3.1
Collection of samples 
Blood samples for the determination of anifrolumab in serum will be taken at the times 
presented in the study plan (Table 3, Table 4).  A post-dose sample after should be collected 4 
days (Day 5 or  Day 6, 7, 8) after the first dose of investigational product administration to 
access anifrolumab concentration after dosing.  For all pharmacokinetic samples, it is very 
important that the date, time of anifrolumab administration, and the sample collection are 
recorded.  
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 anifrolumab concentration will be analysed using a validated 
bioanalytical method.  Placebo samples will be analysed.  Full details of the analytical method 
used will be described in the methods section of the pharmacokinetic subreport or study 
report. 


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5.3.3
Storage and destruction of pharmacokinetic samples 
Pharmacokinetic (PK) samples will be disposed of after the study report finalization or six 
months after issuance of the draft study report (whichever is earlier), unless requested for 
future analyses.   
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
5.4
Immunogenicity 
Instructions for immunogenicity (antidrug antibody [ADA] and neutralising antibodies [nAb]) 
sample collection, processing, storage, and shipment can be found in the separate laboratory 
manual provided to the study centers. 
5.4.1
Anti-drug antibodies 
The pre-dose and follow-up serum samples to measure presence of ADA will be collected 
according to the Study Plan (Table 3, Table 4).  The presence or absence of ADA will be 
determined in the serum samples using validated bioanalytical methods. 
5.4.2
Neutralising antibodies  
Neutralising antibodies testing will only occur on samples that are ADA positive.  Samples 
that are ADA negative will not be tested for nAb.  The presence or absence of neutralizing 
ADA will be determined using a validated bioanalytical method. 
5.5
Pharmacodynamics 
5.5.1
21-gene type I IFN PD signature in whole blood (PD marker) 
Type I IFN inducible signature in whole blood will be assessed by a 21-gene assay to be used 
as a PD marker to follow the biologic effect of anifrolumab on its target throughout the study. 
Whole blood will be collected for RNA isolation at the visits indicated in the Study Plan 
(Table 3 and Table 4) in order to evaluate the mRNA expression levels of 21 type I IFN-
inducible genes.  The remaining mRNA from the PD sample may be utilised for additional 
biomarker work to further characterise the effects of anifrolumab on its target. 
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the study centers. 
Pharmacodynamic samples are exhausted in the isolation process.  Any remaining back up 
whole blood 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. 
5.5.2
4-gene type I IFN test  
At screening the IFN test will be used for assessment of 4 type I IFN inducible transcripts in 
whole blood.  The primary intent is to prospectively identify subjects as IFN “test-high” or 
“test-low” for the purpose of randomization of subjects into the study.  Only subjects with a 
“test-high” result will be eligible for participation in the study.  The kit uses the expression of 


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the transcripts IFI27, IFI44, IFI44L and RSAD2 compared with 3 reference transcripts; 18S, 
ACTB and GAPDH.  The result is expressed as a score that is compared with a pre-
established cut-off that classifies subjects into 2 groups with low or high levels of IFN 
inducible transcript expression.  The results of the test will not be shared with the investigative 
site (i.e., all site personnel will remain blinded to IFN test results).  The IFN test will be 
conducted at a designated central laboratory and a detailed description of the test procedure 
will be included in the laboratory manual.  The data will be evaluated for development of a 
companion diagnostic. 
The IFN test utilizes the analysis of mRNA and does not include the assessment of any DNA 
sequences.  There are no pharmacogenetic analyses planned in this study.  
5.5.3
Exploratory Transcriptome Analysis (optional) 
Whole transcriptome and specific inflammatory pathway RNA transcript analyses using RNA 
isolated from whole blood and skin tape strip samples will be performed as an optional part of 
study.  The purpose of these analyses will be to retrospectively evaluate whole blood 
transcript biomarkers predictive of subject response at baseline, prior to investigational 
product administration, as well as to potentially identify additional PD biomarkers in whole 
blood and skin.
Whole blood
RNA isolated from whole blood samples collected for 21-gene type I IFN analysis according 
to Study Plan in Table 3 and Table 4 as described in Section 5.5.1 will be used for 
transcriptome analyses. 
Skin tape strips 
Skin tape strips will be collected at Week 0 and Week 12 from subjects consenting to this 
optional part of study.  The skin tape strips will be collected using non-invasive adhesive 
patches applied to lesional and non-lesional skin.  
Instructions for sample collection, processing, storage, and shipment of skin tape strips can be 
found in the separate laboratory manual provided to the study centers. 
5.6
Pharmacogenetics (Not Applicable) 
5.7
Biomarker analysis (Not Applicable) 
5.8
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.   
5.9
Labelling and shipment of biological samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 


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containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B ‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
5.10
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. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
5.11
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. 
The Principal Investigator: 
x
Ensures subjects’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca 
x
Ensures that biological samples from that subject, if stored at the study 
site, are immediately identified, disposed of /destroyed, and the action 
documented 
x
Ensures the laboratory(ies) 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 
x
Ensures that the subject and AstraZeneca are informed about the sample 
disposal. 
AstraZeneca ensures the central laboratory(ies) 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. 


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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 an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
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: 
x
Results in death 
x
Is immediately life-threatening 
x
Requires in-patient hospitalisation or prolongation of existing 
hospitalisation  
x
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions 
x
Is a congenital abnormality or birth defect 
x
Is an important medical event that may jeopardize 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 and SAEs will be collected from time of signature of informed consent 
throughout the treatment period and including the follow-up period (10 weeks post final dose). 


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6.3.2
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study 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; 
x
AE (verbatim) 
x
The date and time when the AE started and stopped 
x
Maximum intensity  
x
Whether the AE is serious or not 
x
Investigator causality rating against the Investigational Product (yes or 
no) 
x
Action taken with regard to investigational product 
x
Outcome. 
In addition, the following variables will be collected for SAEs: 
x
Date AE met criteria for serious AE 
x
Date Investigator became aware of serious AE 
x
AE is serious due to 
- Date of hospitalisation 
- Date of discharge 
- Probable cause of death 
- Date of death 
- Autopsy performed 
x
Causality assessment in relation to Study procedure(s) 
x
Description of AE. 


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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 (e.g., OCS, azathioprine, antimalarials, mycophenolate 
mofetil/mycophenolic acid, methotrexate, and mizoribine). Note that for SAEs that could be 
associated with any study procedure the causal relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol. 
6.3.5
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or care provider or reported in response to the 
open question from the study personnel: ‘Have you/the child had any health problems since 
the previous visit/you were last asked?’, 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 protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs, and other safety assessments 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). 


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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 C for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law. 
6.3.8
Disease progression/worsening of SLE 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
SLE.  It may be an increase in the severity of the existing of manifestations of SLE or the 
appearance of new manifestations.  Worsening of SLE should not be reported as an AE, unless 
the signs and symptoms meet criteria for an SAE.   
New manifestation or worsening of existing manifestations of SLE should be captured per 
PI’s judgement.  
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 personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 


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The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.  
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug Anifrolumab.  
6.5
Overdose 
An overdose in this study is defined as a subject receiving a dose of investigational product 
that is greater than the dose that was intended to be given  
x
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. 
x
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 pregnancy outcomes should be reported to AstraZeneca. 
6.6.1
Maternal exposure 
The required methods of contraception are described in Section 3.1.  If a subject becomes 
pregnant during the course of the study IP should be discontinued immediately.  Pregnancy is 
not regarded as an AE unless the IP under study is suspected to have interfered with 
effectiveness of the contraceptive medication used.  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 should 
be followed up and documented even if the subject was discontinued from the study. 
If a pregnancy occurs during the study, the Investigator or other site personnel must inform 
the appropriate AstraZeneca representatives immediately but no later than 24 hours of when 
he or she becomes aware of it. 


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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. 
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 as described in Section 
3.1.  Pregnancy of the subject’s partner is not considered as an AE, but the outcome of all 
pregnancies (or any conception) should if possible be followed up and documented. 
Information on the pregnancy of a subject’s partner must be obtained directly from the 
subject’s partner. Therefore, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the subject’s partner. 
6.7
Adverse Events of Special Interest  
An AESI is an AE of scientific and medical concern specific to understanding biologics and 
requires close monitoring and rapid communication by the Investigator to the 
Sponsor/Sponsor’s delegate. An AESI may be serious or non-serious. 
Adverse Events of Special Interest in this protocol will be assessed at each visit in the CRF. 
The events of interest are serious infections, including non-opportunistic serious infections, 
opportunistic infections, anaphylaxis, malignancy, herpes zoster, TB (including latent TB), 
influenza, vasculitis (non-SLE), and MACE (including non-fatal myocardial infarction, non-
fatal stroke, and CV death). 
An AESI that meets 1 of the seriousness outcomes listed in Section 6.2 will be categorised as 
an SAE for the purposes of follow-up responsibility and safety reporting.  A non-serious AESI 
will be categorised as an AE.  For reporting of AESIs, see Section 6.8. 
6.7.1
Non-opportunistic serious infection 
A serious non-opportunistic infection is any non-opportunistic infection that meets the SAE 
criteria in Section 6.2.  Serious non-opportunistic infection adverse events are reported as 
SAEs and AESIs.  It is expected that culture results and all diagnostic or therapeutic procedure 
results performed on a subject experiencing a serious non-opportunistic infection will be 
provided as an SAE update.  Non-serious non-opportunistic infections will not be captured as 
AESIs. 
6.7.2
Opportunistic serious infection  
An opportunistic infection is an invasive infection caused by microorganisms that are 
normally non-pathogenic or rarely pathogenic in individuals with normal immune function or 
cause an infection of a type or severity not seen in the normal host. 


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Examples of opportunistic infections that may occur in SLE subjects include: herpes zoster 
meningoencephalitis, Salmonella bacteremia, Pneumocystis jiroveci pneumonia or progressive 
multifocal leukoencephalopathy.  It is expected that culture results and all diagnostic or 
therapeutic procedure results performed on a subject experiencing a serious opportunistic 
infection will be provided as an SAE update.  Since anifrolumab is an immunomodulatory 
agent and the sponsor needs to understand the safety profile of this investigational product, 
including assessment of how anifrolumab may affect resistance to different types of 
infections, investigators are asked to undertake appropriate microbiologic identification 
including culture and report culture results for all patients who develop serious infections. 
6.7.3
Anaphylaxis 
Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after 
contact with an allergy-causing substance, such as investigational product.  For the purposes 
of this study, the definition detailed in Appendix K is provided as a simple and rapid means to 
make the diagnosis of anaphylaxis during injection with investigational product.  This 
definition was a product of a symposium convened by the National Institute of Allergy and 
Infectious Diseases and Food Allergy and Anaphylaxis Network (Sampson et al, 2006). 
6.7.4
Malignancy  
Malignancy is a neoplasm characterised by cells with abnormal features, uncontrolled rapid 
growth with invasive and/or metastatic tendencies diagnosed based on pathologic and clinical 
standards.  Understanding risk of developing different malignancies is critical to establishing 
the benefit: risk profile for anifrolumab.  Investigators are therefore requested to obtain biopsy 
results and pertinent biomarker and/or genetic testing results performed and to report these for 
any malignancies reported during the study. 
6.7.5
Herpes zoster  
Herpes zoster is a viral infection characterized by a cutaneous vesicular eruption on an 
erythematous base presenting along dermatome(s) and usually associated with prodromal 
pain. Herpes zoster results from the reactivation of varicella-zoster virus; multiple 
dermatomes may be involved (>3 indicates disseminated disease) and organ or systemic 
infection may occur (invasive; therefore an opportunistic infection).  Polymerase chain 
reaction testing of samples from vesicles, biopsy, or other specimens (for example, 
cerebrospinal fluid) may confirm the presence of varicella-zoster virus. 
For additional information regarding Herpes zoster, refer to the Investigator Brochure.  As this 
is an event of special interest, the Sponsor will collect information including whether or not 
subjects have received vaccination for Herpes zoster.  The Herpes zoster vaccine will be 
captured in the appropriate sections of the CRF. 
6.7.6
Tuberculosis 
Tuberculosis is a mycobacterial infectious disease generally presenting as cough with 
systemic symptoms of infection diagnosed by skin test (purified protein derivative), blood test 
(IFN-gamma release assay), radiographic imaging, body fluid and tissue sampling; 


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presentation may include disseminated or latent disease.  An infection may be new (at least 
conversion of a TB test to positive) or reactivation of dormant disease (new active disease in a 
previously TB test positive subject without prior evidence of active disease). 
x
A bacteriologically confirmed TB case is case where a biological 
specimen is positively by smear microscopy, culture or rapid diagnostic 
such as PCR or nucleic acid amplification test (Xpert MTB/RIF) 
x
A clinically diagnosed TB case is a case where the subject dose not fulfil 
the criteria for bacteriological confirmation, but has been diagnosed with 
active TB by a clinician or other medical practitioner who has decided to 
give the subject a full course of TB treatment.  This definition includes 
cases diagnosed on the basis of x-ray abnormalities or suggestive 
histology and extra-pulmonary cases without laboratory confirmation. 
Clinically diagnosed cases subsequently found to be bacteriologically 
positive (before or after starting treatment) should be reclassified as 
bacteriologically confirmed.   
Bacteriologically confirmed or clinically diagnosed cases of TB are also classified according 
to: anatomical site of disease; history of previous treatment; drug resistance; HIV status 
(World Health Organization, 2014). 
Latent TB is a mycobacterial infection without clinical, bacteriological findings, or radiologic 
findings consistent with active TB and a TB blood test such as an IGRA (QuantiFERON 
Gold) or purified protein derivative skin test that is positive both at the time of provisional 
diagnosis and on repeat assessment. 
Subjects identified with latent TB will be assessed by a local TB specialist to confirm the 
diagnosis and local SOC that will be used in treatment.  Once latent TB is confirmed, 
treatment must be instituted immediately and no investigational product may be administered 
until treatment of latent TB has begun.  Additionally, subjects with newly diagnosed latent TB 
must agree to complete a locally recommended course of treatment for latent TB in order to 
continue receiving IP. 
6.7.7
Influenza 
Influenza is a severe viral infection that includes the following symptoms: temperature greater 
than 100.8eF (38.2eC), and malaise, headache, or myalgia.  It is often accompanied by 
nausea, vomiting, and diarrhea, and at least 1 of the following respiratory symptoms: cough, 
sore throat, or shortness of breath. 
Laboratory criteria for influenza include at least 1 of the following: isolation of influenza virus 
from a clinical specimen, detection of influenza virus nucleic acid in a clinical specimen, 
identification of influenza virus antigen by direct fluorescent antibody test in a clinical 
specimen, OR influenza-specific antibody response. 


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A confirmed case of influenza meets the clinical and laboratory criteria for the viral illness. 
Laboratory confirmation should be done using locally available, rapid, commercial tests 
approved by Regulatory Agencies and sampling respiratory specimens. 
Not all upper respiratory viral infections or gastrointestinal viral infections are influenza.  In 
the case where a subject reports a viral infection severe enough to be considered, in the 
opinion of the Investigator, influenza, a viral test should be performed (if possible) to confirm 
the diagnosis.  If, in the opinion of the Investigator, the subject has had influenza (the specific 
viral infection), this should be reported as an AESI, whether or not a test to confirm the 
diagnosis has been performed.  Less severe viral infection should be reported as an AE only. 
6.7.8
Vasculitis (non-Systemic Lupus Erythematosus)  
Vasculitis (non-SLE) is defined as an inflammatory disorder of blood vessels involving 
arteries and/or veins and characterized by characteristic clinical signs/symptoms and 
diagnosed by biopsy, imaging such as angiography or blood tests such as findings of 
antineutrophil cytoplasmic antibodies consistent with the diagnosis.  Underlying causes should 
be identified, such as medications including study drug, infections or systemic inflammatory 
syndromes, wherever possible.  See Appendix N for a list of vasculitic syndromes excluded 
from the study. 
6.7.9
Major acute cardiovascular events 
As a measure of enhanced Pharmacovigilance, an independent Cardiovascular Event 
Adjudication Committee (CV-EAC) will review deaths (due to any cause) and all SAEs in 
both the Cardiac and Vascular MedDRA System Organ Classes and all SAEs in the Central 
Nervous System Vascular Disorders Standard Medical Query for evaluation.  The CV-EAC 
chair may adjudicate some events that do not fall into the above categories. 
The CV-EAC will review cases of interest to determine if they meet accepted diagnostic 
criteria.  Causality assessments will not be made by the CV-EAC, nor will the committee 
possess governance authority.  The CV-EAC will be blinded regarding any information 
relating to the randomization group. Please refer to the adjudication charter for details. 
6.8
Reporting of adverse events of special interest 
Adverse Events of Special Interest will be assessed by the Investigator for severity, 
relationship to the investigational product, possible aetiologies, and whether the event also 
meets criteria of an SAE.  All AESIs (serious or non-serious) will be recorded on the AE CRF 
(using a recognized medical term or diagnosis that accurately reflects the event). 
The reporting period for AESIs is the period immediately following the time that written 
informed consent is obtained through the end of subject participation in the study.  Following 
detection of an AESI (non-serious), reporting is required within 72 hours of knowledge of the 
event, and for serious AESIs the standard 24-hour timeline for reporting to the appropriate 
AstraZeneca representative or designee applies. 


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6.9
Management of IP related toxicities  
6.9.1
Anaphylaxis, hypersensitivity, and injection-related reactions 
Hypersensitivity reactions including anaphylaxis have been reported with the subcutaneous 
administration of monoclonal antibodies. As with any antibody, allergic reactions to dose 
administration are possible. Therefore, appropriate drugs and medical equipment to treat acute 
anaphylactic reactions must be immediately available, and study personnel must be trained to 
recognize and treat anaphylaxis.  
Subjects should not be premedicated unless they have had a prior hypersensitivity reaction to 
anifrolumab.  However, if a prior hypersensitivity reaction has been documented, the 
Investigator may elect to administer an appropriate medication prophylactically potentially 
including an antihistamine and/or acetaminophen/paracetamol for the comfort and safety of 
the subject prior to subsequent investigational product administration.  Prophylactic use of 
glucocorticosteroids prior to subsequent injection is not permitted. 
6.9.2
Infections 
When an infection is reported as an SAE or AESI, cultures should be obtained and culture 
results should be reported with the event.  Other specific laboratory or other investigations 
(e.g., chest x-ray for pneumonia) that confirm or aid in the diagnosis or treatment should be 
obtained when indicated and results should be reported with the SAE or AESI.  
Subjects who develop a new infection while undergoing treatment with investigational 
product should receive appropriate medical therapy, as determined by local standards, and be 
monitored closely until the condition resolves.  Investigational product should not be 
administered to a subject with a clinically significant, active infection as determined by the 
Investigator.  For any active infection (e.g., varicella zoster infection/chickenpox) or 
significant exposure to any infection (e.g., varicella zoster infection in a naive subject, 
bacterial pneumonia), the Investigator should consider whether to interrupt investigational 
product administration and should notify the medical monitor. 
Similarly, if a subject presents with signs or symptoms where opportunistic infections are 
considered (e.g., CNS symptoms consistent with progressive multifocal leukoencephalopathy 
or herpes encephalitis or atypical pneumonia suggesting pneumocystis jiroveci pneumonia), 
investigational product should be interrupted until the Investigator confirms the symptoms and 
signs of infection have resolved or that no active infection has developed. 
If dosing is resumed after resolution of a safety concern (i.e., infection or other AE) the 
investigational product must be administered within 14 days of the scheduled time of the 
missed dose.  If this is not possible, dosing should be resumed at the time of the next 
scheduled dose. 


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6.10
Study governance and oversight 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives.  Issues identified will be addressed; for instance this could 
involve amendments to the study protocol and letters to Investigators. 
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Anifrolumab (MEDI-546) 
150 mg/mL solution of anifrolumab 
intended for SC administration  
MedImmune, LLC 
Placebo 
Solution intended for SC 
administration  
MedImmune, LLC 
Each vial of investigational product or placebo contains 1.3mL fill volume. Investigational 
product and placebo will be supplied to the site as follows: 
For the 150 mg anifrolumab and matched placebo groups = one kit will be dispensed per visit 
from the IXRS  
x
Sixteen subjects will be randomized at a 3:1 ratio to receive anifrolumab 
at a fixed dose of 150 mg (12 subjects) as added to SOC or placebo (4 
subjects) plus SOC, given Q2W as one SC injection (= 1 mL) 
For the 300 mg anifrolumab and matched placebo groups = two kits will be dispensed per visit 
from the IXRS 
x
Sixteen subjects will be randomized at a 3:1 ratio to receive anifrolumab 
at a fixed dose of 300 mg (12 subjects) as added to SOC or placebo (4 
subjects) plus SOC, given Q2W as two SC injections (=2 x 1 mL). 
Each kit will have a unique number that will be printed on all labels within the kit (i.e., the 
outer carton label and the label on the vial within the carton). 
Preparation of investigational product and placebo must be performed by a trained unblinded 
team member (e.g., pharmacist, study nurse) at the site.   
AstraZeneca will provide detailed preparation, storage and handling instructions for each 
product and treatment. 
7.2
Dose and treatment regimens 
Anifrolumab or placebo, will be administered as SC injections Q2W.  Anifrolumab 150 mg 
and corresponding placebo will be given as one injection in a total volume of 1 mL and 
anifrolumab 300 mg and corresponding placebo will be given as two injections of a volume of 
1 mL each. IP dosing must be at least 10 days apart. 


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All investigational products will be labelled in a double-blind fashion.  AstraZeneca will 
provide anifrolumab (MEDI-546) 150 mg and Placebo kits containing 1 vial/kit.  1 vial of 150 
mg anifrolumab or 1 vial of placebo.  The vial will be labelled with a blinded booklet label.  
7.2.1
Investigational product administration procedures 
An unblinded qualified study site personel, who will not be involved in the management of the 
subjects, will inject the IP into the SC tissue of the anterior thigh or abdomen.  Two injections 
(150 mg per injection) are required in order to administer anifrolumab at the 300 mg dose and 
for the corresponding placebo.  Therefore at each administration of anifrolumab 300 mg, and 
corresponding placebo, two separate injection sites on the anterior thigh or abdomen at least 3 
cm apart and on the same side for both injections should be used.  Injection sites should be 
rotated at each visit.  The time of the first SC injection will be recorded for each subject. 
The IP will be administered via a 27-gauge 1/2-inch needle.  The person administering the 
dose will wipe the skin surface of the anterior thigh or abdomen with alcohol and allow to air 
dry. The skin will be pinched to isolate the SC tissue from the muscle.  The needle will be 
inserted at a 90-degree angle approximately halfway into the SC tissue.  The IP will be slowly 
injected (at least 5-second duration is recommended) into the SC tissue using gentle pressure.  
The area should not be massaged after injection. 
7.2.2
Monitoring of investigational product administration 
Vital signs (blood pressure, temperature, pulse rate, and respiration rate) will be obtained 
before IP administration on all treatment visits.  After IP administration, subjects will be 
monitored for immediate drug reactions; vital signs will be taken immediately after 
administration of IP and at least every 30 minutes (± 5 minutes) thereafter.  In addition, 
injection sites will be visually inspected..  For the first 3 doses of IP (Weeks 0, 2, and 4), 
subjects will remain at site for a minimum of 2 hours or until stable, whichever is later.  If no 
safety concerns subjects will remain at site for a minimum of 1 hour or until stable, whichever 
is later, for the subsequent IP doses, i.e., from dose 4 (Week 6) and onwards.  Discharge from 
site will be determined by the investigator.  
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements and medical device 
directive for labelling.  Label text will be translated into local language. 
Before the kit is dispensed to the subject, the investigator must fill in the required information 
on the empty lines on the front cover page, locate the page with local label text, and 
demonstrate to the subject.  Booklet labels must be opened to find full label text in local 
language. 
7.4
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product should be stored at 2 to 8°C (36 to 46°F) and must not be frozen. 


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7.5
Compliance 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form.  The investigator product will be 
administered by study personnel, who will monitor compliance.  
7.6
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs administered to the subjects. 
The Investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records.  Upon completion of the study, copies 
of investigational product accountability records will be returned to AstraZeneca or designee. 
The investigator will either return any unused IP to AstraZeneca or its designate, or destroy IP 
at the site depending on local regulations.  If the IP is destroyed at site, the site personnel will 
count for all unused IP or appropriated destruction.  If the IP is returned to AstraZeneca or its 
designate, the study site personnel or the AstraZeneca monitor will account for all received IP 
received at the site, unused IP and for appropriated destruction. 
7.7
Concomitant treatment 
As anifrolumab is an investigational immunomodulatory agent, non-protocol permitted 
changes to immune modifiers or immunosuppressants during the study are not allowed.  If a 
subject receives any of the prohibited medications the administration of IP must be 
immediately discontinued and AstraZeneca study physician notified immediately.  If a subject 
is given any of the allowed, but restricted, medications in unpermitted doses or time periods 
the Investigator must notify AstraZeneca Study Physician immediately.  The subject will be 
considered as a non-responder for exploratory efficacy assessments and AstraZeneca Study 
Physician will determine if the subject may continue to receive IP or not. 
From Day 1 through the end of the study subjects must be instructed not to take any 
medications, including over-the-counter products, without first consulting the Investigator. 
7.7.1
Standard of Care treatment for SLE 
Permitted medications for SOC treatment for SLE are listed below and must be kept at 
stable doses within the dose ranges described below from indicated time points and 
throughout the treatment period. 
Concomitant medications should only be administered after all visit assessments, including IP 
administration and, if applicable, post-injection PK blood tests. 
Antimalarials, oral corticosteroids and other immunosuppressants (azathioprine, methotrexate, 
and mycophenolate mofetil/mycophenolic acid, and mizoribine) are permitted, and at least 1 is 
required, as part of SLE therapy on Day 1.  Dose regimens must remain stable from Day 1 to 
the completion of Week 52 but may be decreased for toxicity or to optimise management of 


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an AE, such as infection.  The toxicity/event must be confirmed as a documented AE.  The 
dose can be returned to the Day 1 level if the toxicity/event resolves and if clinically indicated. 
Antimalarials/immunosuppressants should not be changed if a subject has increased SLE 
disease activity during the OCS tapering period. 
Permitted SLE SOC treatment Maximal dose allowed 
Stable dose prior 
to randomization
Methotrexate (oral, sc, or im) 
25 mg per weeka 
8 weeks 
Hydroxychloroquine,  
400 mg per day 
8 weeks 
Chloroquine, quinacrine 
200 mg per day 
8 weeks 
Azathioprine 
200 mg per day 
8 weeks 
Mycophenolate mofetil 
2000 mg per day 
8 weeks 
Mycophenolic acid  
1440 mg per day 
8 weeks 
OCS 
<40 mg per day prednisone or equivalent 
2 weeks 
Topical treatment for skin 
symptoms 
According to recommended maximal dosing 
2 weeks 
aRoute of administration must remain stable.  
 
All permitted SOC SLE therapies received from initiation of screening through the end of the 
study will be recorded on the source document and CRF, and will include the specific 
indication for use (e.g., general SLE activity, skin involvement, nephritis, pleurisy) as well as 
the dose, start and stop dates, frequency, and route of administration.  In addition, any change 
in permitted SOC SLE therapy and the reason for change must be documented.  
7.7.2
Corticosteroid treatment  
7.7.2.1
Protocol-specified corticosteroid tapering 
Oral corticosteroid doses should remain stable through week 12 unless there is a clinical, 
safety, or ethical reason to taper earlier, in which case OCS dose reductions may be permitted 
from Week 4.  Corticosteroid tapering must be attempted in all subjects with an OCS dose 
10.0 mg per day of prednisone or equivalent at randomization and aim for a target OCS dose 
of 7.5 mg/day at Week 40.  Tapering will start at Week 12 and may continue until end of 
study unless at least 1 of the following criteria is met: 
x
SLEDAI-2K activity which is worsened compared to baseline in major 
organ systems (renal, CNS, cardiopulmonary, vasculitis, fever, 
thrombocytopenia, or haemolytic anaemia, or gastrointestinal activity) 
x
Newly-affected organ system(s) based on the SLEDAI-2K, excluding 
serological abnormalities (dsDNA antibodies, hypocomplementemia) 


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x
Persistent moderately to severely active skin manifestations as reflected 
by a CLASI activity score of 10. 
x
Moderate to severe arthritis disease as reflected by an active joint count 
of 8 tender and/or swollen joints 
Tapering can be started on the scheduled study visit day (e.g., Week 12 Visit) based on 
clinical manifestations and the laboratory values from the previous visit.  If laboratory values 
or clinical evaluation of the current visit show increased or persistent SLE activity the tapering 
can be reversed.  Steroid tapering must be started within 14 days of the visit.  If steroid 
tapering is not attempted in an eligible subject, the AstraZeneca study physician must be 
contacted immediately.  The recommended steroid-tapering regimen is provided in Appendix 
H but Investigators will have flexibility in how the OCS dose is reduced at each visit. 
Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
7.5 mg/day up to end of study based on disease activity.  If a subject experience increased 
disease activity secondary to OCS tapering, the dose may be increased up to a maximum of 
the baseline OCS dose for up to 2 weeks followed by a new tapering attempt. 
7.7.2.2
Corticosteroid bursts 
Week 0 to Week 12 
In order to allow adequate time for the investigational product to achieve significant clinical 
benefit, Investigators may administer 1 burst and taper of corticosteroids between Week 0 
(Day 1) and Week 12 for increased SLE disease activity/non-SLE activity.  After Week 12 
additional steroid bursts may be given as per investigators judgement of clinical need. 
A steroid burst as described below is defined as 1 of the following: 
x
OCS increase up to a maximum daily dose of 40 mg/day prednisone (or 
equivalent) for up to a total of 14 days and that must be fully 
administered and tapered to less than or equal to the Day 1 dose by the 
end of the 14th day.; or 
x
Intramuscular methylprednisone (80 mg) or equivalent administered as 
a single dose between Day 1 and Week 12; or 
x
A maximum of 2 intra-articular/tendon sheath/bursal injections (for a 
total methylprednisolone 80 mg or equivalent) can be given. 
Subjects who receive any intra-articular/tendon sheath/bursal injections should not receive 
OCS or intramuscular burst between Day 1 and Week 12.  Subjects who receive more than 1 
steroid burst and taper from Week 0 (Day 1) to Week 12, or who violate any of the criteria 
above, may continue in the study, but AZ study physician should be contacted. 


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From Week 12 until end of study 
After Week 12 and up until end of study, additional steroid bursts, defined as above, may be 
given for SLE increased disease activity. 
Adjustments of OCS doses above Day 1 dose for increased SLE activity may be allowed after 
Week 12 with the AZ study physician approval. 
Intra-articular/tendon sheath/bursal injections are allowed for non-SLE related disorders from 
Week 12 and onwards. The injection should be administered after the completion of all 
assessments, including IP administration and post-injection PK blood test (if applicable). 
7.7.2.3
Increase in oral corticosteroids for intercurrent disease or to prevent adrenal 
insufficiency 
Steroid bursts for non-SLE causes (e.g., asthma or COPD exacerbation) are allowed 
throughout the study but the AstraZeneca study physician should be informed.  A burst may 
include OCS up to 20 mg/day of prednisone (or equivalent) for up to a total of 14 days and 
must be tapered to less than or equal to the Day 1 dose within 14 days.  The non-SLE reason 
for the burst must be clearly indicated in the source documents.  If a subject receives >40 mg 
prednisone or equivalent) or a dose above baseline level for more than 14 days, it must be 
reported to the AstraZeneca study physician, whom will determine if the subject may continue 
to receive IP. 
In addition to the burst and tapers described above, subjects who are taking 7.5 mg/day 
prednisone or equivalent will be allowed to receive up to an additional 7.5 mg/day to a total of 
15 mg/day prednisone or equivalent for a total of up to 14 days or a single dose of IV 
hydrocortisone (100 mg hydrocortisone followed by half that dose for 2 days before 
returning to their usual dose) for severe illness, surgery, or symptoms of adrenal insufficiency 
or corticosteroid withdrawal if clinically warranted from Day 1 to Week 52. 
7.7.2.4
Topical therapy 
Concurrent use of topical therapy for cutaneous lupus erythematosus (e.g., topical 
corticosteroids, topical immunosuppressants) is permitted.  During the study, topical therapy 
may be reduced or discontinued based on clinical manifestations and Investigator discretion. 
Should cutaneous skin manifestations reoccur, the same topical therapy may be resumed at 
same dose as was being used at the time of randomization.  It is encouraged that no new 
dermatologic preparations be initiated for the duration of the study.  Subjects should use 
sunscreen (list as concomitant medication for SLE) and avoid sun exposure for the duration of 
the study. 
7.7.3
Anti-hypertensive agents and statins 
Anti-hypertensive agents including; Angiotensin-Converting-Enzyme Inhibitor (ACEI),  
Angiotensin II Receptor Blockers (ARB), calcium channel blockers, beta blockers, Į receptor 
blockers, are allowed and doses may be adjusted as clinically indicated. 


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Statins must be kept at stable doses after Day 1.  Decreases in the dose are allowed only to 
reduce statin-related side effects. 
Cholestyramine must be discontinued prior to the day of randomization. 
7.7.4
NSAIDs 
Prescription NSAIDs may be used within label-approved dose ranges.  Prescription NSAIDs 
cannot be administered with other NSAIDs (including over-the-counter non-steroidals) except 
for low-dose aspirin (325 mg/day).  On a given visit day, prescription NSAIDs should not be 
taken until after all assessments have been completed.  
7.7.5
Acetaminophen or equivalent 
Pain medications should not be used within a minimum of 6 to 12 hours (based on known 
duration of effect) of a scheduled visit.  Normal release (not extended release) acetaminophen 
or equivalent (e.g., paracetamol) may be used for pain as required. 
7.7.6
Low-dose aspirin 
Low-dose aspirin (maximum of 325 mg/day) for cardiovascular disease is permitted. 
7.7.7
Narcotic analgesics 
These can be used during the study as clinically indicated. 
7.7.8
Other concomitant treatment 
Other medication other than that described above, 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 CRF. 
7.8
Prohibited medications 
The prohibited medications listed below are not allowed at any time point after enrolment 
and must be discontinued prior to signing ICF in accordance with the time periods below.  
Prohibited Medication 
Discontinuation 
prior to signing ICF
Abatacept (CTLA 4 Ig) 
24 weeks 
Acthar gel 
6 weeks 
Adalimumab 
12 weeks 
Anakinra 
12 weeks 
Alefacept 
12 weeks 
Apremilast 
4 weeks 
Atacicept (TACI-Ig) 
40 weeks 


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Prohibited Medication 
Discontinuation 
prior to signing ICF
Baricitinib 
4 weeks 
Belimumab 
12 weeks 
Blisibimod (AMG 623) 
12 weeks 
Certolizumab pegol 
24 weeks 
Chlorambucil 
24 weeks 
Corticosteroid pulse treatment (oral or IV) with doses >500 mg 
methylprednisolone or equivalent 
24 weeks 
Cyclophosphamide (or any other alkylating agent) 
24 weeks 
Cyclosporine (oral) 
8 weeks 
Cytokines (eg IFN) 
Wash out time 
Dapsone 
4 weeks 
Danazol 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
12 weeks 
Etanercept 
4 weeks 
Golimumab 
12 weeks 
Infliximab 
12 weeks 
Intravenous immunoglobulins 
4 weeks 
Lenalidomide 
8 weeks 
Lupuzor (IPP-201101) 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Obinutuzumab 
26 weeks 
Ocrelizumab 
26 weeks 
Ofatumumab 
26 weeks 
Pimecrolimus 
4 weeks 
Plasmapheresis or plasma exchange 
24 weeks 
Retinoids 
4 weeks 
Rituximab 
26 weeks 
Sirolimus 
4 weeks 


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Prohibited Medication 
Discontinuation 
prior to signing ICF
Tabalumab 
12 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 
Tofacitinib 
4 weeks 
MEDI-545 (sifalimumab) 
26 weeks 
Sirolimus 
4 weeks 
NOTE: If any of the medications listed above is started at any time after ICF is signed, it will 
lead to immediate discontinuation of the IP as per Section 3.9. 
7.9
Post Study Access to Study Treatment 
At the end of the study, the sponsor will not continue to supply study drug to 
subjects/investigators unless the sponsor chooses to extend the study.  The investigator should 
ensure that the subject receives appropriate SOC treatment for the condition under study. 
8.
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1
Statistical considerations 
Summary data will be presented in tabular format.  Continuous variables will be summarised 
by descriptive statistics, including number, mean, standard deviation, median, minimum, 
maximum and coefficient of variance [%CV].  Confidence intervals (CIs) will be two-sided, 
unless otherwise stated.  Categorical data will be summarized by the number and percentage 
of subjects in each category. 
The study will be double-blind until the database lock, performed after all subjects complete 
Week 12.  Thereafter, the sponsor will be unblinded, whilst the investigators and subjects will 
remain blinded throughout the remainder of study, including the treatment period up to Week 
52 and the follow-up period up to Week 60.  Analyses will be performed by AstraZeneca or 
its representatives. 
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first subject 
enrolled and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data at Week 12.  Details of endpoint analyses will be 
described in the SAP. 




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8.4.1
Primary outcome measures 
8.4.1.1
Pharmacodynamics (PD) 
The 21-gene type 1 IFN signature score and neutralization ratio (relative to baseline) will be 
used to characterize PD over time, with the primary time point at Week 12. 
8.4.1.2
Pharmacokinetics (PK) 
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed steady-state serum trough (predose) concentrations, Ctrough. Maximum concentration 
after the first dose will also be evaluated.  Additional PK parameters may be determined 
where appropriate. 
8.4.2
Secondary outcome measures 
8.4.2.1
Immunogenicity 
ADA assessments will be conducted utilising a tiered approach (screen, confirm, titre).  The 
presence of nAb will be tested in all ADA-positive samples using appropriate summary 
statistics. 
8.4.2.2
Safety 
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
chest x-ray, haematology, serum chemistry, urinalysis, reported AEs and SAEs (including 
AEs of special interest, see Section 6.7) and C-SSRS.  Marked abnormal ECG values or 
changes from baseline will be identified based on pre-determined criteria. Occurrence of 
suicidal behaviour and ideation, based on the C-SSRS, from baseline up to Week 52 will be 
explored. Other safety assessments: Coagulation Tests, Hemoglobin A1c (only diabetics), 
Serum ȕ-hCG pregnancy test, Follicle-stimulating hormone, Pap smear, B cell count (only if 
prior B cell-depleting treatment), HIV, Hepatitis B and C, QuantiFERON-TB Gold test, TB 
questionnaire. 
Change from baseline to each post-treatment time point where scheduled assessments were 
made will be calculated for relevant measurements.  Adverse events will be summarised by 
means of descriptive statistics and qualitative summaries. 
Other significant adverse events: During the evaluation of the AE data, a medically qualified 
expert from Sponsor/Designee team will review: 
x
AESI: The AESI are listed in Section 6.7. These will be reported in the 
CSR. 
x
A list of AEs that were not reported as SAEs, or AEs leading to 
discontinuations: significant AEs of particular clinical importance may, 
after consultation with the Astra Zeneca Global Patient Safety Physician, 
be considered as other significant AEs (OAEs) and reported as such in 
the CSR.  Examples of these are marked haematological and other 


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laboratory abnormalities, and certain events that lead to intervention 
(other than those already classified as serious), dose reduction, or 
significant additional treatment.  
8.4.3
Exploratory outcome measures 
8.4.3.1
Efficacy 
The efficacy outcomes for anifrolumab groups and placebo will be explored using the 
following outcome measures. 
CLASI activity score 
The effect of anifrolumab on skin will primarily be characterized by a  50% improvement in 
CLASI activity score from baseline. 
Additionally, the absolute levels, as well as the change from baseline in CLASI activity scores 
will be characterized over time. 
SLEDAI-2K score and Physician global assessment of disease activity (PGA) 
The SLE disease activity will be characterized by SLEDAI and PGA. 
SLEDAI will be characterized longitudinally over time by the absolute levels and changes 
from baseline in SLEDAI-2K. 
Physician global assessment (PGA) will be characterized longitudinally over time using the 
change from baseline in PGA (VAS scale 0-100 mm). 
Autoantibodies and inflammatory markers 
The outcome variables for disease-related autoantibodies including; anti-nuclear antibody 
(ANA), parameters of the biological domain (complements C3, C4 and CH50), and the 
inflammatory marker ESR, will be measured by change from baseline, longitudinally over 
time. 
8.4.3.2
Oral corticosteroid management 
OCS management will be characterized over time. 
8.4.3.3
Skin tape test (optional) 
The skin tape test will be characterized by the 21-gene type 1 IFN signature scores.  Further 
details will be presented in the SAP. 
8.5
Methods for statistical analyses 
No formal comparisons will be made between treatment groups, and all results will be 
presented by treatment.  The two placebo arms will be pooled for the analyses.  In addition, if 


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deemed appropriate, data from the two anifrolumab arms may be pooled for the exploratory 
analyses of efficacy, and details for when to do this will be presented in the SAP. 
Missing data 
Subjects who discontinue IP will be encouraged to come to visits 4, 6, 8, 10, 12, 14, 16, 18, 
20, 22, 24, 26, and 28 (as applicable) (or for a minimum of 10 weeks after last dose of 
investigational product for subjects for whom investigational product was discontinued within 
10 weeks prior to Week 52). After subjects discontinue IP, visits that they are not required to 
attend, and do not attend, will be classified as missing. 
 Presentation of results 
Data will be presented by treatment groups.  Descriptive statistics (number, mean, standard 
deviation [SD], median, minimum, maximum and coefficient of variance [%CV]) will be 
provided for continuous variables, and counts and percentages will be presented for 
categorical variables.  
8.5.1
Analysis of the primary variable (s) 
The primary characterization of the effect of anifrolumab on the 21-gene type I IFN PD 
signature will be carried out through the individual and median 21-gene type 1 IFN signature 
scores and neutralization ratios at Week 12.  The PD gene signature will also be explored over 
time.  A subset of the full analysis set will be used, defined as subjects who are randomized, 
received at least 1 dose of investigational product (modified Intention-To-Treat) and did not 
discontinue IP, will be used.  
The primary characterization of anifrolumab PK will be done by descriptive statistics of the 
derived PK parameters.  Individual and mean anifrolumab concentrations will also be plotted 
over time. 
8.5.2
Analysis of the secondary variables 
8.5.2.1
Safety 
Adverse events (including AESIs) will be summarised by means of counts summaries by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred 
Term (PT).  All AEs will be listed. 
Laboratory data for haematology and clinical chemistry will be summarised.  The frequency 
of changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated.  Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given.  Shifts from normal to abnormal between baseline 
and each post-baseline time point will be characterized for urinalysis. 
The incidence of markedly abnormal values and changes from baseline in the ECG parameters 
will be summarised by treatment group, with placebo pooled. 


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The proportion of subjects with suicidal behaviour and suicidal ideation throughout the study 
based on the C-SSRS will be presented for each treatment group.  The proportion of subjects 
within each of the 4 suicidal behaviour categories and within each of the 5 suicidal ideation 
sub-categories will also be presented for each treatment group.  Descriptive statistics on the 
total number of attempts, total number of interrupted attempts, and total number of aborted 
attempts will be summarised for each treatment group, with placebo pooled.  Other safety 
variables may be summarised as appropriate.  Further details will be provided in the SAP. 
8.5.2.2
Immunogenicity 
Antibodies to anifrolumab will be summarised using descriptive statistics at each visit by 
treatment group.  ADA titres-time profiles of anifrolumab by treatment group will be 
generated.  The impact of ADA on PK and PD endpoints will be assessed.  The potential 
association of ADA with safety and efficacy will be explored. 
8.5.3
Interim analysis 
The treatment period will be double-blind up until the data base lock performed after all 
randomized subjects complete Week 12 or discontinue the study prior to Week 12 (the main 
analysis).  At this time point Sponsor personnel will be unblinded whereas investigators and 
subjects will remain blinded throughout the entire study.  An additional data base lock will 
take place once all subjects have completed Week 60 or discontinued the study prior to Week 
60.  Further details will be presented in the SAP (end of extension analysis). 
8.5.4
Sensitivity analysis 
Various missing data assumptions may be explored for the primary PD outcome and 
exploratory outcomes.  Further details will be provided in the SAP. 
8.5.5
Analysis methods for exploratory outcome measures 
8.5.5.1
Efficacy 
The efficacy outcomes for anifrolumab groups and placebo will be explored using the analysis 
methods stated below.  These analyses will be performed on individual and pooled 
anifrolumab treatment groups, where appropriate.  Placebo groups will be pooled for all 
analyses. 
CLASI activity score 
CLASI activity will be characterized at Week 12 by the proportion of subjects achieving a  
50% improvement in CLASI activity score from baseline.  The proportion of patients 
achieving a  50% improvement in CLASI activity score from baseline will also be 
characterized longitudinally from Week 2 up until Week 52. 
Change from baseline and overall CLASI activity scores will be characterized up to Week 12 
for subjects using line charts.  This will also be characterized longitudinally up to study end. 


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Shift plots in overall CLASI activity score from baseline to Week 12 and baseline to Week 52 
will be created. 
Further details will be presented in the SAP. 
SLEDAI-2K score 
SLEDAI-2K will be characterized by summary statistics for change from baseline and overall 
score at Week 12.  Summary statistics for change from baseline and overall score will also be 
characterized longitudinally from up until Week 52. 
Change from baseline and overall SLEDAI-2K scores will be characterized up to Week 12 for 
subjects using line charts.  This will also be characterized longitudinally up to Week 52. 
Physician global assessment of disease activity (PGA) 
Physician global assessment (PGA) will be characterized by summary statistics for change 
from baseline and overall score at Week 12.  Summary statistics for change from baseline and 
overall score will also be characterized longitudinally up until Week 52. 
Autoantibodies and inflammatory markers 
The outcome variables for disease-related autoantibodies including; anti-nuclear antibody 
(ANA), parameters of the biological domain (complements C3, C4 and CH50), and the 
inflammatory marker ESR, will be characterized by summary statistics for change from 
baseline, longitudinally over time. 
Further details will be provided in the SAP. 
8.5.5.2
Oral corticosteroid management 
Shift tables and plots of the OCS dose at baseline and; Week 12, Week 24, and Week 52, will 
be produced.  The potential association between change in OCS dose and CLASI will also be 
explored graphically.  Further details will be presented in the SAP. 
8.5.5.3
Skin tape test 
Skin tape test outcome measures will be summarised as appropriate.  Further details will be 
provided in the SAP. 
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1
Training of study site personnel 
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. 


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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: 
x
Provide information and support to the Investigator(s) 
x
Confirm that facilities remain acceptable 
x
Confirm that the investigational team is adhering to the 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 
x
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) 
x
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. 
9.2.2
Study agreements 
The Principal Investigator at each 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. 


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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 is expected to start in Q4 2016 and to end by Q4 2018. 
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 anifrolumab.  
9.4
Data management by AstraZeneca or delegate 
Data management will be performed by AstraZeneca Data Management Centre staff 
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 AstraZeneca Drug Dictionary.  All coding will be 
performed by the Medical Coding Team at the AstraZeneca Data Management Centre.  
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 
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  


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Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
Management of external data 
The data collected through third party sources will be obtained and reconciled against study 
data. 
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. 
10.3
Ethics and regulatory review 
An Ethics Committee (EC)/Institutional Review Board (IRB) should approve the final 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 EC/IRB, and to the study site staff. 
The opinion of the EC/IRB should be given in writing. The Investigator should submit the 
written approval to AstraZeneca before enrolment of any subject into the study.  
The EC/IRB 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 protocol should be re-approved by the EC/IRB annually. 
Before enrolment of any subject into the study, the final 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. 


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AstraZeneca will provide Regulatory Authorities, EC/IRB and Principal Investigators with 
safety updates/reports according to local requirements. 
Each Principal Investigator is responsible for providing the EC/IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
10.4
Informed consent 
The Principal Investigator(s) at each centre will: 
x
Ensure each subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study 
x
Ensure each subject is notified that they are free to discontinue from the 
study at any time 
x
Ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided 
x
Ensure each subject provides signed and dated informed consent before 
conducting any procedure specifically for the study 
x
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
x
Ensure a copy of the signed Informed Consent Form is given to the 
subject 
x
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 EC/IRB. 
10.5
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then a new version of the study 
protocol will be generated. 
The amendment is to be approved by the relevant EC/IRB and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised protocols. 


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AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to EC/IRB see Section 10.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s EC/IRB are to approve the revised Informed Consent Form before the revised 
form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB. 
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 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. 
11.
LIST OF REFERENCES 
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American Psychiatric Association, 1994 
American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental 
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Bengtsson et al, 2000 
Bengtsson AA, Sturfelt G, Truedsson L, Blomberg J, Alm G, Vallin H, et al. Activation of 
type I interferon system in systemic lupus erythematosus correlates with disease activity but 
not with antiretroviral antibodies. Lupus. 2000;9:664-71. 
Bertsias et al, 2008 
Bertsias G, Ioannidis JPA, Boletis J, Bombardieri S, Cervera R, Dostal C, et al. EULAR 
recommendations for the management of systemic lupus erythematosus. Report of a Task 
Force of the EULAR Standing Committee for International Clinical Studies Including 
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Blomberg S et al, 2001 
Blomberg S, Eloranta ML, Cederblad B, Nordlin K, Alm GV, Rönnblom L. Presence of 
cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus. 
Lupus. 2001;10(7):484-90. 
Cellestis, 2005 
Clinicians Guide to QuantiFERON®-TB Gold. 
CHMP, February 2015 
CHMP Guideline on clinical investigation of medicinal products for the treatment of 
systemiclupus erythematosus and lupus nephritis (26 February 2015; 
EMA/CHMP/51230/2013). 
Cooper et al, 1998 
Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CG, Gilkeson GS. Hormonal, 
environmental, and infectious risk factors for developing systemic lupus erythematosus. 
Arthritis Rheum. 1998;41(10):1714-24. 
Dall’era et al, 2005 
Dall'era MC, Cardarelli PM, Preston BT, Witte A, Davis Jr, JC. Type I Interferon correlates 
with clinical and serologic manifestations of systemic lupus erythematosus. Ann Rheum Dis. 
2005; 64:1692-7. 
Doria and Briani, 2008 
Doria A, Briani C. Lupus: improving long-term prognosis. Lupus. 2008;17(3):166-70. 
Farkas et al, 2001 
Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells 
(natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus 
lesions. Am J Pathol. 2001;159(1):237-43. 
Grönhagen CM et al, 2010  
Grönhagen, C. M., Gunnarsson, I., Svenungsson, E., & Nyberg, F. Cutaneous manifestations 
and serological findings in 260 patients with systemic lupus erythematosus. Lupus, 2010 
19(10), 1187-1194. 
Kapadia N et al, 1996 
Kapadia, N., & Haroon, T. S. Cutaneous manifestations of systemic lupus erythematosus: 
study from Lahore, Pakistan. International journal of dermatology, 1996. 35(6), 408-409. 
Lahita, 1999 
Lahita RG. The role of sex hormones in systemic lupus erythematosus. Curr Opin Rheumatol. 
1999;11(5):352-6. 


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Merrill, 2014 
Merrill, J.M. Guidelines for use of the SLEDAI-2K to assess disease activity (modified 
forassessment over one month). Lupus Foundation of America. Accessed 08 December 2014 
at:http://www.lupus.org/ 
Petri, 2001 
Petri M. Long-term outcomes in lupus. Am J Managed Care. 2001;7(16) Suppl: S480-5. 
Posner et al, 2007 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s 
PediatricSuicidal Risk Analysis of Antidepressants Am J Psychiatry 2007; 164(7):1035-1043 
Ramsey-Goldman and Manzi, 2000 
Ramsey-Goldman R, Manzi S. Systemic lupus erythematosus. Women and health. Academic 
Press 2000:704. 
Rothfield N et al, 2006 
Rothfield, N., Sontheimer, R. D., & Bernstein, M. Lupus erythematosus: systemic and 
cutaneous manifestations. Clinics in dermatology. 2006; 24(5), 348-362. 
Sampson et al, 2006 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-second 
National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
World Health Organization, 2014 
World Health Organization. Definitions and reporting framework for tuberculosis - 2013 
revision (updated December 2014) 
http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345 eng.pdf 
Wysenbeek AJ et al, 1992 
Wysenbeek, A. J., Guedj, D., Amit, M., & Weinberger, A. Rash in systemic lupus 
erythematosus: prevalence and relation to cutaneous and non-cutaneous disease 
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Yao et al, 2009 
Yao Y, Richman L, Higgs BW, Morehouse CA, de los Reyes M, Brohawn P, et al. 
Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I 
trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus. 
Arthritis Rheum. 2009 Jun;60(6):1785-96. 
Zonana-Nanach et al, 2000 
Zonana-Nanach A, Barr SG, Magder LS, Petri M. Damage in systemic lupus erythematosus 
and its association with corticosteroids. Arthritis Rheum. 2000;43(8):1801-8. 


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Appendix A 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
x
Angioedema not severe enough to require intubation but requiring iv 
hydrocortisone treatment 
x
Hepatotoxicity caused by paracetamol (acetaminophen) overdose 
requiring treatment with N-acetylcysteine 
x
Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
x
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, 
etc) or convulsions that do not result in hospitalisation 
Development of drug dependency or drug abuse 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 


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


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Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
x
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
x
UN 3373 – Biological Substance, Category B 
x
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
x
Clinical trial samples will fall into Category B or exempt under IATA 
regulations 
x
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging  
x
Biological samples transported in dry ice require additional dangerous 
goods specification for the dry-ice content 
x
IATA compliant courier and packaging materials should be used for 
packing and transportation and packing should be done by an IATA 
certified person, as applicable 
x
Samples routinely transported by road or rail are subject to local 
regulations which require that they are also packed and transported in a 
safe and appropriate way to contain any risk of infection or 
contamination by using approved couriers and packaging / containment 
materials at all times.  The IATA 650 biological sample containment 


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standards are encouraged wherever possible when road or rail transport is 
used. 


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Appendix C 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)  3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL)  2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).  
Hy’s Law (HL) 
AST or ALT  3x ULN  together with TBL  2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
x
ALT  3xULN 


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x
AST  3xULN 
x
TBL  2xULN 
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will: 
x
Notify the AstraZeneca representative 
x
Request a repeat of the test (new blood draw) by the central laboratory 
x
Complete the appropriate unscheduled laboratory CRF module(s) with 
the original local laboratory test result 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
x
Determine whether the patient meets PHL criteria (see Definitions within 
this Appendix for definition) by reviewing laboratory reports from all 
previous visits (including both central and local laboratory results) 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
x
Notify the AstraZeneca representative 
x
Determine whether the patient meets PHL criteria (see Definitions within 
this Appendix for definition) by reviewing laboratory reports from all 
previous visits 
x
Promptly enter the laboratory data into the laboratory CRF 
Follow-up
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
x
Inform the AstraZeneca representative that the patient has not met PHL 
criteria. 
x
Perform follow-up on subsequent laboratory results according to the 
guidance provided in the Clinical Study Protocol. 


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Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
x
Notify the AstraZeneca representative who will then inform the central 
Study Team   
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 
x
Monitor the patient until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as 
long as medically indicated  
x
Investigate the etiology of the event and perform diagnostic 
investigations as discussed with the Study Physician.   
x
Complete the three Liver CRF Modules as information becomes available  
x
If at any time (in consultation with the Study Physician) the PHL case 
meets serious criteria, report it as an SAE using standard reporting 
procedures 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
x
If the alternative explanation is not an AE, record the alternative 
explanation on the appropriate CRF 
x
If the alternative explanation is an AE/SAE, record the AE /SAE in the 
CRF accordingly and follow the AZ standard processes 


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
x
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca 
standard processes.  
- The ‘Medically Important’ serious criterion should be used if no other 
serious criteria apply 
- As there is no alternative explanation for the HL case, a causality 
assessment of ‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
x
Report an SAE (report term ‘Potential Hy’s Law’) applying serious 
criteria and causality assessment as per above 
x
Continue follow-up and review according to agreed plan.  Once the 
necessary supplementary information is obtained, repeat the review and 
assessment to determine whether HL criteria are met.  Update the SAE 
report according to the outcome of the review 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 
 


Clinical Study Protocol Appendix D 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
108 (131) 
Appendix D 
American College of Rheumatology Criteria for Systemic 
Lupus Erythematosus Classification 
ACR Criteria for SLE Classification 
Item 
Definition 
Malar rash 
 
 
 
Fixed erythema, flat or raised, over the malar eminences, sparing the nasolabial 
folds 
Discoid rash 
 
Erythematous, raised patches with adherent keratotic scaling and follicular 
plugging: atrophic scarring may occur in older lesions 
Photosensitivity   
Skin rash as a result of unusual reaction to sunlight, by patient history or physician 
observation 
Oral ulcers  
 
 
 
Oral or nasopharyngeal ulceration, usually painless, observed by a physician 
Nonerosive arthritis  
 
 
Involving 2 or more peripheral joints, characterized by tenderness, swelling, or 
effusion 
Pleuritis or pericarditis 
   
 
a. Pleuritis--convincing history of pleuritic pain or rub heard by a physician or 
evidence of pleural effusion 
OR
b. Pericarditis – documented by electrocardiogram or rub or evidence of 
pericardial effusion 
Renal disorder 
 
 
 
a. Persistent proteinuria > 0.5 gm per day or > 3+ if quantitation not performed 
OR 
b. Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed 
Neurologic disorder 
 
a. Seizures--in the absence of offending drugs or known metabolic derangement, 
eg, uremia, ketoacidosis, or electrolyte imbalance 
 
OR 
b. Psychosis--in the absence of offending drugs or known metabolic derangement, 
eg, uremia, ketoacidosis, or electrolyte imbalance 
Hematologic disorder 
 
 
a. Hemolytic anemia with reticulocytosis 
 
OR 
b. Leukopenia--< 4,000/mm3 on  2 occasions 
 
 
OR 
c. Lymphopenia--< 1,500/mm3 on  2 occasions 
 
OR 
d. Thrombocytopenia--< 100,000/mm3 in the absence of offending drugs 


Clinical Study Protocol Appendix D 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
109 (131) 
ACR Criteria for SLE Classification 
Item 
Definition 
Immunologic disorder 
 
 
 
a. Anti-DNA: antibody to native DNA in abnormal titer 
 
OR 
b. Anti-Sm: presence of antibody to Sm nuclear antigen 
 
OR 
c. Positive finding of antiphospholipid antibodies based on: 1) an abnormal serum 
level of IgG or IgM anticardiolipin antibodies; 2) a positive test result for lupus 
anticoagulant using a standard method; or 3) a false-positive test result for at 
least 6 months and confirmed by Treponema pallidum immobilization or 
fluorescent treponemal antibody absorption test. 
Positive antinuclear 
antibody   
 
An abnormal titer of antinuclear antibody by immunofluorescence or an 
equivalent assay at any point in time in the absence of drug. 
 
 
 


Clinical Study Protocol Appendix E 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
110 (131) 
Appendix E 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SLEDAI 2K  
(Modified for assessment over one month) 
Study No.:   
 
 
Patient Name:    
 
 
Visit Date:   
 
(Enter weight in SLEDAI Score column if descriptor is present at the time of the visit or in the preceding 14 days.)


Clinical Study Protocol Appendix E 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
111 (131) 
 


Clinical Study Protocol Appendix F 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
112 (131) 
Appendix F 
Cutaneous Lupus Erythematosus Disease Area and Severity 
Index 
 
 


Clinical Study Protocol Appendix G 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
113 (131) 
 
Appendix G 
Physician global assessment  
 


Clinical Study Protocol Appendix H 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
114 (131) 
Appendix H 
Oral Corticosteroid Guidance    
Examples of Equivalent Doses of Oral Prednisone 
Oral Prednisone and 
Equivalents 
Equivalent Dose 
Oral Prednisone  
7.5 mg 
10 mg 
20 mg 
30 mg 
40 mg 
Cortisone 
37.5 mg 
50 mg 
100 mg 
150 mg 
200 mg 
Hydrocortisone 
30 mg 
40 mg 
80 mg 
120 mg 
160 mg 
Methylprednisolone 
6 mg 
8 mg 
16 mg 
24 mg 
32 mg 
Prednisolone 
7.5 mg 
10 mg 
20 mg 
30 mg 
40 mg 
Triamcinolone 
8 mg 
8 mg 
16 mg 
24 mg 
32 mg 
 
Example of OCS Tapering Schedule 
Time point 
Initial Dose of Oral Prednisone or Equivalent (mg/day) 
40 
35 
30 
25 
20 
15 
10 
Week 12 
35 
30 
25 
20 
15 
12.5 
10 
Week 16 
30 
25 
20 
15 
12.5 
12.5 
10 
Week 20 
25 
20 
15 
12.5 
12.5 
12.5 
7.5 
Week 24 
20 
15 
12.5 
12.5 
10 
10 
7.5 
Week 28 
15 
12.5 
12.5 
10 
10 
10 
7.5 
Week 32 
12.5 
10 
10 
10 
7.5 
7.5 
7.5 
Week 36 
10 
10 
7.5 
7.5 
7.5 
7.5 
7.5 
Week 40 
7.5 
7.5 
7.5 
7.5 
7.5 
7.5 
7.5 
* 
Note: patients on OCS doses equivalent to 10 mg prednisone/day may tolerate tapering by 1 mg/day per 
visit rather than an abrupt drop from 10 mg/day to 7.5 mg/day. The stepwise tapering of OCS dose should 
be performed at the discretion of the Investigator. 


Clinical Study Protocol Appendix I 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
115 (131) 
Appendix I 
General guidance for Determination of Major Surgery 
The goal of this guidance is to maximize the benefit/risk for each patient entering this study. 
An important aspect to this goal is taking into account all relevant history, including recent 
surgeries and/or injuries that could influence the safety of the patient potentially being 
exposed to an additional immunomodulatory medication or could bias the efficacy endpoints 
of the trial. 
Given the advancement and availability of surgical techniques, major surgery is in the 
judgment of the Investigator and his/her evaluation of the following criteria, regardless of the 
specific surgical procedure: 
1.
Has the patient completely recovered (mentally, emotionally, and physically) from 
the surgery and is not receiving additional medications related to the prior surgery 
(ie, antibiotics)? 
2.
Has the patient completed all follow-up visits related to the surgery, including 
ancillary services such as physical and/or occupational therapy? 
3.
Has the patient resumed all of their prior activities? 
4.
Has the patient returned to his/her baseline medications for SLE and non-SLE 
indications? 


Clinical Study Protocol Appendix J 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
116 (131) 
Appendix J 
Guidance for abnormal Pap-smear results 
Pap Smear Result 
Abbreviatio
n
Also Known As 
Suggested Action 
Atypical squamous cells–
undetermined significance 
ASC–US 
— 
Permitted to enter study 
Atypical squamous cells–
cannot exclude HSIL 
ASC–H 
— 
Permitted to enter study 
Atypical glandular cells 
AGC 
— 
Permitted to enter study 
Low-grade squamous 
intraepithelial lesion 
LSIL 
 
Mild dysplasia 
Cervical intraepithelial 
neoplasia–1 (CIN–1) 
Permitted to enter study 
High-grade squamous 
intraepithelial lesion 
HSIL 
 
Moderate dysplasia 
CIN-2 / CIN II 
Permitted to enter study 
High-grade squamous 
intraepithelial lesion 
HSIL 
 
CIN–3 / CIN III 
Carcinoma in situ (CIS) 
Exclude/discontinue subject 
Endocervical 
adenocarcinoma in situ 
AIS 
— 
Exclude/discontinue subject 
 
 


Clinical Study Protocol Appendix K 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
117 (131) 
Appendix K 
Anaphylaxis 
In adults, anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled: 
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips, 
tongue and/or uvula)  
AND AT LEAST ONE OF THE FOLLOWING: 
x
Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxaemia) 
x
Reduced BP (see number 3 below for definition) or associated symptoms 
of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence) 
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):  
x
Involvement of the skin-mucosal tissue (eg, generalised hives, itch, flush, 
swollen lips, tongue and/or uvula) 
x
Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxaemia) 
x
Reduced BP (see number 3 below for definition) or associated symptoms 
(eg, hypotonia [collapse], syncope, incontinence) 
x
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, 
vomiting) 
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours); for adults a systolic BP of less than 90 mm Hg or greater than 30% decrease 
from that person’s baseline BP (taken at or immediately prior to the injection), 
whichever BP is lower (Sampson et al, 2006). 
The following definitions are provided for the purposes of this study: 
Hypersensitivity reaction: an acute onset of an illness with involvement of the skin, mucosal 
tissue, or both during or after the injection of investigational product (but does not meet the 
definition of anaphylaxis described above). 
 
To assist with the mitigation of these AEs, see Table 6, which categorizes reactions by 
severity of symptoms, proposes severity-specific treatment and offers guidance on 
management of investigational product. Final treatment is at the discretion of the Investigator 
and should reflect local SOC. 


Clinical Study Protocol Appendix K 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
118 (131) 
Table 6 
An approach to management of anaphylactic and hypersensitivity 
Severity of symptoms 
Treatment 
Investigational product 
Mild reactions 
(hypersensitivity) 
Mild reactions such as 
headache, nausea, non-
pruritic rash, or mild 
hypersensitivity 
reactions including 
localised cutaneous 
reactions such as mild 
pruritus, flushing, rash, 
dizziness, headache, 
20 mmHg change in 
systolic BP from 
pre-injection 
measurement 
Evaluate patient, including close 
monitoring of vital signs  
At the discretion of the Investigator, 
treat patient, for example, with: 
-
Normal saline (~500 to 
1000 mL/hour IV) and/or 
-
Diphenhydramine 50 mg IV or 
equivalent and/or 
-
Acetaminophen 500 to 650 mg 
or equivalent dose of 
paracetamol and/or 
-
Topical antihistamines and/or 
low-potency topical 
corticosteroid preparations 
and/or 
-
Anti-nausea medication, as 
needed 
Stop investigational product 
injection immediately 
Option 1: do not resume 
investigational product injection; 
Option 2: discontinue any 
further administration of 
investigational product; OR at 
the discretion of the Investigator, 
continue future investigational 
product administrations and 
pretreating patient 1.5 to 0.5 
hours prior to investigational 
product administration, for 
example with: 
-
Diphenhydramine 50 mg IV 
or equivalent 
-
Acetaminophen 500 to 
650 mg or equivalent dose 
of paracetamol 
Moderate reactions ( 
hypersensitivity)
IP related reaction such 
as those listed above 
under mild reactions but 
excluding moderate 
hypersensitivity 
reactions (see below) 
Evaluate patient, including close 
monitoring of vital signs  
Treat patient, for example, with: 
-
Normal saline (~500 to 
1000 mL/hour IV) and/or 
-
Diphenhydramine 50 mg IV or 
equivalent and/or 
-
Acetaminophen 500 to 650 mg 
or equivalent dose of 
paracetamol and/or 
-
Anti-nausea and/or antiemetic 
intramuscular, as needed 
Stop investigational product 
injection immediately 
Option 1: do not resume 
investigational product injection; 
OR based on risk/benefit 
evaluation, at the discretion of 
the Investigator, resume current 
investigational product injection 
under observation after treatment 
of current signs and symptoms 
as suggested (eg, normal saline 
and/or Tylenol and/or topical 
antihistamines) 


Clinical Study Protocol Appendix K 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
119 (131) 
Severity of symptoms 
Treatment 
Investigational product 
 
 
Additional Options for Future 
Administration of investigational 
product 
Discontinue any further 
administrations of 
investigational product; OR 
Further investigational product 
injections, at the discretion of 
the Investigator, continue 
investigational product 
administration and pretreating 
patient 0.5 to 1.5 hours prior to 
investigational product 
administration, for example 
with: 
-
Diphenhydramine 50 mg IV 
or equivalent 
-
Acetaminophen 500 to 
650 mg or equivalent dose 
of paracetamol 
-
Anti-nausea and/or 
antiemetic by mouth 
If moderate event recurs in the 
same patient, discontinue further 
investigational product 
administration 
Moderate 
hypersensitivity
reactions 
IP- related reactions 
which may include 
generalised rash or 
urticaria, palpitations, 
chest discomfort, 
shortness of breath, 
hypo- or hypertension 
with >20 mmHg change 
in systolic BP from 
pre-injection 
measurement 
Evaluate patient, including close 
monitoring of vital signs  
Treat patient, for example, with: 
-
Normal saline (~500 to 
1000 mL/hour IV) and/or 
-
Diphenhydramine 50 mg IV or 
equivalent and/or 
-
Acetaminophen 500 to 650 mg 
or equivalent dose of 
paracetamol and/or 
-
IV corticosteroids, such as 
hydrocortisone 100 mg or 
methylprednisolone 20 to 40 mg 
Stop investigational product 
injection immediately 
DO NOT resume current 
injection 
Discontinue any further 
administrations of 
investigational product 
Consider need for additional oral 
antihistamine administration or 
oral corticosteroid 
administration to prevent 
reoccurrence of symptoms over 
subsequent 2 to 3 days 
 


Clinical Study Protocol Appendix K 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
120 (131) 
Severity of symptoms 
Treatment 
Investigational product 
Severe 
Above plus fever with 
rigors, hypo- or 
hypertension with 40 
mmHg change in 
systolic BP, signs of end 
organ dysfunction (eg, 
symptomatic 
hypotension such as 
hypotonia, syncope, 
incontinence, seizure) 
from pre-injection 
measurement, or 
wheezing, angioedema, 
or stridor 
OR 
 
Life-threatening 
Defined as a reaction 
that is life-threatening 
and requires pressor 
and/or ventilator support 
or shock associated with 
acidemia and impairing 
vital organ function due 
to tissue hypoperfusion 
Evaluate patient, including close 
monitoring of vital signs 
Maintain airway, oxygen if available 
Treat patient immediately, for 
example with: 
-
Normal saline (~500 to 
1000 mL/hour IV) 
-
Epinephrine for bronchospasm, 
hypotension unresponsive to IV 
fluids, or angioedema. Dose and 
route as per local SOC, 
example, epinephrine 1:1000, 
0.5 to 1.0 mL administered SC 
for mild cases and 
intramuscular for more severe 
cases 
-
IV corticosteroids, such as 
hydrocortisone 100 mg or 
methylprednisolone 20 to 40 mg 
-
Diphenhydramine 50 mg IV or 
equivalent 
-
Acetaminophen 500 to 650 mg 
or equivalent dose of 
paracetamol 
Call emergency medical transport for 
transport to emergency hospital 
based on judgment of the 
Investigator 
Grade 3 wheezing, hypotension or 
angioedema is unresponsive to single 
dose of epinephrine 
Grade 4 event 
At the discretion of the Investigator 
Stop investigational product 
injection immediately 
Permanently discontinue 
investigational product 
administration 
Consider need for additional oral 
antihistamine administration or 
oral corticosteroid 
administration to prevent 
reoccurrence of symptoms over 
subsequent 2 to 3 days 
 


Clinical Study Protocol Appendix L 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
Version 1.0 
Date 20 Sep 2016 
121 (131) 
Appendix L 
Classification criteria for catastrophic anti-phospholipid 
syndrome 
 
Classification Criteria for Catastrophic Antiphospholipid Syndrome 
Criteria 
1.
Evidence of involvement of three or more organs, systems and/or tissues 
2.
Development of manifestations simultaneously or in less than a week 
3.
Confirmation by histopathology of small vessel occlusion in at least one organ or 
tissue 
4.
Laboratory confirmation of the presence of anti-phospholipid antibodies (lupus 
anticoagulants and/or anticardiolipin antibodies) 
Classification 
 
Definite catastrophic antiphospholipid syndrome 
Requires all four criteria 
 
Probable catastrophic antiphospholipid syndrome 

All four criteria, except for only two organs, systems, and/or sites of tissue involvement 
or 

All four criteria, except for the laboratory confirmation at least 6 weeks apart due to early 
death of a patient never tested for antiphospholipid before catastrophic antiphospholipid 
syndrome or 

Criteria 1, 2, and 4 above, or 

Criteria 1, 3, and 4, and the development of a third event in more than a week, but less 
than a month, despite anticoagulation 
Adapted from Asherson R, Cervera R, de Groot P, Erkan D, Boffa MC, Piette JC, et al. Catastrophic 
antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. 
Lupus. 2003;12(7): 530–534. 




Clinical Study Protocol Appendix M 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
123 (131) 


Clinical Study Protocol Appendix M 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
124 (131) 




Clinical Study Protocol Appendix M 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
126 (131) 


Clinical Study Protocol Appendix M 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
127 (131) 


Clinical Study Protocol Appendix N 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
128 (131) 
Appendix N 
Vasculitic syndromes excluded from the study 
Subjects with a history or current diagnosis of the following vasculitis syndromes are 
excluded from participating in the study. Vasculitis due to SLE is allowed in the study. 
x
Behçet’s Disease 
x
Buerger’s Disease 
x
Central Nervous System Vasculitis 
x
Churg Strauss Syndrome 
x
Cryoglobulinemia 
x
Giant Cell Arteritis 
x
Henoch-Schönlein Purpura 
x
Kawasaki Disease 
x
Microscopic Polyangiitis 
x
Polyarteritis Nodosa 
x
Polymyalgia Rheumatica 
x
Takayasu’s Arteritis 
x
Wegener’s Granulomatosis 


Clinical Study Protocol Appendix O 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
129 (131) 
Appendix O 
Patient Survey at Week 12 
Participant Questionnaire on Study Experience  
Thank you for your participation in D3461C00008 study. In this questionnaire, we would like 
to ask you a few questions about your experience of the study with specific focus on study 
design, the study medication injections, and procedures during the study visits. Your response 
is very valuable and will allow us to make future trials better tailored to patient´s need. For 
each question below, please mark the box that best matches your experience and feelings 
about the study. 
1
Did you think the information you received before joining the study was consistent with your 
experience during the study? 
[   ] Yes, it was consistent 
[   ] No there was some inconsistency, please specify:  
________________________________________________________________________
________________________________________________________________________
2
Do you believe you received enough information before and during the study? 
[   ] Yes 
[   ] No 
What additional information should we have shared with you before and during the study? 
________________________________________________________________________
________________________________________________________________________
3
You had 25% chance of receiving placebo, rather than the active study medication. Was this a 
concern and did this affect your willingness to participate in the study? 
[   ] No, I had no concern 
[   ] Yes, I had some concern but still wanted to participate in the trial 
4
You might have had to stop taking medications after joining this study. If you had to do so, 
how did you feel about that? 
[   ] I did not have to stop taking any medication. 
[   ] Reasonable 
[   ] Unreasonable but acceptable 
[   ] Unacceptable, please specify the name of medications. 
______________________________________________________________________
5
How did you feel about the frequency of visits (every 2 week on-site visit) in this study? 
[   ] Comfortable 


Clinical Study Protocol Appendix O 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
130 (131) 
[   ] Inconvenient but acceptable 
[   ] Uncomfortable 
6
How did you feel about having the injections once every second week? 
[   ] Comfortable 
[   ] Inconvenient but acceptable 
[   ] Very inconvenient, please give us some advice: 
________________________________________________________________________
7
How did you feel about having to come to the clinic for the injections? 
[   ] Comfortable 
[   ] Inconvenient but acceptable 
[   ] Very inconvenient 
8
Would you prefer to perform the subcutaneous injections yourself at home? 
[   ] Yes, I would prefer to inject myself 
[   ] No, I prefer injections administered by my doctor or nurse 
9
If training were to be provided, would you prefer to give yourself study drug injections? 
[   ] Yes 
[   ] No 
10
Were you comfortable with blood samples being taken during the study? 
[   ] Yes 
[   ] No 
 If no, please select reasons below. 
[   ] Frequency of blood samples taken 
[   ] Volume of blood samples taken 
[   ] Pain associated with venous puncture 
11
What did you find most challenging in this study? 
________________________________________________________________________ 
 
________________________________________________________________________ 
 
________________________________________________________________________ 
 
_______________________________________________________________________ 


Clinical Study Protocol Appendix O 
Drug Substance Anifrolumab (MEDI-546)  
Study Code D3461C00008 
 
Version 1.0 
Date 20 Sep 2016 
131 (131) 
12
Is there anything we could do to improve your experience during this study? (For example, 
study design, study procedure and site service, etc.) 
________________________________________________________________________ 
 
________________________________________________________________________ 
 
________________________________________________________________________ 
________________________________________________________________________ 
13
Do you see any other advantages or disadvantages as a result of participating in the study? 
________________________________________________________________________ 
 
________________________________________________________________________ 
14
If we run another study with similar design, would you want to participate? 
[   ] Yes 
[   ] No, please specify the reason:  
 
________________________________________________________________________  
 

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D3461C00008
Edition Number
2
Date
27/02/2018
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2
Study Characterizing the Pharmacokinetics, Pharmacodynamics, and 
Safety of Anifrolumab following subcutaneous administration in Adult 
Systemic Lupus Erythematosus Subjects with Type I Interferon test high 
result and active skin manifestations


PPD


PPD


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................1
SIGNATURE OF STUDY STATISTICIAN.............................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .......................................3
TABLE OF CONTENTS..........................................................................................4
LIST OF ABBREVIATIONS ...................................................................................6
AMENDMENT HISTORY.......................................................................................8
1.
STUDY DETAILS..................................................................................11
1.1
Study objectives......................................................................................11
1.1.1
Primary objective....................................................................................11
1.1.2
Secondary objectives...............................................................................11
1.1.3
Safety objectives.....................................................................................11
1.1.4
Exploratory objectives ............................................................................11
1.2
Study design ...........................................................................................12
1.2.1
Steroid Tapering .....................................................................................13
1.2.2
Steroid Burst...........................................................................................14
1.3
Number of subjects .................................................................................15
2.
ANALYSIS SETS ..................................................................................15
2.1
Definition of analysis sets .......................................................................15
2.1.1
All subjects analysis set...........................................................................15
2.1.2
Full analysis set.......................................................................................15
2.1.3
PK analysis set........................................................................................15
2.1.4
PD analysis set........................................................................................15
2.2
Violations and deviations ........................................................................16
3.
PRIMARY AND SECONDARY VARIABLES......................................16
3.1
Primary variables ....................................................................................17
3.1.1
Pharmacodynamics (PD).........................................................................17
3.1.2
Pharmacokinetics (PK)............................................................................17
3.2
Secondary variables ................................................................................17
3.2.1
Immunogenicity......................................................................................17
3.2.2
Safety......................................................................................................18
3.2.2.1
Adverse Events .......................................................................................18
3.2.2.2
Laboratory variables ...............................................................................21
3.2.2.3
ECGs ......................................................................................................21


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
5
3.2.2.4
Physical examination ..............................................................................22
3.2.2.5
Vital signs...............................................................................................22
3.2.2.6
Colombia-Suicide Severity Rating Scale (C-SSRS).................................22
3.3
Exploratory variables ..............................................................................23
3.3.1
Efficacy ..................................................................................................23
3.3.2
Oral corticosteroid management..............................................................25
3.3.3
Skin tape test (optional)...........................................................................25
3.4
Assessment of study population ..............................................................25
3.4.1
Subject disposition variables ...................................................................25
3.4.2
Demographic and baseline characteristic variables..................................26
3.4.3
Surgical and medical history ...................................................................26
3.4.4
Prior and concomitant medications..........................................................26
3.4.5
Exposure of investigational product ........................................................27
4.
ANALYSIS METHODS.........................................................................28
4.1
General principles...................................................................................28
4.1.1
Visit windows.........................................................................................28
4.1.2
30
4.1.3
Presentation of results .............................................................................30
4.1.4
Missing Data...........................................................................................30
4.2
Analysis methods....................................................................................31
4.2.1
Primary variable analysis ........................................................................31
4.2.1.1
Pharmacodynamics (PD).........................................................................31
4.2.1.2
Pharmacokinetics (PK)............................................................................32
4.2.2
Secondary variable analysis ....................................................................32
4.2.2.1
Immunogenicity......................................................................................33
4.2.2.2
Analysis methods for safety variables......................................................34
4.2.3
Exploratory variable analysis ..................................................................38
4.2.3.1
Efficacy ..................................................................................................38
4.2.3.2
OCS management analysis......................................................................39
4.2.3.3
Skin tape test (optional)...........................................................................40
4.2.4
Assessment methods for the study population .........................................40
4.2.4.1
Subject disposition..................................................................................40
4.2.4.2
Demographic and baseline characteristics ...............................................40
4.2.4.3
Exposure of investigational product ........................................................41
5.
INTERIM ANALYSES ..........................................................................41
6.
CHANGES OF ANALYSIS FROM PROTOCOL ..................................41
7.
REFERENCES .......................................................................................42
8.
APPENDIX ............................................................................................42


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
6
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
DA
AE
AESI
ALT
ANA
AST
AUC
Cmax
Ctrough
CLASI
CNS
CRF
CSP
CSR
C-SSRS
CV%
C3, C4, CH50
EDV
ESR
DBL
dsDNA
ECG
GGT
ICF
IFN
IP
IPD
LLOQ
MACE
nAb
OCS
PD
Anti-Drug Antibodies
Adverse Event
Adverse Event of Special Interest
Alanine Transaminase
Anti-Nuclear Antibodies
Aspartate Transaminase
Area Under the Curve
Maximum plasma (peak) drug concentration after single dose
Administration
Trough concentration
Cutaneous Lupus erythematosus disease Area and Severity Index
Central Nervous System
Case Report Form
Clinical Study Protocol
Clinical Study Report
Columbia Suicide Severity Rating Scale
Coefficient of Variation
Major Complement Proteins
Early Discontinuation Visit
Erythrocyte Sedimentation Rate
Database Lock
Double Stranded Deoxyribonucleic Acid
Electrocardiogram
Gamma Glutamyl Transferase
Informed Consent Form
Interferon
Investigational Product
Important Protocol Deviation
Lower Limit of Quantification
Major Adverse Cardiovascular Events
Neutralizing Antibodies
Oral Corticosteroids
Pharmacodynamics


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
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Abbreviation or 
special term
Explanation
PGA
PK
PT
PTT
Q2W
Q4W
SAE
SC
SD
SE
SI
SLE
SLEDAI-2K
SOC
Tmax
TB
TELVC
VAS
Physician Global Assessment
Pharmacokinetic
Prothrombin Time
Partial Thromboplastin Time
Every 2 Weeks
Every 4 Weeks
Serious Adverse Event
Subcutaneous
Standard Deviation
Standard Error
International System of Units
Systemic Lupus Erythematosus
Systemic Lupus Erythematosus Disease Activity Index 2000
Standard of Care
Time when Cmax is observed
Tuberculosis
Treatment Emergent Laboratory/Vital signs Changes
Visual Analogue Scale


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
8
AMENDMENT HISTORY
Date
Brief description of change
26 Feb 2018
An update to the pharmacodynamic variable names; 
!
“absolute score” to “fold change”
!
“neutralization ratio” to “percent suppression of fold change”
!
An addition of a pharmacodynamic analysis set definition.
!
Update protocol deviation definitions have been reworded to be consistent 
with the study protocol deviation document.
!
The addition of a how to handle early discontinuation visits for appropriate 
outputs.
!
Clarified CLASI objective to remove ambiguity.
!
Corrected when and how many blinded delivery review meetings will 
occur.
!
Important protocol deviations will be tabulated only, not tabulated and 
listed.
!
Removed unnecessary mention of treatment emergent event.
!
Added the definition of acute adverse event, injection related reaction, 
infections, hypersensitivity.
!
Added herpes zoster category definitions.
!
Clarified event rates by including formula.
!
Correct last date of exposure to IP from +28 days to +14 days.
!
Corrected wording surrounding laboratory variables for clarity.
!
Added ECG “Note done” category.
!
Clarify which vital signs measurement will be summarized.
!
Clarified ≥ 50% reduction in CLASI activity responder variable.
!
Corrected how autoantibodies and inflammatory markers will be analyzed.
!
Clarified OCS AUC calculations.
!
Corrected the definition of bursts which will be summarized and over 
which time periods.
!
Clarified that skin tape test output would not be reported for the study 
reports.
!
Added missing summary for subject disposition “subjects not randomized 
including reason”
!
Separated out surgical and medical history.
!
Added reporting of prior and concomitant medications. 


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
9
Date
Brief description of change
!
Added exposure scenarios for the Week 12 analysis.
!
Removed injection count table.
!
Clarified that PK post-dose will not be mapped according to Table 1 visit 
windows.
!
Clarified that prohibited medication would make a subject a non-responder 
for responder variables.
!
Treatment compliance analysis added.
!
Clarified the CLASI damage missing component imputation for 
dyspigmentation.
!
Added the handling of percentage change from baseline for subjects with a 
baseline value of zero.
!
Clarified how early discontinuation visits will be handled.
!
Clarified that, where mentioned, change from baseline refers to absolute 
change from baseline.
!
Added fold change table categorization - <2 and ≥2.
!
Removed PD histogram.
!
PK scatter plots changed from arithmetic mean to geometric mean.
!
Added spaghetti plots for individual Ctrough measurements.
!
Serum concentrations below LLOQ will be set to a value of LLOQ/2, not 
zero.
!
Removal of the imputation of “missing” for consecutive PK serum 
concentrations of values below LLOQ.
!
Add acute AEs to the overall AE summary table.
!
Clarified that reported MACE events will be those according to the 
Cardiovascular Event Adjudication Committee.
!
Clarified what treatment periods AEs will be reported for.
!
Shift tables for physical examination have been removed.
!
Longitudinal plot of the proportion of responders for CLASI activity was 
removed.
!
Single line plots for each subject and their change from baseline in CLASI 
activity score was removed.
!
CLASI activity and damage histogram have been removed.
!
Change from baseline in PGA was changed from a table to a longitudinal 
plot.


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
10
Date
Brief description of change
!
Table for the frequency and percentage of subjects remaining on 
treatment, discontinued IP but still in the study and withdrawn from the 
study has been added.
!
All data collected up until the date of data cut-off will be used, not only up 
to Week 12 for each subject.
!
Added inflammatory marker TELVC thresholds to the appendix.
!
Typos corrected


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
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1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
Primary Objective:
Outcome Measures:
To characterize the PK and PD of 150 mg 
and 300 mg anifrolumab administered as 
SC injections Q2W as measured by 
anifrolumab concentrations, PK parameters, 
21-gene type 1 IFN PD fold change and 
percent suppression of fold change Week 
12.
Anifrolumab concentrations and PK parameters 
including maximum concentration (Cmax) after first 
dose and trough concentration (Ctrough) for subsequent 
dosing.
21-gene type 1 IFN PD signature fold change and 
percent suppression of fold change (relative to 
baseline).
1.1.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To characterize the safety and tolerability of 
anifrolumab when SC administered for a 52 
Week treatment period.
Adverse events (AE); serious adverse events (SAEs);
Adverse events of special interest (AESIs) including 
herpes zoster, influenza, opportunistic infections, 
non-opportunistic serious infections, tuberculosis
(TB), malignancies, non-SLE related vasculitis,
anaphylaxis, and major adverse cardiovascular events
(MACE); laboratory variables; physical
examinations; vital signs; and ECG.
To characterize the immunogenicity of
anifrolumab when administered SC for a 52
Week treatment period.
Anti-drug antibodies (ADA)
1.1.3
Safety objectives
Safety Objective:
Outcome Measure:
See above.
1.1.4
Exploratory objectives
Exploratory Objective:
Outcome Measure:
To characterize the efficacy of SC 
administered anifrolumab on SLE skin 
manifestations as measured by the change 
in Cutaneous Lupus erythematosus disease 
Area and Severity Index (CLASI) score 
from baseline.
Proportion of subjects achieving ≥50% improvement
in CLASI activity score from baseline to Week 12.
Proportion of subjects achieving ≥50% improvement 
in CLASI activity score from baseline to Week 52.
To explore the effects of SC administered 
anifrolumab on type I IFN and other 
pathway related gene expression in skin 
tissue (optional part of study).
21-gene type 1 IFN and other pathway-related gene 
expression in skin tissue at baseline and at Week 12.


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
12
1.2
Study design
This is a Phase 2, multicentre, double-blind, randomized, placebo-controlled study
characterizing the pharmacokinetics (PK), pharmacodynamics (PD) and safety of two fixed 
doses of anifrolumab administered as subcutaneous (SC) injections in adult systemic lupus 
erythematosus (SLE) subjects with type I interferon (IFN) test-high result and active skin 
manifestations while on stable standard of care (SOC) treatment. The study will be double-
blind until database lock (DBL) for the primary analysis performed after all subjects have
completed Week 12. Thereafter, the sponsor will be unblinded whilst the investigators and 
subjects will remain blinded throughout the remainder of the study.
Approximately 32 subjects will be randomized to one of the four treatment groups in a 3:1:3:1
ratio receiving:
!
anifrolumab at a fixed dose of 150mg as added to SOC, given every 2 weeks (Q2W)
as one SC injection in a volume of 1mL (12 subjects);
!
placebo as added to SOC, given Q2W as one SC injection in a volume of 1mL (4 
subjects);
!
anifrolumab at a fixed dose of 300mg as added to SOC, given Q2W as two SC 
injections in a volume of 1mL each (12 subjects) or
!
placebo as added to SOC, given Q2W as two SC injections in a volume of 1mL 
each (4 subjects).
Subjects must be taking either one or any combination of the following: oral corticosteroids 
(OCS), antimalarial, or immunosuppressants at stable doses. Specific medication restrictions
are contained in the eligibility criteria as described in Sections 3.1 and 3.2.2 of the clinical 
study protocol (CSP). OCS doses should remain stable through Week 12, unless there is a 
clinical, safety or ethical reason to taper in which case reduction of OCS dose may be 
permitted from Week 4. Starting at Week 12 a mandatory steroid tapering attempt will be 
required for all subjects with an OCS dose ≥10.0 mg per day of prednisone or equivalent at 
randomization as described in Section 7.7.2.1 of the CSP.
See Figure 1 for the outline of the study design. 
This study includes:
A screening period of up to 30 days;
A treatment period of 52 weeks;
A follow-up period of 8 weeks.
The investigational product (IP) will be administered at study visits for 26 doses (Week 0 to 
Week 50) and the last follow-up visit will be 10 weeks after the last IP dose.


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
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Figure 1
Study flow chart 
1.2.1
Steroid Tapering
Oral corticosteroid doses should remain stable through to Week 12 unless there is a clinical, 
safety, or ethical reason to taper earlier, in which case OCS dose reductions may be permitted 
from Week 4. Corticosteroid tapering must be attempted in all subjects with an OCS dose 
≥10.0 mg/day (of prednisone or equivalent) at randomization and aim for a target OCS dose of 
≤7.5 mg/day at Week 40 (starting at Week 12). Tapering will start at Week 12 and may 
continue until end of study unless at least one of the following criteria is met:
!
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) activity 
which is worsened compared to baseline in major organ systems (renal, CNS, 
cardiopulmonary, vasculitis, fever, thrombocytopenia, or haemolytic anaemia, or 
gastrointestinal activity).
!
Newly affected organ system(s) based on the SLEDAI-2K, excluding serological 
abnormalities (dsDNA antibodies, hypocomplementemia).
!
Persistent moderately to severely active skin manifestations as reflected by a 
Cutaneous Lupus erythematosus disease Area and Severity Index (CLASI) activity 
score of ≥10.


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
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!
Moderate to severe arthritis disease as reflected by an active joint count of ≥8 tender 
and/or swollen joints.
Tapering can be started on the scheduled study visit day (e.g., Week 12, Visit 8) based on
clinical manifestations and the laboratory values from the previous visit. If laboratory values
or clinical evaluation of the current visit show increased or persistent SLE activity the tapering
can be reversed. Steroid tapering must be started within 14 days of the visit. If steroid tapering 
is not attempted in an eligible subject, the AstraZeneca study physician must be contacted 
immediately. The recommended steroid-tapering regimen is provided in Appendix A but 
Investigators will have flexibility in how the OCS dose is reduced at each visit. Investigators 
will not be required, but may continue, to taper OCS dose beyond the target of ≤7.5 mg/day 
up to end of study based on disease activity. If a subject experiences increased disease activity 
secondary to OCS tapering, the dose may be increased up to a maximum of the baseline OCS 
dose for up to 2 weeks followed by a new tapering attempt.
1.2.2
Steroid Burst
Week 0 to Week 12
To allow adequate time for the investigational product to achieve significant clinical benefit, 
Investigators may administer one burst and taper of corticosteroids between Week 0 (Day 1) 
and Week 12 for increased SLE disease activity/non-SLE activity. After Week 12, additional 
steroid bursts may be given as per investigators judgement of clinical need.
A steroid burst is defined as one of the following:
!
OCS increase up to a maximum daily dose of 40 mg/day prednisone (or equivalent) 
for up to a total of 14 days and that must be fully administered and tapered to less 
than or equal to the Day 1 dose by the end of the 14th day.; or
!
Intramuscular methylprednisone (≤80 mg) or equivalent administered as a single 
dose between Day 1 and Week 12; or
!
A maximum of 2 intra-articular/tendon sheath/bursal injections (for a total 
methylprednisolone ≤80 mg or equivalent) can be given.
Subjects who receive any intra-articular/tendon sheath/bursal injections should not receive
OCS or intramuscular burst between Day 1 and Week 12. Subjects who receive more than one 
steroid burst and taper from Week 0 (Day 1) to Week 12, or who violate any of the criteria
above, may continue in the study, but AZ study physician should be contacted.
From Week 12 until end of study
After Week 12 and up until end of study, additional steroid bursts, defined as above, may be
given for SLE increased disease activity.
Adjustments of OCS doses above Day 1 dose for increased SLE activity may be allowed after 
Week 12 with the AZ study physician approval.


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
15
Intra-articular/tendon sheath/bursal injections are allowed for non-SLE related disorders from 
Week 12 and onwards. The injection should be administered after the completion of all
assessments, including IP administration and post-injection PK blood test (if applicable).
1.3
Number of subjects
There is no formal power calculation as there will be no hypothesis testing. The data collected 
in this study will be used to inform further study design and development. Subjects will be 
randomized at a 3:1 ratio, receiving active:placebo (12 subjects on active and 4 subjects on 
placebo) for the two dosing levels (300 mg and 150 mg).
 
 
 
 
 
 
 
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
All subjects analysis set
This analysis set will be comprised of all subjects screened for the study and will be used for
reporting of disposition and screening failures.
2.1.2
Full analysis set
The full analysis set will be used as the primary population for reporting efficacy and safety 
data. This comprises of all subjects randomized into the study who receive at least one dose of 
IP, and will be analyzed according to randomized treatment (modified Intention-To-Treat). 
Any important deviations from randomized treatment will be considered when interpreting the
data.
2.1.3
PK analysis set
All subjects who received anifrolumab and who had at least one quantifiable serum PK
observation post first dose will be included in the PK analysis dataset. All PK summaries will 
be based on this analysis set.
2.1.4
PD analysis set
Subjects in the full analysis set who are 21-gene IFN test high at baseline.
CCI


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
16
2.2
Violations and deviations
Important protocol deviations (IPDs) are a subset of protocol deviations that may significantly
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject's rights, safety, or well-being.
IPDs that have a very high likelihood of affecting the interpretation of the primary and/or key 
secondary study results include:
!
Subject did not fulfil inclusion criteria but are entered into the study.
!
Subject fulfilled exclusion criteria but are entered into the study.
!
Investigational product deviations, for example, subject received incorrect IP kit.
!
Use of the prohibited medications listed in section 7.8 of the CSP.
!
Subject met discontinuation criteria described in section 3.9 of the CSP but 
continued to receive IP.
!
Assessment-related deviations, for example, PD and/or PK sample not collected as 
per protocol from Week 0 to Week 12.
!
Safety reporting deviations, for example, delay in SAE/overdose/pregnancy 
reporting according to AZ SOP/CSP/local regulatory requirement.
!
Good clinical practice violation.
In this study, all protocol deviations will be reported in IMPACT, AstraZeneca’s internal 
protocol deviation capture system.
A list of all protocol deviations that have occurred in the study up until the last subject has 
completed Week 12 will be completed and documented prior to unblinding the study data and 
will be based on deviations as defined in the Protocol Deviation Document. Additionally, a 
final list of protocol deviations will be completed and documented for the end of study 
analysis.
During the blinded delivery review (BDR) meeting, which will take place when 
approximately 10 subjects have completed Week 12, protocol deviations will be classified as 
important or other. Only important protocol deviations will be tabulated in the study reports.
3.
PRIMARY AND SECONDARY VARIABLES
The term baseline refers to the last measurement prior to randomization and dose 
administration on Day 1. If the Day 1 value is missing, invalid or is collected after 


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
17
administration of IP, the latest assessment prior to dose administration on Day 1 will serve as 
baseline.
All variables and their analyses described below will be presented in the Week 12 and Week 
52 study reports.
3.1
Primary variables
3.1.1
Pharmacodynamics (PD)
The two primary variables used to characterize PD are the 21-gene type 1 IFN signature fold 
change and percent suppression of fold change. 
For the derivation of the percent suppression of fold change see Appendix F.
These variables will be characterized at every visit where the assessments are taken, with the 
primary time-point being at Week 12.
Missing values will not be imputed and only observed values will be used for main analyses.
3.1.2
Pharmacokinetics (PK)
The primary variables used to characterize PK are observed anifrolumab trough 
concentrations (predose). For the first dose, maximum concentration (post-dose [Cmax]) and 
time when Cmax is observed (Tmax) will also be reported. Additional PK parameters will also 
be estimated if the data allows. Individual concentrations will be reviewed for exclusion from 
descriptive statistics by identifying outliers and reviewing dosing information and sample 
collection times. Analysis to determine if the identified concentrations should be excluded 
includes visual inspection of PK-time profiles and comparison of descriptive statistics with 
identified concentrations excluded and included. The method of data handling will be detailed 
in the Week 12 and Week 52 study reports.
These variables will be characterized at every visit where the assessments are taken, with the 
primary time-point being at Week 12.
Missing values will not be imputed and only observed values will be used for the analyses.
3.2
Secondary variables
3.2.1
Immunogenicity
Anti-drug antibodies (ADA) assessments will be conducted utilizing a tiered approach 
(screen, confirm, titre). The presence or absence of ADA will be determined in the serum 
samples using validated bioanalytical methods. Only ADA positive samples will be analyzed 
for the presence of neutralizing antibodies (nAb). Samples that are ADA negative will not be 
tested for (nAb). The presence or absence of neutralizing ADA will be determined using a 
validated bioanalytical method.


Statistical Analysis Plan 
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3.2.2
Safety
3.2.2.1
Adverse Events
Adverse events will be collected throughout the entire study and will be coded using the latest 
version of MedDRA.
Adverse event data will be categorized according to their onset date into the following study 
periods:
!
AEs occurring during screening: 
An AE during screening is defined as an AE with a date of onset ≥ date of first 
screening visit and < date of the first dose of IP.
AEs occurring during screening will only be listed.
!
AEs occurring during treatment:
An AE during treatment is defined as an AE with a date of onset ≥ day of first dose 
of IP and ≤ date of last dose of IP + 14 days.
!
AEs occurring during follow-up:
An AE during follow-up is defined as an AE with a date of onset > date of last dose
of IP + 14 days and ≤ date of last dose of IP + 70 days.
!
AEs occurring after follow-up:
An AE after follow-up is defined as an AE with a date of onset > date of last dose 
of investigational product + 70 days.
AEs occurring after follow-up will only be listed.
If an AE has a missing onset date, then unless the stop date of the AE indicates otherwise, this 
will be considered as an AE during treatment. 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 an AE 
during treatment.
Adverse events of special interest (AESI) are marked as such in the electronic case report 
form (eCRF). Major acute cardiovascular events (MACE) will be determined according to the 
assessments of the Cardiovascular Event Adjudication Committee. The events of interest are 
serious infections, including non-opportunistic serious infections, opportunistic infections, 
anaphylaxis, malignancy, herpes zoster, TB (including latent TB), influenza, vasculitis (non-
SLE), and MACE (non-fatal myocardial infarction, non-fatal stroke, and CV death).
An AESI that meets one of the seriousness outcomes listed in Section 6.2 of the CSP will be 
categorised as a serious adverse event (SAE) for the purposes of follow-up responsibility and
safety reporting. A non-serious AESI will be categorised as an AE. For reporting of AESIs, 
see Section 6.8 of the CSP.
An acute AE is defined as an AE with a time and date of onset after first administration of 
investigational product to +24 hours after administration of IP. If an AE has a missing time 
and/or date, then unless the stop date of the AE indicates otherwise, this will be considered as 


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an acute AE. 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 acute AE.
An injection-related reaction (investigator) is defined as an AE with a related preferred term.
An infection is defined as an AE within the SOC infections and infestations. Opportunistic 
infections are defined as given by the investigator and non-opportunistic infections are all 
infections not marked as opportunistic by the investigator. Hypersensitivity is defined 
according to the narrow MedDRA SMQ Hypersensitivity.
Herpes zoster is further classified according to the information given on the Herpes zoster log 
as follows:
Category
Rash
[Y/N]
Episode status of 
HZ Event
[localized/
disseminated]
Specify 
Disseminated
[cutaneous/
systemic]
Any organ 
involvement
[Y/N]
Cutaneous (localised) herpes zoster
Y
Localized
[no rule]
N
Cutaneous disseminated herpes 
zoster
Y
Disseminated
Cutaneous
[no rule]
Visceral disseminated herpes zoster
[no rule]
Disseminated
Systemic 
[no rule]
Adverse events with missing intensity will be assumed severe. Events with missing 
relationship to study medication per the investigator will be assumed to be related. If no 
information about seriousness is available, the AE will be considered serious.
Adverse events will be presented by the time of first onset of the event. For this analysis, 
repeated events with the same preferred term will not be considered (i.e. if a subject has more 
than one event with the same preferred term, only the event with the earliest date of onset will 
be used). For partial or missing dates, the rules as described above will be used.
The event rate per 100 subject years is defined as;
	 
  ℎ 
 
 
	    
	    ℎ   × 36525
For herpes zoster (any AE with preferred name “Herpes zoster”) and other possible AESIs, an 
alternative event rate per 100 subject years will be derived as;
	 
  ℎℎ	 !
	
 
 
	   	"   
	    ℎ   × 36525


Statistical Analysis Plan 
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The time at risk is defined as time (including start and end date) from start of period (e.g. date 
of first administration of IP for events during treatment) to the date of first event, death, 
withdrawal of consent, or end of period, whatever comes first. This alternative event rate may 
also be calculated for other AESIs if suggested by data. This will be discussed during the BDR 
meetings and the decision will be made before unblinding the data for the end of study
analysis.
The time to first onset of herpes zoster during treatment will be derived as date of first onset 
of herpes zoster – date of first administration of IP + 1. AEs with an onset date before the date 
of first administration of IP and AEs with an onset after 14 days after the date of last 
administration of IP will not be considered for the time to first onset of herpes zoster during 
treatment. If a subject has no herpes zoster during treatment, the time to first onset will be 
censored at the date of last administration of IP + 14 days.
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date and time when the AE started and stopped
!
Maximum intensity
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken regarding IP
!
AE caused subject’s withdrawal from study (yes or no) 
!
Outcome
In addition, the following variables will be collected for serious adverse events (SAEs):
!
Reason for being classified as an SAE
Other significant adverse events
During the characterization of the AE data, a medically qualified expert will review the list of 
AEs that were not reported as an SAE or AEs leading to discontinuation.
Based on the expert’s judgment, significant AEs of clinical importance may, after consultation 
with the AstraZeneca Global Patient Safety Physician, be considered other significant AEs 
and reported as such in the study reports.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.


Statistical Analysis Plan 
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3.2.2.2
Laboratory variables
The parameters haematology, clinical chemistry, urinalysis (outlined in Table 5 in 
Section 5.2.1 of the clinical study protocol) and of fasting lipid profile (high density 
lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides) will be 
explored.
Laboratory data will be reported in International System of Units (SI). Changes from baseline 
in haematology, clinical chemistry and lipid profile variables will be calculated.
Absolute values will be compared to the reference range as given in Appendix D and 
classified as low (below range), normal (within range or on limits) or high (above range). All 
values (absolute and change) falling outside the reference ranges will be flagged.
Treatment emergent laboratory/vital signs changes (TELVC) will be defined for on-treatment 
values according to the reference ranges given in Appendix D. 
Urinalysis data will be categorised as negative (0), positive (+), or strongly positive (++, +++, 
or >+++) at each time-point. Treatment-emergent changes will also be assessed. 
Treatment-emergent changes of urinalysis data are defined as 
!
Negative/+ at baseline to ++, +++, ++++ at any on-treatment value OR 
!
Increase of from baseline of at least ++ at any on-treatment value.
For the liver function tests: aspartate transaminase (AST), alanine transaminase (ALT), 
alkaline phosphatase, gamma glutamyl transferase (GGT) and total bilirubin, the multiple of 
the upper limit of the normal (ULN) range (see Appendix D) will be calculated for each data 
point. Multiple = Value / ULN, ie, if the ALT value was 72 IU/L (ULN = 36) then the 
multiple would be 2. Subjects with AST or ALT ≥ 3xULN and TBL ≥2xULN at any point 
during the study irrespective of increase in ALP will be flagged for Hy’s law (potential Hy’s 
Law).
Additionally, to the above safety laboratory panel, coagulation tests will be performed: 
prothrombin time (PT) and partial thromboplastin time (PTT) will be recorded as part of the 
enrolment/screening tests and at various time points during the Active Treatment and Follow-
up periods; please refer to Sections 4.2 and 4.3 from the CSP.
3.2.2.3
ECGs
The outcome of the 12-lead ECG measurements will be assessed by investigators as normal or 
abnormal. It is the investigator’s judgment whether the findings/results are clinically relevant 
or not. The following categories are used for analysis:
!
Normal
!
Abnormal, not clinically significant
!
Abnormal, clinically significant


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!
Not done
Clinically significant abnormalities registered after screening visit should be reported as AEs.
3.2.2.4
Physical examination
Body height will be captured at screening only. Subjects will be weighed at Week 12 and 
Week 52. Weight (kg) will be characterized using change from baseline. Medically significant 
changes from the baseline physical examination / Visit 2 will be recorded as AEs unless 
related to SLE.
A targeted physical examination will include an assessment of the organ systems required to
complete protocol-specified assessment tools (SLEDAI-2K and CLASI). Additional
assessment should be done as clinically indicated. Abnormal findings will be recorded as part
of AE, SAE, AESI, or SLE activity, if appropriate.
3.2.2.5
Vital signs
The following variables will be characterized:
!
Pulse rate (beats per minute)
!
Systolic blood pressure (mmHg)
!
Diastolic blood pressure (mmHg)
!
Respiration rate (breaths per minute)
!
Body temperature (°C)
Changes from baseline will be calculated.
Where applicable, absolute values will be compared to the reference ranges given in Appendix 
E and classified as low (below range), normal (within range or on limits) or high (above 
range). All values (absolute and change) falling outside the reference ranges will be flagged.
On-treatment values will be classified as TELVC according to reference ranges given in 
Appendix E.
At dosing visits, only measurements before start of IP will be considered for ‘by visit’ 
presentations. In case of multiple measurements before the start of investigational product, the 
first measurement will be used for ‘by visit’ presentations but all measurements will be 
considered for the TELVC classification.
3.2.2.6
Colombia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an assessment tool that characterizes suicidal ideation and behaviour. 


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The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale in an increasing order of severity from 
1 to 10 to facilitate the definitions of the comparative variables.
!
Category 1 – Wish to be Dead
!
Category 2 – Non-specific Active Suicidal Thoughts
!
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act
!
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan
!
Category 5 – Active Suicidal Ideation with Specific Plan and Intent
!
Category 6 – Preparatory Acts or Behaviour
!
Category 7 – Aborted Attempt
!
Category 8 – Interrupted Attempt
!
Category 9 – Actual Attempt (non-fatal)
!
Category 10 – Completed Suicide
The Suicidal Ideation or Behaviour score will be derived from the C-SSRS categories as the 
maximum suicidal ideation or behaviour category (1-10 on the C-SSRS) present at the 
assessment. The score will be derived at each assessment for each subject. Non-suicidal 
self-injurious behaviour will be assigned if no ideation or behaviour is present.
Composite variables based on the above re-ordered categories are defined for assessments 
during screening, during treatment, and during follow-up, respectively (with the same 
definitions for the study periods as given for AEs in Section 3.2.2.1), as follows:
!
Suicidal ideation: A “yes” answer at any time in the respective study period to any 
one of the 5 (re-ordered) suicidal ideation questions (Categories 1-5) on the 
C-SSRS.
!
Suicidal behaviour: A “yes” answer at any time in the respective study period, to 
any one of the 5 (re-ordered) suicidal behaviour questions (Categories 6-10) on the 
C-SSRS.
!
No suicidal ideation or behaviour: No “yes” answer at any time in the respective 
study period to any one of the 10 (re-ordered) suicidal ideation and behaviour 
questions (Categories 1-10) on the C-SSRS.
3.3
Exploratory variables
3.3.1
Efficacy
Efficacy endpoints will be characterized using the following variables.


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CLASI activity and damage scores
The exploratory variable used to characterize the effect of anifrolumab on skin activity is a ≥ 
50% improvement in CLASI activity score from baseline, responder variable. A ≥ 50% 
responder in CLASI activity score from baseline is defined as having:
[CLASI activity baseline score – Post baseline CLASI activity score]*100 / [CLASI activity 
baseline score] ≥ 50.
Additionally, the absolute scores, as well as the change from baseline in CLASI activity and 
damage scores will be characterized.
These variables will be characterized at every visit where the assessments are taken, with the 
primary time-point being at Week 12.
Missing values will not be imputed and only observed values will be used for the main
analyses.
SLEDAI-2K score and Physician Global Assessment of disease activity (PGA)
The SLE disease activity will be characterized by variables for SLEDAI-2K and physician 
global assessment (PGA).
SLEDAI-2K will be characterized by the absolute scores and changes from baseline in 
SLEDAI-2K.
PGA will be characterized using absolute scores and changes from baseline in a 3-point PGA
VAS (Visual Analogue Scale), with 0 (no disease) to 3 (severe) disease activity.
These variables will be characterized at every visit where the assessments are taken, with the 
primary time-point being at Week 12.
Missing values will not be imputed and only observed values will be used for the main 
analyses.
Autoantibodies and inflammatory markers
The outcome variables for disease-related autoantibodies including anti-nuclear antibody
(ANA) and anti-dsDNA will be the categorisations as negative, positive and missing. 
Parameters of the biological domain complements C3 and C4 will be categorised as low, 
normal and missing. CH50 will be categorised as normal, high and missing.
The inflammatory markers ESR, IgM, IgG and IgA, will be measured by absolute levels and 
change from baseline.
These variables will be characterized at every visit where the assessments are taken.


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Missing values will not be imputed and only observed values will be used for the main 
analyses.
3.3.2
Oral corticosteroid management
The outcome variable for OCS management is the daily dose taken by subjects in the unit of 
mg/day.
The standardised area under the curve (AUC) of OCS dose from baseline to Week 12, 
baseline to Week 24 and baseline up to Week 52 will be calculated for all subjects as follows:
For each single daily dose, the duration of the single dose will be calculated as end date – start 
date + 1. If the start date is before Day 1, Day 1 will be used instead. If the end date is after 
the date of Week 12 for the primary analysis (date of Visit 8), the date of Visit 8 will be used 
instead. The AUC for each single dose will be derived by the daily dose (mg/day) multiplied 
with the duration (days). The AUC is the sum of the AUCs of the single doses. For subjects 
who discontinued the study before Visit 8, the AUC will be calculated up to the date of study 
discontinuation. The standardised AUC will be derived as AUC multiplied by 84 (12 weeks)
and divided by the available days (date of Visit 8 or date of early discontinuation – date of 
Day 1 + 1). The same method applies for baseline to Week 24 and baseline to Week 52
analyses.
The number of steroid bursts subjects experienced between baseline and Week 12, baseline 
and Week 24, and baseline and Week 52, will also be characterized. For this variable, bursts 
are defined as any increase from baseline in daily OCS dose. Subjects can have multiple 
bursts if their OCS dose returns to baseline or less, before increasing above baseline again. For
the baseline to Week 12 summary, bursts reported between date of first dose and date of the 
subject’s Week 10 visit +14 days will be summarized. For the baseline to Week 24 summary, 
bursts reported between date of first dose and date of the subject’s Week 24 visit +14 days 
will be summarized.
3.3.3
Skin tape test (optional)
The outcome variable for the skin tape test is the 21-gene type 1 IFN signature fold change
and percent suppression of fold change will be recorded but will not be presented in the study 
reports.
3.4
Assessment of study population
3.4.1
Subject disposition variables
The following variables will be used to characterize subject disposition:
!
Subjects enrolled
!
Subjects randomized
!
Subjects not randomized including reason


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!
Subjects who received treatment
!
Subjects who completed treatment up to and including Week 10 for the primary 
time point analysis and Week 50 for the last dosing time-point.
!
Subjects who discontinued treatment including reason for withdrawal, up to and 
including Week 12 for the primary time point analysis and Week 50 for the last 
dosing time-point.
!
Subjects who completed the study up to and including Week 12 for the primary 
time point analysis and Week 52 for the last visit.
!
Subjects withdrew from the study including reason for withdrawal, up to and 
including Week 12 for the primary time point analysis and Week 60 for the last
visit.
A subject’s country and site will be summarized.
Furthermore, the number and percentage of subjects remaining on investigational product, 
discontinued investigational product but remain on study and withdrawn from study will be 
summarized by visit up to Week 50 for the full analysis set.
3.4.2
Demographic and baseline characteristic variables
Demographic characteristics (age, age group, sex, ethnicity and race) and baseline 
characteristics (including height, weight, body mass index [BMI] and disease characteristics) 
will be summarized using the full analysis set. Disease characteristics include SLEDAI-2K, 
CLASI activity and damage score, OCS dose, PGA, disease duration (time from initial SLE 
diagnosis to randomization [months]), ANA, anti-dsDNA levels, anti-Sm antibodies, anti-
RNP antibodies, complement C3, C4 and CH50 levels and 21-gene type 1 IFN score.
Permitted SLE SOC treatment will also be summarized at baseline by frequency and 
proportion of subjects taking the SOC treatments, mentioned in section 7.7.1 of the CSP.
3.4.3
Surgical and medical history
Surgical and medical histories will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Medical history will be evaluated separately for past 
and current conditions as given in the eCRF.
3.4.4
Prior and concomitant medications
Prior medications are reported according to the eCRF completion guidelines (ie, dependent of 
the relevance of the medication, the intake during the last few weeks before the first 
administration of IP, all medication taken during lifetime, or anything in-between will be 
reported). All medications will be coded using the latest version of World Health Organization 
Drug Dictionary (WHO-DD).


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Any medications taken by the subject prior to the first dose date of investigational product will 
be considered prior medication. Any medication taken by the subject at any time between the 
date of the first dose (including the date of the first dose) of investigational product up to 
Week 52 (Visit 28) or discontinuation visit, inclusive, will be considered concomitant 
medication. Any medication started prior to the first dose of investigational product and ended
after the first dose up to Week 52 (Visit 28) or discontinuation visit / was ongoing will be 
considered as both prior and concomitant medication.
Disease related treatments at baseline are defined as all medications with therapy reason given 
as “disease under study” with an intake at the date of first dose of investigational product (ie, 
start date on or before the date of first dose and end date on or after date of first dose or 
ongoing). The medications will be presented in the following categories:
!
Anti-malarial
defined as medications with an ATC code level 3 of P01B (antimalarials)
!
Azathioprine
defined as medications with preferred terms of azathioprine or azathioprine sodium
!
Methotrexate
defined as medications with preferred terms of methotrexate or methotrexate
sodium
!
Mycophenolate/Mycophenolic acid
defined as medications with preferred terms of mycophenolate mofetil and 
mycophenolate sodium
!
Mizoribine
defined as medications with a preferred term of mizoribine
!
OCS
!
Other SLE medication
defined as SLE medications not covered within the above categories
Restricted and prohibited medications are mentioned in Section 7.7 and 7.8 of the clinical 
study protocol.
If a medication cannot be classified as prior or concomitant due to missing or partial dates, the 
imputation rules as given in Appendix C will be applied.
3.4.5
Exposure of investigational product
The duration of exposure to the IP per subject is defined as the number of days between the 
start and the end dates of IP plus the dosing frequency time:
Duration of exposure (days) = (Last dosing date + 14 days) – first dosing date + 1.
For the Week 12 analysis there is a potential for exposure to be over or underestimated. To 
minimise the over or underestimation of exposure, the following rules will be applied.


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!
If a subject has completed the study (Week 52), the last date of exposure would be the 
date of last dose +14 days.
!
If a subject has received their latest scheduled dose but has not completed the study, 
the last date of exposure would be the date of data cut-off.
!
If a subject discontinues IP ≥14 days prior to the data cut, the last date of exposure 
would be the date of last dose +14 days.
!
If a subject discontinues IP <14 days prior to the data cut, the last date of exposure 
would be the date of data cut-off.
!
If a subject missed their latest scheduled dose but has not completed the study or 
discontinued IP, the last date of exposure would be the date of last dose +14 days.
For the final analysis at Week 52, the last date of exposure would be the date of last dose +14 
days.
Study treatment compliance will be reported as the total number of dosing occasions divided 
by the total number of dosing occasions expected, multiplied by 100. If a subject discontinues 
IP, the number of expected dosing occasions are the number of visits up to discontinuation.
For treatment compliance up to Week 12, the expected number of visits is 8 (up to Week 10) 
or the number of visits up to discontinuation of IP, whichever is smaller.
4.
ANALYSIS METHODS
4.1
General principles
4.1.1
Visit windows
For visit-based analyses, the variables will be summarized based on the scheduled days with 
adjusted analysis-defined visit windows. The adjusted analysis-defined windows are 
summarized below:
Table 1
Visit windows
Adjusted Defined Windows Visit
Scheduled Study Day
Maximum Windows
Baseline
1 
Study Day ≤1 
Week 2
15
2≤ Study Day ≤21
Week 4 
29 
22≤ Study Day ≤35
Week 6
43
36≤ Study Day ≤49
Week 8 
57 
50≤ Study Day ≤63
Week 10
71
64≤ Study Day ≤77
Week 12 
85 
78≤ Study Day ≤91


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Adjusted Defined Windows Visit
Scheduled Study Day
Maximum Windows
Week 14
99
92≤ Study Day ≤105
Week 16 
113 
106≤ Study Day ≤119
Week 18
127
120≤ Study Day ≤133
Week 20 
141 
134≤ Study Day ≤147
Week 22
155
148≤ Study Day ≤161
Week 24 
169 
162≤ Study Day ≤175
Week 26
183
176≤ Study Day ≤189
Week 28 
197 
190≤ Study Day ≤ 203
Week 30
211
204≤ Study Day ≤ 217
Week 32 
225 
218≤ Study Day ≤231
Week 34
239
232≤ Study Day ≤245
Week 36 
253 
246≤ Study Day ≤259
Week 38
267
260≤ Study Day ≤273
Week 40 
281 
274≤ Study Day ≤287
Week 42
295
288≤ Study Day ≤301
Week 44
309 
302≤ Study Day ≤315
Week 46
323
316≤ Study Day ≤329
Week 48 
337 
330≤ Study Day ≤343
Week 50
351
344≤ Study Day ≤357
Week 52
365
358≤ Study Day ≤371
Week 56
393 
372≤ Study Day ≤406 
Week 60 
421
407≤ Study Day ≤433 
The PK post-dose visit 2 measurement will not be mapped according to the windows above 
and will instead be mapped to baseline in all cases.
For assignment of data to time points using the visit windows, study day will be defined as,
(Date of assessment – date of first administration of IP) +1. 
Using this definition, the day of first dose of IP will be baseline and the scheduled visit date of 
Week 2 will be study day 15 (=14+1) for example.
If multiple readings are recorded within a single visit window, the following rules will be 
followed. 


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!
If there are two or more observations within the same visit window, then the non-
missing one closest to the scheduled visit will be used in the analysis.
!
If two observations are equidistant from the scheduled visit, then the non-missing 
observation with the earlier collection date will be used in the analysis. 
!
If two observations are collected on the same day, then the non-missing one with 
the earlier collection time will be included in the analysis. 
If a visit window does not contain any observations, then the data will remain missing.
For overall analyses not based on any particular study visit, all data will be listed and/or 
analysed, including any repeat or unscheduled visits, unless otherwise specified.
4.1.2
4.1.3
Presentation of results
All analyses will use SAS® version 9.3 or higher. A separate document will be produced 
containing the template table, listing, and figure shells.
Due to the small sample size, which is purposely not sized to detect a difference between 
treatment groups, there will be no formal comparisons made for all variables. Results will be 
presented by treatment, with the two placebo arms pooled for the analyses. If deemed 
appropriate, data from the two anifrolumab treatment arms may be pooled for the exploratory 
analyses regarding efficacy. Details for when the pooling takes place is specified for each 
analysis.
Unless otherwise noted, categorical data will be presented using counts and percentages with 
the denominator for percentages being the number of subjects in the analysis set by treatment 
group. Percentages will be rounded to 1 decimal place; except 100%, which will be displayed 
without any decimal places. Percentages will not be displayed for zero counts.
Unless otherwise noted, continuous variables will be summarized using the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. The 
minimum and maximum values will be displayed to the same level of precision as the raw 
data, the mean and median to a further decimal place and the SD to two additional decimal 
places. Confidence intervals may be used in some descriptive statistics when specified.
Individual subject data (including derived variables) will be presented in listings sorted by 
treatment group and subject number.
4.1.4
Missing Data
Subjects who discontinue IP will be asked to come to visits 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 
24, 26, and 28 (as applicable) (or for a minimum of 10 weeks after last dose of IP for subjects 
for whom IP was discontinued within 10 weeks prior to Week 52). After subjects discontinue 
IP, visits that they are not required to attend and do not attend will be classified as missing.


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For responder variables, there are 2 criteria that correspond to a non-responder imputation for 
subjects who prematurely discontinue from investigational product, or who receive prohibited 
medications or restricted medications beyond the protocol-allowed threshold.
Missing data will not be imputed for PD, PK, or exploratory efficacy endpoints. 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of <x (ie, below the lower limit of quantification) or >x (ie, above the upper limit of 
quantification) will be imputed as x in the calculation of summary statistics but displayed as 
<x or >x in the listings.
Details about imputation of partial or missing dates are given in Appendix C. The imputation 
of single missing items for the derivation of a total score is described in Appendix B.
4.2
Analysis methods
Wherever mentioned, change from baseline refers to absolute change from baseline.
4.2.1
Primary variable analysis
Unless otherwise specified, early discontinuation visits (EDV) will be mapped to the visit 
windows specified in Section 4.1.1 for ‘at visit’ based reporting.
4.2.1.1
Pharmacodynamics (PD)
The primary time-point for the 21-gene type 1 IFN PD signature fold change and percent 
suppression of fold change is at Week 12.
The following PD analysis will be created using the PD analysis set, by visit and with the
treatment groups anifrolumab 300 mg, anifrolumab 150 mg, pooled active arms (if deemed 
appropriate) and pooled placebo.
A table of summary statistics will be created for fold change and percent suppression of fold 
change for the treatment groups.
A table will be created for the frequency and percentage of subjects by treatment group in the 
following percent suppression of fold change categories; < 50%, ≥ 50% and < 75%, ≥ 75%, 
and missing.
Additionally, a table of fold change will be categorized as < 2, ≥2 and missing.
Spaghetti plots of 21-gene type 1 IFN PD signature percent suppression of fold change for 
each treatment group will be created. After the point at which a subject discontinues IP or has 
received restricted medication over the protocol allowed threshold, their plotted lines will be 
dashed. A boxplot will also be created for Week 12, Week 24 and Week 52.


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Median percent suppression of fold change for the treatment groups will also be displayed 
graphically using a longitudinal plot with precision bars (median absolute deviation) and the 
number of subjects in the analysis displayed at each time point.
4.2.1.2
Pharmacokinetics (PK)
All analyses of PK data will be performed using the PK analysis set separately for each active
treatment arm.
A listing of PK blood sample collection times, as well as derived sampling time deviations 
will be provided. Serum concentrations and PK parameters of anifrolumab will be 
summarized by treatment (dose level of anifrolumab) using descriptive statistics. Where 
possible, the following descriptive statistics will be presented: n (number of non-missing 
values), m (number of values above LLOQ), geometric mean, geometric CV%, arithmetic 
mean, SD, arithmetic CV%, median, minimum and maximum. If applicable, this summary 
will be repeated including individual concentrations excluded from descriptive statistics.
Serum concentration-time profiles of anifrolumab will be generated as plots of arithmetic 
mean values (including SD) by time point in a semi-log scale and a linear scale. This will be 
presented for all values and additionally for values measured before administration (Ctrough).
Scatter plots showing the individual PK parameters and geometric mean versus dose level will 
be presented for Cmax and Ctrough (select time points).
Spaghetti plots of individual Ctrough measurements will created for both anifrolumab treatment 
arms.
Data from subjects excluded from the PK analysis set will be included in the data listings.
Serum concentrations below lower limit of quantification (LLOQ) prior to the first 
quantifiable concentration will be set to a value of LLOQ/2. 
Due to the limited sampling schedule, the relationship between PK and PD may be explored 
on a population level (i.e. population PK/PD modelling). In addition, anifrolumab 
concentrations may be compared to historical data via intravenous route to understand the 
drug exposure after subcutaneous dosing. These analyses will be performed by MedImmune’s 
Clinical Pharmacology and DMPK group and will not be reported in the study reports.
4.2.2
Secondary variable analysis
All analyses of the secondary outcome variables will be conducted with the full analysis set.
Unless otherwise specified, for outputs with summaries by visit, EDVs will be presented on 
their own row.


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4.2.2.1
Immunogenicity
ADA assessments will be conducted utilising a tiered approach (screen, confirm, titre). The 
presence of nAb will be tested in all ADA-positive samples.
EDVs will be mapped to the visit windows specified in Section 4.1.1 for outputs which are 
summarised by visit for immunogenicity.
Week 12 analysis (primary analysis time-point)
A listing of all ADA positive subjects at baseline and/or post baseline will be presented for the 
Week 12 analysis (including available nAb, PK and PD results).
End of Study analysis
The following ADA results will be characterized by treatment group (anifrolumab 300 mg, 
anifrolumab 150 mg and pooled placebo) when all subjects have reached the study end. The 
frequency and percentage of:
!
Subjects who are ADA positive at any time (including baseline).
!
Subjects who are ADA positive at baseline only.
!
Subjects who are ADA positive at baseline and post baseline.
!
Subjects who are ADA positive post-baseline and not positive at baseline.
!
Subjects who are persistently positive are defined as having at least 2 post-baseline 
ADA positive measurements (with ≥ 16 weeks between first and last positive) or an 
ADA positive result at the last available post-baseline assessment.
!
Subjects who are transiently positive, defined as at least one post-baseline ADA 
positive measurement and not fulfilling the conditions for persistently positive.
!
Subjects who are ADA positive by visit.
!
Subjects who are ADA positive at a post-baseline measurement for the first time by 
visit.
The presence of neutralising antibodies (nAb) will be tested only in samples that were 
previously found to contain ADA, using a ligand binding assay. The following variables will 
be characterized:
!
Number and proportion of subjects who are nAb positive among the ADA-positive 
subjects (at any time).
!
Number and proportion of subjects who are nAb positive for the first time by visit 
(with baseline nAb negative or missing) among the ADA-positive subjects (at any 
time).
The variables above, regarding neutralizing antibodies, will be summarized presenting the 
frequency and percentage.


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ADA titres-time profiles (line plots for subject values by visit) will be generated separately for 
each treatment group (anifrolumab 300 mg, anifrolumab 150 mg and pooled placebo). Titres 
of positive measurements reported as ≤30 (limit of detection) will be imputed as 30.
The impact of ADA on PK will be explored by spaghetti plots of individual concentration data 
over time using different styles by ADA result (positive at any time/negative). This will be 
presented for all PK values and additionally for values measured before administration 
(Ctrough).
The impact of ADA on the IFN 21 gene PD signature will be explored using spaghetti plots of 
21-gene type 1 IFN PD percent suppression of fold change over time using different styles by 
ADA result (positive at any time/negative).
Due to the small sample size, analyses regarding the impact of ADA on safety and efficacy 
may be explored if warranted.
If there are three or less subjects with ADA positive results, the summary tables and plots will 
not be created, other than those that characterize the impact of ADA on PK and PD. Instead, 
results will be presented in a listing similar to the Week 12 analysis.
4.2.2.2
Analysis methods for safety variables
Safety variables will be summarized by treatment group (anifrolumab 300 mg, anifrolumab 
150 mg, pooled anifrolumab arms, pooled placebo) for the full analysis set.
Adverse events
If not stated otherwise, all summaries described below will be presented separately for 
!
AEs during treatment
!
AEs during follow-up
For summaries during follow-up, only subjects with any study documentation after the date of 
last dose of IP + 14 days will be considered.
An overall summary of the frequency and percentage of subjects with at least one AE in the 
following categories will be presented:
!
Any AE
!
Any acute AE
!
Any AE with outcome = death
!
Any SAE (including events with outcome = death)
!
Any AE leading to discontinuation of IP
!
Any AE related to IP
!
Any AE of severe intensity
!
Any AESI 


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-
Any AESI of non-opportunistic serious infections
-
Any AESI of opportunistic infections
-
Any AESI of anaphylaxis
-
Any AESI of malignancy
-
Any AESI of herpes zoster
-
Any AESI of tuberculosis (including latent tuberculosis)
-
Any AESI of influenza
-
Any AESI of vasculitis (non SLE)
-
Any AESI of major acute cardiovascular events according to the 
Cardiovascular Event Adjudication Committee (CV-EAC)
!
Any other significant AE may be presented if necessary
The frequency and percentage of subjects with at least one AE (ie, multiple occurrences of an 
AE in one subject will only be counted once) will be summarized by MedDRA System Organ 
Class and preferred term for the following AE categories. These summaries will also include 
the event rate per 100 subject years, as well as the exposure in years, unless otherwise 
specified. Event rates will generally not be included in summaries presented for AEs follow-
up or during treatment and follow-up.
!
Any AE
!
Any AE above reporting threshold of 10% in the anifrolumab total treatment group
This summary will be presented for AEs during treatment only.
!
Non-serious AE above reporting threshold of 10% in the anifrolumab total 
treatment group
This summary will be presented for AEs during treatment only.
!
Any AE with outcome = death
This summary will be presented for AEs during treatment and follow-up only.
!
Any SAE (including events with outcome = death)
!
Any AE leading to discontinuation of IP
This summary will be presented for AEs during treatment only.
!
Any AE by relationship to IP (yes, no)
(multiple occurrences of an AE in one subject will only be counted once as related 
if at least one AE is related and as not related if all occurrences are not related)
This summary will be presented for AEs during treatment only.
!
Any AE by maximum intensity (mild, moderate, severe) 
(ie, multiple occurrences of an AE in 1 subjects will only be counted once with the 
maximum intensity in this AE)
This summary will be presented for AEs during treatment only.
!
Any AESI
This summary will not be presented by System Organ Class but by AESI category 
(non-opportunistic serious infections, opportunistic infections, anaphylaxis, 


Statistical Analysis Plan 
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malignancy, herpes zoster, tuberculosis, influenza, vasculitis, and major acute 
cardiovascular events).
!
Any other significant AE may be summarized if necessary
This summary will be presented for AEs during treatment only.
Cardiovascular outcome events as determined by the CV-EAC will be presented separately, 
summarizing the number of AEs submitted for adjudication and the outcomes of the 
adjudication including MACE classification. Site reported cardiovascular AEs and their 
corresponding adjudicated outcomes will be listed.
A table of the number and percentage of subjects with at least one anaphylaxis will be 
summarized for the following respective subcategories: SAE (including events with outcome 
of death), AE leading to discontinuation. Additionally, hypersensitivity, and injection-related 
reactions (investigator), will be summarized overall as well as for the following respective 
subcategories: SAE (including events with outcome of death), AE leading to discontinuation, 
and AE by maximum intensity (mild, moderate, and severe).
Infections and opportunistic infections will be summarized with the same subcategories as 
given above.
The time to first onset of herpes zoster during treatment will be presented as Kaplan-Meier 
plot including the number of subjects at risk at each visit. 
Furthermore, the alternative event rates per 100 subject years for herpes zoster (and other
possible AESIs) will be summarized for events during treatment and follow-up, during 
treatment, and during follow-up.
Key subject information for subjects with an AE with outcome of death, subjects with SAEs, 
subjects with an AE leading to discontinuation of IP and subjects with AESIs, respectively, 
will be listed.
Laboratory variables
Laboratory variables will be created using the full analysis set and will have the treatment 
groups of anifrolumab 150 mg, anifrolumab 300 mg, placebo 150 mg and placebo 300 mg.
Observed values and changes from baseline of laboratory data for haematology, clinical
chemistry and fasting lipid profile will be summarized by visit. The summary statistics 
presented will be minimum, 1st quartile, median, 3rd quartile, maximum, mean, and SD.
If any laboratory variables show any unusual features (high or low values or a general shift in 
the data points) at specific visits then shift plots of these data may also be produced. This will 
be discussed and agreed upon during the BDR meeting.


Statistical Analysis Plan 
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For each laboratory parameter with available criteria, the frequency and percentage of subjects 
with TELVC values will be summarized by visit. Additionally, the frequency and percentage
of subjects with at least one TELVC value will be presented. 
The frequency and percentage of subjects with laboratory values below, within or above the 
corresponding normal range will be presented as shift tables from baseline to maximum and 
minimum on-treatment value, respectively. 
Urinalysis and urine protein-creatinine ratio will be summarized as shift tables from baseline 
to the last on-treatment value for each parameter. Furthermore, the frequency and percentage
of subjects with treatment-emergent changes will be summarized by parameter.
To identify potential Hy’s Law cases, a table of number and percentage of subjects with 
maximum post baseline total bilirubin <2xULN and ≥2xULN will be presented against 
maximum post baseline ALT and AST <3xULN, ≥3 and <5 ULN, and ≥5xULN.
For all subjects who meet the biochemical criteria for Hy’s law (potential Hy’s Law), a 
Subject Safety Narrative will be produced, and the relevant laboratory parameters will be 
tabulated showing all visits for these subjects. Subjects with elevated ALT or AST, and 
elevated total bilirubin, at any time may be explored further graphically using individual 
subject profile plots presenting AST, ALT, Alkaline phosphatase, GGT, and total bilirubin as 
multiples of ULN in a log scale.
ECGs
The frequency and percentage of subjects with normal, abnormal (not clinically significant), 
abnormal (clinically significant) and not done ECG results will be presented as a shift table 
from baseline to Week 52/early discontinuation visit (EDV).
Physical examination
Observed values and changes from baseline of body weight will be summarized.
Vital Signs
Observed values and changes from baseline of pulse, systolic blood pressure, diastolic blood 
pressure, respiration rate, and body temperature, respectively, will be summarized by visit. 
Shift tables for each of the parameters presenting baseline values versus minimum post-
baseline values and maximum post-baseline values, respectively, will be provided. 
For each parameter with available criteria, the frequency and percentage of subjects with 
TELVC values will be summarized by visit. Additionally, the frequency and percentage of 
subjects with at least one TELVC value will be presented. For each parameter, the frequency 
and percentage of subjects with values below, within or above the corresponding normal range 
will be presented by visit. In addition, this information will be presented in a shift table from 
baseline to each post-baseline visit.


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
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38
Colombia-Suicide Severity Rating Scale (C-SSRS)
The frequency and percentage of subjects with suicidal ideation (overall and by maximum 
category), suicidal behaviour (overall and by maximum category), and no suicidal ideation or 
behaviour will be given for assessments during screening, during treatment, and during 
follow-up, respectively, for each treatment group.
The proportion of subjects within each of the 4 suicidal behaviour categories and within each 
of the 5 suicidal ideation sub-categories during screening, during treatment, and during 
follow-up, respectively, will also be presented for each treatment group.
Furthermore, descriptive statistics on the total number of attempts, total number of interrupted 
attempts, and total number of aborted attempts will be summarized for attempts during 
screening, during treatment and during follow-up, respectively, for each treatment group.
4.2.3
Exploratory variable analysis
Unless otherwise specified, for outputs with summaries by visit, EDVs will be presented on 
their own row.
4.2.3.1
Efficacy
CLASI activity and damage scores
For the following CLASI activity and damage score analysis, the treatment groups are 
anifrolumab 300 mg, anifrolumab 150 mg, pooled active arms (if deemed appropriate) and 
pooled placebo.
A table of summary statistics will be used to characterize the ≥ 50% improvement in CLASI 
activity score from baseline responder variable for each visit, displaying the frequency and 
percentage of responders with a 95% confidence interval, by treatment group. Subjects treated 
with restricted medication beyond protocol allowed threshold or discontinue IP are regarded 
as non-responders. If any of the conditions cannot be evaluated at the respective time point, 
the subject is regarded as a non-responder. Subjects with a CLASI activity score of zero at 
baseline will be excluded from this analysis.
Tables of summary statistics will be used to characterize the absolute CLASI activity and 
damage scores and change from baseline at each visit by treatment group and pooled 
treatment groups using; number of observations (n), mean, standard deviation (SD), median, 
minimum and maximum.
Spaghetti plots of change from baseline in CLASI activity score for each treatment group will 
be created with the number of subject data displayed at each time point. A boxplot will be 
created at Week 12, 24 and 52 for each treatment group.
Mean change from baseline in CLASI activity score for the treatment groups will be displayed 
graphically using a longitudinal plot with ± standard error (SE) and the number of subject data 
displayed at each time point.


Statistical Analysis Plan 
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The relationship between CLASI activity score and OCS dose will be explored using shift 
plots by treatment group. The following shift plots will be created:
!
Baseline CLASI activity score versus Week 12, 24 and 52 CLASI activity score, 
split by an increase, decrease or no change in OCS dose at the respective time-
points.
!
Baseline OCS dose versus Week 12, 24 and 52 OCS dose, split by 50% reduction in 
CLASI activity response at the respective time-points.
The number of subjects for each subgroup will be displayed on the plots.
SLEDAI-2K score and Physician Global Assessment of disease activity (PGA)
The SLE disease activity will be characterized by variables for SLEDAI-2K and physician 
global assessment (PGA). 
For the following SLEDAI-2K and PGA analysis, the treatment groups are anifrolumab 300 
mg, anifrolumab 150 mg, pooled active arms (if deemed appropriate) and pooled placebo.
SLEDAI-2K will be characterized by a summary table of the absolute scores and changes 
from baseline at each visit; displaying number of observations (n), mean, standard deviation 
(SD), median, minimum and maximum.
EDV assessments performed at a visit where the SLEDAI-2K assessment was due to take 
place will be summarized at the visit. For EDV assessments performed at visits where the 
SLEDAI-2K assessment was not due to take place will not be reported in the table and will 
instead be reported in a listing.
Mean change from baseline in PGA will be characterized graphically by a longitudinal plot 
with ± standard error (SE) and the number of subject data displayed at each time point.
Autoantibodies and inflammatory markers
Tables for the total scores and change in baseline for the inflammatory markers ESR, IgM, 
IgG and IgA will be created by treatment group (anifrolumab 300 mg, anifrolumab 150 mg,
placebo 300 mg and placebo 150 mg). These tables will display; number of observations (n), 
mean, standard deviation (SD), median, minimum and maximum.
Shift tables will be created for the disease related autoantibodies, anti-nuclear antibody 
(ANA), anti-dsDNA, parameters of the biological domain (complements C3, C4 and CH50) 
from baseline to Week 12 and baseline to Week 52.
4.2.3.2
OCS management analysis
For the following OCS (prednisone or equivalent) analysis, the treatment groups are 
anifrolumab 300 mg, anifrolumab 150 mg, pooled active arms and pooled placebo.


Statistical Analysis Plan 
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Edition Number 2.0 
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Tables with summary statistics showing the frequency and percentage of subjects with zero to 
the maximum number of observed steroid bursts will be summarized during the periods of 
baseline to Week 12, baseline to Week 24 and baseline to Week 52, by treatment group.
Tables with summary statistics of daily dose and change from baseline by treatment group
will be produced displaying; number of observations (n), mean, standard deviation (SD), 
median, minimum and maximum. OCS daily dose reported for a visit will be the final dose 
during the last visit in a visit window.
Furthermore, the standardised AUC up to Week 12, 24 and 52 will be summarized by 
treatment group for all subjects.
4.2.3.3
Skin tape test (optional)
There will be no outputs for the skin tape test in the study reports.
4.2.4
Assessment methods for the study population
4.2.4.1
Subject disposition
Frequency and percentage of subject disposition variables mentioned in Section 3.4.1 will be 
presented by treatment group (anifrolumab 150 mg, anifrolumab 300 mg, pooled anifrolumab,
placebo 150 mg, placebo 300mg and pooled placebo) and overall.
In addition, the frequency and percentage of subjects in each analysis set will be provided. 
Percentages will be based on all randomized subjects. 
The frequency and percentage of subjects remaining on treatment, discontinued IP but still in 
study and withdrawn from the study will be presented by visit.
Important protocol deviations will be summarized by frequency and percentage, using the full 
analysis Set.
4.2.4.2
Demographic and baseline characteristics
Demographics and subject characteristics will be summarized by treatment group 
(anifrolumab 300 mg, anifrolumab 150 mg, pooled anifrolumab, placebo 300 mg and placebo 
150 mg, placebo pooled) and overall, using frequency and percentages (for categorical 
variables) and descriptive statistics of mean, standard deviation, minimum, median, and 
maximum (for continuous variables) using the full analysis set.
Surgical history and past and current medical history will be summarized separately by 
MedDRA System Organ Class and preferred term by the frequency and percentage of subjects 
for each treatment group (anifrolumab 300 mg, anifrolumab 150 mg, pooled anifrolumab,
placebo 300 mg, placebo 150 mg, pooled placebo) and overall.
The prior medications, categorized according to the WHO Drug Reference List dictionary, 
which employs the Anatomical Therapeutic Chemical (ATC) classification system, will be 
summarized by treatment group (anifrolumab 300 mg, anifrolumab 150 mg, pooled 


Statistical Analysis Plan 
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41
anifrolumab, placebo 300 mg, placebo 150 mg, pooled placebo and overall) as frequency and 
percentage of subjects reporting usage.
The concomitant medication will be categorized according to the WHO Drug Reference List 
dictionary, which employs the Anatomical Therapeutic Chemical (ATC) classification system. 
The frequency and percentage of subjects taking concomitant medications and non-drug 
therapies during the treatment period will be summarized by drug class and drug name using 
ATC code. Disease related treatments at baseline will be summarized by the categories given 
in Section 3.4.4. Concomitant medication beyond protocol allowed threshold will be 
summarized by preferred term.
4.2.4.3
Exposure of investigational product
Exposure will be summarized by treatment group (anifrolumab 300 mg, anifrolumab 150 mg, 
placebo 300 mg and placebo 150 mg), pooled treatment groups (pooled active arms and 
pooled placebo) and all subjects for the full analysis set.
Summary statistics will be provided for the duration of exposure. Additionally, the frequency 
and percentage of subjects treated ≥15 days, ≥29 days, and up to ≥365 days in 2-weekly 
intervals will be provided. 
The frequency and percentage of subjects dosed will be presented in 2-weekly intervals (ie, 2 
weeks, 4 weeks, 6 weeks, …, 50 weeks).
Furthermore, the time to discontinuation of IP will be presented as Kaplan-Meier plot 
including the number of subjects at risk (ie, still on IP).
Treatment compliance will be summarized by number, mean, SD, median, min and max for 
baseline up to Week 12 and baseline up to Week 52.
5.
INTERIM ANALYSES
The primary analysis will be carried out after all subjects have completed the Week 12 visit or 
discontinued the study prior to Week 12. All subject data, including that collected after Week 
12 will be used. At Week 12, the Sponsor personnel will be unblinded whereas investigators 
and subjects will remain blinded throughout the entire study. The DBL at study end will take 
place once all subjects have completed Week 60 or discontinued the study prior to Week 60.
The Week 52 assessment is included in the treatment period.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
The following changes have been made to the analysis from the protocol. 


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
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!
Subject data collected for visits after Week 12 will be reported for if it was collected before the 
data-cut off for the primary DBL.
!
The phrasing of “neutralization ratio” has been changed to “percent suppression of fold 
change” to be aligned with other anifrolumab studies.
!
A pharmacodynamic analysis set has been added for clarity.
!
The PGA VAS scale is not 0-100 mm but a 3-point PGA VAS.
!
Skin tape test results will not be included in the study reports for the primary and end of study 
analyses.
7.
REFERENCES
N/A
8.
APPENDIX
Appendix A: Oral Corticosteroid Guidance
Appendix B: Derivation rules for missing components of efficacy variables
Appendix C: Derivation rules for imputation of partial or missing dates
Appendix D: Reference ranges and TELVC for laboratory values
Appendix E: Reference ranges and TELVC for vital signs
Appendix F: Percent suppression calculation


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
43
Appendix A
Oral Corticosteroid Guidance
Examples of Equivalent Doses of Oral Prednisone
Oral Prednisone and
Equivalents
Equivalent Dose
Oral Prednisone 
7.5 mg 
10 mg 
20 mg 
30 mg 
40 mg
Cortisone 
37.5 mg
50 mg 
100 mg 
150 mg 
200 mg
Hydrocortisone 
30 mg 
40 mg 
80 mg 
120 mg 
160 mg
Methylprednisolone
6 mg 
8 mg 
16 mg 
24 mg 
32 mg
Prednisolone
7.5 mg 
10 mg 
20 mg 
30 mg 
40 mg
Triamcinolone
6 mg
8 mg
16 mg
24 mg
32 mg
Example of OCS Tapering Schedule
Time point 
Initial Dose of Oral Prednisone or Equivalent (mg/day)
40 
35 
30 
25 
20 
15 
10
Week 12 
35 
30 
25 
20 
15 
12.5
10
Week 16 
30 
25 
20 
15 
12.5 
12.5 
10
Week 20 
25 
20 
15 
12.5 
12.5 
12.5 
7.5
Week 24 
20 
15 
12.5 
12.5 
10 
10 
7.5
Week 28 
15 
12.5 
12.5 
10 
10 
10 
7.5
Week 32 
12.5 
10 
10 
10 
7.5
7.5
7.5
Week 36 
10
10
7.5
7.5
7.5
7.5
7.5
Week 40
7.5
7.5
7.5
7.5
7.5
≤7.5
≤7.5
* Note: subjects on OCS doses equivalent to 10 mg prednisone/day may tolerate tapering by 1 
mg/day per visit rather than an abrupt drop from 10 mg/day to 7.5 mg/day. The stepwise 
tapering of OCS dose should be performed at the discretion of the Investigator.


Statistical Analysis Plan 
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Edition Number 2.0 
Date 27/02/2018
44
Appendix B
Derivation rules for missing components of efficacy variables
If one or more components of SLEDAI 2K are missing, then the last observation carried forward 
approach will be used to impute the missing component score.
If one or more components of CLASI are missing, then the last observation carried forward approach 
will be used to impute the missing components with one exception. For CLASI damage imputation, if 
dyspigmentation is not present at a visit, the dyspigmentation duration will not be imputed.  


Statistical Analysis Plan 
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Edition Number 2.0 
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45
Appendix C
Derivation rules for imputation of partial or missing dates
If any medications reported are not able to be determined as prior or concomitant due to missing or 
partial start dates and/or stop dates, the following imputation rules will be implemented:
!
If the year is present but the month and day are missing, then 01JAN will be imputed for 
the start date and 31DEC for the stop date.
!
If the year and month are present but the day is missing, then 01 will be imputed for the 
start date and the last day of the month for the stop date.
!
If the start date is completely missing and the end date is prior to the signing of the ICF, the 
medication will be considered prior. 
!
If the start date is completely missing and the end date is missing or on or after the signing 
of the ICF, the medication will be considered prior and concomitant.
!
If the end date is completely missing and the start date is on or after the signing of the ICF
the medication will be treated as concomitant. 
!
If the end date is completely missing and the start date is prior to the signing of the ICF the 
medication will be considered prior and concomitant.


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
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46
Appendix D
Reference ranges and TELVC for laboratory values
Parameter
Unit
Low
value
Low decrease
High value
High increase
Haematology
Haemoglobin
g/L
≤60
NA
≥200
NA
≤70 and decrease from BL 
≥15
Haematocrit
V/V
≤0.18
NA
≥0.64
NA
≤0.21 and decrease from BL 
≥15%
WBC
10E9/L
≤2, <1
NA
≥20
NA
Neutrophils
10E9/L
<0.5
NA
≥20
NA
<1.0 and decrease from BL
≥0.5
Lymphocyte
10E9/L
≤0.5, 
≤0.25
NA
≥10.0
NA
Monocytes
10E9/L
NA
NA
≥1.4, ≥5.0
NA
Eosinophils
10E9/L
NA
NA
≥1.5, ≥5.0
NA
Basophils
10E9/L
NA
NA
≥1.0, ≥2.0
NA
Platelet Count
10E9/L
≤20
≥600
NA
≤50 and decrease from BL 
≥25
INR
NA
NA
≥4.5
NA
Biochemistry
ALT
IU/L
NA
NA
≥3 x ULN, 
≥5 x ULN
NA
AST
IU/L
NA
NA
≥3 x ULN, 
≥5 x ULN
NA
ALP
IU/L
NA
NA
≥3 x ULN
NA
CK
IU/L
NA
NA
≥500, 
≥2000
NA
GGT
IU/L
NA
NA
≥5 x ULN
NA
Total Bilirubin
μmol/L
NA
NA
≥2 x ULN
NA


Statistical Analysis Plan 
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Parameter
Unit
Low
value
Low decrease
High value
High increase
Albumin
g/L
≤20
NA
≥100
NA
≤25 and decrease from BL 
≥10
≥70 and increase from BL 
≥10
BUN
mmol/L
NA
NA
≥18
NA
Creatinine
umol/L
NA
NA
≥140, ≥190
NA
Sodium
mmol/L
≤132
NA
≥152
NA
Potassium
mmol/L
≤3
NA
≥5.5
NA
Chloride
mmol/L
≤90
NA
≥120
NA
Fasting Glucose
mmol/L
≤2.5
NA
≥7.0, ≥11.1
NA
Total Cholesterol
mmol/L
NA
NA
≥7.25
NA
IgG
mg/L
<=4.0
<6.5 and 
>=20% 
decrease from 
baseline
NA
NA
IgA
mg/L
NA
<=200 and > 
20% decrease 
from baseline
>=6000
NA
IgM
mg/L
NA
<=200 and >
20% decrease 
from baseline
>=6000
NA
Bicarb
mmol/L
<=12
NA
>=40
NA
eGFR
mL/min/1.73m2
<=25
<=50 and 
>=25% 
decrease from 
baseline
>=150 and>=25% increase 
from baseline
Urinalysis
Urine protein/
creatinine ratio
g/mmol
NA
NA
≥0.395
NA
Fasting lipid profile
HDL
mmol/L
≤0.8
NA
NA
NA
LDL
mmol/L
NA
NA
≥5.2
NA
Triglycerides
mmol/L
NA
NA
≥3.6, ≥5.4
NA


Statistical Analysis Plan 
Study Code D3461C00008
Edition Number 2.0 
Date 27/02/2018
48
Appendix E
Reference ranges and TELVC for vital signs
Parameter
Unit
Low value
Low decrease
High value
High increase
Pulse
Beats 
per 
minute
≤50
NA
≥120
NA
≤50 and decrease from BL ≥20
≥120 and increase from BL  ≥20
Systolic blood 
pressure
mmHg
≤90
NA
≥160
NA
≤90 and decrease from BL ≥20
≥160 and increase from BL  ≥20
Diastolic blood 
pressure
mmHg
≤50
NA
≥100
NA
≤50 and decrease from BL ≥10
≥100 and increase from BL  ≥10


Statistical Analysis Plan 
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Edition Number 2.0 
Date 27/02/2018
49
Appendix F
Percent suppression calculation
1. Obtain Ct values for test samples (from clinical trial subjects) and the pooled normal 
control. This data consists of 3 endogenous control genes (18S, ACTB, and GAPDH) and 21 
IFN-inducible genes.
2. Calculate ∀Ct values for each sample (unique subject and time point) by subtracting the 
average endogenous control gene Ct value from each of the 21 IFN-inducible genes (done for 
both the test samples and the pooled control sample).
3. Calculate ∀∀Ct values for each test sample by subtracting the pooled control ∀Ct values 
from the test sample ∀Ct values for each gene (e.g. Test Sample ∀Ct(EPSTI1) - Pooled Control 
∀Ct(EPSTI1)).
4. Multiply each ∀∀Ct value by -1 (for magnitude directionality purposes).  Calculate the 
power of 2 for each of the adjusted values.  The ∀∀Ct values are now in a linear scale format.
5. Calculate the observed target neutralization (tn) value for each gene for all available 
individual subject time points (X) relative to their baseline adjusted ∀∀Ct values using the 
formula below;
tn = ((Baseline adj. ∀∀Ct - Day-X adj. ∀∀Ct)/ Baseline adj. ∀∀Ct) * 100
6. Calculate the median target neutralization across all 21-gene for a particular subject and 
time point.
7. Adjust the median target neutralization value by subtracting it from 100.  This normalizes 
all target neutralization values to a baseline value of 100%.  This value is utilized as the final 
percent suppression value for further evaluation.  A value <100% represent a target 
suppression relative to a particular subjects’ baseline levels, while a value >100% represents 
an induction.