A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus
Phase: PHASE3
Conditions: Active Systemic Lupus Erythematosus
Sponsor: AstraZeneca

Revised Clinical Study Protocol
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00004
Edition Number
6
Date
23 May 2019
A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects 
with Active Systemic Lupus Erythematosus
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
EudraCT number: 2014-004632-19
This submission document contains trade secrets and confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
The following Amendment(s) and Administrative Changes are included in this revised protocol:
Amendment No.
Date of Amendment
Local Amendment No.
Date of local Amendment
01
09 April 2015
02
01 February 2016
03
23 March 2016
04
18 May 2016
05
23 May 2019
Administrative 
change No.
Date of Administrative 
Change
Local Administrative 
change No.
Date of local 
Administrative Change
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 Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects 
with Active Systemic Lupus Erythematosus
International Coordinating Investigator
Eric F Morand MB, BS (Hons); FRACP: PhD
Head, School of Clinical Sciences at Monash Health
Monash University Faculty of Medicine, Nursing & Health Sciences
Level 3, Block E, Monash Medical Centre
246 Clayton Road
Clayton VIC 3168
Australia
Study site(s) and number of subjects planned
Approximately 360 subjects are planned at approximately 135 sites.
Study period
Phase of development
Estimated date of first subject enrolled
Q2 2015
3
Estimated date of last subject completed
Q3 2018
Study design
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of an intravenous (IV) treatment regimen of 300 mg 
anifrolumab versus placebo in subjects with moderately to severely active, 
autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care
(SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age.
Approximately 360 subjects receiving SOC treatment will be randomised in a 1:1 ratio to 
receive a fixed IV dose of 300 mg anifrolumab or placebo every 4 weeks (Q4W) for a total of 
13 doses (Week 0 to Week 48), with the primary endpoint evaluated at the Week 52 visit.
Investigational product will be administered as an IV infusion via an infusion pump over a 
minimum of 30 minutes, Q4W. Subjects must be taking either 1 or any combination of the 
following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants.
Randomisation will be stratified using the following factors: SLE Disease Activity Index 2000 
(SLEDAI-2K) score at screening (<10 points versus ≥10 points); Week 0 (Day 1) OCS dose 

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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(<10 mg/day versus ≥10 mg/day prednisone or equivalent); and results of a type 1 interferon 
(IFN) test (high versus low).
This study includes:
!
A Screening Period: Up to 30 days 
!
Treatment Period: A 52-week double-blind treatment period with investigational 
product administration Q4W from Week 0 to Week 48 for a total of 13 doses 
!
At Week 52, subjects will have 2 options:
-
If eligible, enrol into the long-term extension (LTE) study 
OR
-
Continue in the current study for another 8 weeks to complete a 12-week safety 
follow-up after the last dose of investigational product (last dose of 
investigational product will be given in Week 48)
Objectives
Primary Objective:
Outcome Measures:
To evaluate the effect of anifrolumab 
compared to placebo on disease activity as 
measured by the difference in the proportion of 
subjects achieving the British Isles Lupus 
Assessment Group-based Composite Lupus 
Assessment (BICLA) response at Week 52
Composite endpoint (BICLA), defined by meeting all 
of the following criteria:
-
Reduction of all baseline British Isles Lupus 
Assessment Group (BILAG)-2004 A to B/C/D 
and baseline BILAG-2004 B to C/D, and no 
BILAG-2004 worsening in other organ systems, 
as defined by ≥1 new BILAG-2004 A or ≥2 new 
BILAG-2004 B
-
No worsening from baseline in SLEDAI-2K, 
where worsening is defined as an increase from 
baseline of >0 points in SLEDAI-2K
-
No worsening from baseline in subjects’ lupus 
disease activity, where worsening is defined by 
an increase ≥0.30 points on a 3-point Physician’s 
Global Assessment (PGA) visual analogue scale 
(VAS)
-
No discontinuation of investigational product
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment

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Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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Key Secondary Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab compared to placebo on:
The proportion of subjects with BICLA 
response at Week 52 in the IFN test-high 
subgroup
BICLA (see outcome measure for primary objective)
The proportion of subjects who achieve an 
OCS dose ≤7.5 mg/day at Week 40, which is 
maintained through Week 52 in the subgroup 
of subjects with baseline OCS ≥10 mg/day
Maintained OCS reduction defined by meeting all of 
the following criteria: 
-
Achieve an OCS dose of ≤7.5 mg/day 
prednisone or equivalent by Week 40
-
Maintain an OCS dose ≤7.5 mg/day prednisone 
or equivalent from Week 40 to Week 52 
-
No discontinuation of investigational product
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment
The proportion of subjects with a ≥50% 
reduction in Cutaneous Lupus Erythematosus 
Disease Area and Severity Index (CLASI) 
activity score at Week 12 in the subgroup of 
subjects with baseline CLASI activity score 
≥10
50% reduction in CLASI activity score compared to 
baseline defined by meeting all of the following 
criteria:
-
Achieve ≥50% reduction of CLASI activity 
score at Week 12 compared to baseline
-
No discontinuation of investigational product
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment
The proportion of subjects with ≥50% 
reduction in joint counts at Week 52 in the 
subgroup of subjects with ≥6 swollen and 
≥6 tender joints at baseline 
50% reduction in the number of swollen and tender 
joints compared to baseline defined by meeting all of 
the following criteria:
-
Achieve ≥50% reduction in the number of 
swollen and tender joints, separately
-
No discontinuation of investigational product 
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment
The annualised flare rate through 52 weeks
Annualised flare rate with flare defined as either 1 or 
more new BILAG-2004 A or 2 or more new 
BILAG-2004 B items compared to the previous visit

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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
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Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of 
anifrolumab
Adverse events (AEs) (including adverse events of 
special interest [AESIs]), vital signs, physical 
examination, 12-lead electrocardiograms, flares as 
defined by a modification of the SELENA Flare 
Index using the SLEDAI-2K, clinical laboratory tests 
(haematology, clinical chemistry, urinalysis), 
Columbia Suicide Severity Rating Scale, and 
Personal Health Questionnaire Depression Scale-8
a
Restricted medication is described in Section 3.3 and additional details are given in the Statistical Analysis 
Plan. 

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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
PROTOCOL SYNOPSIS.....................................................................................................2
TABLE OF CONTENTS.....................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................................16
1.
INTRODUCTION .............................................................................................20
1.1
Background........................................................................................................20
1.2
Rationale for study design, doses and control groups..........................................22
1.2.1
Rationale for study design.................................................................................. 22
1.2.2
Rationale for primary endpoint selection............................................................23
1.2.3
Rationale for dose selection................................................................................ 23
1.2.4
Rationale for duration of infusion.......................................................................24
1.2.5
Interferon test background..................................................................................24
1.3
Benefit/risk and ethical assessment ....................................................................25
1.4
Study design ...................................................................................................... 29
1.4.1
Steroid burst.......................................................................................................30
1.4.2
Protocol-specified steroid tapering .....................................................................30
2.
STUDY OBJECTIVES......................................................................................33
2.1
Primary objective...............................................................................................33
2.2
Secondary objectives.......................................................................................... 33
2.3
Safety objective..................................................................................................35
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL.....................35
3.1
Inclusion criteria ................................................................................................35
3.2
Exclusion criteria ............................................................................................... 40
3.2.1
General exclusion criteria................................................................................... 40
3.2.2
Exclusion criteria related to concomitant medications ........................................41
3.2.3
Exclusion criteria related to systemic lupus erythematosus and other 
diseases..............................................................................................................43
3.2.4
Exclusion criteria related to infection and malignancy risk factors......................44
3.3
Restrictions and concomitant medications..........................................................45
3.3.1
Excluded medications: Day 1 through the end of the study.................................45
3.3.1.1
Medications that lead to immediate discontinuation of investigational 
product...............................................................................................................45
3.3.1.2
Restricted medications .......................................................................................46

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Study Code D3461C00004
Edition Number 6
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3.3.1.3
Other concomitant medications ..........................................................................47
3.3.2
Concomitant medications for Systemic Lupus Erythematosus standard of 
care during the study..........................................................................................47
3.3.2.1
Steroid burst and taper Week 0 (Day 1) to Week 12 ...........................................50
3.3.2.2
Increase in corticosteroids from Week 12 to Week 40 ........................................50
3.3.2.3
Increase in oral corticosteroids after Week 40 ....................................................51
3.3.2.4
Increase in oral corticosteroids for intercurrent disease or to prevent 
adrenal insufficiency..........................................................................................51
3.3.2.5
Protocol-specified steroid tapering Week 8 to Week 40......................................51
3.3.3
Other restrictions................................................................................................52
3.3.3.1
Fasting lipid profile............................................................................................52
3.3.3.2
Perioperative management of investigational product.........................................52
3.4
Subject enrolment and randomisation.................................................................53
3.5
Methods for ensuring blinding ...........................................................................54
3.6
Unblinding......................................................................................................... 54
3.6.1
Unblinding for Data and Safety Monitoring Board.............................................54
3.7
Discontinuation of investigational product .........................................................55
3.7.1
Subject decision to discontinue investigational product......................................56
3.7.2
Withdrawal of the informed consent...................................................................56
3.7.3
Lost to follow-up ...............................................................................................56
3.7.4
Study completion and end of study..................................................................... 56
3.7.5
Procedures for discontinuation of a subject from investigational product............57
3.8
Criteria for withdrawal.......................................................................................57
3.8.1
Screen failures ...................................................................................................57
3.9
Discontinuation of the study...............................................................................57
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................................58
4.1
Enrolment/Screening Period............................................................................... 67
4.1.1
Other considerations for screening .....................................................................67
4.1.1.1
Oral examination................................................................................................67
4.1.1.2
Mammography...................................................................................................67
4.1.2
Re-screening subjects who screen fail ................................................................67
4.2
Treatment Period................................................................................................ 68
4.2.1
Premature discontinuation of investigational product .........................................68
4.3
Unscheduled Visit.............................................................................................. 69
4.4
Follow-up Period ............................................................................................... 70
5.
STUDY ASSESSMENTS..................................................................................70
5.1
Description of study procedures .........................................................................70
5.2
Efficacy assessments.......................................................................................... 70
5.2.1
Training and certification for Systemic Lupus Erythematosus assessments......... 70

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Edition Number 6
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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
ADL
Activity of daily living
AE
Adverse event
AESI
Adverse event of special interest
AIS
Adenocarcinoma in situ 
ALT
Alanine aminotransferase
ANA
Antinuclear antibody
Anti-Sm
Anti-Smith 
Anti-RNP
Anti-Ribonucleoprotein
Anti-SSA
Anti-Sjogren’s Syndrome-related antigen A
Anti-SSB
Anti-Sjogren’s Syndrome-related antigen B
AST
Aspartate aminotransferase
β-hCG
β-human chorionic gonadotropin
BCG
Bacillus Calmette-Guerin
BICLA
British Isles Lupus Assessment Group-based Composite Lupus Assessment
BILAG
British Isles Lupus Assessment Group
BP
Blood pressure
C3
Third component of complement
C4
Fourth component of complement
CH50
Total haemolytic complement
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
CIN III
Cervical intraepithelial neoplasia grade III 
CIS
Carcinoma in situ 
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CLE
Cutaneous Lupus Erythematosus

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Drug Substance Anifrolumab (MEDI-546)
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Edition Number 6
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Abbreviation or 
special term
Explanation
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
C-SSRS
Columbia Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
Computed tomography
CV-EAC
Cardiovascular Event Adjudication Committee 
dECG
Digital electrocardiogram
DEHP
Diethylhexyl phthalate
DSMB
Data and Safety Monitoring Board
DNA
Deoxyribonucleic acid 
dsDNA
Double-stranded deoxyribonucleic acid
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
EDC
Electronic data capture 
EMA
European Medicines Agency
EudraCT
European Clinical Trials Database
EULAR
European League Against Rheumatism
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV DNA
Hepatitis B virus DNA
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus

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Abbreviation or 
special term
Explanation
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive care unit
IFA
Immunofluorescent assay
IFIGx
Interferon-inducible gene expression
IFN
Interferon
Ig
Immunoglobulin
IGRA
Interferon-gamma release assay
International 
Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or 
activities internationally.
IV
Intravenous
IXRS
Interactive voice/web response system
LLOQ
Lower limit of quantitation
LTE
Long-term extension
MACE
Major adverse cardiovascular events 
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI 
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
 
NSAIDs
Nonsteroidal anti-inflammatory drugs
OCS
Oral corticosteroids
PGA
Physician’s Global Assessment
PHQ-8
Personal Health Questionnaire Depression Scale-8
PI
Principal Investigator 
PIP
Proximal interphalangeal

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1.
INTRODUCTION
1.1
Background
Systemic lupus erythematosus (SLE) is a chronic, multisystemic, disabling autoimmune 
rheumatic disease of unknown aetiology. Systemic lupus erythematosus predominantly affects 
women of childbearing years (Cooper et al, 1998; Lahita, 1999) with a review reporting the 
female-to-male ratio in the childbearing years to be 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. Although off-label therapy has improved 
management options in recent years, long-term prognosis remains poor for many subjects. 
Compared to the general population, the overall mortality in SLE is increased with a 
standardised mortality ratio (SMR; defined as the ratio of the number of deaths observed to 
deaths expected) of 2.4, (2.3 to 2.5 95% confidence interval [CI]) in a large international 
cohort of 9,457 subjects followed for over 70000 subject-years (Bernatsky et al, 2006).
Clinical manifestations of SLE include, but are not limited to, constitutional symptoms, 
alopecia, rashes, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, 
haemolytic anaemia, cognitive dysfunction and other nervous system involvement. These 
disease manifestations cause a significant burden of illness and can lead to reduced physical 
function, loss of employment, lower health-related quality of life (QoL), and a lifespan 
shortened by about 10 years (ACR ad hoc committee, September 1999). Increased 
hospitalisations and side effects of medications including chronic oral corticosteroids (OCS)
and other immunosuppressive treatments add to disease burden in SLE (Doria and Briani, 
2008; Petri, 2001; Zonana-Nanach et al, 2000).
All of the therapies currently used for the treatment of SLE have well known adverse effect 
profiles and there is a medical need to identify new targeted therapies, particularly agents that 
may reduce the requirement for corticosteroids and cytotoxic agents.
There has been only 1 new treatment (belimumab) for SLE approved by the US Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) in the approximately
50 years since hydroxychloroquine was approved for use in discoid lupus and SLE. However, 
belimumab is not approved everywhere, and the uptake has been modest. Many agents 
currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate 
mofetil/mycophenolic acid, have not been approved for the disease. Furthermore these drugs 
all have well-documented safety issues and are not effective in all patients for all
manifestations of lupus. Antimalarial agents (eg, hydroxychloroquine) and corticosteroids 
may be used to control arthralgia, arthritis, and rashes. Other treatments include nonsteroidal 
anti-inflammatory drugs (NSAIDs); analgesics for fever, arthralgia, and arthritis; and topical 
sunscreens to minimise photosensitivity. It is often difficult to taper subjects with moderate or 
severe disease completely off corticosteroids, which cause long-term morbidity and may 
contribute to early cardiovascular mortality (Petri, 2001; Urowitz et al, 1976). Even small 
daily doses of 5 to 10 mg prednisone used long-term carry increased risks of side effects such 
as cataracts, osteoporosis, and coronary artery disease (Petri, 2001).

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Study Code D3461C00004
Edition Number 6
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Multiple lines of evidence indicate a role of type I interferons (IFNs) in the pathogenesis of 
SLE:
!
Genetic polymorphisms associated with type I IFNs are associated with 
susceptibility to SLE (Criswell, 2008, Sigurdsson, Göring et al, 2008; Sigurdsson, 
Nordmark et al, 2008).
!
High IFN-α levels and type I IFN activity have been reported in SLE (Bengtsson et 
al, 2000, Dall’era et al, 2005).
!
Increased levels of messenger ribonucleic acid (mRNA), whose transcription is 
induced by type I IFNs (type I IFN signature), are prominent in peripheral blood 
mononuclear cells and whole blood in approximately 60% of SLE subjects and are 
associated with greater disease activity (Baechler et al, 2003, Bennett et al, 2003, 
Crow and Wohlgemuth, 2003, Feng X et al, 2006, Kirou et al, 2004, Kirou et al, 
2005). Transcripts induced by type I IFN are the most overexpressed transcripts in 
SLE (Yao et al, 2010).
!
Proteins induced by IFN are increased in subjects with SLE (Huang et al, 2008, 
Hylton et al, 1986, Okamoto et al, 2004).
!
Overexpression of type I IFN, type I IFN signature, and proteins induced by type I 
IFNs have been associated with greater disease activity and organ system 
involvement in SLE.
Subjects with high anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibody titres, 
lupus nephritis, and progressive skin rashes have high serum levels of type I IFN (Bengtsson 
et al, 2000). In addition, subjects with acute skin involvement tend to have elevated IFN in 
blood and skin (Dall’era et al, 2005). Skin biopsies from subjects with SLE also show
increased type I IFN signature (Blomberg S et al, 2001, Farkas et al, 2001, Yao et al, 2009).
Proteins induced by IFN are increased in subjects with active central nervous system (CNS)
symptoms (Okamoto et al, 2004).
Immune complexes containing SLE autoantibodies, such as anti-dsDNA or 
antiribonucleoprotein (anti-RNP) antibodies, can activate type I IFN production (Bengtsson et 
al, 2000, Rönnblom and Alm, 2003). After internalisation through Fc receptors, 
autoantibody-containing immune complexes bind endosomal toll-like receptor 7 (TLR7) and 
toll-like receptor 9 (TLR9), stimulating production of type I IFN. Type I IFN stimulates 
monocyte derived dendritic cell maturation, which promotes loss of tolerance and generation 
of autoreactive T and B cells, autoantibody production, immune complex formation, and 
further production of type I IFN, creating a self-perpetuating cycle of autoimmunity 
(Banchereau et al, 2004, Pascual et al, 2006, Rönnblom and Pascual, 2008).
With the growing evidence that type I IFNs play an important role in autoimmune diseases 
such as SLE, inhibition of the biological activity of type I IFNs with anifrolumab may, 
therefore, be a novel efficacious therapy for the treatment of SLE and its significant unmet 
medical need.

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Anifrolumab (MEDI-546) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal 
antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). It is 
composed of 2 identical light chains and 2 identical heavy chains, with an overall molecular 
weight of approximately 148 kDa. Anifrolumab inhibits binding of type I IFN to type I 
interferon receptor (IFNAR) and inhibits the biologic activity of all type I IFNs. 
1.2
Rationale for study design, doses and control groups
1.2.1
Rationale for study design
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of an intravenous (IV) treatment regimen of 300 mg 
anifrolumab versus placebo in adult subjects with moderately to severely active, 
autoantibody-positive SLE while receiving standard of care (SOC) treatment.
It is thought that neutralisation of IFN signalling through the human type I IFN receptor with 
anifrolumab will reduce the severity of disease activity in subjects with chronic, moderately to
severely active SLE, and that anifrolumab will be well tolerated when given at the proposed 
dose for the duration of the study.
To ensure adequate treatment, all subjects will receive SOC treatment with at least 1 of the 
following: OCS, antimalarial, or immunosuppressants, in addition to investigational product. 
This is consistent with the 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.
The study will be randomised, placebo-controlled, and double-blind to ensure a robust design 
and minimise bias. This is the preferred design as outlined in the June 2010 FDA Guidance for 
Industry Systemic Lupus 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 lupus nephritis (CHMP, 
February 2015).
Randomisation will be stratified by Systemic Lupus Erythematosus Disease Activity Index 
2000 (SLEDAI-2K, see 
 score at screening (<10 points versus ≥10 points), Day 1 
OCS dose (<10 mg/day versus ≥10 mg/day of prednisone or equivalent), and the results of the 
IFN test (high versus low). Stratification is implemented in order to minimise the risk for 
baseline imbalance(s) across treatment arms on potentially confounding variables. Baseline 
imbalances of these factors could impact efficacy and/or safety assessments of anifrolumab 
versus placebo.
A treatment period of 52 weeks is an appropriate study duration to determine the 
investigational product’s long-term efficacy and safety profile.

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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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1.2.2
Rationale for primary endpoint selection
The primary outcome measure is the proportion of subjects achieving the British Isles Lupus 
Assessment Group-based Composite Lupus Assessment (BICLA) response at Week 52.
The BICLA is driven by improvement in the BILAG-2004 score, which measures 
organ-specific activity (Wallace et al 2011). The BILAG-2004 incorporates a comprehensive, 
organ-specific, 97-question assessment, which requires the Investigator to score organ 
manifestations as improving, same, worse, or new over the previous 4 weeks. The scores (A, 
B, C, D) derived from the assessments (improving, same, worse, or new) will determine 
whether further treatment is needed to resolve disease activity. The change in treatment does 
not determine the scoring (Yee et al 2009). The BICLA was used as the primary endpoint in a 
Phase 2b (Wallace et al 2014) and in a Phase 3 SLE trial of epratuzumab (Clowse et al 2017). 
It was also used as a secondary endpoint in the anifrolumab Phase 2b study and the Phase 3 
study D3461C00005. 
Given the clinical relevance for the use of BICLA and its ability to discern effect as suggested 
in the anifrolumab Phase 2b study and the Phase 3 study D3461C00005, the BICLA was 
chosen as the primary endpoint.
1.2.3
Rationale for dose selection
The selection of a dose of 300 mg anifrolumab every 4 weeks (Q4W) for this study is based 
on safety and efficacy results from the interim analysis of a Phase 2b study where 2 doses of 
anifrolumab (300 mg and 1000 mg) are evaluated relative to placebo as well as dose-response 
modelling and simulation. In the interim analysis of the Phase 2b study, clinically meaningful 
benefit was observed with the 300 mg dose, with no incremental benefit at 1000 mg, see 
Section 1.3 for details. In addition, a higher proportion of subjects reporting Herpes zoster
reactivations was observed at 1000 mg compared to 300 mg. Given the comparable efficacy 
between the 300 and 1000 mg anifrolumab doses and the increased frequency of Herpes 
zoster events in the 1000 mg dose group relative to the 300 mg dose group, the benefit:risk 
profile appears to favour the 300 mg dose. Further, from the PK/efficacy model, minimal 
improvement in efficacy was predicted for doses higher than 300 mg, consistent with the 
observed Phase 2b study interim analysis data. The model also predicted that doses lower than 
300 mg will result in lower efficacy since trough concentrations (Ctrough) from doses lower 
than 300 mg will fall below the model-predicted concentrations corresponding to 80% of 
maximum SRI(4) efficacy. The non-linear PK properties of anifrolumab cause a large increase 
in Ctrough variability at doses below 300 mg, so as anifrolumab dose is lowered, a large 
proportion of subjects are predicted to have very rapid clearance and negligible exposure to 
anifrolumab. For these reasons, the selection of a dose of 300 mg anifrolumab is justified for 
this study.
A companion 3-arm study (D3461C00005) evaluating the efficacy, safety, and PK of 
anifrolumab is being conducted to verify that a lower dose (150 mg) of anifrolumab will be 
suboptimal.

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1.3
Benefit/risk and ethical assessment
A detailed up-to-date assessment of the overall risk/benefit of anifrolumab is discussed in the 
Investigator’s Brochure (IB).
There is significant unmet medical need for the treatment of subjects with chronic, moderately
to severely active SLE. Since type I IFNs have a role in SLE, a therapy such as anifrolumab, 
that targets type I IFN receptors, may be beneficial in the treatment of these subjects.
Anifrolumab has been or is being investigated in 5 MedImmune/AstraZeneca-sponsored 
clinical studies in adult subjects with systemic sclerosis or SLE as follows: 
!
Study MI-CP180 was a Phase 1, open-label, dose-escalation study of single and 
multiple IV doses of anifrolumab in adult subjects with systemic sclerosis 
(completed study). 
!
Study CD-IA-MEDI-546-1013 is an ongoing Phase 2b, randomised, double-blind, 
placebo-controlled study of anifrolumab (300 and 1000 mg) in adult subjects with 
moderately to severely active SLE (ongoing at the time of writing this protocol).
!
Study CD-IA-MEDI-546-1145 is the ongoing open-label extension (OLE) for 
subjects completing Study CD-IA-MEDI-546-1013 (ongoing at the time of writing 
this protocol).
!
Study D3461C00002 is an ongoing study in Japanese adult subjects with SLE
(ongoing at the time of writing this protocol).
!
Study D3461C00007 is an ongoing study in adult subjects with lupus nephritis 
(ongoing at the time of amending this protocol). 
Study CD-IA-MEDI-546-1013 is a Phase 2b, randomised, double-blind, placebo-controlled, 
parallel group study to evaluate the efficacy and safety of anifrolumab in adult subjects with 
chronic, moderately to severely active SLE with an inadequate response to SOC treatment for 
SLE. Subjects were randomised 1:1:1 to placebo, anifrolumab 300 mg or anifrolumab 
1000 mg while continuing their SOC treatment. Enrolment in the study is complete. An 
interim analysis (including the analysis of the primary endpoint) was conducted after all 
subjects completed the Day 169 visit or discontinued from study treatment early. As of the 
data cut-off date of August 15, 2014, a total of 305 subjects had been treated with 
investigational product (2 subjects discontinued from the study prior to dosing). 
Efficacy in anifrolumab Phase 2b study
The primary efficacy endpoint of the Phase 2b study was the proportion of subjects achieving 
response in Systemic Lupus Erythematosus Responder Index (4) (SRI[4]) with sustained 
reduction of OCS (<10 mg/day and less than or equal to the dose received on Day 1 by Day 85 
and maintained between Days 85 and 169) at Day 169. There were higher proportions of 
subjects in the 300 mg (34.3%) and 1000 mg (28.8%) anifrolumab groups than in the placebo 
(17.6%) group who met the primary endpoint at Day 169. Similar results were also observed 
in the other co-primary population, the IFN test-high subjects (representing approximately 

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75% of the study population) but not in the IFN test-low subjects at Day 169 (it is important to 
note that the sample size is low in this subpopulation). Further, compared to the placebo 
group, numerically higher proportions of subjects in the anifrolumab groups met the
secondary endpoints of SRI(4) with sustained reduction of OCS (<10 mg/day and less than or 
equal to the dose received on Day 1 by Day 281 and maintained between Days 281 and 365) 
at Day 365 (placebo [25.5%], 300 mg [51.5%] and 1000 mg [38.5%]) and reduction of 
background OCS dose to ≤7.5 mg/day at Day 365 in those taking ≥10 mg/day at baseline 
(placebo [26.6%], 300 mg [56.4%], and 1000 mg [31.7%]).
The efficacy observed with the primary and secondary endpoints was supported by a wide 
range of evidence. A numerically higher proportion of subjects receiving anifrolumab met SRI 
response criteria without the OCS taper requirement at Day 169 and Day 365 compared to 
placebo. Furthermore, compared to the placebo group numerically higher proportions of 
anifrolumab treated subjects achieved SRI(5), SRI(6), SRI(7), and SRI(8) response, as well as 
BICLA response.
Higher response rates were also observed in organ specific measures for anifrolumab-treated 
subjects compared with placebo. In subjects with moderate or severe skin disease (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index [CLASI] activity score ≥10) at 
baseline, a numerically higher proportion of subjects achieved at least 50% improvement from 
baseline in the CLASI activity score following anifrolumab treatment compared to subjects 
receiving placebo. In subjects with moderate or severe arthritis (≥8 swollen and tender joints) 
at baseline, a numerically higher proportion of subjects treated with 300 mg anifrolumab 
achieved at least 50% improvement in swollen and tender joint counts compared to subjects 
treated with placebo.
Amongst subjects with a dose of ≥10 mg/day oral prednisone or equivalent at baseline, a 
numerically higher proportion of subjects in the 300 mg anifrolumab group than in the 
placebo group were able to reduce OCS to ≤7.5 mg/day prednisone or equivalent by Day 169. 
Similar results were seen at Day 365. No apparent differences were seen when comparing the 
1000 mg anifrolumab and placebo groups.
Serum complement and anti-dsDNA antibody levels are often indicative of active disease in 
SLE. In subjects with detectable anti-dsDNA autoantibody levels at baseline, those treated 
with 300 mg anifrolumab demonstrated a numerically larger decrease from baseline in 
anti-dsDNA antibody levels at Day 365 than those who were treated with placebo. In subjects 
with abnormal third component of complement (C3) levels at baseline, those treated with 
anifrolumab demonstrated a numerically larger increase from baseline in C3 levels at Day 169 
and 365 than those who were treated with placebo.
Expression of type I IFN-inducible genes in whole blood using a 21-gene panel 
(pharmacodynamic [PD] marker) decreased following anifrolumab administration for all dose 
groups in subjects with a baseline positive type I IFN signature in whole blood. Both the 
300 mg and 1000 mg anifrolumab dose achieved and maintained 82 to 90% neutralisation of 
the gene signature. In the placebo group no neutralisation of the gene signature (>6%) was 
observed at any time point.

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Safety experience in anifrolumab Phase 2b study through August 2014 
Although the safety profile for anifrolumab is acceptable, an imbalance was seen in the rate of 
occurrence of uncomplicated Herpes zoster reactivation.
The overall number of subjects with adverse events (AEs), serious adverse events (SAEs) and 
adverse events of special interest (AESIs) (new or reactivated tuberculosis [TB], malignancy, 
infusion or hypersensitivity or anaphylactic reaction and non SLE-related vasculitis) were 
similar between the placebo and anifrolumab groups. Serious adverse events related to the 
investigational product were observed in 5.9% of the subjects in the placebo, 3.0% in the 
300 mg and 1.0% in the 1000 mg anifrolumab group. Adverse events leading to 
discontinuation of the investigational product were observed in 7.9% in the placebo, 3.0% in 
the 300 mg and 9.5% in the 1000 mg anifrolumab group. There was 1 death in the 1000 mg 
anifrolumab group (acute colitis) and none in the other 2 treatment groups.
There was a higher number of subjects 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%). This 
was due primarily to more reports of uncomplicated cases of Herpes zoster in the anifrolumab 
treated subjects (300 mg: 5.1%; 1000 mg: 9.5%) compared to placebo (2.0%). Importantly, 
subjects with Herpes zoster infection responded to standard antiviral treatment. One 
treatment-emergent SAE of transverse myelitis with a positive varicella zoster virus 
polymerase chain reaction in cerebrospinal fluid was reported. The subject recovered 
following treatment with pulsed steroid and standard antiviral medication.
There was a higher number of subjects with infections reported as influenza in the 
anifrolumab groups (300 mg: 6.1%; 1000 mg: 7.6%) compared to 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 subjects: 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.
Overall benefit:risk assessment 
Anifrolumab demonstrated a clinically relevant benefit in subjects with moderate to severe 
SLE treated with SOC. 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 also observed compared with 
placebo, while no apparent difference was observed comparing the 1000 mg group and 
placebo.
Anifrolumab was generally well tolerated. A dose-related increase in the number of subjects 
with uncomplicated Herpes zoster infections was observed in subjects receiving anifrolumab 
compared with placebo. To date, in clinical trials of anifrolumab, hypersensitivity events or 
anaphylaxis/anaphylactoid events have not occurred more frequently in subjects who were 

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treated with anifrolumab 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. Acute allergic reactions may include hypotension, 
dyspnoea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, and 
unresponsiveness. Reports of infusion-related reactions from clinical trials conducted to date 
suggest that the frequency, severity and characteristics of these reactions are similar across all 
treatment groups.
Although anifrolumab is a human monoclonal antibody, subjects can develop 
anti-anifrolumab antibodies 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 this study, anifrolumab will be administered at a fixed IV dose of 300 mg Q4W for 
52 weeks, equivalent to the lower dose in the Phase 2 study (CD-IA-MEDI-546-1013).
Anifrolumab has been generally well tolerated to date with no dose-related safety signal 
observed with the exception of an imbalance in observed events of uncomplicated Herpes 
zoster infections. 
In order to minimise the risk of treatment with anifrolumab, subjects with risk factors for 
serious infection, 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, vasculitis (non 
SLE), and major adverse cardiovascular events (MACE) (including stroke, myocardial 
infarction [MI], or cardiovascular death) are designated as AESIs in this study. 
Major adverse cardiovascular events are also designated as AESIs. An external independent 
adjudication committee will assess all deaths and cardiovascular SAEs to determine if they 
meet criteria for MACE (stroke, MI, or cardiovascular death). Specific details will be 
addressed in a cardiovascular event adjudication charter. There have been no imbalances in 
reporting rates of MACE or other non-MACE cardiovascular events observed either with 
anifrolumab 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 signal detection activity across treatment arms. 
Compared to the general population, subjects with SLE have a higher rate of depression and 
suicide. Therefore, subjects will be screened for suicidality and those who are at high risk at 
baseline will be excluded from participation in the study.

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In order to provide an independent periodic review of safety throughout the trial, in addition to 
the ongoing, blinded review provided by the Medical Monitor, an independent Data and 
Safety Monitoring Board (DSMB) will review blinded and unblinded safety data on a regular 
basis throughout the study (see Section 6.10.1).
In conclusion, AstraZeneca believes that the available nonclinical and clinical data indicate an 
acceptable safety profile for anifrolumab. The proposed dosing regimens for Protocol 
D3461C0004 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 
further clinical evaluation in subjects with active SLE.
1.4
Study design 
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of an IV treatment regimen of 300 mg anifrolumab 
versus placebo in adult subjects with moderately to severely active, autoantibody-positive 
SLE while receiving SOC treatment. The study will be performed in adult subjects aged 18 to 
70 years of age.
Approximately 360 subjects receiving SOC treatment will be randomised in a 1:1 ratio to 
receive a fixed IV dose of 300 mg anifrolumab or placebo Q4W for a total of 13 doses 
(Week 0 to Week 48) with the primary endpoint evaluated at the Week 52 visit.
Investigational product will be administered as an IV infusion via an infusion pump over a 
minimum of 30 minutes, Q4W.
Subjects must be taking either 1 or any combination of the following: OCS, antimalarial, or 
immunosuppressants. Specific medication restrictions are contained in the eligibility criteria 
and Section 3.3. See Figure 2 for an outline of the study design.
Randomisation will be stratified using the following factors: 
!
SLEDAI-2K score at screening (<10 points versus ≥10 points)
!
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or 
equivalent)
!
Results of the IFN test (high versus low)
This study includes:
!
A Screening Period: Up to 30 days 
!
Treatment Period: A 52-week double-blind treatment period with investigational 
product administration Q4W from Week 0 to Week 48 for a total of 13 doses 
!
At Week 52, subjects will have 2 options:
-
If eligible, enrol into the long-term extension (LTE) study 

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OR
-
Continue in the current study for another 8 weeks to complete a 12-week safety 
follow-up after the last dose of investigational product (last dose of 
investigational product will be given in Week 48)
The total study duration could be up to approximately 64 weeks for subjects who do not enrol
into the LTE study (including screening period) and up to approximately 56 weeks (including 
screening period) for those subjects who do enrol into the LTE study.
1.4.1
Steroid burst
Section 3.3.2 provides specific details on steroid burst and tapers. From Week 0 (Day 1) to 
Week 12, subjects may receive only 1 burst of corticosteroids for an increase in SLE disease 
activity or to control non-SLE related disease (eg, asthma or chronic obstructive pulmonary 
disease [COPD] exacerbation). Subjects receiving more than 1 burst during the first 12 weeks 
of treatment will be considered non-responders for subsequent assessments of disease activity
(details are defined in the Statistical Analysis Plan [SAP]), regardless of the reason for the 
burst (SLE or non-SLE activity). 
1.4.2
Protocol-specified steroid tapering
An important secondary objective in this study is assessing whether anifrolumab improves the 
ability to reduce corticosteroid dose in patients to <7.5 mg prednisone or equivalent per day. 
For this reason, steroid tapering to a target OCS dose of ≤7.5 mg/day must be attempted in all 
subjects with a baseline OCS dose ≥10.0 mg/day. This will commence at Week 8 and continue 
stepwise until the target dose is reached, unless at least 1 of the following criteria is met:
!
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) 
!
Moderate to severe skin disease as reflected by a CLASI activity score of ≥10 
!
Moderate to severe arthritis disease as reflected by an active joint count of ≥8 tender 
and/or swollen joints
A recommended steroid-tapering regimen is provided in 
 but Investigators will 
have flexibility in how the OCS dose is reduced at each visit. If steroid tapering is not 
attempted in an eligible subject, the Sponsor or Sponsor’s designee must be contacted 
immediately.
Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
7.5 mg/day up to Week 40 based on disease activity. If a subject has an increase in disease 
activity secondary to OCS tapering, they may increase the dose up to a maximum of the 
baseline OCS therapy dose from Week 8 up to Week 40 without the subject being considered
a non-responder for subsequent assessments of disease activity (details are defined in the 

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Edition Number 6
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SAP). Subjects who require OCS dose above their baseline level may continue in the study 
but could be considered non-responders for subsequent assessments of disease activity.
Steroid tapering will not be permitted after Week 40.

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Figure 2
Study flow chart
IFN = interferon; IV = intravenous; N = number of subjects; OCS = oral corticosteroid; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index; 
Q4W = every 4 weeks; V = Visit; W = Week

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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measures:
To evaluate the effect of anifrolumab 
compared to placebo on disease activity as 
measured by the difference in the proportion 
of subjects achieving BICLA response at 
Week 52
Composite endpoint (BICLA), defined by meeting all 
of the following criteria:
-
Reduction of all baseline BILAG-2004 A to 
B/C/D and baseline BILAG-2004 B to C/D, and 
no BILAG-2004 worsening in other organ 
systems, as defined by ≥1 new BILAG-2004 A 
or ≥2 new BILAG-2004 B
-
No worsening from baseline in SLEDAI-2K, 
where worsening is defined as an increase from 
baseline of >0 points in SLEDAI-2K
-
No worsening from baseline in subjects’ lupus 
disease activity, where worsening is defined by 
an increase ≥0.30 points on a 3-point PGA
visual analogue scale (VAS)
-
No discontinuation of investigational product
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment
a
Restricted medication is described in Section 3.3 and additional details are given in the SAP.
2.2
Secondary objectives
Key Secondary Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab compared to placebo on:
The proportion of subjects with BICLA 
response at Week 52 in the IFN test-high 
subgroup
BICLA (see outcome measure for primary objective)
The proportion of subjects who achieve an 
OCS dose ≤7.5 mg/day at Week 40, which is 
maintained through Week 52 in the subgroup 
of subjects with baseline OCS ≥10 mg/day
Maintained OCS reduction defined by meeting all of
the following criteria:
-
Achieve an OCS dose of ≤7.5 mg/day 
prednisone or equivalent by Week 40
-
Maintain an OCS dose ≤7.5 mg/day prednisone 
or equivalent from Week 40 to Week 52 
-
No discontinuation of investigational product
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment

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Edition Number 6
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The proportion of subjects with a ≥50% 
reduction in CLASI activity score at Week 12 
in the subgroup of subjects with baseline 
CLASI activity score ≥10
50% reduction in CLASI activity score compared to 
baseline defined by meeting all of the following 
criteria:
-
Achieve ≥50% reduction of CLASI activity 
score at Week 12 compared to baseline
-
No discontinuation of investigational product
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment
The proportion of subjects with ≥50% 
reduction in joint counts at Week 52 in the 
subgroup of subjects with ≥6 swollen and 
≥6 tender joints at baseline 
50% reduction in the number of swollen and tender 
joints compared to baseline defined by meeting all of 
the following criteria:
-
Achieve ≥50% reduction in the number of 
swollen and tender joints, separately
-
No discontinuation of investigational product 
-
No use of restricted medications beyond the 
protocol-allowed thresholda before assessment
The annualised flare rate through 52 weeks
Annualised flare rate with flare defined as either 1 or 
more new BILAG-2004 A or 2 or more new 
BILAG-2004 B items compared to the previous visit

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2.3
Safety objective
Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of 
anifrolumab
Adverse events (including AESIs), vital signs, 
physical examination, 12-lead electrocardiograms
(ECG), flares as defined by a modification of the 
SELENA Flare Index using the SLEDAI-2K, clinical 
laboratory tests (haematology, clinical chemistry, 
urinalysis), Columbia Suicide Severity Rating Scale 
(C-SSRS), and Personal Health Questionnaire 
Depression Scale-8 (PHQ-8)
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
Subjects must meet all the following criteria:
1.
Aged 18 through 70 years at the time of screening
2.
Written informed consent and any locally required authorisation (eg, Health 
Insurance Portability and Accountability Act [HIPAA] in the USA, Data Privacy 
Directive in the EU) obtained from the subject prior to performing any 
protocol-related procedures, including screening evaluations
3.
Completion of all screening procedures needed to determine subject eligibility and 
stratification within 30 days after signing the informed consent form (ICF)
4.
Weigh ≥40.0 kg at Screening
5.
Adequate peripheral venous access
6.
Diagnosis of paediatric or adult SLE with a diagnosis of SLE according to the ACR 
1982 revised criteria (Tan et al, 1982) ≥24 weeks prior to signing the ICF

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7.
Currently receiving at least 1 of the following*:
(a)
Where prednisone is the single SOC medication (ie, the subject is not 
concurrently receiving any medication listed in inclusion criterion 7(c)), 
a dose of oral prednisone ≥7.5 mg/day but ≤40 mg/day (or prednisone 
equivalent**) for a minimum of 8 weeks prior to Day 1. In addition, the 
dose of oral prednisone or prednisone equivalent the subject is taking 
must be stable for a minimum of 2 weeks prior to randomisation
(b)
Where prednisone is not the single SOC medication (ie, the subject is 
concurrently receiving at least one medication listed in inclusion 
criterion 7(c)), a dose of oral prednisone ≤40 mg/day (or prednisone 
equivalent**) for a minimum of 2 weeks prior to signing of the ICF. In 
addition, the dose of oral prednisone or prednisone equivalent the 
subject is taking must be stable for a minimum of 2 weeks prior to 
randomisation
(c)
Any of the following medications administered for a minimum of 
12 weeks prior to signing the informed consent, and at a stable dose for 
a minimum of 8 weeks prior to signing the informed consent 
through Day 1:
(i)
Azathioprine ≤200 mg/day
(ii)
Antimalarial (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) and an additional agent, the dose duration 
and maximum allowable dosages for both (b) and (c) must be met
**See 
 for examples of prednisone equivalency
8.
Fulfils at least 4 of the 11 ACR modified 1982 classification criteria for SLE (see 
 at least 1 of which must be:
(a)
Positive antinuclear antibody (ANA) test at screening by 
immunofluorescent assay (IFA) at the central laboratory with titre
≥1:80; OR

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(b)
Anti-dsDNA antibodies at screening elevated to above normal 
(including indeterminate), as per the central laboratory; OR
(c)
Anti-Smith (anti-Sm) antibody at screening elevated to above normal
(including indeterminate) as per the central laboratory
9.
At Screening, Disease Activity Adjudication Group confirmation of:
(a)
SLEDAI-2K Criteria: SLEDAI-2K score ≥6 points and “Clinical” 
SLEDAI-2K score ≥4 points. The “Clinical” SLEDAI-2K is the 
SLEDAI-2K assessment score without the inclusion of points 
attributable to any urine or laboratory results including immunologic 
measures:
(i)
Includes points from the following clinical components: 
arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, 
pericarditis, or vasculitis
(ii)
Excludes points attributed to a fever, an SLE headache, and 
organic brain syndrome
(b)
BILAG-2004 Level Criteria: At least 1 of the following:
(i)
BILAG-2004 level A disease in ≥1 organ system
(ii)
BILAG-2004 level B disease in ≥2 organ systems
(c)
Physician’s Global Assessment (PGA) score ≥1.0 on a 0 to 3 VAS at 
screening
10.
Negative serum β-human chorionic gonadotropin (β-hCG) test at screening (females 
of childbearing potential only)
11.
Females of childbearing potential must use 2 effective methods of avoiding 
pregnancy, one of which is a barrier method, from Screening until 12 weeks after 
the final dose of investigational product unless the subject is surgically sterile (ie,
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy), has a 
sterile male partner, is 1 year postmenopausal, or practices abstinence. Cessation of 
birth control after the 12-week follow-up period should be discussed with a 
responsible physician
!
Sustained abstinence is an acceptable practice; however, periodic 
abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception

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!
Postmenopausal is defined as at least 1 year since last menses and the 
subject has an elevated follicle-stimulating hormone (FSH) level within
the central laboratory value of postmenopausal at screening
Effective methods of birth control include those listed in Table 1.
Table 1
Effective methods of birth control
Barrier Methods
Intrauterine Device Methods
Hormonal Methods
Male condom (with spermicide*)
Progesterone T 
Implants
Cap (with spermicide cream or 
jelly*) 
Copper T 
Hormone shot or injection
Diaphragm (with spermicide
cream or jelly*) 
Combined pill
Minipill
Patch
*where commercially available
12.
Nonsterilised males who are sexually active with a female partner of childbearing 
potential must use a condom (with spermicide where commercially available) from 
Day 1 until at least 12 weeks after receipt of the final dose of investigational 
product
13.
Females with an intact cervix must have documentation of a normal Pap smear with 
no documented malignancy (eg, cervical intraepithelial neoplasia grade III
[CIN III], carcinoma in situ [CIS], or adenocarcinoma in situ [AIS]) within 2 years 
prior to randomisation (see 
for guidance on abnormal Pap smear 
results)
*Any abnormal Pap smear result documented within 2 years prior to randomisation 
must be repeated to confirm patient eligibility
14.
Willing to forego other forms of experimental treatment during the study
15.
Meets all of the following TB criteria:
(a)
No history of active TB prior to any Screening visit
(b)
No history of latent TB prior to initial Screening visit, with the 
exception of latent TB with documented completion of appropriate 
treatment
Note: Subjects with no history of latent TB prior to the initial Screening 
visit, but who are diagnosed with latent TB during screening, may be 
considered eligible if appropriate treatment is initiated prior to 
randomisation. Such subjects may be re-screened if necessary to allow 

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
39(128)
for local guidelines on latent TB treatment initiation.
(c)
No signs or symptoms suggestive of active TB from medical history or 
physical examination
(d)
No recent 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 randomisation (documented appropriately 
in source), and, if warranted, receipt of appropriate treatment for latent 
TB at or before the first administration of investigational product
(e)
Must meet 1 of the following criteria:
(i)
Negative QuantiFERON-TB Gold [QFT-G] test result for 
TB obtained from the study Central Laboratory within 
3 months prior to randomisation OR
(ii)
Positive QFT-G test result for TB obtained during the 
Screening Period from the study Central Laboratory for 
which active TB has been ruled out and appropriate 
treatment for latent TB has been initiated prior to the first 
investigational product administration OR
(iii)
Indeterminate (confirmed on retest) QFT-G test result for 
TB obtained during the Screening Period from the study 
Central Laboratory with ongoing QFT-G testing for TB 
according to the Study Plan 
(f)
A chest radiograph with no evidence of current active infection (eg, TB) 
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 informed consent
16.
Day 1 “Clinical” SLEDAI-2K score ≥4 points
17.
OCS dose stable for at least 2 weeks prior to randomisation
18.
Stable SLE SOC treatment (see Section 3.3.2) at the time of randomisation
19.
Women of childbearing potential must have a negative urine pregnancy test at 
randomisation (Day 1), prior to administration of investigational product
20.
In the opinion of the Investigator, must be able to comprehend the ICF and all 
protocol related assessments, such that the patient can complete all study required 
documents, procedures, and outcome measures

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
40(128)
3.2
Exclusion criteria
Any of the following would exclude the subject from participation in the study:
3.2.1
General exclusion criteria
1.
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of the investigational product or interpretation of subject safety or study 
results
2.
Concurrent enrolment in another clinical study with an investigational product
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 investigational product
5.
Current alcohol, drug or chemical abuse, or a history of such abuse within 1 year 
before Week 0 (Day 1)
6.
Major surgery within 8 weeks before signing the ICF or elective major surgery 
planned during the study period (see 
)
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:
(a)
Aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN)
(b)
Alanine aminotransferase (ALT) >2.0 × ULN
(c)
Total bilirubin >ULN (unless due to Gilbert's syndrome)
(d)
Serum creatinine >2.0 mg/dL (or >181 μmol/L)
(e)
Urine protein/creatinine ratio >2.0 mg/mg (or >226.30 mg/mmol)
(f)
Neutrophil count <1000/μL (or <1.0 × 109/L)
(g)
Platelet count <25000/μL (or <25 × 109/L)
(h)
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

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
41(128)
(i)
Glycosylated haemoglobin (HbA1c) >8% (or >0.08) at screening 
(diabetic subjects only)
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 of the following:
(a)
Where prednisone is the single SOC medication (ie, the subject is not 
concurrently receiving any medication listed in inclusion criterion 7(c)), 
any addition of a new oral prednisone therapy (or equivalent) any time 
in the 8 weeks prior to Day 1, OR any change in/ discontinuation of 
current oral prednisone dose (or equivalent) anytime within the 2 weeks 
prior to randomisation (see 
for examples of prednisone 
equivalency)
(b)
Where prednisone is not the single SOC medication (ie, the subject is 
concurrently receiving at least one medication listed in inclusion 
criterion 7(c)): 
(i)
Any addition of a new oral prednisone therapy (or 
equivalent) any time from 2 weeks prior to signing of the 
ICF through Day 1, OR any change in/ discontinuation of 
current oral prednisone dose (or equivalent) anytime within 
the 2 weeks prior to randomisation (see 
 for 
examples of prednisone equivalency)
(ii)
Any addition of a new dose of any of the following anytime 
in the 12 weeks prior to signing of the informed consent 
through Day 1, or change in / discontinuation of current dose 
anytime in the 8 weeks prior to signing of the informed 
consent through Day 1: azathioprine; any antimalarial (eg,
chloroquine, hydroxychloroquine, quinacrine); 
mycophenolate mofetil/mycophenolic acid; oral, SC, or 
intramuscular methotrexate; mizoribine
10.
Receipt of any of the following:
(a)
Azathioprine >200 mg/day
(b)
Mycophenolate mofetil >2 g/day or mycophenolic acid >1.44 g/day
(c)
Oral, SC, or intramuscular methotrexate >25 mg/week

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
42(128)
(d)
Mizoribine >150 mg/day
(e)
Any change in route of administration of oral, SC, or intramuscular 
methotrexate anytime within the 8 weeks prior to signing of the 
informed consent through Day 1
11.
Receipt of any investigational product (small molecule or biologic agent) within 
4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater (see
12.
Prior receipt of anifrolumab
13.
Receipt of any commercially available biologic agent within 5 half-lives (see 
 prior to signing of the ICF
14.
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab, 
ofatumumab, atacicept, obinutuzumab, or rituximab) 
!
<26 weeks prior to signing the ICF; <40 weeks for atacicept
(see
)
!
or if therapy was administered ≥26 weeks ago (40 weeks for atacicept),
absolute B cell less than the lower limit of normal or baseline value prior to 
receipt of B cell-depleting therapy (whichever is lower) 
15.
Receipt of epratuzumab or tabalumab <26 weeks prior to signing the ICF, or 
belimumab <12 weeks prior to signing the ICF
16.
A known history of allergy or reaction to any component of the investigational 
product formulation or history of anaphylaxis to any human gamma globulin 
therapy
17.
Regular use of >1 NSAID within 2 weeks prior to Week 0 (Day 1); OR receipt of 
fluctuating doses of a NSAID within 2 weeks prior to Week 0 (Day 1)
18.
Receipt of any of the following:
(a)
Intra-articular, intramuscular or IV glucocorticosteroids within 6 weeks 
prior to Day 1
(b)
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)

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
43(128)
(c)
Bacillus Calmette-Guerin (BCG) vaccine within 1 year of signing the 
ICF
(d)
Any restricted medication listed in 
if the washout period is
not met
(e)
Blood transfusion within 4 weeks prior to signing the ICF
3.2.3
Exclusion criteria related to systemic lupus erythematosus and other diseases
19.
History of, or current diagnosis of, a clinically significant non SLE-related
vasculitis syndrome (see 
Vasculitis due to SLE is allowed in the study
20.
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
21.
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:
(a)
That would make the subject unable to fully understand the ICF OR
(b)
Where, in the opinion of the Principal Investigator (PI), 
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 
22.
Active severe SLE-driven renal disease where, in the opinion of the PI, 
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
23.
Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or 
any history of overlap syndromes of SLE and systemic sclerosis, as noted in A or B 
below: 
(a)
An overlap syndrome of SLE with myositis or rheumatoid arthritis at 
screening is permitted provided the subject also meets the criteria for the 
classification as SLE; or

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
44(128)
(b)
A past history of mixed connective tissue disease, which over time has 
developed into a diagnosis of SLE, is permitted provided diagnosis of 
SLE has been present for at least 1 year
24.
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.
25.
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 assessments
26.
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
3.2.4
Exclusion criteria related to infection and malignancy risk factors
27.
Known history of a primary immunodeficiency, splenectomy, or any underlying 
condition that predisposes the subject to infection, or a positive result for human 
immunodeficiency virus (HIV) infection confirmed by central laboratory at 
screening. Subjects refusing HIV testing during the screening period will not be 
eligible for study participation
28.
Confirmed positive test for hepatitis B serology for:
(a)
Hepatitis B surface antigen (HBsAg), OR
(b)
Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA 
detected above the lower limit of quantitation (LLOQ) by reflex testing 
by the central laboratory at screening 
Note: Subjects 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 levels must remain below the 
LLOQ as per the central laboratory.
29.
Positive test for hepatitis C antibody as confirmed by central laboratory
30.
Any severe herpes infection at any time prior to Week 0 (Day 1), 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)
31.
Any Herpes zoster, cytomegalovirus (CMV) or Epstein-Barr virus infection that has 
not completely resolved within 12 weeks prior to signing the ICF
32.
Opportunistic infection requiring hospitalisation or IV antimicrobial treatment 
within 3 years of randomisation 

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
45(128)
33.
Any of the following:
(a)
Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis, 
etc) within 8 weeks prior to signing the ICF (chronic nail infections are 
allowed)
(b)
Any infection requiring hospitalisation or treatment with IV 
anti-infectives not completed at least 4 weeks prior to signing the ICF
34.
Any infection requiring oral anti-infectives (including antivirals) within 2 weeks 
prior to Day 1
35.
History of cancer, apart from: 
(a)
Squamous or basal cell carcinoma of the skin treated with documented 
success of curative therapy ≥3 months prior to Week 0 (Day 1)
(b)
Cervical cancer in situ treated with apparent success with curative 
therapy ≥1 year prior to Week 0 (Day 1)
3.3
Restrictions and concomitant medications
3.3.1
Excluded medications: 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.
3.3.1.1
Medications that lead to immediate discontinuation of investigational product
(a)
Cyclophosphamide
(b)
IFN therapy (alpha 2a and 2b, beta 1a and 1b, and pegylated IFNs alpha 2a and 2b)
(c)
Investigational agents
(d)
Biologic immunomodulators (including, but not limited to, belimumab, abatacept, 
or rituxumab)
(e)
Live or attenuated vaccines (the Sponsor recommends that Investigators ensure all 
subjects are up to date with required vaccinations prior to entry into the study)
(f)
Plasmapheresis
(g)
BCG vaccine
(h)
Any immunoglobulin (Ig) therapy
(i)
Intravenous corticosteroids >1 gm methylprednisolone or equivalent

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
46(128)
(j)
Any medications listed in 
(please see the sulfasalazine, danazol, and 
dapsone restrictions in Section 3.3.1.2), except restrictions below.
3.3.1.2
Restricted medications
As anifrolumab is an investigative immunomodulatory agent, non-protocol permitted changes
to immune modifiers or immunosuppressants on study are strongly discouraged.
If a subject receives 1 of the following, the Investigator must notify the PRA Medical Monitor 
immediately. The PRA Medical Monitor will determine with the Sponsor if the subject may 
continue to receive investigational product. Details on handling the analysis of data from
subjects who may use restricted medications are described in the SAP.
(a)
Sulfasalazine
(b)
Danazol
(c)
Dapsone
(d)
Azathioprine >200 mg/day or at a daily dose greater than that at Week 0 (Day 1)
(e)
Mycophenolate mofetil >2.0 g/day or mycophenolic acid >1.44 g/day or at a daily 
dose greater than that at Week 0 (Day 1)
(f)
Oral, SC, or intramuscular methotrexate >25 mg/week or at a daily dose greater 
than that at Week 0 (Day 1)
(g)
Mizoribine >150 mg/day or at a daily dose greater than that at Week 0 (Day 1)
(h)
Any change in route of administration of oral, SC, or intramuscular methotrexate
(i)
Intravenous corticosteroids >40 mg/day but ≤1 gm/day methylprednisolone or 
equivalent
(j)
Intramuscular corticosteroids >80 mg/day methylprednisolone or equivalent
(k)
Subcutaneous or intramuscular corticosteroid precursors
(l)
Treatment with OCS >40 mg/day prednisone or equivalent 
(m)
Treatment with OCS above Day 1 dose for a dosing period >14 days 
(n)
Corticosteroids with a long biologic half-life (eg, dexamethasone, betamethasone)
(o)
Other immunosuppressants including but not limited to calcineurin inhibitors (eg, 
cyclosporine, tacrolimus [including topical]) or leflunomide. 
Note: Cyclosporine eye drops are acceptable for use in the study.

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
47(128)
3.3.1.3
Other concomitant medications
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 Case Report form (CRF).
3.3.2
Concomitant medications for Systemic Lupus Erythematosus standard of care 
during the study
Permitted medications for SOC SLE are described below. Concomitant medications should 
only be administered after all visit assessments, including investigational product 
administration and post-infusion PK blood draws (if applicable), with the exception of a 
subject with a previous infusion-related reaction who is to receive acetaminophen or 
equivalent. The acetaminophen or equivalent should be given after all visit assessments other 
than the infusion have been completed, and prior to starting the infusion.
Permitted SOC SLE
Limitations of Use
OCS
-
Oral prednisone or equivalent up to ≤40 mg/day is permitted 
from at least 2 weeks prior to signing the informed consent. 
The dose of oral prednisone must remain stable at least 2 weeks 
prior to randomisation
-
Where prednisone is the single SOC medication (ie, the subject 
is not concurrently receiving any medication listed in inclusion 
criterion 7(c)), a dose of oral prednisone ≥7.5 mg/day but ≤40 
mg/day (or prednisone equivalent) for a minimum of 8 weeks 
prior to Day 1 is required
-
Subjects with increased SLE disease activity may receive 1 
permitted burst and taper of OCS between Day 1 and Week 12. 
Additional details on burst and taper for SLE and non-SLE (eg, 
asthma or COPD exacerbation) disease activity are provided in 
Sections 3.3.2.1 to 3.3.2.4
Intramuscular corticosteroids
-
Subjects with increased SLE disease activity may receive 1 
intramuscular injection of corticosteroids (methylprednisolone 
≤80 mg or equivalent) instead of a burst and taper of OCS 
described above between Day 1 and Week 12
-
May only be administered after all assessments and 
investigational product infusion have been completed at the visit
-
Additional details on burst and taper for SLE and non SLE 
disease activity are provided in Sections 3.3.2.1 to 3.3.2.4

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Drug Substance Anifrolumab (MEDI-546)
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Edition Number 6
Date 23 May 2019
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Permitted SOC SLE
Limitations of Use
Intra-articular/tendon 
sheath/bursal corticosteroid 
injections
-
Intra-articular/tendon sheath/bursal injection should be 
minimised. Subjects may receive a maximum of 2 injections (for 
a total dose of ≤80 mg methylprednisolone or equivalent) instead 
of a burst and taper of OCS described above, between Day 1 and 
Week 12
-
An intra-articular/tendon sheath/bursal injection may be allowed
for non-SLE related disorders up to Week 40 if the symptoms of 
the disorder do not interfere with the ability to assess 
SLE-related endpoints. The Investigator must contact the 
medical monitor for permission to administer an 
intra-articular/tendon sheath/bursal corticosteroid injection prior 
to administration of corticosteroids for non-SLE related 
disorders
-
If permission is given, the injection should not be administered 
until after the completion of all assessments, including 
investigational product administration and post-infusion PK 
blood draw (if applicable)
Antimalarials and 
immunosuppressants 
(azathioprine, methotrexate, 
and mycophenolate 
mofetil/mycophenolic acid, 
and mizoribine)
-
Antimalarials and immunosuppressants (azathioprine, 
methotrexate, mycophenolate mofetil/mycophenolic acid, and 
mizoribine) are permitted, and at least 1 is required, as part of 
SLE therapy on Day 1 if the subject is not on OCS 
-
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 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
Prescription NSAIDs
-
Prescription NSAIDs must remain stable from screening through 
Week 52 but can be reduced for reasons of toxicity but not 
efficacy. Prescription NSAIDs cannot be administered with 
other NSAIDs (including over-the-counter non-steroidals) 
except for low-dose aspirin
-
On a given visit day, prescription NSAIDs should not be taken 
until after all assessments have been completed and should be 
taken according to SOC

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Drug Substance Anifrolumab (MEDI-546)
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Edition Number 6
Date 23 May 2019
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Permitted SOC SLE
Limitations of Use
Non-prescription NSAIDS
-
NSAIDs should not be taken on the day of a scheduled visit until 
all assessments are complete
-
NSAIDs for analgesic purposes that never exceed 
label-approved doses of NSAIDs may be used for pain as 
required, based on Investigator judgment for up to 1 week at a 
time
-
NSAIDs cannot be used in combination with another NSAID at 
any dose, except low-dose aspirin (≤325 mg/day); topical 
NSAIDs may be used in combination with one oral NSAID
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 (eg, paracetamol) may be used for pain as required
-
In a subject with a previous infusion-related reaction, 
acetaminophen or equivalent can be given after all visit 
assessments have been completed and prior to starting the 
infusion
Low-dose aspirin
-
Low-dose aspirin (maximum of 325 mg/day) for cardiovascular 
disease is permitted
Topical therapy
-
Concurrent use of topical therapy for cutaneous lupus 
erythematosus (eg, corticosteroids) is permitted. Topical 
moisturisers are also permitted
-
Topical therapy must be the same being used at signing of the 
informed consent and the dose and frequency of application 
must be stable during screening 
-
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 up to the Day 1 dose
-
It is encouraged that no new dermatologic preparations be used 
for the duration of the study. It is also recommended that 
subjects use sunscreen (list as concomitant medication for SLE) 
and avoid sun exposure during the study
NSAIDs = nonsteroidal anti-inflammatory drugs; OCS = oral corticosteroids; SLE = systemic lupus
erythematosus; SOC = standard of care 
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 (eg, 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.

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Study Code D3461C00004
Edition Number 6
Date 23 May 2019
50(128)
3.3.2.1
Steroid burst and taper Week 0 (Day 1) 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.
A steroid burst as described below is defined as 1 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. Any course of OCS 
above the Day 1 dose must not extend beyond Week 12, regardless of when the 
course was started;
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 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 will be considered 
non-responders for subsequent assessments of disease activity (details are defined in the SAP), 
regardless of whether the OCS burst was administered for increased SLE activity or non-SLE 
causes.
3.3.2.2
Increase in corticosteroids from Week 12 to Week 40
Between Week 12 and Week 40, an increase in corticosteroid dose for increased SLE activity 
is not allowed. A subject receiving a steroid dose above his or her Week 0 (Day 1) dose may 
continue in the study, but will be considered a non-responder for subsequent assessments of 
disease activity (details are defined in the SAP).
An increase in OCS for non-SLE causes (eg, asthma or COPD exacerbation) is allowed 
ONCE with medical monitor approval between Week 12 and Week 40. This might include a 
non-SLE OCS up to ≤20 mg/day of prednisone (or equivalent) for up to a total of 14 days and 
must be fully administered and tapered to less than or equal to the Day 1 dose by the end of 
the 14th day and by the Week 40 visit day. This will be captured as burst and taper not 
attributable to SLE. The non-SLE indication must be clearly indicated in the source 
documents.
Subjects who receive non-SLE prednisone (or equivalent) at a total dose >20 mg/day but 
≤40 mg/day for a dosing period of greater than 14 days may continue in the study but will be 

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
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Edition Number 6
Date 23 May 2019
51(128)
considered non-responders for subsequent assessments of disease activity (details are defined 
in the SAP). 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 PRA Medical Monitor. The PRA 
Medical Monitor will determine with the Sponsor if the subject may continue to receive 
investigational product.
3.3.2.3
Increase in oral corticosteroids after Week 40
No increase in OCS is allowed after Week 40 (except for the management of AEs or as a 
prophylaxis for adrenal insufficiency as described below). Subjects who receive an increase in 
their OCS after Week 40 will be considered non-responders for subsequent assessments of 
disease activity.
3.3.2.4
Increase in oral corticosteroids for intercurrent disease or to prevent adrenal 
insufficiency
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 40. 
3.3.2.5
Protocol-specified steroid tapering Week 8 to Week 40
On treatment days, tapering will start after all assessments have been completed and 
investigational product has been administered. Tapering can be started on the scheduled study 
visit day (eg, Week 8 Visit) based on clinical manifestations and the laboratory values from 
the previous visit. If laboratory values of the current visit show SLE activity consistent with 
exception rule No. 1 or No. 2 below, the tapering can be reversed.
Beginning at Week 8 and continuing through Week 40, steroid tapering to an OCS dose of 
≤7.5 mg/day MUST be attempted in all subjects with OCS dose ≥10.0 mg/day at Baseline, 
unless at least 1 of the following criteria is met:
!
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) 
!
Moderate to severe skin disease as reflected by a CLASI activity score of ≥10 
!
Moderate to severe arthritis disease as reflected by an active joint count of ≥8 tender 
and/or swollen joints
Steroid tapering must be started within 14 days of the visit. If steroid tapering is not attempted 
in an eligible subject, the Sponsor or Sponsor’s designee must be contacted immediately. The 
recommended steroid-tapering regimen is provided in 
, but due to variability in 

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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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subject responses to steroid treatment and tolerability of taper 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 Week 40 based on disease activity. Steroid tapering will not be permitted 
after Week 40.
A subject experiencing an increase in disease activity secondary to OCS tapering may increase 
the dose up to a maximum of the baseline OCS therapy dose from Week 8 up to Week 40 
without the subject being considered a non-responder for subsequent assessments of disease 
activity. Subjects who require OCS dose above their baseline level may continue in the study 
but could be considered non-responders for subsequent assessments of disease activity (details
are defined in the SAP).
3.3.3
Other restrictions
3.3.3.1
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 the Treatment Period Study Plan (Table 3). If the subject has not fasted, 
they should fast before the next visit, and the test can be done at that visit.
3.3.3.2
Perioperative management of investigational product
Elective surgery should be avoided during the study if clinically feasible.
Major surgery
Pre-operative management of investigational product: if a non-urgent major surgical 
procedure becomes necessary during the study, it should be scheduled at least 4 weeks after 
the last administration of investigational product, if clinically feasible. 
Non-major surgery
The decision to withhold investigational product administration is at the Investigator’s 
discretion. 
Postoperative management of investigational product: investigational product administration 
can be resumed at the Investigator’s discretion after all of the following criteria are met:
-
External wound healing is complete, and 
-
Any postoperative antibiotic course is completed, and
-
All acute surgical complications have resolved

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Drug Substance Anifrolumab (MEDI-546)
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Edition Number 6
Date 23 May 2019
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3.4
Subject enrolment and randomisation
Investigator(s) should keep a record of subjects considered for, and included in the study. The 
pre-screening/screening log will be evaluated periodically during routine monitoring visits.
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. During screening, the Disease Activity Adjudication
Group (see Section 5.2.2) will confirm eligibility criteria based on the data captured
in the electronic data capture (EDC) system and from the Central Laboratory. Sites
will be notified to either randomise or screen fail the subject.
4.
On Day 1, the Investigator will confirm that all eligibility criteria still are fulfilled
(including that the “Clinical” SLEDAI-2K score is ≥4 points [see Inclusion
Criterion No. 9 for “Clinical SLEDAI-2K” definition], OCS dose has been stable
for the last 2 weeks) and will then perform the randomisation transaction in the
IXRS.
5.
At randomisation the IXRS will assign eligible subjects a unique randomisation
code and blinded investigational product kit number(s) to the subject.
Specific information concerning the use of the IXRS will be provided in the separate user 
manual. 
Block randomisation using an IXRS will be used to randomise subjects in a 1:1 ratio to 
receive a fixed IV dose of 300 mg anifrolumab or placebo. AstraZeneca Biostatistics group is 
responsible for generating the randomisation scheme for this study using the GRand system.
The randomisation will be stratified using the following factors: 
!
SLEDAI-2K score at screening (<10 points versus ≥10 points)
!
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or
equivalent)
!
Results of the IFN test (high versus low)
Investigational product (anifrolumab or placebo) should, if possible, be administered the same 
day the investigational product kit number is assigned.

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Edition Number 6
Date 23 May 2019
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3.5
Methods for ensuring blinding
This is a double-blind study in which anifrolumab and placebo are distinguishable during the 
final preparation step of the investigational infusion bag. All packaging and labelling of 
investigational product is done in such way as to ensure blinding for all Sponsor and 
investigational site staff other than the unblinded investigational product manager. The kits on
the shelf, and the infusion bags when prepared, look identical. Since anifrolumab and placebo 
can be distinguished at the preparation step, investigational product will be prepared by an 
unblinded investigational product manager at the site, who will not be involved in the 
management of study subjects.
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 the 
treatment received. 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.
3.6
Unblinding
In the event of a medical emergency, the Investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS manual. The Investigator should 
promptly document and explain any premature unblinding to the Sponsor, without revealing 
the treatment given to patient to the Sponsor. In general, unblinding should only occur if 
management of the medical emergency would be different based on the subject having 
received investigational product. In the majority of cases, the management of a medical 
emergency would be the same whether or not investigational product was received by the 
subject. If this was the case, the investigational product allocation should not be unblinded.
AstraZeneca or its designee retains the right to break the code for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities. Treatment codes will not be broken for 
the planned analyses of data until all decisions on the evaluability of the data from each 
individual subject have been made and documented.
Subjects who have been unblinded by AstraZeneca Patient Safety or designee (and who have 
not been unblinded to the Investigator or Medical Monitor) will not, based on the unblinding 
alone, be discontinued from further receipt of investigational product.
3.6.1
Unblinding for Data and Safety Monitoring Board
An independent DSMB will review safety data throughout the study. The DSMB will be 
provided with partially unblinded data (data that are summarised by treatment group using 
masked treatment group labels). The DSMB may choose to unblind the data for additional 
review as specified in the DSMB charter. The Sponsor and the study team at PRA will remain 
blinded to all data transfers provided to the DSMB. Details about the DSMB will be included 
in the DSMB Charter. For further details on the DSMB, see Section 6.10.1.

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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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3.7
Discontinuation of investigational product
Subjects may be discontinued from investigational product in the following situations:
1.
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment. The primary reason should be documented as 1 of the 
following:
(a)
Subject perceives the investigational product to be ineffective
(b)
Subject is unable to comply with protocol-specified visits and/or 
procedures due to conflicts not related to clinical trial
(c)
Subject perceives logistics to be unacceptable
(d)
Subject wishes to participate in another clinical trial 
(e)
Subject wishes to take a treatment that is not allowed in this study
(f)
An AE or laboratory abnormality is of concern to the subject, but not 
clinically significant to physician
(g)
Other, please specify reason
2.
Lost to follow-up: must be documented by time and date of telephone calls, emails, 
text messages, numbers called, individuals spoken to if not subject, and at least 
2 attempts to contact the subject via certified letter
3.
AE that, in the opinion of the Investigator or the Sponsor/Sponsor’s delegate 
Medical Monitor, contraindicates further dosing with investigational product
4.
Severe noncompliance with the study protocol 
5.
The Investigator or Sponsor/Sponsor’s delegate Medical Monitor deems withdrawal 
as being in the subject's best interest
6.
Pregnancy, positive pregnancy test, or subject expresses an interest to become 
pregnant 
7.
Isolated HBc positivity with HBV DNA confirmed by the central laboratory
8.
Receipt of any medications identified in Section 3.3.1.1
9.
The use of restricted medications listed in Section 3.3.1.2
if the PRA Medical Monitor, in consultation with the Sponsor,
determines the subject must be discontinued

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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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10.
A diagnosis of active TB, premature discontinuation of treatment for latent TB, or 
noncompliance with TB therapy. Note: duration of treatment for latent TB should 
follow the local practice. If local practice is not defined, then Centers for Disease 
Control guidance should be used.
Additional restrictions related to concomitant medications are discussed in Section 3.3.1.3.
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment, and will not be eligible for the LTE study.
3.7.1
Subject decision to discontinue investigational product 
If the subject decides to discontinue investigational product for any reason, including but not 
limited to those outlined in Section 3.7 above, the subject will not receive any further 
investigational product. The subject may also refuse to continue any further study observation.
3.7.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) (see Section 3.7) 
and the presence of any AEs. The Investigator will follow-up AEs outside of the clinical 
study.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation
code cannot be reused. Withdrawn subjects will not be replaced.
3.7.3
Lost to follow-up
Subjects will be considered lost to follow-up only if no contact has been established by the 
time the study is completed such that there is insufficient information to determine the 
subject’s status at Follow-up Visit 2. A subject is considered lost to follow up when the 
following attempts to contact the subject are unsuccessful: 
!
Either phone calls, faxes or emails, and
!
Having sent 2 registered letters/certified mail, and
!
One attempt to check the status of the subject using publicly available sources, if 
allowed by local regulations
“Lost to follow-up” as a reason for study discontinuation must be documented by time and
date of telephone calls, emails, text messages, numbers called, individuals spoken to if not 
subject, and documentation that 2 certified/registered letters were sent.
3.7.4
Study completion and end of study
An individual subject will be considered to have completed the study if the subject was 
followed up until the end of the study (Week 60, or Week 52 for those enrolling in the LTE 

Revised Clinical Study Protocol
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Edition Number 6
Date 23 May 2019
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study, or Week 52 for those subjects who prematurely discontinue the investigational product
and complete a minimum of 12 weeks of follow-up), regardless of the number of doses of 
investigational product that were received. The end of the study (“study completion”) is 
defined as the date of the last protocol-specified visit/assessment for the last subject in the 
study.
3.7.5
Procedures for discontinuation of a subject from investigational product
Discontinuation of investigational product does not necessarily mean discontinuation of 
follow-up or termination of study participation. Compliant subjects who are discontinued from 
the investigational product should be encouraged to continue to undergo all study-related 
visits/procedures for the full treatment period (Table 3) in order to support the final efficacy 
and safety analysis for anifrolumab (see Section 8). The reason for premature discontinuation 
of investigational product will be documented in the source documents and recorded in the 
CRF.
It is essential to collect as much data as possible for all subjects throughout the study and 
especially all potential endpoint events. Complete withdrawal from the study (ie, withdrawal 
of consent) has a direct negative impact on the potential validity of all study data and should 
be avoided wherever possible. If the subject permanently discontinues investigational product 
prior to their completion of the study and wishes to continue with only selected study 
assessments; prioritised assessments are listed in Section 4.2.1.
For subjects who wish to withdraw from the study completely refer to Section 3.7.2.
3.8
Criteria for withdrawal 
3.8.1
Screen failures 
Screening failures are subjects who have provided informed consent and who subsequently do 
not fulfil the eligibility criteria for the study, and therefore must not be randomised. These 
subjects should have the reason for study withdrawal recorded as “Eligibility Criteria Not 
Fulfilled” (ie, subject does not meet the required inclusion/exclusion criteria). This reason for 
study withdrawal is only valid for screen failures (not randomised subjects). Rescreening of a 
subject will be permitted once.
3.9
Discontinuation of the study
The study may be stopped if, in the judgment of the Sponsor, trial subjects are placed at undue 
risk because of clinically significant findings that:
!
Meet individual stopping criteria or are otherwise considered significant (see 
Section 3.7 for reasons for discontinuation of investigational product)
!
Are assessed as causally related to study drug 
!
Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for subjects at the time of 
discontinuation of follow-up must be recorded in the CRF.

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Edition Number 6
Date 23 May 2019
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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
Study plan detailing the procedures at screening
Study Period
Screening
Written informed consent / assignment of 
X
Medical history a
X
Physical examination, weight and height
X
Vital signs
X
ECG
X
Serum chemistry, haematology, and urinalysis
X
Urine protein/creatinine ratio
X
ANA, anti-dsDNA antibodies, anti-Sm antibody b
X
B cell count c
X
Chest x-ray (only in subjects who have not had a chest x-ray within 12 
weeks prior to signing the ICF) d
X e
FSH in postmenopausal females
X
Serum pregnancy test in all females of childbearing potential
X
Blood test for TB f
X
Hepatitis B and C
X
HIV test g
X
IFN test b
X
Pap smear (only in females with an intact cervix who have not had a 
normal Pap smear within 2 years prior to randomisation)
X e
C3, C4, CH50 complement
X 
BILAG-2004 associated laboratory tests (anticardiolipin, lupus 
anticoagulant, haptoglobin, and Coombs h)
X
C-SSRS
X
BILAG-2004 
X i
CLASI
X i
Skin photography, if applicable j
X i
SLEDAI-2K 
X i
PGA
X i

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Edition Number 6
Date 23 May 2019
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Study Period
Screening
Joint count
X i
TB questionnaire
X
Assessment of AESIs
X
Assessment of AEs/SAEs
X
ACR classification criteria
X
Concomitant medications, including SLE medications
X
Verify eligibility criteria
X
ACR = American College of Rheumatology; AE = adverse event; AESI = adverse event of special interest; 
ANA = antinuclear antibody; BILAG = British Isles Lupus Assessment Group; C3 = third component of 
complement; C4 = fourth component of complement; CH50 = total haemolytic complement; CLASI = Cutaneous 
Lupus Erythematosus Disease Area and Severity Index; C-SSRS = Columbia Suicide Severity Rating Scale; 
dsDNA = Double stranded deoxyribonucleic acid; ECG = electrocardiogram; PGA = Physician’s Global 
Assessment; SAE = serious adverse event; SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 
2000; TB = tuberculosis
a
Medical History will include details for each body system contained in the BILAG-2004 assessment 
(BILAG Related History).
b
Redraw for ANA/anti-dsDNA, or IFN test can be done within the 30-day screening window, however,
results needed to determine eligibility and stratification must be available within the 30-day screening 
window for subjects to be randomised.
c
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab, ofatumumab, atacicept, 
obinutuzumab, or rituximab) <26 weeks prior to signing the ICF (<40 weeks for atacicept [see 
 
) and if therapy was administered ≥26 weeks ago (40 weeks for atacicept), absolute B cell less than the 
lower limit of normal or baseline value prior to receipt of B cell-depleting therapy (whichever is lower).
d
Anterio-posterior and lateral images are required whenever possible, or per standard of care.
e
Assessments are allowed anytime during the screening period as long as they are completed within 30 days 
after signing the informed consent form.
f
Interferon-gamma release assay (IGRAs) using QuantiFERON®-TB Gold In-Tube Test (QFT-GIT).
g
Subjects within the treatment or follow-up period at the time of amendment 4 approval will undergo HIV 
testing at the time of amendment 4 ICF signature.
h
Direct Coombs test samples will only be collected per the Investigator’s opinion, measured by local 
laboratory, and applicable BILAG assessment requirements for determining haemolytic anaemia.
i
These assessments must all be completed at the same visit (SLEDAI-2K, BILAG-2004, joint count, PGA, 
CLASI, and skin photography [if applicable]).
j
Photography will be conducted at selected sites in subjects who sign an additional optional consent, and 
have a screening CLASI score of ≥10. If no baseline skin activity or photos can be captured at the patient’s 
Screening or Day 1 visit, no further photography will be done.

Revised Clinical Study Protocol
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Edition Number 6
Date 23 May 2019
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l
BILAG-2004 laboratory tests to include anticardiolipin, lupus anticoagulant, haptoglobin, and Coombs (Coombs will be performed as applicable per 
BILAG assessment requirements). Note: In order to avoid having to bring the subject back for a separate phlebotomy, the anticardiolipin, lupus 
anticoagulant, and haptoglobin blood specimens will be collected at all specified visits, however the blood will be stored at the central laboratory and the 
analyses performed only if the Investigator indicates that these tests need to be completed because of clinical suspicion of haemolytic anaemia or 
antiphospholipid syndrome. Direct Coombs test samples will only be collected per the Investigator's opinion, measured by local laboratory, and 
applicable BILAG assessment requirements for determining haemolytic anaemia.
m
Photography will be conducted at selected sites in subjects who sign an additional optional consent, and have a screening CLASI score of ≥10. If no 
baseline skin activity or photos can be captured at the patient’s Screening or Day 1 visit, no further photography will be done.
n
Investigational product will be administered as an IV infusion via an infusion pump over a minimum of 30 minutes.

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Edition Number 6
Date 23 May 2019
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Table 4
Study plan detailing the procedures during Follow-up
Visit Number
Follow-up Visit 1 a
Follow-up Visit 2 a
Study Week
8 weeks post final dose
12 weeks post final dose
Procedure/Visit Window
PHQ-8
X
Physical examination, weight
X
Vital signs
X
X
Serum chemistry, haematology, and urinalysis
X
X
Urine pregnancy test in females of childbearing potential
X
X
TB questionnaire
X
X
SLEDAI-2K associated laboratory tests b
X
X
BILAG-2004 associated laboratory tests c
X
X
C-SSRS
X
X
BILAG-2004
X
X
CLASI
X
X
Skin photography, if applicable d
X
SLEDAI-2K 
X
X
PGA
X
X
Joint count
X
X

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4.1
Enrolment/Screening Period
At Screening, 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 these criteria must not be randomised into the study.
Screening procedures will be performed according to the Screening Study Plan (Table 2), 
from Day -30 to Day -1. 
Once screening assessments are complete, all necessary laboratory results are reported, and 
adjudication is complete, a subject may be randomised. There does not need to be 30 days 
between screening and Week 0 (Day 1).
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 randomisation. 
If a subject does not meet eligibility criteria on the basis of a laboratory value then the 
laboratory value may be repeated once within the screening period.
4.1.1
Other considerations for screening
4.1.1.1
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.
4.1.1.2
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.
4.1.2
Re-screening subjects who screen fail
If a subject fails screening for inadequate disease activity, or other reason, which, in the 
opinion of the Investigator, may change to make the subject eligible, the subject may be 
re-screened 1 time. In this case, the subject will re-sign the informed consent document. If the 
subject fails screening twice, they may not undergo further screening for this study. Initial 
screening procedures completed within the 30 days prior to subject randomisation need not be 
repeated during the re-screen visit.

Revised Clinical Study Protocol
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4.2
Treatment Period
Procedures during the Treatment Period will be performed according to the Treatment Period 
Study Plan (Table 3), from Week 0 (Day 1) to Week 52. The subject-reported outcome
assessments should be completed by the subject (unassisted by spouse, family members or 
friends) prior to all other evaluations, and prior to the infusion, as disease assessments/clinical 
evaluations may confound the results. 
Before scheduling the Week 0 (Day 1) visit, ensure notification from the Disease Activity 
Adjudication Group has been received, confirming that subject meets adjudicated eligibility 
criteria (Inclusion Criterion No. 9). The Disease Activity Adjudication Group will review all 
data necessary to characterise subject SLE in relation to the SLEDAI-2K, BILAG-2004, and 
PGA assessments (including central laboratory results).
On Day 1, ensure subject meets eligibility criteria, including Day 1 assessments according to 
the Treatment Period Study Plan (Table 3).
Subjects confirmed to be eligible will be randomised. 
Subjects will have scheduled visits at 4-week intervals to complete protocol-specified 
assessments and investigational product administration according to the Treatment Period 
Study Plan (Table 3).
The last dose of investigational product will be administered on Week 48. At Week 52, 
subjects will have an End of Treatment (EOT) visit. For subjects who prematurely discontinue 
investigational product and are not willing to continue to participate in the study refer to 
Section 3.7.
4.2.1
Premature discontinuation of investigational product
Subjects who discontinue investigational product will be asked to return for all regularly 
scheduled clinic visits. If the subject is unwilling to complete all regularly scheduled clinic 
visits, the subject should complete the EDV (Week 52) visit within 4 weeks of the last dose of 
investigational product, as well as Follow-up Visit 1 and Follow-up Visit 2 (8 and 12 weeks 
after the EDV visit) unless consent is withdrawn. If the subject is unwilling to continue with 
any study visits, including EDV, at a minimum, the following assessments should be 
completed:
!
SLEDAI-2K and the associated laboratory tests (anti-dsDNA antibodies, C3, C4, 
CH50)
!
BILAG-2004 and the associated laboratory tests (anticardiolipin, lupus 
anticoagulant, haptoglobin, and Coombs [Coombs will be performed as applicable 
per BILAG assessment requirements]). Note: In order to avoid having to bring the 
subject back for a separate phlebotomy, the anticardiolipin, lupus anticoagulant, and 
haptoglobin blood specimens will be collected at all specified visits, however the 
blood will be stored at the central laboratory and the analyses performed only if the 
Investigator indicates that these tests need to be completed because of clinical 

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suspicion of haemolytic anaemia or antiphospholipid syndrome. Direct Coombs test 
samples will only be collected per the Investigator's opinion, measured by local 
laboratory, and applicable BILAG assessment requirements for determining 
haemolytic anaemia.
!
CLASI
!
PGA (physician global assessment)
!
Skin photography, if indicated
!
Joint count
The following safety assessments will also be completed:
!
Serum chemistry, haematology, urinalysis
!
Urine for protein, creatinine and urine-protein-creatinine ratio
!
Lipid Profile defined in Section 5.3.11.1
!
Immunology Profile defined in Section 5.3.11.2
!
Vital signs
!
Physical examination, weight
!
Adverse events including AESIs
!
Cardiovascular risk assessment
!
TB questionnaire
!
Concomitant medications
If the subject does not agree to do this, they will be asked if they can be followed on a 
monthly basis via telephone calls. At these calls, they will be asked about AEs/SAEs, lupus 
symptoms, and lupus medications. Steroid bursts will also be captured. 
Adverse events will be followed up per Section 6.6.2.
4.3
Unscheduled Visit
There may be times a subject needs to have an unscheduled visit. The Investigator should 
determine the assessments to be completed based on the reason for the unscheduled visit and 
for subject safety. Concomitant medications and AEs should be completed whenever a subject
has an unscheduled visit.
If a subject presents for an unscheduled visit in lieu of a regularly scheduled visit (ie, the 
subject is seen for safety and efficacy assessments when a regularly scheduled dosing or 
follow-up visit is missed), the Investigator should complete all possible safety and efficacy 
assessments applicable to the missed visit. Unscheduled efficacy assessments should not be 
collected in between completed regular study visits. 

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4.4
Follow-up Period
Procedures will be performed according to the Follow-up Period Study Plan (Table 4). 
Subjects who complete the Week 52 visit may be eligible to participate in a LTE study. 
Subjects who complete the double-blind treatment period will have follow-up visits at 
Week 56 and Week 60, unless they enrol in the LTE study. Subjects who are withdrawn from 
the study, and do not agree to complete the 52-week study period, should complete the early 
discontinuation visit (Week 52 procedures) within 4 weeks of the last dose of investigational 
product, and be followed 8 and 12 weeks after the EDV visit by completing the Follow-up 
Visit 1 and 2 assessments (see Section 3.7).
5.
STUDY ASSESSMENTS
5.1
Description of study procedures
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study.
5.2
Efficacy assessments
Efficacy measurements will be made at the times indicated in the Study Plan (see Table 2 for 
assessments to be performed at Screening, Table 3 for Treatment Period, and Table 4 for 
Follow-up). Subject-reported outcome assessments should be completed by the subject, 
unassisted by spouse, family members or friends.
5.2.1
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 Investigators and designated site personnel who will be completing the 
disease evaluations listed below will be conducted.
!
SLEDAI-2K
!
BILAG-2004
!
PGA
!
CLASI
!
Swollen and tender joint count evaluation
The SLEDAI-2K, BILAG-2004, PGA, and CLASI 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 per the 
study central review plan. The joint count evaluation can be completed by other site personnel 
who, as per Investigator discretion, are qualified to perform the assessments and have at least 
1 year of experience administering the joint count evaluation. Training will include printed 

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training materials, digital video disks (DVDs) and formal presentations, as well as web-based 
training modules.
After attending study presentations (ie, Investigator Meeting) or after completion of online 
training modules, all Investigators and designated site physicians must pass an online 
examination in order to obtain certification for all disease evaluation assessments, with the 
exception of the joint count evaluation. Investigators and designated site personnel must be 
trained and certified prior to subjects entering screening at their respective sites. All 
assessments and certifications must be renewed via the study online training website prior to 
expiration and must remain current (not expire) throughout the course of the study. If there is 
a change in site personnel over the course of the study, new Investigators or physicians must 
be certified prior to performing the SLEDAI-2K, BILAG-2004, PGA, and CLASI 
assessments.
It is expected that the Investigator will ensure all joint count assessors have adequate 
experience (minimum of 1 year) and training qualifications to perform the swollen and tender 
joint count assessment. Assessors (including any new Investigators or site personnel) must 
complete the online joint count training module and obtain certification prior to performing 
any joint assessment. 
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.
5.2.2
Disease Activity Adjudication Group
PRA has a Disease Activity Adjudication Group who are medically-qualified individuals 
and/or support staff who assist in the ongoing management of this trial. The Disease Activity 
Adjudication Group will review all data necessary to characterise subject SLE in relation to 
the SLEDAI-2K, BILAG-2004, and PGA assessments (including central laboratory results); 
however, the group will remain blinded for the duration of the study. Adjudication group 
members will have access to an independent expert on SLE disease activity indices for 
unanticipated issues with regard to interpretation of these indices.
The Disease Activity Adjudication Group will be utilised to confirm eligibility during 
screening and will be utilised throughout the study to confirm SLEDAI-2K, BILAG-2004, and 
PGA scoring. The Adjudication Group will also ensure that the completion of efficacy 
assessments by Investigators is of proper quality and consistency. 
If there is inconsistency between assessments, additional clarification and training on these 
assessments will be provided through the Disease Activity Adjudication Group. 

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5.2.3
Systemic Lupus Erythematosus Disease Activity Index 2000 
The SLEDAI-2K disease activity index (see
) consists of a list of organ 
manifestations, each with a definition. A certified Investigator or designated physician will 
complete the SLEDAI-2K assessment and decide whether each manifestation is “present” or 
“absent” in the last 4 weeks. The assessment also includes 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 
descriptors are multiplied by 4 and central nervous descriptors 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 scores are valid, reliable, and sensitive 
clinical assessments of lupus disease activity. The SLEDAI-2K calculated using a timeframe 
of 30 days prior to a visit for clinical and laboratory values has been shown to be similar to the 
SLEDAI-2K with a 10-day window (Touma et al, 2010). A timeframe of 28 days will be used 
in this study.
The “Clinical” SLEDAI-2K score is the SLEDAI-2K assessment score without the inclusion 
of points attributable to any urine or laboratory results including immunologic measures. Its 
use may permit earlier clinical decisions to be made without waiting for immunologic 
measures 
However, in any circumstance where the “Clinical” SLEDAI-2K score is used, sites must 
subsequently update the SLEDAI-2K assessment when laboratory data become available so 
that the full SLEDAI-2K score is made available to the Sponsor.
A quick Reference Guide will be provided to all study personnel, which contains detailed 
protocol-specific clarifications and extensions of SLEDAI-2K clinical parameter definitions 
and a guidance for correlating SLEDAI-2K and BILAG-2004 clinical parameters.
5.2.4
British Isles Lupus Assessment Group-2004
The BILAG-2004 is a translational index with 9 organ systems (General, Mucocutaneous, 
Neuropsychiatric, Musculoskeletal, Cardiorespiratory, Gastrointestinal, Ophthalmic, Renal 
and Haematology) that is able to capture changing severity of clinical manifestations (see 
It has ordinal scales by design and does not have a global score; rather it records 
disease activity across the different organ systems at a glance by comparing the immediate 
past 4 weeks to the 4 weeks preceding them. It is based on the principle of physicians’ 
Intention-to-Treat and categorises disease activity into 5 different levels from A to E:
!
Grade A represents very active disease requiring immunosuppressive drugs and/or a 
prednisone dose of >20 mg/day or equivalent
!
Grade B represents moderate disease activity requiring a lower dose of 
corticosteroids, topical steroids, topical immunosuppressives, antimalarials, or 
NSAIDs
!
Grade C indicates mild stable disease

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!
Grade D implies no disease activity but the system has previously been affected
!
Grade E indicates no current or previous disease activity
Although the BILAG-2004 was developed based on the principle of Intention-to-Treat, the 
treatment has no bearing on the scoring index. Only the presence of active manifestations 
influences the scoring.
5.2.4.1
Protocol-specific clarification and extension of BILAG-2004 definitions
A quick Reference Guide will be provided to all study personnel, which contains detailed 
protocol-specific clarifications and extensions of BILAG-2004 clinical parameter definitions 
and guidance for correlating SLEDAI-2K and BILAG-2004 clinical parameters. Please refer 
to this guide when completing disease activity assessments. Important extensions of selected 
BILAG-2004 glossary definitions are included as follows:
Protocol-specific extensions of BILAG-2004 and SLEDAI-2K clinical parameter definitions:
(i)
BILAG-2004 A or B score in the musculoskeletal organ system due to active 
polyarthritis, defined as follows:
-
“BILAG-2004 A”: severe arthritis (BILAG-2004 #41) manifested by observed 
active synovitis in ≥2 joints with marked loss of functional range of movements 
and significant impairment of basic activities of daily living (ADL), that has 
been present on several days cumulatively over the past 4 weeks, including at 
the time of the Screening visit. Basic ADL are defined as the following 
activities which require assistance or assistive devices (at least 1 must be present
and documented in source): ambulation, toileting, grooming including bathing, 
dressing, feeding oneself (not responsive to steroids up to 10 mg/day, 
antimalarials, NSAIDs).
-
“BILAG-2004 B”: moderate arthritis or tendonitis or tenosynovitis 
(BILAG-2004 #42) defined as tendonitis/tenosynovitis or active synovitis in 
≥1 joint (observed or through history) with some loss of functional range of 
movements which leads to some loss of functional range of motion as
manifested by effects on instrumental ADLs (such as cooking, driving, using the
telephone or computer, shopping, cleaning, etc), which has been present on 
several days over the last 4 weeks and is present at the time of the Screening 
visit.
(ii)
BILAG-2004 and SLEDAI-2K “lupus headache”: lupus headache is rare, migraine, 
tension or cluster headaches should not be recorded. Lupus headache should only be 
recorded if it is disabling, lasts at least 3 days, and does not respond to narcotics. It 
is expected that its severity would prompt formal testing (lumbar puncture, 
magnetic resonance imaging [MRI], computed tomography [CT], etc) and require 
corticosteroids and/or immunosuppressants and potentially hospitalisation for 
treatment. Lupus headache is considered a manifestation of lupus cerebritis.

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5.2.4.2
Modified BILAG 2004
The majority of BILAG As and BILAG Bs assigned via the scoring algorithms of the BILAG 
2004 are considered a legitimate representation of clinically significant worsening disease 
activity; however, there is a feature within the BILAG-2004 Index Scoring algorithms that can 
result in an A or B assigned to a body system which had improved, and then remained at the 
‘same’ level of improvement compared to previous visits. Items marked ‘same’ frequently 
warrant assignment of an A or a B category following the BILAG-2004 Index Scoring based 
on the BILAG principle of Intention-to-Treat. These are “false” A or B categories because 
they are not true worsening of disease activity but are due to unchanged or the same disease 
activity that has previously improved. These “false” A and B can only be determined and 
subsequently re-scored after a subject had completed a series of visits that define true state of 
SLE disease activity. 
The Disease Activity Adjudication Group will differentiate "false" A and B scores from true 
clinically significant worsening by reviewing all BILAG-2004 Index scores for each subject’s 
visits. A modified BILAG-2004 Index Scoring Rules will be used. The modified BILAG rules 
and the review process and scoring as well as references used that justify the modification are 
detailed in a charter developed for this exercise.
5.2.5
Physician Global Assessment 
A trained and certified Investigator will complete the PGA (see
). 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 over the last 4 weeks. 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 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 a global assessment, 
factoring in all aspects of the subject’s lupus disease activity. It should not reflect non-lupus 
medical conditions.
5.2.6
Oral corticosteroid reduction
Please refer to Section 3.3.2 for all information regarding steroid tapering. 

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5.3.3
Physical examination
Body height will be captured at screening only. Subjects will be weighed at each study visit. 
Medically significant changes from the Screening physical examination will be recorded as 
AEs.
5.3.3.1
Complete physical examination
A complete physical examination will be performed at the visits specified in the Study Plan
(Table 2, Table 3, and Table 4), and will include an assessment of the following: general 
appearance, head and neck, breast, respiratory, cardiovascular, abdomen, 
musculoskeletal/extremities, neurological, skin, lymph nodes, and thyroid.
5.3.3.2
Focused physical examination
The focused physical examination will include an assessment of the organ systems required to 
complete protocol-specified assessment tools (SLEDAI-2K, BILAG-2004, joint count, and 
CLASI). Additional assessments should be done as clinically indicated. Abnormal findings 
will be recorded as part of AE, SAE, AESI, or lupus activity, as appropriate. 
5.3.3.3
Pap smear
Most cases of cervical cancer appear to be related to infection with papilloma virus. Because 
of the potential for viral reactivation due to blockade of the interferon pathway, we are 
assessing cervical dysplasia in this study, although to date there has been no signal in the 
anifrolumab studies. 
Abnormal Pap smear results received anytime within the 2 years prior to randomisation must 
be repeated to ensure subject eligibility. If a Pap smear performed within 2 years prior to 
randomisation was normal with no documented malignancy (eg, 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 (HSIL) 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 refer to
 
for guidance. 
Subjects should have a Pap smear between Week 48 and Week 52 to ensure that there is no 
evidence of new cervical dysplasia. Since access to a Pap smear may vary by country, the 
Sponsor recommends that local guidelines for obtaining Pap smears in subjects who have 
received immunomodulators or immunosuppressive treatment be followed. If a Pap smear was 
performed between Week 48 and Week 52 and was not normal but showed no evidence of 
malignancy (eg, CIN III, CIS, or AIS), it should be repeated as per the patient’s 
gynaecologist’s recommendations. If the patient’s gynaecologist has recommended a repeat 
Pap smear be performed at a specified interval, the Pap smear should be obtained as 
recommended and the report provided in the source document.

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5.3.3.4
Assessment of Cushingoid features
Subjects will be assessed for Cushingoid features at the visits specified in the Treatment 
Period Study Plan (Table 3). Features, such as moon face, buffalo hump, purple or violaceous 
striae, central obesity, hirsutism, acne, easy bruising, and fragile skin, will be captured 
separately to evaluate whether resolution of same can occur overtime with OCS reduction.
5.3.4
Assessment of cardiovascular risk
To understand the contribution of the chronic inflammatory response in SLE to dyslipidaemia
(as a potential risk for accelerated subclinical arteriosclerotic cardiovascular disease) and the 
potential effects of anifrolumab treatment, both lipid (including LDL and HDL, triglycerides 
[see Section 5.3.11.1]) and inflammatory profiles will be obtained during the study. Various 
risk factors for atherosclerosis will be assessed as part of the subject demographics at 
screening according to the Adult Treatment Panel (ATP) III Guidelines. Current and previous 
concomitant medications received for cardiovascular indications should be collected and 
recorded.
5.3.5
Columbia Suicide Severity Rating Scale 
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 (see 
 
The C-SSRS will be administered at all study visits by a trained rater. The trained rater will 
record the clinical observation on the scale, which will be used as the source document. If at 
all possible, the same individual should perform the assessment at each visit to reduce scoring 
variability. In the event the primary rater is not available, a designated back-up rater who 
meets the same qualifications may perform the C-SSRS. An Investigator physician will review 
completed C-SSRS responses on the day of assessment and document review within the 
source. 
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 a rater 
other than the Primary Investigator, it is recommended that the Primary Investigator confirms 
suicidal ideation before making a referral to mental health services; however, this should not 
delay the referral. 
5.3.6
Personal Health Questionnaire Depression Scale-8
The PHQ-8 consists of 8 of the 9 criteria on which the DSM-IV diagnosis of depressive 
disorders is based (American Psychiatric Association, 1994, see 
It assesses 
symptoms of depression over the last 2 weeks. The PHQ-8 is completed by the subject and 
scored by the Investigator at visits specified in the Treatment and Follow-up Study Plans 

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(Table 3 and Table 4). In addition to the 8 questions on depression, there is also a non-scored 
question to assess how the depressive symptoms affect the subject’s level of functioning.
5.3.7
Electrocardiogram
Digital ECGs (dECG) for all subjects at all centres will be conducted at the centre using a
machine provided by the central ECG vendor and will be transmitted to the central ECG
laboratory. Digital ECGs will be performed at Screening, Randomisation, and at Visit 14 
(Week 52). Digital ECGs will be performed in triplicate at Randomisation and at Visit 14 
(Week 52). Digital ECGs will be obtained after the subject has been resting in a supine
position for at least 10 minutes. All dECGs will be documented by recording the date, time, 
heart rate, QRS duration, PR interval, RR interval, QT, and corrected QT interval. The 
corrected QT intervals will be calculated using the Fridericia formula.
The Investigator will judge the overall interpretation as normal or abnormal. If abnormal, it
will be decided as to whether or not the abnormality is clinically significant or not clinically
significant and the reason for the abnormality will be recorded on the eCRF, if the Investigator 
considers it clinically significant. Abnormal values shall not be recorded as AEs unless
deemed clinically significant.
Quality assurance of the ECG waveform and subject demographics will be conducted by a
central ECG laboratory operator at the central ECG laboratory. Electrocardiogram reports will 
be provided to the study sites once the analysis is complete. It is the Investigator’s judgment 
whether the findings/results on the central ECG laboratory report are clinically relevant or not. 
5.3.8
Tuberculosis screening and monitoring
5.3.8.1
Screening evaluation
A blood test for TB will be done at screening using the interferon-gamma release assay 
(IGRAs) test (ie, QuantiFERON® -TB Gold In-Tube Test [QFT-GIT]). Evaluation of all 
subjects by QFT-GIT test will be performed by the central clinical laboratory, and chest x-rays 
will be completed at screening. If an adequate (anterio-posterior and lateral or per local SOC) 
chest x-ray was performed within 12 weeks prior to signing the ICF, it does not need to be 
repeated at the Screening visit. 
Compared to culture confirmed TB, overall, 87.6% of subjects have a positive QFT-GIT 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 tuberculosis disease. The guide also states that “Medical treatments or conditions that 
impair immune functions can potentially reduce IFN-γ 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 the SLE study, false negative tests are possible, so a 
chest x-ray is a relevant technique for detecting active pulmonary disease and minimising 
potential risk to study subjects.

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5.3.8.2
Tuberculosis results from screening evaluations
!
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 randomised without prophylaxis.
!
If the screening QFT-G test is newly positive and chest radiograph shows no 
evidence of active TB, and the subject has no symptoms or medical history 
consistent with active TB, the subject must have a retest, and if retest is positive, the 
subject must start on prophylaxis prior to randomisation.
!
If the screening QFT-G test is positive at the initial Screening visit, but the subject
is not newly positive as of the initial Screening visit, the subject must have been 
diagnosed with latent TB and must have documentation confirming completion of 
appropriate treatment. Subjects with no history of latent TB prior to the initial 
Screening visit, but who are diagnosed with latent TB during screening, may be 
considered eligible if appropriate treatment is initiated prior to randomisation. Such 
subjects may be re-screened if necessary to allow for local guidelines on latent TB 
treatment initiation.
!
If the screening QFT-G test is indeterminate, the test must be repeated at least once
by the central laboratory as soon as possible. 
-
If the result remains indeterminate, the chest radiograph shows no evidence of 
active TB, there are no signs or symptoms of active TB, no recent contact with 
anyone with active TB, and there is no history of latent (unless diagnosed with 
documentation of completion of appropriate treatment) or active TB, the subject
may be randomised and will have additional QFT-G testing performed 
according to the Study Plan (Table 2, Table 3, and Table 4). Additionally, in the 
opinion of the Investigator and after discussion with the medical monitor, an 
expert specialising in TB may be consulted prior to randomisation. 
5.3.8.3
Tuberculosis monitoring during the study
If, during the trial a subject who had an indeterminate TB result at screening is determined to 
have a:
!
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 USA guidelines may be followed. 
This should also be reported as an AESI.
!
Negative QFT-G test result, then the subject does not need to continue TB testing 
outlined for subjects with indeterminate results at screening
For subjects with negative QFT at baseline and no symptoms of active TB:
!
Week 52 QFT negative: no further testing
!
Week 52 QFT indeterminate: repeat at Week 56. If negative no further testing, 
however if indeterminate repeat again at Week 60.

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!
QFT positive at Week 52 or later. Confirm positive QFT 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 at every visit 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 subjects may present as 
disseminated disease or with extrapulmonary features and should be referred for appropriate 
treatment.
5.3.9
Modified flare index
A modified SELENA flare index, using the SLEDAI-2K instead of the SELENA SLEDAI 
(see 
), will be completed every 3 months as an exploratory outcome to further 
characterise flares as safety events. 
The modified flare assessment should be completed by the Investigator or delegated/qualified 
physician as per protocol schedule of assessments. Assessment of flare should be scored in 
comparison to the subject’s previous visit (ie, over the past 28 days) and should only include 
findings which, in the option of the Investigator, are due to SLE disease activity within that 
timeframe. Flare will be defined as any 1 criterion present in either the Mild/Moderate Flare 
or Severe Flare categories. New or worsened manifestations should only be reported for 
manifestations of SLE.
5.3.10
Clinical laboratory tests
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 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. Abnormal safety laboratory results should be repeated 
as clinically indicated, as soon as possible (preferably within 24 to 48 hours).
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 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 the 

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centre as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.6.6.
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer to 
‘Actions Required in Cases of Combined Increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.
The following laboratory variables will be measured:
Table 5
Clinical laboratory tests
Screening
ANA, anti-dsDNA antibodies, anti-Sm antibody, anti-RNP, anti-Sjogren’s Syndrome-related antigen A 
[SSA], and anti-Sjogren’s Syndrome-related antigen B [SSB]
HbA1c in diabetic subjects only
Peripheral blood B lymphocyte count (only for subjects who received B cell-depleting therapy prior to 
signing the ICF, including but not limited to ocrelizumab, ofatumumab, atacicept, obinutuzumab, or 
rituximab)
BILAG-2004 associated laboratory tests analysed for all subjects at screening (anticardiolipin, lupus 
anticoagulant, haptoglobin, and Coombs [Coombs will be performed as applicable per BILAG 
assessment requirements])*
Hepatitis B surface antigen
Hepatitis B core antibody (reflex DNA testing if isolated HBc positive)
Hepatitis C antibody 
HIV test**
CK 
C3, C4, CH50 complement
Urine protein/creatinine ratio
QFT-G test
Haematology
Haematology/Haemostasis (whole blood)
WBC count with differential
RBC count
Haematocrit
Haemoglobin
Platelet count
MCV
MCHC

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Serum Chemistry 
Calcium
Chloride
Potassium
Sodium
AST*
ALT*
ALP*
GGT
BUN
Creatinine
Total bilirubin* (reflexively fractionated if elevated)
Glucose
Albumin
CK
*Note for serum chemistry: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and 
assessed concurrently.
Urinalysis
Colour
Appearance
Specific gravity
pH
Protein dipstick
Glucose
Ketones
Blood
Bilirubin
Microscopy including WBC/HPF, RBC/HPF, casts
Urine creatinine and protein, urine protein/creatinine ratio
Pregnancy Test 
Serum β-hCG (at screening only)
Urine β-hCG (at every visit after screening, using a dipstick)
Serum FSH (at screening only) in postmenopausal females with menses absent for ≥1 year

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be reported as SAEs. Please refer to 
 for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.4
Other events of special interest
6.4.1
Overdose
An overdose (ie, having been administered a greater dose of study drug than specified in this 
protocol) with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modules in the CRF and in the Overdose Report.
An overdose without associated symptoms is only reported in the Overdose Report.
If an overdose of investigational product occurs during the study, then the Investigator or 
other site personnel inform the appropriate AstraZeneca representative or designee
immediately or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative or designee works with the Investigator to ensure 
that all relevant information is provided to the PRA Safety Management data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.7.
For other overdoses, reporting must occur within 30 days.
6.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.4.3
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative or designee works with the Investigator to ensure 
that all relevant information is provided to PRA Safety Management and to AstraZeneca 
within 1 or 3 calendar days for SAEs (see Section 6.6) and within 30 days for all other 
pregnancies.

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The same timelines apply when outcome information is available.
Any subject who becomes pregnant during the course of the study will be followed so that 
pregnancy outcome can be determined and reported to AstraZeneca and the regulatory 
authorities.
6.4.4
Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
12 weeks following the last dose.
Pregnancy of the subject’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should if possible be followed up and documented.
The outcome of any conception occurring from the date of the first investigational product 
administration until 12 weeks after the last investigational product administration should 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.
6.5
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 nonserious.
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 stroke, MI, or cardiovascular death).
Lupus nephritis (associated with SLE; WHO or ISN/RPS Classification Class III, IV or V) is 
defined not as an AESI but as a new BILAG-2004 A adjudicated AE.
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 nonserious AESI 
will be categorised as an AE. For reporting of AESIs, see Section 6.8.
6.5.1
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.

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6.5.2
Opportunistic 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. 
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.
6.5.3
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 
is provided as a simple and rapid means to 
make the diagnosis of anaphylaxis during infusion 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).
6.5.4
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.
6.5.5
Herpes zoster
Herpes zoster is a viral infection characterised 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.

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6.5.6
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; 
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).
!
A bacteriologically confirmed TB case is a case where a biological specimen is 
positive by smear microscopy, culture or rapid diagnostic such as PCR or nucleic 
acid amplification test (Xpert MTB/RIF).
!
A clinically diagnosed TB case is a case where the subject does 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
(Wallace et al, 2011
Wallace DJ, Strand V, Furie R, Petri MA, Kalunian K, Pike M, et al. Evaluation of treatment 
success in systemic lupus erythematosus clinical trials: Development of the British Isles 
Lupus Assessment Group-Based Composite Lupus Assessment endpoint. Presented at: ACR 
2011: Poster 2265.
Wallace et al, 2014
Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M, et al. Efficacy and safety 
of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results 
from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. 
Ann Rheum Dis. 2014 Jan;73(1):183-90.
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 

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agree to complete a locally recommended course of treatment for latent TB in order to 
continue receiving the investigational product.
6.5.7
Influenza
Influenza is a severe viral infection that includes the following symptoms: temperature greater 
than 100.8°F (38.2°C), and malaise, headache, or myalgia. It is often accompanied by nausea, 
vomiting, and diarrhoea, 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.
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.
6.5.8
Vasculitis (non-Systemic Lupus Erythematosus)
Vasculitis (non-SLE) is defined as an inflammatory disorder of blood vessels involving 
arteries and/or veins and characterised 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 
for a list of vasculitic syndromes excluded 
from the study. 
6.5.9
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 the 
cardiovascular SOC for evaluation as to whether to classify as MACE events (stroke, MI, or 
cardiovascular death).
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 randomisation group.

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6.6
Recording of adverse events
6.6.1
Time period for collection of adverse events
Adverse Events and SAEs will be collected from the time of signature of informed consent, 
throughout the treatment period and including the follow-up period until Follow-up Visit 2 
(12 weeks post final dose) or Week 52 for the subjects who enrol in the LTE study.
6.6.2
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 
study staff for as long as medically indicated. The Sponsor 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.
6.6.3
Variables 
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 investigational product (yes or no)
!
Action taken with regard to investigational product
!
Outcome of AE 
In addition, the following variables will be collected for SAEs:
!
Onset Date (Date AE met criteria for serious AE)
!
Detection Date (Date Investigator became aware of serious AE)
!
AE is serious due to:
(a)
Death
-
Date of death
-
Autopsy performed
-
Primary/secondary cause of death
(b)
Life threatening
(c)
Inpatient hospitalisation or prolongation of existing hospitalisation
-
Date of hospitalisation
-
Date of discharge

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(d)
Congenital abnormality or birth defect
(e)
Important medical event
(f)
Suspected transmission via a medicinal product of an infectious agent
!
Description of AE
!
Investigator causality assessment to concomitant medications
!
Investigator causality assessment to study procedures (yes or no)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity, whereas seriousness is defined by the criteria defined above. 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. 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. The Investigator should provide an assessment of the severity of each AE/SAE.
6.6.4
Causality collection
The Investigator will assess causal relationship between investigational product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures 
and additional study drug (such as 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 
6.6.5
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 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.
6.6.6
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 (CSR). Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs, ECGs, and other safety assessments should therefore only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the investigational product.

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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 will 
use the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE.
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 (or SAE, as appropriate).
6.6.7
Disease progression/worsening of systemic lupus erythematosus
Disease progression can be considered as a worsening of a subject’s condition attributable to 
SLE. It may be an increase in the activity or severity of the existing 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 reported as “new” or “worsening” in the 
BILAG-2004, and recorded in the SLEDAI-2K, as appropriate.
6.7
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF. PRA Safety 
Management is to be sent all safety forms and supporting documentation including laboratory
tests, imaging reports, diagnostic test results, biopsy reports and discharge summaries.
If any SAE occurs in the course of the study, then the Investigator or other site personnel 
inform PRA Safety Management within 1 day, ie, immediately but no later than 24 hours of 
when he or she becomes aware of it.
PRA Safety Management works with the Investigator to ensure that all the necessary 
information is provided to the data entry site within 1 calendar day of initial receipt for fatal 
and life threatening events (if received for instance during a weekend or a public holiday, the 
information is forwarded as early as possible on the first business day following the weekend 
or holiday) and within 3 calendar days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform PRA Safety 
Management of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious or is an AESI in the 
Datalabs system, an automated email alert is sent to the designated PRA and AstraZeneca
representative(s).

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If the Datalabs system is not available, then the Investigator or other study site personnel 
reports the SAE to PRA Safety Management on the study specific paper SAE form by 
telephone, fax, or email. The SAE report form must be completed in the electronic system as 
soon as the system is available again.
PRA Safety Management contact information for SAE reporting: 
FAX: +44 1792 525 720
E-mail: MHGsafety@prahs.com
Telephone: +49 621 8782 154
PRA, on behalf of AstraZeneca, is responsible for reporting certain SAEs as expedited safety 
reports to applicable Regulatory Authorities, Ethics Committees (ECs), and participating 
Investigators, in accordance with International Conference on Harmonisation (ICH) 
Guidelines and/or local regulatory requirements. PRA may be required to report certain SAEs 
to regulatory authorities within 7 calendar days of being notified about the event; therefore, it 
is important that Investigators submit additional information requested by AstraZeneca or 
PRA as soon as it becomes available.
The reference document for definition of expectedness/listedness is the IB.
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 nonserious) will be recorded on the AE CRF 
(using a recognised 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. 
6.9
Management of investigational product-related toxicities 
6.9.1
Anaphylaxis, hypersensitivity, and infusion-related reactions
Infusion-related reactions have been reported with the administration of IV Ig and 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 recognise and treat 
anaphylaxis. For a definition of anaphylaxis, hypersensitivity reactions, and infusion-related 
reactions, see 
Subjects should not be premedicated unless they have had a prior infusion-related reaction to 
anifrolumab. However, if a prior infusion-related reaction has been documented, the 

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Investigator may elect to administer prophylactically an antihistamine and/or 
acetaminophen/paracetamol for the comfort and safety of the subject prior to subsequent 
infusions. Prophylactic use of glucocorticosteroids prior to subsequent infusions 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 (eg, 
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 (see Section 3.7). For any active infection (eg, Varicella zoster
infection/chickenpox) or significant exposure to any infection (eg, 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 (eg, 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 (ie, 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
6.10
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with PRA Safety Management. Issues identified
will be addressed; for instance, this could involve amendments to the study protocol and 
letters to Investigators.
6.10.1
Data and Safety Monitoring Board 
An independent DSMB will perform evaluations of safety data at specified regular intervals 
throughout the study and make recommendations to the Sponsor regarding further conduct of 
the study. The DSMB will be provided with data that are summarised by treatment group 
using masked treatment group labels (eg, A and B). After reviewing the data by masked
treatment group, the DSMB may choose to unblind the treatment groups for additional review. 
The DSMB may also ask for unblinded efficacy data, if during the performance of a 

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7.2
Dose and treatment regimens
The investigational product, anifrolumab 300 mg or placebo, will be administered via 
controlled IV infusion pump into a peripheral vein over at least 30 minutes Q4W. Each dose 
must be at least 14 days apart.
7.2.1
Dose preparation steps
From a 100 mL IV infusion bag of 0.9% normal saline, withdraw and discard a volume of 
saline equal to 2.0 mL. Then add 1.0 mL from each of the 2 vials in the kit into the infusion
bag and mix by gentle inversion. Due to approximately 10% overfill of normal saline, the final 
volume of the dilution will be greater than 100 mL.
7.2.2
Prior to administering the investigational product
!
Confirm subject was evaluated for signs and symptoms of TB
!
Women of childbearing potential must have a negative urine pregnancy test prior to 
receiving investigational product.
!
Subjects should not have clinically significant, active infection as determined by the 
Investigator. 
!
There should be at least 14 days between doses. If the previous investigational 
product infusion was given within 14 days, delay visit until >14 days has elapsed 
and contact the PRA medical monitor. 
!
Pre-dose blood samples will be collected
!
Subjects should not be premedicated unless they have had a prior infusion-related
reaction to anifrolumab. However, if a prior infusion-related reaction has been 
documented, the Investigator may elect to administer prophylactically an 
antihistamine or acetaminophen/paracetamol for the comfort and safety of the 
subject prior to subsequent infusions. The medications should be given after visit 
assessments have been completed. Prophylactic use of glucocorticosteroids prior to 
subsequent infusions is not permitted.
7.2.3
Investigational product administration procedures
!
Investigational product must be administered within 4 hours after preparation and 
may be stored at room temperature until administration. Total in-use storage time 
from dilution of anifrolumab to start of administration should not exceed 4 hours at 
room temperature. If refrigerated at 2 to 8°C (36 to 46°F), storage time should not 
exceed 24 hours. If storage time exceeds these limits, a new dose must be prepared 
from new vials.
!
Investigational product must be administered at room temperature by controlled 
infusion via an infusion pump into a peripheral vein. A physician must be present at 
the site or immediately available to respond to emergencies during all 
administrations of investigational product.
!
Because compatibility of anifrolumab with IV medications and solutions other than 
0.9% sodium chloride for injection, (United States Pharmacopeia), is not known, 

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!
Duration of infusion: the amount of time elapsed from the infusion start time to the 
infusion stop time. Infusion start time is defined as the time point where 
investigational product is first infused into the subject. Infusion stop time is defined 
as the time point where the infusion pump completes infusion of the investigational 
product, not including the saline flush.
For example: an infusion with a start time of 12:00 PM would have a duration of 
infusion recorded as 30 minutes (a time between 12:00 PM and 12:30 PM).
!
Duration of administration: the amount of time elapsed from the infusion pump start 
time to the infusion pump stop time PLUS the time required to complete the 
additional flush of saline. The duration of administration will always be greater than 
the duration of infusion and will always include the additional flush of saline.
Initial IV bag compatibility studies demonstrate that anifrolumab is compatible with IV bags 
composed of polyolefin that is latex-free, polyvinyl chloride (PVC)-free, and diethylhexyl 
phthalate (DEHP)-free, and IV administration lines composed of PVC and polyethylene that 
are latex free and DEHP-free. Additional studies demonstrate that anifrolumab is compatible 
with IV bags and ancillaries comprised of materials as described in Table 6 and Table 7.
Table 6
Compatible materials of construction for IV bags
IV Bag Diluent
Materials of Construction
0.9% saline
Glass
0.9% saline
Polyolefin copolymer, ethylene and propylene
0.9% saline
PVC and DEHP
0.9% saline
Polyethylene
0.9% saline
Polypropylene
0.9% saline
Ethylene polyvinyl acetate
Table 7
Compatible materials of construction for ancillaries (eg, infusion 
tubing)
Materials of Construction
Polyethylene
PVC with DEHP
PVC with 2-ethylhexyltrimellitate
Polybutadiene
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language.

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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.
7.5
Compliance
The administration of all study drugs (including investigational product) should be recorded in 
the appropriate sections of the CRF. The investigational product will be administered by study 
site 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 drug 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.
All unused investigational product will be returned to an AstraZeneca or designee-authorised
depot or disposed of upon authorisation by AstraZeneca or designee or other written 
instructions provided by AstraZeneca or designee (for contact information and specific 
shipping instructions).
Details regarding supplies, dose preparation, process for reporting product complaints, and 
accountability for the investigational product will be provided to the sites.
7.7
Post study access to study treatment
Upon evaluation at Week 52, subjects will either be followed for a 12-week Follow-up Period,
or transition to an LTE study (if eligible) that will continue for approximately 3 years after the 
completion of the Week 52 visit.
8.
STATISTICAL ANALYSES 
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and identification of protocol violations. Analyses will be performed by AstraZeneca or its 
representatives. 
A comprehensive SAP will be prepared prior to the first subject in to the study. Any 
subsequent amendments to the SAP will be documented, with final amendments completed 
prior to unblinding of the data for the analysis. Details of all analyses, including sensitivity 
analyses, will be fully documented in the SAP.

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8.4.1
Primary outcome variable
The primary endpoint used to evaluate the effect of anifrolumab compared to placebo on 
disease activity is the difference in the proportion of subjects achieving BICLA response at 
Week 52, where a subject is a BICLA responder if all of the following criteria are met:
!
Reduction of all baseline BILAG-2004 A to B/C/D and baseline BILAG-2004 B to 
C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new 
BILAG-2004 A or ≥2 new BILAG-2004 B
!
No worsening from baseline in SLEDAI-2K, where worsening is defined as an 
increase from baseline of >0 points in SLEDAI-2K
!
No worsening from baseline in the subjects’ lupus disease activity, where 
worsening is defined by an increase ≥0.30 points on a 3-point PGA VAS
!
No discontinuation of investigational product
!
No use of restricted medications beyond the protocol-allowed threshold before 
assessment. Restricted medication is defined in Section 3.3 and additional details 
are given in the SAP.
As supportive to the primary endpoint, time to BICLA response sustained up to Week 52 will 
also be assessed.
8.4.2
Key secondary outcome variables
8.4.2.1
BICLA response at Week 52 in interferon test-high subjects
The key secondary endpoint used to evaluate the effect of anifrolumab compared to placebo 
on disease activity in the IFN test-high subgroup is the difference in the proportion of subjects 
achieving BICLA response at Week 52 in subjects classified as IFN test-high. BICLA 
response is defined in Section 8.4.1.
8.4.2.2
Oral corticosteroid management
The key secondary endpoint used to evaluate the effect of anifrolumab versus placebo on the 
ability to reduce the OCS dose in subjects with baseline OCS ≥10 mg/day prednisone or 
equivalent is the difference in the proportion of subjects meeting all the following criteria: 
!
Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40
!
Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to 
Week 52
!
No discontinuation of investigational product
!
No use of restricted medications beyond the protocol-allowed threshold before 
assessment (see Section 3.3 and SAP for additional details).
8.4.2.3
Skin lesions
The key secondary endpoint used to evaluate the effect of anifrolumab versus placebo on 
inflammatory cutaneous lupus lesions in subjects with baseline CLASI activity score ≥10 is 
the difference in the proportion of subjects who meet all of the following criteria: 

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Edition Number 6
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Presentation of results
All data will be presented by treatment group. Descriptive statistics (number, mean, standard 
deviation [SD], median, minimum, and maximum) will be provided for continuous variables, 
and counts and percentages will be presented for categorical variables.
95% CIs will be presented for treatment comparisons. If a model is used to estimate the 
treatment difference, the corresponding CI according to the model will be presented. 
Otherwise, the unadjusted CI will be used. Nominal p-values may be presented for secondary 
endpoints not included in the strategy for preserving the type I error rate. Statistical 
significance cannot be interpreted from these p-values. 
Demography and baseline characteristics will be summarised by treatment group for the full 
analysis set. 
8.5.1
Analysis of the primary variable 
The primary endpoint used to evaluate the effect of anifrolumab 300 mg compared to placebo 
on disease activity is the difference in the proportion of subjects achieving BICLA response at 
Week 52. 
The estimand of primary interest is the difference in the proportions of response between 
anifrolumab and placebo at Week 52 in the full analysis set, where the response is captured 
with a composite binary endpoint and is defined by improvement from baseline in disease 
activity as measured by BILAG, no worsening in SLEDAI-2K and PGA and ability to adhere 
to the planned course of the treatment. The intercurrent events: discontinuation of 
investigational product and receipt of restricted medications are unfavourable outcomes. 
Therefore, subjects treated with restricted medications beyond protocol-allowed threshold, and 
those who discontinued the investigational product for any reasons, will be non-responders. 
This estimand answers a clinically relevant question comparing the number of subjects able to 
both complete the study treatment and to achieve adequate response without further 
medication being required. The response is measured by the primary efficacy endpoint, 
defined as the difference in the proportion of subjects achieving BICLA response at Week 52, 
comparing the anifrolumab to the placebo groups.
The null hypothesis is that the proportion of subjects achieving BICLA response on 
anifrolumab is equal to that of placebo. The alternative hypothesis is that the proportion of 
subjects achieving BICLA response on anifrolumab is not equal to that on placebo, ie,
H0: difference in proportion achieving BICLA response (anifrolumab vs Placebo) = 0
Ha: difference in proportion achieving BICLA response (anifrolumab vs Placebo) ≠ 0
The proportion of subjects achieving BICLA response in the anifrolumab treatment group will 
be compared to that in the placebo group using a Cochran-Mantel-Haenszel (CMH) approach 
(Clowse et al, 2017

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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Clowse ME, Wallace DJ, Furie RA, Petri MA, Pike MC, Leszczyński P, et al. Efficacy and 
safety of epratuzumab in moderately to severely active systemic lupus erythematosus: Results 
from two phase III randomized, double-blind, placebo-controlled trials. Arthritis Rheumatol 
2017 Feb;69(2): 362–75.
Cochran, 1954) stratified by: 
!
SLEDAI-2K score at screening (<10 points versus ≥10 points)
!
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or 
equivalent)
!
Results of a type 1 IFN test (high versus low)
Strata with low counts will be collapsed prior to the analysis. Details for collapsing of strata 
will be pre-specified in the SAP.
The estimated treatment effect (ie, the difference in response rate for anifrolumab versus 
placebo), corresponding 95% CI, and 2-sided p-value for the difference at Week 52 will be 
presented. In addition, the response rate and the corresponding 95% CI within each treatment 
group will be presented.
The time to BICLA response sustained up to Week 52 will be analysed as a supportive 
measure to the primary endpoint to assess if treatment with anifrolumab reduces the time 
needed to achieve an improvement in disease activity that is maintained throughout the study 
compared with placebo. A Cox proportional hazard model will be fitted to data including the 
covariates of treatment and the stratification factors. Details will be presented in the SAP.
Further, longitudinal presentations of results over time based on the same analysis, with the 
corresponding 95% CI, will be created. In addition, the individual components of the 
composite BICLA endpoints will be summarised by treatment group, and a sensitivity analysis 
using modified BILAG will be conducted.
8.5.2
Analysis of the secondary variables
8.5.2.1
Analysis methods for key secondary efficacy variables
All key secondary endpoints, with the exception of the difference in annualised flare rate 
through Week 52 (which will be analysed using a negative binomial regression model), will 
be analysed and presented similarly to the primary endpoint as described in Section 8.5.1. 
Details will be described in the SAP.
The flare rate in the anifrolumab treatment group will be compared to the flare rate in the 
placebo group using a negative binomial model. The response variable in the model will be 
the number of flares over the 52-week treatment period. The model will include covariates of 
treatment group, and the stratification factors. The logarithm of the follow-up time will be 
used as an offset variable in the model to adjust for subjects having different exposure times. 
The estimated treatment effect and the corresponding 95% CI as well as the 2-sided p-value 

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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 CSA shall prevail.
Agreements between PRA, on behalf of AstraZeneca, and the PI must be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.1.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.2
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 Quarter 2, 2015 and to end by Quarter 3, 2018.
The study may be terminated at individual centres 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.
9.3
Data management
Data management will be performed by PRA, according to the Clinical Informatics Plan.
The PRA Datalabs system will be used for data collection and query handling. The 
Investigator will ensure that data are recorded on the CRFs 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 
the provision of answers to data queries according to the CSA. The Investigator will sign the 
completed CRFs. A copy of the completed CRFs will be archived at the study site.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the MedDRA. Medications will be classified according to the 
AstraZeneca Drug Dictionary. All coding will be performed by the PRA coding group. 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 Clinical Informatics Plan and Edit Specifications 
Document. 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 Clinical Informatics 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.

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Edition Number 6
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Serious adverse event reconciliation
Serious adverse event reconciliation reports are produced and reconciled with the subject
safety database and/or the investigational site. SAE reconciliation between safety data and 
clinical data will be performed by PRA. The frequency depends on the expected volume of 
SAE reports and will be defined in the AE/SAE Reconciliation Plan.
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/GCP, applicable regulatory requirements 
and the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
Subject data protection
The ICF 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 EC should approve the final study protocol, including the final version of the ICF 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, and to the study site staff.
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to AstraZeneca or designee before enrolment of any subject into the study.
The EC should approve all advertising used to recruit subjects for the study.
AstraZeneca or designee should approve any modifications to the ICF that are needed to meet 
local requirements.
If required by local regulations, the protocol should be re-approved by the EC annually.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca or designee will handle the distribution of any of these documents to the national 
regulatory authorities.

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Edition Number 6
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AstraZeneca or designee will provide Regulatory Authorities, ECs and PIs with safety 
updates/reports according to local requirements.
Each PI is responsible for providing the EC with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product.
AstraZeneca or designee will provide this information to the PI so that he/she can meet these 
reporting requirements.
10.4
Informed consent
The PI(s) at each centre will:
!
Ensure each subject is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study
!
Ensure each subject is notified that they are free to discontinue from the study at 
any time
!
Ensure that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided
!
Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study
!
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File
!
Ensure a copy of the signed ICF(s) is/are given to the subject
!
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 ICF(s) that is/are approved by an EC.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International 
coordinating Investigator and AstraZeneca or designee.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant EC and if applicable, the national regulatory 
authority, before implementation. Local requirements are to be followed for revised protocols.
AstraZeneca or designee will distribute any subsequent amendments and new versions of the 
protocol to each PI. For distribution to the ECs, see Section 10.3.
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca or designee and the 
centre’s EC are to approve the revised ICF before the revised form is used.
If local regulations require, any administrative change will be communicated to or approved 
by each EC.

Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
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10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an EC 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, GCP, guidelines of the ICH, and 
any applicable regulatory requirements. The Investigator will contact AstraZeneca or designee 
immediately if contacted by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
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Baechler et al, 2003
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Bertsias G, Ioannidis JPA, Boletis J, Bombardieri S, Cervera R, Dostal C, et al. EULAR 
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Clowse ME, Wallace DJ, Furie RA, Petri MA, Pike MC, Leszczyński P, et al. Efficacy and 
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Edition Number 6
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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
128(128)
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