Conditions: Active Systemic Lupus Erythematosus
Keywords: Active Systemic Lupus Erythematosus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 373
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab versus placebo in adult participants with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE).

Detailed description:
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab versus placebo in participants with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. Participants must be taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants. The study will be performed in adult participants aged 18 to 70 years of age.

Approximately 360 participants receiving SOC treatment will be randomised in a 1:1 ratio to receive a fixed intravenous dose of anifrolumab 300 mg or placebo every 4 weeks 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 intravenous infusion (IV) via an infusion pump over a minimum of 30 minutes, every 4 weeks.

Arms:
arm 1: Anifrolumab 300 mg intravenous infusion (IV) administered every 4 weeks for a total of 13 doses. arm 2: Placebo intravenous infusion (IV) administered every 4 weeks for a total of 13 doses.

Interventions: intervention 1: Anifrolumab intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous infusion (IV) intervention 2: Intravenous infusion (IV)

Protocol document:
Prot_002.pdf: 
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
Date 23 May 2019
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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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Study Code D3461C00004
Edition Number 6
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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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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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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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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
Date 23 May 2019
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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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Edition Number 6
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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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Edition Number 6
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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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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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Edition Number 6
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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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Edition Number 6
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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)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
48(128)
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


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
49(128)
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.


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
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)
Study Code D3461C00004
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)
Study Code D3461C00004
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.


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
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
55(128)
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
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
57(128)
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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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
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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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
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
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
64(128)
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.


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
65(128)
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




Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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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
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
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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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Study Code D3461C00004
Edition Number 6
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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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Edition Number 6
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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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Study Code D3461C00004
Edition Number 6
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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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Edition Number 6
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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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Drug Substance Anifrolumab (MEDI-546)
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Edition Number 6
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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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Edition Number 6
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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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Edition Number 6
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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.






Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
106(128)
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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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
114(128)
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
115(128)
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 








Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
119(128)
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.


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
120(128)
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.


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
121(128)
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
Date 23 May 2019
122(128)
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
ACR ad hoc committee, September 1999
ACR ad hoc committee. Guidelines for Referral and Management of systemic Lupus 
Erythematosus in Adults. Arthritis & Rheumatism Vol. 42, No. 9, September 1999, 
pp 1785-1796).
American Psychiatric Association, 1994
American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental 
Disorders, 4th Edition. American Psychiatric Association, Washington, DC.
Baechler et al, 2003
Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. 
Interferon-inducible gene expression signature in peripheral blood cells of patients with severe 
lupus. Proc Natl Acad Sci USA. 2003;100(5):2610-5.
Banchereau et al, 2004
Banchereau J, Pascual V, Palucka AC. Autoimmunity through cytokine-induced dendritic cell 
activation. Immunity. 2004;20:539–50.
Bengtsson et al, 2000
Bengtsson AA, Sturfelt G, Truedsson L, Blomberg J, Alm G, Vallin H, et al. Activation of 
type I interferon system in systemic lupus erythematosus correlates with disease activity but 
not with antiretroviral antibodies. Lupus. 2000;9:664-71.
Bennett et al, 2003
Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, et al. Interferon and 
granulopoiesis signatures in systemic lupus erythmatosus blood. Journal of Experimental 
Medicine. 2003;197(6):711-23.
Bernatsky et al, 2006
Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in 
systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2550-7.


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
123(128)
Bertsias et al, 2008
Bertsias G, Ioannidis JPA, Boletis J, Bombardieri S, Cervera R, Dostal C, et al. EULAR 
recommendations for the management of systemic lupus erythematosus. Report of a Task 
Force of the EULAR Standing Committee for International Clinical Studies Including 
Therapeutics, Ann Rheum Dis 2008;67:195–205).
Blomberg S et al, 2001
Blomberg S, Eloranta ML, Cederblad B, Nordlin K, Alm GV, Rönnblom L. Presence of 
cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus. 
Lupus. 2001;10(7):484-90.
Burman, 2009
Burman CF, Sonesson C, Guilbaud O, 2009. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stats in Med. 2009;28:739–761.
Cella et al, 2002
Cella DF, Eton DT, Lai JS, Peterman AH, Merkel DE. Combining anchor and distribution-
based methods to derive minimal clinically important differences on the functional assessment 
of cancer therapy (FACT) anaemia and fatigue scales. J Pain Symptom Manage. 
2002;24:547-61.
Cellestis, 2005
Clinicians Guide to QuantiFERON®-TB Gold.
Cervera et al, 2006 
Cervera R, Abarca-Costalago M, Abramovicz D, Allegri F, Annunziata P, Aydintug AO, et al. 
Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the 
"Euro-Lupus Project". Autoimmun Rev. 2006;5(3):180-6.
CHMP, February 2015
CHMP Guideline on clinical investigation of medicinal products for the treatment of systemic 
lupus erythematosus, and lupus nephritis (26 February 2015; EMA/CHMP/51230/2013).
Clowse et al, 2017
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
Cochran, W. G. 1954. Some Methods for Strengthening the Common χ2 Tests. Biometrics 
10:417-451.








Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
127(128)
Touma et al, 2010
Touma Z, Urowitz MB, Gladmann DD. SLEDAI-2K for a 30-day window. Lupus. 
2010;19:49-50.
Urowitz et al, 1976
Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smyth HA, Ogryzlo MA. The bimodal 
mortality pattern of systemic lupus erythematosus. Am J Med. 1976 Feb;60(2):221-5.
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
World Health Organization. Definitions and reporting framework for tuberculosis – 2013 
revision (updated December 2014) http://apps.who.int/iris/bitstream/10665/79199/1/ 
9789241505345 eng.pdf 
Yao et al, 2009
Yao Y, Richman L, Higgs BW, Morehouse CA, de los Reyes M, Brohawn P, et al. 
Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I 
trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus. 
Arthritis Rheum. 2009 Jun;60(6):1785-96.
Yao et al, 2010
Yao Y, Higgs BW, Richman L, White B, Jallal B. Use of type I interferon-inducible mRNAs 
as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an 
anti-IFNalpha antibody, in systemic lupus erythematosus. Arthritis Res Ther. 2010 Apr 14;12 
Suppl 1:S6.
Yee et al, 2009
Yee CS, Farewell V, Isenberg DA, Griffiths B, Teh LS, Bruce IN, et al. The BILAG-2004 
index is sensitive to change for assessment of SLE disease activity. Rheumatology (Oxford) 
2009;48:691-5.
Yellen et al, 1997
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other 
anaemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage. 1997;13:63-74.


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00004
Edition Number 6
Date 23 May 2019
128(128)
Zonana-Nanach et al, 2000
Zonana-Nanach A, Barr SG, Magder LS, Petri M. Damage in systemic lupus erythematosus 
and its association with corticosteroids. Arthritis Rheum. 2000;43(8):1801-8.






































































































































































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SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D3461C00004
Edition Number 4.0
Date
26 Jul 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






Statistical Analysis Plan 
Study Code D3461C00004
Edition Number 4.0
Date 26 Jul 2019
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
LIST OF ABBREVIATIONS ..............................................................................8
AMENDMENT HISTORY................................................................................11
1.
STUDY DETAILS.............................................................................................14
1.1
Study objectives................................................................................................. 14
1.1.1
Primary objective...............................................................................................14
1.1.2
Secondary objectives..........................................................................................14
1.1.3
Safety objective..................................................................................................16
1.2
Study design ...................................................................................................... 16
1.2.1
Restricted medications leading to non-response for key endpoints......................17
1.2.2
Steroid burst.......................................................................................................18
1.2.3
Protocol-specified steroid tapering .....................................................................18
1.3
Number of subjects ............................................................................................19
1.3.1
Original sample size and power estimation.........................................................19
1.3.2
Updated power estimation..................................................................................20
2.
ANALYSIS SETS .............................................................................................20
2.1
Definition of analysis sets .................................................................................. 20
2.1.1
All subjects ........................................................................................................20
2.1.2
Full analysis set..................................................................................................20
2.2
Protocol deviations............................................................................................. 21
3.
PRIMARY AND SECONDARY VARIABLES.................................................21
3.1
Primary outcome variable .................................................................................. 22
3.2
Key secondary outcome variables ...................................................................... 23
3.2.1
BICLA response at Week 52 in IFN test-high subjects.......................................23
3.2.2
Oral corticosteroid management.........................................................................23
3.2.3
Skin lesions........................................................................................................56
3.2.4
Joints .................................................................................................................56
3.2.5
Flares.................................................................................................................57


Statistical Analysis Plan 
Study Code D3461C00004
Edition Number 4.0
Date 26 Jul 2019
5
3.3.2
Supportive outcome variables of the individual components of BICLA 
 
....................................................................................................................58
3.3.4
Supportive outcome variables for the assessment of OCS use.............................61
3.3.5
Supportive outcome variables for the assessment of skin lesions ........................61
3.3.6
Supportive outcome variables for the assessment of joints..................................61
3.3.7
Supportive outcome variables for the assessment of flares..................................62
3.4
Assessment of study population .........................................................................68
3.4.1
Demographic and baseline characteristic variables.............................................68
3.4.2
Medical history..................................................................................................68
3.4.3
Prior and concomitant medications.....................................................................68
3.4.4
Exposure to investigational product....................................................................78
3.5
Safety variables..................................................................................................78
3.5.1
Adverse events...................................................................................................79
3.5.1.1
Other significant adverse events.........................................................................82
3.5.2
Laboratory variables .......................................................................................... 82
3.5.3
ECGs .................................................................................................................83
3.5.4
Modified SELENA Flare Index based flares....................................................... 83
3.5.5
Physical examination .........................................................................................84
3.5.6
Vital signs..........................................................................................................84
3.5.7
Cushingoid features............................................................................................85
3.5.8
C-SSRS..............................................................................................................85
3.5.9
Personal Health Questionnaire Depression Scale-8.............................................86
4.
ANALYSIS METHODS....................................................................................89
4.1
General principles.............................................................................................. 89
4.1.1
Data excluded from analysis ..............................................................................89
4.1.2
Database lock and unblinding.............................................................................90
4.1.3
Visit windows....................................................................................................90
4.1.4
Presentation of results ........................................................................................91


Statistical Analysis Plan 
Study Code D3461C00004
Edition Number 4.0
Date 26 Jul 2019
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4.1.5
Testing strategy to account for multiplicity considerations .................................92
4.1.6
Missing Data......................................................................................................94
4.1.7
Examination of model assumptions.................................................................. 104
4.2
Analysis methods............................................................................................. 104
4.2.1
Analysis of the primary variable....................................................................... 104
4.2.2
Key secondary outcome variables .................................................................... 109
4.2.2.1
BICLA at Week 52 in IFN test-high subjects ................................................... 109
4.2.2.2
Oral corticosteroid management....................................................................... 110
4.2.2.3
Skin lesions...................................................................................................... 110
4.2.2.4
Joints ............................................................................................................... 111
4.2.2.5
Flares............................................................................................................... 111
4.2.3
Analysis methods for other secondary efficacy variables.................................. 113
4.2.3.1
Assessment of disease activity.......................................................................... 113
4.2.3.2
Subject reported outcome variables.................................................................. 116
4.2.4
Presentation of study population....................................................................... 118
4.2.4.1
Subject disposition........................................................................................... 118
4.2.4.2
Demographic and baseline characteristic.......................................................... 119
4.2.4.3
Restricted medications ..................................................................................... 119
4.2.4.4
Exposure.......................................................................................................... 119
4.2.5
Analysis methods for safety variables............................................................... 119
4.2.5.1
Adverse events................................................................................................. 120
4.2.5.2
Laboratory variables ........................................................................................ 122
4.2.5.3
ECGs ............................................................................................................... 123
4.2.5.4
Modified SELENA Flare Index based flares..................................................... 123
4.2.5.5
Physical examination ....................................................................................... 123
4.2.5.6
Vital signs........................................................................................................ 123
4.2.5.7
Cushingoid features.......................................................................................... 124
4.2.5.8
C-SSRS............................................................................................................ 124
4.2.5.9
Personal Health Questionnaire Depression Scale-8........................................... 124
4.3
Subgroup analysis............................................................................................ 126
5.
INTERIM ANALYSES ................................................................................... 127
6.
CHANGES OF ANALYSIS FROM PROTOCOL ........................................... 127
7.
REFERENCES ................................................................................................ 128
8.
APPENDIX ..................................................................................................... 129
APPENDIX A - SUPPLEMENTAL PROCESS DESCRIPTION: RESTRICTED 
MEDICATIONS.............................................................................................. 130


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APPENDIX B - SUPPLEMENTAL PROCESS DESCRIPTION: ORAL 
CORTICOSTEROIDS..................................................................................... 162
APPENDIX C - DERIVATION RULES FOR IMPUTATION OF PARTIAL OR 
MISSING DATES ........................................................................................... 173
APPENDIX D - REFERENCE RANGES AND TELVC FOR LABORATORY 
VALUES ......................................................................................................... 174
APPENDIX E - ECG: POTENTIALLY CLINICALLY SIGNIFICANT POST 
BASELINE VALUES...................................................................................... 176
APPENDIX F - REFERENCE RANGES AND TELVC FOR VITAL SIGNS................. 177
APPENDIX G - DERIVATION OF IFN21 PARAMETERS ........................................... 178
LIST OF TABLES
Table 4
Visit windows .......................................................................................90
Table 5
Overview of subgroup analyses...........................................................127
LIST OF FIGURES
Figure 1
Alpha recycling.....................................................................................93


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Edition Number 4.0
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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area under the curve
BDR
Blind data review
BICLA
British Isles Lupus Assessment Group-based Composite Lupus Assessment
BILAG
British Isles Lupus Assessment Group
BMI
Body mass index
C-SSRS
Columbia–Suicide Severity Rating Scale
CI
Confidence interval
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CMH
Cochran-Mantel-Haenszel
CSP
Clinical Study Protocol
CSR
Clinical Study Report
DBL
Database lock
ECG
Electrocardiogram
EDV
Early Discontinuation Visit
GGT
Gamma glutamyl transferase
IFN
Interferon
IPD
Important protocol deviation
IV
Intravenous


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Abbreviation or 
special term
Explanation
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward
LTE
Long-term extension
MACE
Major adverse cardiovascular events
MAR
Missing at Random
MCS
Mental Component Score
MedDRA
Medical Dictionary for Regulatory Activities
nAb
Neutralising antibodies
OCS
Oral corticosteroids
PCS
Physical Component Score
PGA
Physician’s Global Assessment
PHQ-8
Personal Health Questionnaire Depression Scale-8
Q
Question
Q-Q
Quartile-quartile
Q4W
Every 4 weeks
SAE
Serious adverse event
SD
Standard deviation
 
SE
Standard Error
SLE
Systemic lupus erythematosus
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000
SOC
Standard of care
TELVC
Treatment emergent laboratory/vital signs changes
TFL
Tables, Figures and Listings


Statistical Analysis Plan 
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Edition Number 4.0
Date 26 Jul 2019
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Abbreviation or 
special term
Explanation
ULN
Upper limit of normal
VAS
Visual analogue scale
WHO-DD
World Health Organization Drug Dictionary


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Study Code D3461C00004
Edition Number 4.0
Date 26 Jul 2019
11
AMENDMENT HISTORY
Date
Brief description of change
15 May 2017
Updates according to the changes in the table, figure and listing (TFL) shells 
after review
Updates to provide additional details to support programming activities
Updates to specify handling and examination of missing data (sensitivity and 
tipping point analyses)
Updates to clarify database lock and unblinding after all subjects completed 
Week 52.


Statistical Analysis Plan 
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Edition Number 4.0
Date 26 Jul 2019
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Date
Brief description of change
24 May 2019(v3.0)
Updates which are editorial in nature and do not impact the analyses are not 
listed.
!
Updates based on blind data review findings, including the removal of SMQ 
to define hypersensitivity reactions. Definition of hypersensitivity added.
!
Added the supplemental process documents for restricted medications 
(Version dated 21-Jan-2019) and oral corticosteroids (Version dated 18-Feb-
2019) into the appendices of the SAP (
 
!
Additional clarification added regarding the impact of restricted medications 
on the definition of non-responders for the primary and secondary efficacy 
endpoints; including BICLA, OCS reduction, CLASI, joints 
!
Updates to the assignment of primary and key secondary endpoints. 
Rationale for these updates are provided in the revised clinical study 
protocol.
!
Addition of supportive analysis for time to BICLA response sustained up to 
Week 52. 
!
Addition of sensitivity analyses for BICLA and flares based on the modified 
BILAG. Added analysis of improvement over time by BILAG body system.
!
 
 
!
 
 
 
 
 


Statistical Analysis Plan 
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Edition Number 4.0
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Date
Brief description of change
24 Jul 2019 (v4.0)
!
Added clarification that tipping point analyses will only be conducted if the 
primary analysis for the endpoint achieves nominal statistical significance.
!
Updates to remove details regarding two separate database locks. A single 
database lock is planned after last subject last visit.
!
Additional details added to document the process used to identify and report 
on important protocol deviations.
!
Added sensitivity analysis for flares using on-treatment data.
!
!
 
!
 
Updates which are editorial in nature and do not impact the analyses are not 
listed.
!
Clarified the date to be used in the determination of the key secondary 
endpoint, maintained OCS reduction.
!
Added clarification to the guidance for missing data when calculating 
scores.
!
Updated the supplemental process documents for restricted medications 
from version dated 21-Jan-2019, to version dated 17-Jul-2019.
!
Addition of sensitivity analysis for BICLA removing the criterion of no use 
of restricted medications beyond the protocol-allowed threshold.


Statistical Analysis Plan 
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Edition Number 4.0
Date 26 Jul 2019
14
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
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 the British Isles Lupus 
Assessment Group-based Composite Lupus 
Assessment (BICLA) response at Week 52
Composite variable (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 Systemic Lupus 
Erythematosus Disease Activity Index 2000 
(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
a
Any medication classified as restricted medications as described in 
1.1.2
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 interferon (IFN) 
test-high sub-group
BICLA (see outcome measure for primary objective)


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The proportion of subjects who achieve an 
Oral corticosteroids (OCS) dose ≤7.5 mg/day 
at Week 40, which is maintained through 
Week 52 in the sub-group 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 sub-group 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 
sub-group 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 joints 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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1.1.3
Safety objective
Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of 
anifrolumab
Adverse events (AEs) (including AEs of special 
interest [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)
1.2
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 SLE who are 
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. 


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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 two options:
-
If eligible, enrol into the long-term extension (LTE) study in which anifrolumab 
300 mg or placebo will be administered Q4W
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.
Database lock (DBL) and unblinding will occur after the Last Subject Last Visit (LSLV). 
Blinding of subjects and investigators will be maintained to the greatest extent possible after 
DBL until LSLV in the LTE study.
1.2.1
Restricted medications leading to non-response for key endpoints
Subjects treated with concomitant medications beyond the protocol allowed threshold 
(restricted medications), as detailed in 
 while on investigational product may be 
considered non-responders for assessments of the primary and secondary efficacy endpoints 
including BICLA, OCS reduction, CLASI, joints 
 
A summary of the categories of restricted medications that may lead to a subject being 
considered as a non-responder is provided below, with a detailed description of the rules 
available in 
!
Corticosteroids
-
Steroid burst and taper (see also Section 1.2.2)
-
Protocol-specified steroid tapering (see also Section 1.2.3)


Statistical Analysis Plan 
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!
Antimalarials and Immunosuppressants 
!
Biologics 
!
NSAIDs
!
Other restricted medications
-
Danazol, Dapsone, Sulfasalazine, Memantine: New or increased dose during the 
treatment period with certain exceptions
-
Investigational agents 
-
Live or attenuated vaccines, BCG vaccine
-
Cyclophosphamide
-
IFN therapy
-
Plasmapheresis
-
Immunoglobulin therapy
-
Acthar gel
-
Retinoids
1.2.2
Steroid burst
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 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, regardless of the reason for the burst (SLE or non-SLE activity). More details 
are given in 
 as well as Section 3.3.2 in the Clinical Study Protocol (CSP).
1.2.3
Protocol-specified steroid tapering
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 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, central nervous system, 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
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 


Statistical Analysis Plan 
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Edition Number 4.0
Date 26 Jul 2019
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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 will be considered 
non-responders for subsequent assessments of disease activity (refer to 
 for 
additional details).
Steroid tapering will not be permitted after Week 40.
1.3
Number of subjects
A total of 360 subjects receiving SOC treatment will be randomised 1:1 to treatment with 
anifrolumab or placebo.
The sample size and power estimations are based on the primary and key secondary endpoints. 
An update was made to the primary and 2 key secondary endpoints; therefore, a power 
analysis was conducted based on the updated primary endpoint
The primary endpoint was 
 
 later 
updated to the difference in the proportion of subjects achieving BICLA response at Week 52. 
The intercurrent events of discontinuation of the investigational product and receipt of 
restricted medications were incorporated into the primary and key secondary endpoints 
(except flares). The rationale for changes to primary and key secondary endpoints is provided 
in the CSP.
1.3.1
Original sample size and power estimation
The sample size is primarily driven by the need to acquire an adequate safety database size, as 
well as the ability to assess key secondary endpoints. 
 
 
 
 
 
 
It is not straightforward to precisely arrive at the power estimate for the assessments of key 
secondary endpoints due to the multiplicity procedure used to preserve the type I error, as well 
as uncertainties of the size of subgroups in most assessments. Approximate estimates of power 
for 2 example endpoints are listed below. These calculations assume that the primary endpoint 
is met, and the testing of the key secondary endpoints is therefore allowed. Each endpoint is 
tested using a weighted Holm procedure, and the alpha given by the assigned weight in the 
first step of the algorithm: 
!
 


Statistical Analysis Plan 
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Edition Number 4.0
Date 26 Jul 2019
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!
Difference in the proportion of subjects who achieve an OCS dose ≤7.5 mg/day at 
Week 40, which is maintained through Week 52 in the sub-group of subjects with 
baseline OCS ≥10 mg/day: Given 60% of subjects have an OCS dose of at least 
10 mg at baseline; proportions of subjects tapering the OCS dose of 32% and 59% 
in the placebo and anifrolumab treatment groups, respectively; a 2-sided alpha of 
0.004 yields 87% power. 
The assumptions of the effect sizes and sizes of subgroups used for the calculations above are 
based on the observed results in the interim analyses of study CD IA MEDI 546-1013.
1.3.2
Updated power estimation
An updated power analysis was performed based on the previously planned sample size and 
amended primary endpoint. There were no changes made to the study sample size. Power 
calculations were performed solely to justify the update to the primary and key secondary 
endpoints.
The primary endpoint is the difference in proportion of subjects achieving BICLA response at 
Week 52, comparing anifrolumab 300 mg to placebo. With assumed proportions of BICLA 
responders of 30% and 46% in the placebo and anifrolumab 300 mg groups, respectively, 180 
subjects/arm yields approximately 88% power to reject the hypothesis of no difference using a 
2-sided alpha of 0.05. The minimal detectable difference in BICLA response between 
anifrolumab 300 mg versus placebo is approximately 10% with this sample size. Calculations 
are based on a 2-group chi-squared test of equal proportions (nQuery version 8.1.2.0).
The assumptions for effect sizes used in the above calculations are based on the observed 
results from study D3461C00005.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
All subjects 
This analysis set will comprise all subjects screened for the study and will be used for 
reporting of disposition and screening failures.
2.1.2
Full analysis set
The full analysis set will be used as the primary population for reporting efficacy and safety 
data. This comprises all subjects randomised into the study who receive at least 1 dose of 
investigational product and will be analysed according to randomised treatment (modified 
Intention-To-Treat). Any major deviations from randomised treatment will be listed and 
considered when interpreting the safety data.


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Edition Number 4.0
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21
 
 
2.2
Protocol deviations
All protocol deviations identified during monitoring of the study will be recorded in the 
clinical trial management system (CTMS). Important protocol deviations (IPDs) are a subset 
of protocol deviations that may significantly impact the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect a subject’s rights, safety, or well-
being. 
Protocol deviations will be classified as important or not important by the PRA Medical 
Monitor as defined in the Protocol Deviation Guidance based on periodic reviews of CTMS 
deviation reports and blinded data reviews (BDR).  The Sponsor then reviews the 
classification and provides the final determination. The list of important protocol deviations 
will be finalized and documented prior to database lock and unblinding. 
Only important protocol deviations will be listed and tabulated in the Clinical Study Report 
(CSR).
3.
PRIMARY AND SECONDARY VARIABLES
Baseline is defined as the last measurement prior to randomisation and dose administration on 
Day 1. If the Day 1 value is missing or is invalid or is collected after administration of 
investigational product, the latest assessment prior to dose administration on Day 1 will serve 
as baseline.
At some sites, the device to collect subject reported outcomes was not synchronized with the 
real time. Therefore, baseline for the following subject reported outcomes will be derived 
based on the date only, and not time of the assessment.
!
C-SSRS


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!
Personal Health Questionnaire Depression Scale – 8 
If not stated otherwise, change from baseline will be calculated as value at the respective time 
point minus value at baseline. The percent change from baseline is defined as change from 
baseline divided by baseline value multiplied with 100.
Values of BILAG-2004, SLEDAI-2K, CLASI, PGA, 
central reviewers, including adjudication of BILAG 
scoring. Modified BILAG values will be used as a sensitivity analysis to the primary endpoint 
and flares. Details regarding modified BILAG are provided in Section 3.3.2 as well as in the 
CSP.
3.1
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 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 as defined as an 
increase from baseline of >0 points in SLEDAI-2K
Increase from baseline corresponds to the change from baseline. SLEDAI-2K will 
be derived as the sum of the scores for all items.
!
No worsening from baseline in subjects’ lupus disease activity, where worsening is 
defined by an increase ≥0.30 points on a 3-point PGA VAS;
!
No permanent premature discontinuation of investigational product (according to 
eCRF form “Discontinuation of Investigational Product”)
!
No use of restricted medications beyond the protocol-allowed threshold on or 
before the date of last Week 52 assessment used to derive BICLA response
Restricted medications are defined in 
.
Subjects with no BILAG A or B at baseline and no worsening in any organ systems, as 
defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B, as well as subjects with a 
baseline PGA VAS score > 2.7 will be considered as having met the criteria for BILAG and 
PGA VAS, respectively. 
If any of the criteria cannot be evaluated at Week 52 (eg, due to missing values) that criterion 
will be imputed using LOCF and BICLA response derived based on the complete data. This 
applies only if Week 48 data is not missing, otherwise the subject will be defined as a BICLA 
non-responder at Week 52. 
In addition, time to BICLA response sustained up to Week 52 will be assessed. Time to 
BICLA response sustained up to Week 52 is defined as the visit of first BICLA response 


Statistical Analysis Plan 
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which is sustained up to, and including, Week 52. A subject is considered to have achieved
BICLA response sustained up to Week 52 if response is achieved at Week 52 with “time to” 
defined as the first timepoint where BICLA response is achieved when maintained through 
Week 52.
Subjects without a BICLA response sustained up to Week 52 will be censored at the date of 
premature discontinuation of IP, or Week 52, whichever occurs earlier. If subject did not 
prematurely discontinue treatment, but did not have a week 52 assessment either, then the date 
of last available BICLA assessment (latest of BILAG, SLEDAI and PGA date) prior to Week 
52 will be used as the censoring date.
The individual conditions of BICLA (reduction of all BILAG-2004 A and B, no worsening 
from baseline in SLEDAI-2K, no worsening in subjects’ lupus disease activity, no permanent 
discontinuation of investigational product, and no use of restricted medication) will be 
assessed at Week 24 and Week 52 by treatment.
The difference between anifrolumab and placebo in the proportion of subjects achieving 
BICLA response will also be assessed longitudinally over time up to Week 52. 
The primary endpoint will also be calculated using the modified BILAG assessments, as 
described in Section 3.3.2. The primary endpoint will also be calculated removing the 
criterion of no use of restricted medications beyond the protocol-allowed threshold.
3.2
Key secondary outcome variables
3.2.1
BICLA response at Week 52 in IFN 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 at baseline. 
BICLA response is defined in Section 3.1.
3.2.2
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 with maintained OCS reduction. A 
maintained OCS reduction is defined as meeting all the following criteria: 


Statistical Analysis Plan 
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Edition Number 4.0
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!
Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40 
The date of last assessment used for efficacy analysis (SLEDAI-2K, PGA and 
BILAG) in the time window of Week 40 (as described in Section 4.1.3) will be used 
as date of Week 40. If no such assessment falls into the respective time window, 
then the target date for the timepoint will be used instead. The dose of OCS at Week 
40 used in the evaluation of this endpoint will be the dose on the date of Week 40 + 
1 day. 
!
Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to 
Week 52
A maintained OCS dose is defined as no dose increase (ie, no dose greater than the 
dose at Week 40 + 1 day) between Week 40 + 2 days and Week 52, inclusive.
The date of last assessment used for efficacy analysis (SLEDAI-2K, PGA and 
BILAG) in the time window of Week 52 (as described in Section 4.1.3) will be used 
as date of Week 52. If no such assessment falls into the respective time window, 
then the target date for the timepoint will be used instead.
!
No permanent premature discontinuation of investigational product (according to 
eCRF form “Discontinuation of Investigational Product”)
!
No use of restricted medications beyond the protocol-allowed threshold on or 
before the date of Week 52 (as given above) 
Restricted medications are defined in 
If any of the conditions cannot be evaluated at Week 52 (eg, due to missing values) the subject 
is defined as not reaching a maintained OCS reduction.
































































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3.2.3
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 with an at least 50% reduction in CLASI activity 
score at Week 12. An at least 50% reduction in CLASI activity score is defined as meeting all 
of the following criteria: 
!
Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline 
The CLASI activity score will be derived as the sum of all single activity scores 
(13 locations of erythema, 13 locations of scale/hypertrophy, mucous membrane 
lesions, recent hair loss, and non-scarring alopecia). A ≥50% reduction is reached if 
the percentage change is ≤-50%.
!
No permanent premature discontinuation of investigational product before 
assessment (ie, duration of exposure ≥ study day of date of CLASI assessment at 
Week 12)
!
No use of restricted medications beyond the protocol allowed threshold on or before 
the date of CLASI assessment at Week 12
Restricted medications are defined in 
If any of the criteria cannot be evaluated at Week 12 (eg, due to missing values) that criterion 
will be imputed using LOCF and an at least 50% reduction in CLASI activity score derived 
based on the complete data. This applies only if Week 8 data is not missing, otherwise the 
subject will be defined as not reaching a ≥50% reduction in CLASI activity score at Week 12.
3.2.4
Joints
The key secondary endpoint used to evaluate the effect of anifrolumab versus placebo on 
swollen and tender joints is the difference in proportion of subjects with at least 6 swollen and 
at least 6 tender joints at baseline who achieve at least a 50% reduction from baseline in both 
the number of swollen and tender joints at Week 52. 
An at least 50% reduction is reached if all the following criteria are met:
!
The percentage reduction from baseline in both the number of swollen joints and 
the number of tender joints, separately, is ≥50% 
!
No permanent premature discontinuation of investigational product (according to 
eCRF form “Discontinuation of Investigational Product”) 
!
No use of restricted medications beyond the protocol allowed threshold on or before 
the assessment
Restricted medications are defined in 


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If the change from baseline in the number of swollen and tender joints cannot be evaluated at 
Week 52 (eg, due to missing values) the change from baseline will be imputed using LOCF. 
This applies only if Week 48 data is not missing, otherwise the subject will be defined as not 
achieving a 50% reduction.
3.2.5
Flares 
The key secondary endpoint used to evaluate the effect of anifrolumab versus placebo on 
flares is the difference in annualized flare rate through Week 52. 
A flare is defined as either 1 or more new BILAG-2004 A or 2 or more new BILAG-2004 B 
items compared to the previous visit (ie, a worsening from an E, D, or C score to a B score in 
at least 2 organ systems or a worsening from an E, D, C, or B score to an A score in any one 
organ system compared to the previous visit). 
The occurrence of a new flare will be checked for each available visit versus the previous 
available visit up to Week 52. If no flare occurred, the number of flares will be set to 0. 
Otherwise all flares will be counted leading to a maximum number of flares of 13. 
The annualized flare rate will be calculated as the number of flares divided by the flare 
exposure time in days multiplied with 365.25. The flare exposure time is the time up to 
Week 52 (date of BILAG-2004 assessment at Week 52) or up to the date of last available 
BILAG-2004 assessment up to and including week 52 in case of premature study 
discontinuation and will be derived as date of Week 52/ date of last BILAG-2004 assessment 
minus date of first administration of investigational product + 1.
For the sensitivity analyses of flares while on treatment, the flare exposure time is the time 
between day of first dose of investigational product and day of last dose of investigational 
product plus 28 days, both inclusive. All flares occurring within the flare exposure time will 
be considered for this analysis (even if occurring after the week 52 visit timepoint).
An additional sensitivity analysis for flare rate through Week 52 will use the modified BILAG 
as described in Section 3.3.2.
 
 
 


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3.3.2
Supportive outcome variables of the individual components of BICLA
 
SLEDAI-2K
SLEDAI-2K (derived as the sum of the scores for all items) will be evaluated using the 
difference in mean change from baseline longitudinally over time to Week 52. 
Scores for the SLEDAI organ systems will be derived in the same way as SLEDAI-2K but 
using the scores for the respective items only. The SLEDAI organ systems are defined as 
follows:
!
Central nervous system: seizure, psychosis, organic brain syndrome, visual 
disturbance, cranial nerve disorder, and lupus headache 
!
Vascular: CVA (cerebrovascular accident) and vasculitis
!
Musculoskeletal: arthritis and myositis
!
Renal: urinary casts, haematuria, proteinuria, and pyuria
!
Mucocutaneous: rash, alopecia, and mucosal ulcers
!
Cardiovascular system and respiratory: pleurisy and pericarditis


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!
Immunology: low complement and increased DNA binding
!
Haematological and fever: fever, thrombocytopenia, and leukopenia
For each SLEDAI organ system, the proportion of subjects with an improvement (ie, a 
SLEDAI organ system score less than the corresponding score at baseline) at Week 24 and 
Week 52, respectively, will be assessed for subjects with an organ system involvement at 
baseline (ie, a SLEDAI organ system score greater than 0). 
Physician’s Global Assessment 
The difference between anifrolumab and placebo in the mean change from baseline in PGA 
(measured on a VAS ranging from 0 to 3) will be assessed by visit up to Week 52.
BILAG-2004
BILAG-2004 contains 97 clinical and laboratory parameters divided into the 9 body systems. 
The first 7 body systems (Constitutional, Mucocutaneous, Neuropsychiatric, Musculoskeletal, 
Cardiorespiratory, Gastrointestinal, Ophthalmic) contain clinical parameters which are 
assessed by the treating physician as new (4), worse (3), same (2), improving (1) and not 
present (0). The Renal and Haematologic scoring is based on laboratory values. The original 
central review process used the 1 September 2009 BILAG 2004 version of the BILAG Index 
Scoring. BILAG body system scores were assigned A, B, C, D or E scores to all study visits 
by strictly following this Index Scoring. Results from the original scores are used for 
calculation of the primary efficacy endpoint, BICLA response at Week 52, defined in Section 
3.1.
The majority of As and 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 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. Modified BILAG rules will be used in 
sensitivity analyses for the primary endpoint and for flares.


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BILAG-2004 grades will be presented by organ system. Furthermore, a BILAG-2004 global 
score will be derived by summing-up the numerical score equivalents for each organ system 
with the numerical score equivalents given as: A = 12, B = 8, C = 1, D = 0, and E = 0.
For each BILAG body system and regardless of involvement at baseline, improvement over 
time will be summarized as the number and percentage of subjects with involvement at 
baseline (A,B, or C), no involvement at baseline (E), or no involvement at baseline but had 
previous experience (D); unchanged at Week X (same score as baseline); improvement at 
Week X (changing score to a lower activity, eg, from A to B/C/D); worsening at Week X (eg, 
from B/C to A); new at Week X (eg, from D or E to A/B/C); missing at Week X. No 
imputation will be performed for missing values. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3.4
Supportive outcome variables for the assessment of OCS use
The total daily OCS dose will be assessed longitudinally over time up to Week 52. For the 
derivation of OCS dose at a specific visit, the target date for the respective visit (as described 
in Section 4.1.3) will be used.
The standardised area under the curve (AUC) of OCS dose up to Week 52 will be calculated 
as follows:
For each single daily dose, the duration of the single dose will be calculated as end date – start 
date + 1. If the start date is before Day 1, Day 1 will be used instead. If the end date is after 
the date of Week 52 (date of Visit 14), the date of Visit 14 will be used instead. The AUC for 
each single dose will be derived by the daily dose (mg/day) multiplied with the duration 
(days). The AUC up to Week 52 is the sum of the AUCs of the single doses. The AUC of 
OCS dose will only be calculated if all necessary data are available up to Visit 14 (ie, daily 
prednisone equivalent OCS dose can be calculated). For subjects who discontinued the study 
before Visit 14, the AUC will be calculated up to the date of study discontinuation. If a subject 
does not receive any OCS dose (ie, no corresponding medication documented) the AUC for 
this subject will be set to 0. The standardised AUC will be derived as AUC divided by the 
available days (date of Visit 14 / date of early discontinuation – date of Day 1 + 1) multiplied 
by 364 (52 weeks). 
3.3.5
Supportive outcome variables for the assessment of skin lesions
For all subjects with a CLASI activity score ≥10 at baseline the reduction of CLASI will be 
compared between Week 12 and Week 52. An at least 50% reduction in CLASI activity score 
at Week 12 is defined in Section 3.2.3. The reduction at Week 52 is defined in the same way 
with using assessments at Week 52 (with allowed LOCF of Week 48 data) instead of Week 12 
and no permanent premature discontinuation of investigational product (according to eCRF 
form “Discontinuation of Investigational Product”). Maintenance of effect in CLASI activity 
score is defined as an at least 50% reduction in CLASI activity score at Week 12 and Week 
52.
The difference between anifrolumab and placebo in the mean change from baseline in CLASI 
activity as well as CLASI damage score will be evaluated longitudinally over time up to 
Week 52. The CLASI damage score will be calculated as the sum of the scores for 
dyspigmentation for 13 locations, scarring/atrophy/panniculitis for 12 locations, and scarring 
of the scalp. If dyspigmentation lasts more than one year, the sum of the dyspigmentation 
scores from the 13 locations will be multiplied with 2 in the above formula.
3.3.6
Supportive outcome variables for the assessment of joints
In addition to the variable in Section 3.2.4, secondary endpoints to evaluate the effect of 
anifrolumab versus placebo on joints are:


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!
Difference in change from baseline to Week 52 in the number of active, swollen, 
and tender joints, respectively; 
!
Difference in proportion of subjects with at least 6 swollen and at least 6 tender 
joints at baseline who achieve at least a 20% reduction from baseline in both the 
number of swollen and tender joints at Week 52, using similar definition as in 
Section 3.2.4;
!
Difference in proportion of subjects with at least 8 swollen and at least 8 tender 
joints at baseline who achieve at least a 20% and at least a 50% reduction, 
respectively, from baseline in both the number of swollen and tender joints at Week 
52, using similar definition as in Section 3.2.4.
An active joint is defined as a joint with both swelling and tenderness.
Furthermore, the change from baseline in the number of active, swollen and tender joints, 
respectively, will be explored longitudinally up to Week 52 for all subjects.
3.3.7
Supportive outcome variables for the assessment of flares
In addition to the variable in Section 3.2.5, the annualised flare rate will also be evaluated for 
the following definition of flares using baseline as the reference point, and will be derived 
similarly as described in Section 3.2.5.
!
A flare is defined as either 1 or more new BILAG-2004 A or 2 or more new 
BILAG-2004 B compared to baseline and a change versus the previous visit. This 
implies that a new BILAG-2004 A score maintained in subsequent visits will not be 
counted as a new flare. However, a change of the situation in a subsequent visit (eg, 
one of the 2 new BILAG-2004 B scores of the previous visit improves to C but 
another worsens to B or an occurrence of a new BILAG-2004 B score in addition to 
the BILAG-2004 A score defining the previous flare) will lead to a new flare.
In addition, time to first flare will be assessed for flares as defined in Section 3.2.5 as well as 
for flares versus baseline as defined above. The time to first flare will be derived as date of 
first flare minus date of first administration of investigational product. If the subject did not 
have a flare, the time to flare will be censored at the end of the flare exposure time (as defined 
in Section 3.2.5).
 
 
 












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3.4
Assessment of study population
3.4.1
Demographic and baseline characteristic variables
Demographic characteristics (including geographic region, age, sex, ethnicity and race) and 
baseline characteristics (including height, weight, body mass index [BMI] and disease 
characteristics) will be assessed.
The clinical SLEDAI-2K score will be derived as the sum of the scores for the SLEDAI-2K 
items vasculitis, arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, and pericarditis.
3.4.2
Medical history
Medical histories will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Medical history will be evaluated separately for past and 
current conditions as given in the eCRF.
3.4.3
Prior and concomitant medications
Prior medications are reported according to the eCRF completion guidelines (ie, dependent of 
the relevance of the medication, the intake during the last few weeks before the first 
administration of IP, all medication taken during lifetime, or anything in-between will be 
reported). All medications will be coded using the latest version of World Health Organization 
Drug Dictionary (WHO-DD).
Any medications taken by the subject prior to the first dose date of investigational product will 
be considered prior medication. Any medication taken by the subject at any time between the 
date of the first dose (including the date of the first dose) of investigational product up to 
Week 52 (Visit 14/EDV), inclusive, will be considered concomitant medication. Any 
medication started prior to the first dose of investigational product and did not end before first 
dose or was ongoing will be considered as both prior and concomitant medication.
Disease related treatments at baseline are defined as all medications with therapy reason 
containing “disease under study” with an intake at the date of first dose of investigational 
product (ie, start date on or before the date of first dose and end date on or after date of first 
dose or was ongoing). The medications will be presented in the following categories:
!
Anti-malarial
defined as medications with an ATC code level 4 of P01BA (aminoquinolones)  and 
P01AX (Other agents against amoebiasis and other protozoal diseases)
!
Any anti-malarial
!
Anti-malarial only
!
Anti-malarial in combination with OCS and/or immunosuppressants
!
Azathioprine
defined as medications with a preferred term of azathioprine or azathioprine sodium


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!
Methotrexate
defined as medications with a preferred term of methotrexate or methotrexate 
sodium
!
Mycophenolate
defined as medications with a preferred term of mycophenolate mofetil or 
mycophenolate sodium or mycophenolic acid
!
Mizoribine
defined as medications with a preferred term of mizoribine
!
OCS
!
Any OCS
!
OCS only
!
OCS in combination with immunosuppressants and/or anti-malarial
!
Time on corticosteroids up to randomisation
!
NSAID
as defined in 
rule # 76. 
!
Other SLE medication
defined as SLE medications not covered within the above categories


















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will be applied to classify medication as prior and/or concomitant, as appropriate. 
Concomitant medications beyond the protocol allowed threshold (restricted medications) that 
are considered in the evaluation of the efficacy endpoints are described in Section 1.2.1 and 
3.4.4
Exposure to investigational product
The duration of exposure to the investigational product per subject is defined as the number of 
days between the start and the end dates of investigational product plus the dosing frequency 
time:
Duration of exposure (days) = (Last dosing date + 28 days) – first dosing date + 1.
The total subject years of exposure is the sum of duration of exposure (days) of all subjects in 
the respective treatment group divided by 365.25 (days/year).
The total number of infusions will be counted per subject. Furthermore, the number of 
subjects with an infusion will be assessed in 4-weekly categories (ie, 4 weeks, 8 weeks, 
12 weeks, …, 48 weeks). An infusion will be counted if it was given in the corresponding 
time window. Missed infusions will not be counted.  Additionally, the number of subjects with 
duration of exposure longer than each of the 4-weekly categories (ie, ≥4 weeks, ≥8 weeks, 
≥12 weeks, …, ≥48 weeks) will be presented. As the duration of exposure takes into account 
the total exposure time from the last dose + 28 days (as defined above), any missed or delayed 
infusions will contribute to exposure time, but not to the number of infusions. For example, if 
a subject interrupted treatment and received no infusion at week 4 he/she will be counted as 
"No infusion" at week 4, but will be counted as having "Exposure >= 8 weeks" if he/she 
received an infusion at any time after week 4.
The time to discontinuation of investigational product is the same as the duration of exposure. 
However, for subjects continuing in the LTE study, the time to discontinuation will be 
censored at the last dosing date + 28 days.
3.5
Safety variables
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, cushingoid features, C-SSRS, PHQ-8, modified 
SELENA Flare Index based flares, and AEs (including AESIs).
Change from baseline to each post-treatment time point where scheduled assessments were 
made will be calculated for relevant measurements. 
If not stated otherwise, on-treatment values are defined as values with an assessment date after 
the first administration of investigational product and on or before the date of last 
administration of investigational product + 28 days.


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3.5.1
Adverse events
Adverse events experienced by the subjects will be collected throughout the entire study and 
will be coded using the latest version of MedDRA.
Adverse event data will be categorized according to their onset date into the following study 
periods:
!
AEs occurring during screening: 
An AE during screening is defined as an AE with a date of onset ≥ date of first 
screening visit (S1) and < date of the first dose of investigational product.
AEs occurring during screening will only be listed.
!
AEs occurring during treatment:
An AE during treatment is defined as an AE with a date of onset ≥ day of first dose 
of investigational product and ≤ date of last dose of investigational product + 
28 days.
!
AEs occurring during follow-up:
An AE during follow-up is defined as an AE with a date of onset > date of last dose 
of investigational product + 28 days and ≤ date of last dose of investigational 
product + 84 days.
!
AEs occurring during treatment and follow-up:
The period “during treatment and follow-up” combines the periods “during 
treatment” and “during follow-up”. An AE during treatment and follow-up is 
defined as an AE with a date of onset ≥day of first dose of investigational product 
and ≤ date of last dose of investigational product + 84 days.
!
AEs occurring after follow-up:
An AE after follow-up is defined as an AE with a date of onset > date of last dose 
of investigational product + 84 days.
AEs occurring after follow-up will only be listed.
If an AE has a missing onset date, then unless the stop date of the AE indicates otherwise, this 
will be considered as an AE during treatment. Similarly, if an AE has a partial onset date, then 
unless the partial onset date or the stop date indicates otherwise, this will be considered an AE 
during treatment.
Adverse events of special interest are marked as such in the eCRF. Major adverse 
cardiovascular events (MACEs) will be determined according to the assessments of the 
Cardiovascular Event Adjudication Committee.
Adverse events with missing intensity will be assumed to be severe. Events with missing 
relationship to study medication per the investigator will be assumed to be related. If no 
information about seriousness is available, the AE will be considered serious.
An infusion-related reaction (as assessed by the investigator) is defined as an AE with a 
preferred term of “Infusion related reaction”. 


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An infection is defined as an AE within the SOC infections and infestations. 
Opportunistic infections are defined by the investigator and non-opportunistic infections are 
all infections not marked as opportunistic by the investigator. 
Hypersensitivity is defined as adverse events with MedDRA preferred term (PT) 
=”Hypersensitivity” and Lower level term (LLT) = “Hypersensitivity reaction”.
Herpes zoster is further classified according to the information given on the Herpes zoster log 
as follows:
Category
Rash
[Y/N]
Episode status of 
HZ Event
[localized/ 
disseminated]
Specify 
Disseminated
[cutaneous/ 
systemic]
Any organ 
involvement
[Y/N]
Cutaneous (localised) herpes zoster
Y
Localized
[no rule]
N
Cutaneous disseminated herpes 
zoster
Y
Disseminated
Cutaneous
[no rule]
Visceral disseminated herpes zoster
[no rule]
Disseminated
Systemic 
[no rule]
Adverse events during treatment will also be presented by time intervals of the first onset of 
the event. For this analysis, repeated events with the same preferred term will not be 
considered (ie, if a subject has more than one event with the same preferred term, only the 
event with the earliest date of onset will be used). For partial or missing dates, the rules as 
described above will be used, i.e. the AE will be considered as an AE during treatment unless 
the available information indicates otherwise and as occurring in the earliest possible time 
interval given the available (start and stop) date information. The following time intervals are 
defined:
!
Day 1 to < Week 12:
AEs with date of onset ≥ date of first administration of investigational product and 
< date of first administration of investigational product plus 84 days
!
Week 12 to < Week 24:
AEs with date of onset ≥ date of first administration of investigational product plus 
84 days and < date of first administration of investigational product plus 168 days
!
Week 24 to < Week 36:
AEs with date of onset ≥ date of first administration of investigational product plus 
168 days and < date of first administration of investigational product plus 252 days
!
Week 36 to < Week 48:
AEs with date of onset ≥ date of first administration of investigational product plus 
252 days and < date of first administration of investigational product plus 336 days


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!
≥ Week 48:
AEs with date of onset ≥ date of first administration of investigational product plus 
336 days
The event rate per 100 subject years is defined as 
Number of subjects with an event / [sum of total exposure time in days/ (365.25*100)].  
The exposure in a time period for each subject will be calculated as end of period – start of 
period + 1 (eg, date of last dose of investigational product + 28 days - day of first dose of 
investigational product + 1 day for summary of AEs during treatment).  If a subject 
discontinued from the study during a period, switched to the LTE study or had the last follow-
up visit earlier than expected, the date of study discontinuation/end of study will be used as 
end of the respective period.
For herpes zoster AESI, an alternative event rate per 100 subject years will be derived as 
Number of subjects with an event / [sum of time at risk in days / (365.25*100)].
The time at risk is defined as time (including start and end date) from start of period (eg, date 
of first administration of investigational product for events during treatment) to the date of 
first event, death, withdrawal of consent, or end of period, whatever comes first. If an AE has 
a (partially) missing onset date, the missing parts will be considered on treatment, unless 
available information indicates otherwise and will be imputed with the earliest possible date 
given the available information before calculating the alternative event rate. This alternative 
event rate may also be calculated for other AESIs if suggested by data. This will be discussed 
during the BDR meeting and the decision will be made before unblinding the data.
The time to first onset of herpes zoster during treatment will be derived as date of first onset 
of herpes zoster – date of first administration of investigational product + 1. AEs with an onset 
date before the date of first administration of investigational product and AEs with an onset 
after 28 days after the date of last administration of investigational product will not be 
considered for the time to first onset of herpes zoster during treatment. If an AE has a 
(partially) missing onset date, the missing parts will be considered on treatment, and the 
missing parts will be imputed with the earliest possible date given the available information 
before calculating time to event. If a subject has no herpes zoster during treatment, the time to 
first onset will be censored at the date of last administration of investigational product + 28 
days.
For the by timepoint analysis of anaphylaxis, hypersensitivity, and infusion related reactions, 
an AE at a visit is defined as an AE with a date of onset ≥day of administration of 
investigational product at the respective visit and ≤ date of administration of investigational 
product at the following visit (or ≤ date of last dose of investigational product + 28 days for 
the last visit with investigational product).


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3.5.1.1
Other significant adverse events
During the evaluation of the AE data, a medically qualified expert will review the list of AEs 
that were not reported as serious AE (SAEs) or AEs leading to discontinuation.
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the AstraZeneca Global Patient Safety Physician, be considered other 
significant AEs and reported as such in the CSR.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
3.5.2
Laboratory variables
The parameters haematology, serum chemistry, urinalysis (outlined in Table 5 in 
Section 5.3.10 of the clinical study protocol) and of fasting lipid profile (high density 
lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides) will be 
explored.
Laboratory data will be reported in SI units. Changes from baseline in haematology, clinical 
chemistry and lipid profile variables will be calculated.
Absolute values will be compared to the reference range as given in 
and 
classified as low (below range), normal (within range or on limits) or high (above range). All 
values (absolute and change) falling outside the reference ranges will be flagged.
Treatment emergent laboratory/vital signs changes (TELVC) will be defined for post-baseline 
values according to the reference ranges given in
 
Urinalysis data will be categorised as negative (0), positive (+), or strongly positive (++, +++, 
or >+++) at each time-point. Treatment-emergent changes will also be assessed. 
Treatment-emergent changes of urinalysis data are defined as 
!
Negative/+ at baseline to ++, +++, ++++ at any post-baseline value OR 
!
Increase of from baseline of at least ++ at any post-baseline value.
For the liver function tests: aspartate transaminase (AST), alanine transaminase (ALT), 
Alkaline phosphatase, gamma glutamyl transferase (GGT) and total bilirubin, the multiple of 
the upper limit of the normal (ULN) range (see 
 will be calculated for each data 
point. Multiple = Value / ULN, ie, if the ALT value was 72 IU/L (ULN = 36) then the 
multiple would be 2. Subjects meeting both of the following biochemical criteria for Hy’s law 
(potential Hy’s Law) at any point during the study (not necessarily at the same time) will be 
flagged:
!
AST ≥3x ULN and/or ALT ≥3x ULN
!
Total bilirubin ≥2xULN


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3.5.3
ECGs
The outcome of the overall evaluation of 12-lead ECG measurements by the central reading 
will be assessed as normal or abnormal. It is the investigator’s judgment whether the 
findings/results on the central ECG laboratory report are clinically relevant or not. The 
combination of both judgments leads to the following categories used for analysis:
!
Normal,
!
Abnormal, not clinically significant
!
Abnormal, clinically significant.
If the overall evaluation by the investigator and the central ECG report don’t match, the 
investigator’s judgement will be used. In case of repeated measurements (triplicates) at a visit, 
the worst category at the respective visit will be used for the analysis.
Changes from baseline of the following variables will be explored:
!
Heart rate (beats per minute)
!
QRS duration (ms)
!
PR interval (ms)
!
RR interval (ms)
!
QT (ms)
!
QTcB (ms)
!
QTcF (ms)
Potentially Clinical Significant post-baseline values or changes from baseline are defined in 
For some parameters, more than one criterion is given. The proportion of 
subjects meeting each criterion will be explored.
In case of repeated measurements (triplicates) at a visit, the mean of all available values at the 
respective visit will be used for the analyses of the continuous ECG variables and the 
determination of Potentially Clinical Significant values.
3.5.4
Modified SELENA Flare Index based flares 
A modification of the classic SELENA Flare Index using the SLEDAI-2K will be used as a 
safety outcome to further characterise flares. The modified SELENA Flare Index-Based Flare 
Assessment Scale has 2 sets of definitions: 
Mild/moderate flare
A mild/moderate flare is defined if at least one of the following criteria are met:
!
Increase from previous visit in SLEDAI-2K of ≥3 points but less than 7 points
!
At least one new or worse manifestation in 
-
Discoid, photosensitive, profundus, cutaneous vasculitis, bullous lupus


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-
Nasopharyngeal ulcers 
-
Pleuritic
-
Pericarditis
-
Arthritis
-
Fever (SLE) 
!
Increase from previous visit in PGA of ≥1 but PGA value of ≤2.5 points
Severe flare
A severe flare is defined if at least one of the following criteria are met:
!
Increase from previous visit in SLEDAI-2K of 7 points or more
!
At least one new or worse manifestation in 
-
Central nervous system SLE
-
Vasculitis, 
-
Nephritis
-
Myositis
-
Haemolytic anaemia
defined as haemoglobin <70 g/L or decrease in haemoglobin >30 g/L with 
positive Coombs AND at least one of the following: decreased haptoglobin, 
increased total bilirubin not due to Gilbert’s disease, increased reticulocyte 
count 
!
Hospitalization due to SLE disease activity
!
Increase from previous visit in PGA to a value >2.5 points
3.5.5
Physical examination
Weight (kg) will be explored using the difference in mean change from baseline longitudinally 
over time.
3.5.6
Vital signs
The following variables will be explored:
!
Pulse (beats per minute)
!
Systolic blood pressure (mmHg)
!
Diastolic blood pressure (mmHg)
!
Respiration rate (breaths per minute)
!
Body temperature (°C)
Changes from baseline will be calculated.


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Where applicable, absolute values will be compared to the reference ranges given in 
 
and classified as low (below range), normal (within range or on limits) or high (above 
range). All values (absolute and change) falling outside the reference ranges will be flagged.
Post-baseline values will be classified as TELVC according to reference ranges given in 
For infusion visits, only measurements before start of investigational product will be 
considered for by visit presentations. In case of multiple measurements before the start of 
investigational product, the first measurement will be used for by visit presentations but all 
measurements will be considered for the TELVC classification.
3.5.7
Cushingoid features
The presence of cushingoid features (moon face, buffalo hump, purple or violaceous striae, 
central obesity, hirsutism, acne, easy bruising, and fragile skin) will be explored by visit.
3.5.8
C-SSRS
The C-SSRS is an assessment tool that evaluates suicidal ideation and behaviour. 
Two different versions of the questionnaire were used:
!
Baseline/Screening version, assessing the last 12 months prior to the assessment
!
Since Last Visit Version, assessing the time since last visit.
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale in an increasing order of severity from 
1 to 10 to facilitate the definitions of the comparative variables.
!
Category 1 – Wish to be Dead
!
Category 2 – Non-specific Active Suicidal Thoughts
!
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act
!
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan
!
Category 5 – Active Suicidal Ideation with Specific Plan and Intent
!
Category 6 – Preparatory Acts or Behaviour
!
Category 7 – Aborted Attempt
!
Category 8 – Interrupted Attempt
!
Category 9 – Actual Attempt (non-fatal)
!
Category 10 – Completed Suicide
The Suicidal Ideation or Behaviour Score will be derived from the C-SSRS categories as the 
maximum suicidal ideation or behaviour category (1-10 on the C-SSRS) present at the 


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assessment. The score will be derived at each assessment for each subject. Non-suicidal 
self-injurious behaviour will be assigned if no ideation or behaviour is present.
Composite variables based on the above re-ordered categories are defined for assessments 
during screening, during treatment, and during follow-up, respectively as follows:
!
Suicidal ideation: A “yes” answer at any time in the respective study period to any 
one of the 5 (re-ordered) suicidal ideation questions (Categories 1-5) on the 
C-SSRS.
!
Suicidal behaviour: A “yes” answer at any time in the respective study period, to 
any one of the 5 (re-ordered) suicidal behaviour questions (Categories 6-10) on the 
C-SSRS.
!
No suicidal ideation or behaviour: No “yes” answer at any time in the respective 
study period to any one of the 10 (re-ordered) suicidal ideation and behaviour 
questions (Categories 1-10) on the C-SSRS.
The total number of attempts, total number of interrupted attempts, and total number of 
aborted attempts will be derived for the different study periods by summing up all respective 
attempts during screening, during treatment and during follow-up, respectively.
For summary of C-SSRS data, the following period definitions will be used:
!
Screening Period: 
Assessments with a date ≥ date of first screening visit (S1) and ≤ date of the first 
dose of investigational product.
!
During treatment Period:
Assessments with a date > date of first dose of investigational product and ≤ date of 
last dose of investigational product + 28 days.
!
Follow-up Period:
Assessments with a date > date of last dose of investigational product + 28 days and 
≤ date of last dose of investigational product + 84 days.
If the wrong questionnaire version (Baseline/Screening rather than Since last visit or vice 
versa) was used for an assessment, the assessment will be assigned to a period based on 
assessment date, regardless of the version that was completed.
3.5.9
Personal Health Questionnaire Depression Scale-8
The PHQ-8 assesses symptoms of depression over the last 2 weeks. The difference between 
anifrolumab and placebo in the mean change from baseline in PHQ-8 total score will be 
assessed by visit up to Week 52. The PHQ-8 total score will be derived as the sum of the 8 
single item scores ranging from 0 (not at all) to 3 (nearly every day).






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4.
ANALYSIS METHODS
4.1
General principles
Due to vendor database limitations in Korea, the site number mapping listed in Table 3 will be 
performed programmatically to link the ePRO vendor data to the correct subjects. 
Table 3
Site ID mapping
Site ID in raw ePRO vendor data
Mapped Site ID for analysis 
4.1.1
Data excluded from analysis
In the rare event that a site needs to be closed during the course of the study for quality 
reasons (eg, suspicion of fraud, non-compliance), all subjects of this site will be excluded 
from all analyses and summaries. In this situation, the SAP will be amended prior to database 
lock and details will be added documenting decisions about site closure and data handling 
(including details of important data to be presented in separate listings).
On 10-Feb-2017, the decision was made to close site 
due to sustained noncompliance 
with protocol procedures and specifications. This included but was not limited to: failure to 
follow protocol stipulated inclusion/exclusion criteria, failure to maintain proper 
documentation in patient source files, and failure to maintain proper principal investigator 
oversight. The Site, FDA, and IRB have been notified of this site’s closure. 
Therefore, the 8 randomised subjects
 
 as well as the 5 screen failures 
 
 at site 
 will not be considered in 
analyses and summaries. Separate listings for exposure, AEs, 
 medical history, 
concomitant medication, and SLEDAI-2K will be provided for the treated subjects.


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4.1.2
Database lock and unblinding
Live unblinded randomisation data will be periodically released to an independent 
 analyst 
and an independent 
analyst from PPD, to allow them to perform 
 analysis. The unblinded randomisation data will only be 
released to specific named personnel for this purpose and will not be made available to any 
staff from AstraZeneca or Sponsor’s delegate.
After completion of LSLV, all data available in the database will undergo a thorough data 
cleaning process.  When all relevant data have been coded, validated, signed, and locked, 
database lock will be declared.
Once database lock is declared, the study will be unblinded. Blinding of subjects and 
investigators will be maintained to the greatest extent possible until LSLV in the LTE study. 
No changes to locked data will be accepted after completion of database lock.
4.1.3
Visit windows
For visit based analyses, the variables will be summarized based on the scheduled days with 
adjusted analysis-defined visit windows. The adjusted analysis-defined windows are 
summarized below:
Table 4
Visit windows
Adjusted Defined Windows Visit
Scheduled Study Day
Maximum Windows
Baseline / Day 1
1 
Study Day ≤1 
Week 4 
29 
2≤ Study Day ≤42 
Week 8 
57 
43≤ Study Day ≤70 
Week 12 
85 
71≤ Study Days ≤98 
Week 16 
113 
99≤ Study Day ≤126 
Week 20 
141 
127≤ Study Day ≤154 
Week 24 
169 
155≤ Study Day ≤182 
Week 28 
197 
183≤ Study Day ≤ 210 
Week 32 
225 
211≤ Study Day ≤238 
Week 36 
253 
239≤ Study Day ≤266 
Week 40 
281 
267≤ Study Day ≤294 
Week 44
309 
295≤ Study Day ≤322 
Week 48 
337 
323≤ Study Day ≤350 
Week 52
365
351≤ Study Day ≤378
Week 56
393 
379≤ Study Day ≤406 
Week 60 
420
407≤ Study Day 


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For assignment of data to time points using the visit windows, study day will be defined as 
(Date of assessment – date of first administration of investigational product) +1. Using this 
definition, the day of first dose of investigational product will be Day 1 and the scheduled visit 
date of Week 4 will be study day 29 (=28+1) for example.
If multiple readings are recorded within a single visit window, the following rules will be 
followed. 
!
If there are two or more observations within the same visit window, then the non-
missing one closest to the scheduled visit will be used in the analysis. 
!
If two observations are equidistant from the scheduled visit, then the non-missing 
observation with the earlier collection date will be used in the analysis. 
!
If two observations are collected on the same day, then the non-missing one with 
the earlier collection time will be included in the analysis. 
If a visit window does not contain any observations, then the data will remain missing. 
For the Baseline / Day 1 visit window, the visit label “Baseline” will be used for all 
measurements before the first administration of IP. If the time of measurement at Study Day 1 
is not available, it is assumed to be prior to first administration of IP. For measurements at 
Study Day 1 with a time of measurement after the start of IP administration, the visit label 
“Day 1” will be used (indicating a post-Baseline measurement).
For overall analyses not based on any particular study visit, data will be listed and/or analysed, 
including any repeat or unscheduled visits, unless otherwise specified.
4.1.4
Presentation of results
All analyses will use SAS® version 9.3 or higher. Summary tables will be presented by
treatment group (anifrolumab 300 mg and placebo). All available data (with the exception as 
described in Section 4.1.1) for each analysis set will be used in the analyses. However, for 
visit based analyses, the variables will be summarized based on the scheduled days with 
adjusted analysis-defined visit windows as given in Section 4.1.3. If not stated otherwise, 
these summaries will be restricted to data up to Week 52. Data (including derived variables) 
will be presented in listings sorted by treatment group and subject number. A separate 
document will be produced containing the template table, listing, and figure shells.
Unless otherwise noted, categorical data will be presented using counts and percentages with 
the denominator for percentages being the number of subjects in the analysis set by treatment 
group. Percentages will be rounded to one decimal place; except 100% which will be 
displayed without any decimal places. Percentages will not be displayed for zero counts.
Unless otherwise noted, continuous variables will be summarized using the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. The 
minimum and maximum values will be displayed to the same level of precision as the raw 


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data, the mean and median to a further decimal place and the SD to two additional decimal 
places. 
95% confidence intervals (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. For the confirmatory treatment 
comparisons, p-values will be presented as described in section 4.1.5 and will be reported to 4 
decimal places. For all other comparisons, no p-values will be presented.
4.1.5
Testing strategy to account for multiplicity considerations
To account for multiplicity to test the primary and five key secondary endpoints, a testing 
strategy will be followed to control the overall type I error rate in the strong sense. The 
primary endpoint, ie, the difference in the proportion of subjects achieving BICLA response at 
Week 52 comparing anifrolumab 300 mg to placebo, will be tested at an alpha level of 0.05. If 
the observed p-value is ≤0.05, a statistically significant difference in BICLA response 
between the treatment groups at Week 52 will be concluded, and the alpha of 0.05 will be 
preserved for testing of the key secondary endpoints. If the observed p-value is >0.05, no 
statistically significant difference between treatment groups will be declared, and no formal 
testing of the key secondary endpoints will be carried out.
If the primary endpoint is statistically significant, then the five key secondary endpoints will 
be tested and the weighted Holm procedure (Zhang, 1997 and Burman, 2009) will be used in 
order to strongly control the family-wise error rate at the 2-sided 5% level. The procedure 
applies alpha recycling according to the weights given in Figure 1. The weights were chosen 
based on a combination of estimated power for the individual key secondary endpoints and 
their relative clinical importance.


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Figure 1
Alpha recycling
In a first step of the weighted Holm procedure, the five key secondary endpoints (BICLA in 
the IFN test-high subgroup, steroid reduction, CLASI, joints, and flare rate) will be tested at 
alpha levels of 0.04, 0.003, 0.003, 0.003, and 0.001, respectively. If 1 or more of the 
hypotheses will be rejected at these levels, the corresponding alpha will be distributed to the 
endpoints not rejected according to the assigned weights. As an example, the null hypothesis 
for BICLA in the IFN test-high sub-group will be rejected with a p-value ≤0.04 and all other 
hypotheses will not be rejected due to p-values >0.003 and 0.001, respectively. The alpha 
level of 0.04 will be distributed to the remaining four key secondary endpoints (steroid 
reduction, CLASI, joints, and flare rate) resulting in new alpha levels of 0.015, 0.015, 0.015, 
and 0.005, respectively. If any of the tests of these four endpoints results in a p-value smaller 
or equal to the corresponding new alpha level, the corresponding alpha level will again be 
distributed across the remaining endpoints.
This corresponds to the following mathematical notation:
We have 5 tests, and each hypothesis has a weight wi for i = 1, …, 5 with sum(wi) = 1
Let pwi = pi/wi. Order the weighted p-values as p(w1) ≤p(w2) ≤ ... ≤ p(w5), being H(wi) the 
hypothesis associated with p-value p(wi) and w(i) the corresponding weights. 
2-sided α=0.05
BICLA at 
Week 52
BICLA
IFN-high
CLASI
Joints
Steroid 
reduction
Flare
rate
0.8
0.06
0.06
0.06
0.02


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The weighted Holm’s method can be described as
1. If p(w1) > α, fail to reject all 5 hypotheses
2. If p(w1) ≤ α, reject H(w1), and move to H(w2)
3. If p(w2) > α/(1-w(1)), fail to reject H(wi) for i ≥2
4. If p(w2) ≤ α/(1-w(1)), reject H(w2), and move to H(w3)
5. Proceed with all remaining hypothesis until the first j such that 
p(wj) > α/[1-sum(w(k))] for k = 1,…, j-1
The adjusted p-values 
corresponding to hypothesis 
will be calculated as 
, where 
. (Wright, 1992) If 
its value will 
be presented as >0.999.
4.1.6
Missing Data
Subjects who discontinue investigational product will be asked to come to each visit for the 
scheduled assessments through Week 52 (Visit 14/EDV). The definition of the primary 
variable includes 2 criteria that correspond to a non-responder imputation for subjects who 
prematurely discontinue from investigational product, or who receive restricted medications 
beyond the protocol-allowed threshold. This is the same for the definitions of key secondary 
binary variables.
Based on the results from the Phase 2 study (CD IA MEDI 546-1013), the majority of missing 
data is expected to be due to permanent discontinuation of IP, which for the binary responder 
endpoints will be imputed as non-responders per the endpoint definitions. It is expected that at 
each visit between 4% and 7% of subjects will have missing data due to a reason other than 
early discontinuation of IP (eg, missing visit [intermediate missing]), based on the results from 
the Phase 2. Given the expected small amount if intermediate missing data, it is expected to 
have a limited impact in the overall conclusions.  
For binary responder efficacy endpoints, any component with missing value will be imputed 
using last observation carried forward (LOCF) if only a single (non-consecutive) visit has 
missing data for that component. In the event of two or more consecutive visits with missing 
data for the same component, LOCF will be used for the first missing value of each sequence, 
after which the data will be imputed as non-responders for the specific responder endpoint. 
The responder endpoint is derived based on the imputed values. If a component (eg, 
SLEDAI-2K) is based on several data points, LOCF will be done for the single data points.
To examine the impact of missing data, including the impact of non-responder imputation due 
to permanent discontinuation of IP, on the primary and key secondary endpoints tipping point 
analyses will be performed. These analyses will vary the assumptions about outcomes among 
the subsets of subjects on the treatment arms who discontinue IP early. For the primary 


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endpoint an extra sensitivity analysis will be performed to examine the impact of intermediate 
missing data.  Tipping point analyses are intended to identify the point at which the results 
would tip from statistically significant to not statistically significant. Thus, the tipping point 
analyses will only be performed for the primary and key secondary endpoints that achieve a 
nominally statistically significant result (ie., nominal p-value<0.05).
For the derivation of the SLEDAI-2K total score, any laboratory items with missing value will 
be imputed using LOCF if only a single (non-consecutive) visit has missing data for that item. 
In the event of two or more consecutive visits with missing data for the same item, LOCF will 
be used for the first missing value of each sequence, after which the data will remain missing. 
Laboratory items of SLEDAI-2K are urinary casts, haematuria, proteinuria, pyuria, low 
complement, increased DNA Binding, thrombocytopenia, and leukopenia.
Unless otherwise defined, scores that are derived from summing up items will be considered 
missing if any of the items are still missing after applying the LOCF rules. 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of <x (ie, below the lower limit of quantification (LLOQ)) or >x (ie, above the upper 
limit of quantification) will be imputed as x in the calculation of summary statistics but 
displayed as <x or >x in the listings.
Anifrolumab serum concentrations reported as below the LLOQ will be imputed with 
LLOQ/2 for analysis. 
 
 


















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4.1.7
Examination of model assumptions
Model assumptions for repeated measures models will be checked with graphical displays 
(plot of residuals versus predicted values, a histogram with normal density overlaid, and a 
quantile-quantile (Q-Q) plot showing the residual quantiles versus quantiles of a normal 
distribution). If the model assumptions are not met, appropriate data transformations or the use 
of non-parametric approaches will be discussed during the BDR meeting. The decision about 
an appropriate approach will be made before unblinding the data.
The assumption of proportionality for Cox proportional hazard models will be assessed by 
producing complementary log-log plots presenting log (-log (estimated survivor function)) 
versus log (time). (In the presence of non-proportionality, the hazard ratio will be interpreted 
as an average hazard ratio over the flare exposure time.) If these raise concerns, a time 
dependent covariate would be fitted to assess the extent to which this represents random 
variation. This will be discussed during the BDR meeting and the decision about an 
appropriate approach will be made before unblinding the data.
4.2
Analysis methods
4.2.1
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 proportion of subjects achieving BICLA response at 
Week 52, as defined in Section 3.1.
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-2004, no worsening in SLEDAI-2K and PGA and ability to 
adhere to the planned course of the treatment. The intercurrent events: discontinuation of IP 
and receipt of restricted medications are unfavourable outcomes. Therefore, subjects treated 
with restricted medications beyond protocol-allowed threshold, and those who discontinued IP 
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 on 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. 


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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 
(Stokes, 2012) stratified by: 
!
SLEDAI-2K score at screening (<10 points versus ≥10 points) 
If different measurements are available for re-screened subjects, the value at re-
screening will be used.
!
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or 
equivalent) 
For the classification, the derived OCS dose rounded to 1 decimal place will be 
used. 
!
Results of a type 1 IFN test (high versus low) 
SLEDAI-2K score at Screening and Week 0 (Day 1) OCS strata will be derived 
programmatically from the data recorded in the database. Type 1 IFN test stratum will be 
taken as recorded at randomisation by the Interactive voice/web response system (IXRS). 
Strata with low counts will be pooled with adjacent strata prior to the analysis. If a sub-
stratum within the IFN-low stratum has less than 20 subjects (in the pooled treatment group), 
then all IFN-low strata will be pooled together. If a sub-stratum within the IFN-high stratum 
has less than 20 subjects (in the pooled treatment group), then within the IFN-high stratum the 
SLEDAI-2K score <10 points sub-strata will be pooled together and the SLEDAI-2K score 
≥10 points sub-strata will be pooled together. If any of these two sub-strata within the IFN-
high stratum still has less than 20 subjects (in the pooled treatment group), then all IFN-high 
sub-strata will be pooled together. If all IFN-low sub-strata are pooled together and all IFN-
high sub-strata are pooled together and any of these strata has less than 20 subjects (in the 
pooled treatment group) then all strata are pooled together.
The analysis can be described as follows:
A.
There are nij subjects in each stratum, where i is the stratum, and j is the treatment 
group. The number of subjects achieving BICLA response is xij. The proportion of 
subjects achieving BICLA response is denoted as pij = xij / nij.. 
B.
For each stratum, the difference in proportion of subjects achieving BICLA response is 
calculated as di = piA – piP, where A and P denote the different treatment groups 
(anifrolumab and placebo, respectively). 
C.
Weights for each stratum, wi, are calculated as niP * niA / (niA + niP). The weighted 
difference is calculated as
D.
The standard error (SE) of the weighted difference under the null hypothesis is given 
by 


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where 
and
E.
For deriving the CI for the weighted difference in proportions, a correction will be 
applied to the variance, providing a CI with more accurate coverage. This will be 
applied to all strata, and is derived as follows.
with
The 95% CI can be generated using the weighted difference ± z0.975 * SE. 
The value of the test statistic is calculated as 
. The p-value from the two-sided test 
of no difference in treatment groups is calculated as 
, where 
Prob() is the distribution function of the standard normal distribution.
F.
The 95% CI for the weighted proportion (
) in a treatment group j can be 
generated using a normal approximation and assuming independence between strata, 
where pij* are used as above.
, 
If the resulting lower or upper limit is <0% or >100%, it will be set to 0% or 100%, 
respectively.
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 estimated response rate (weighted proportion) and the 
corresponding 95% CI within each treatment group will be presented. 
The supportive outcome of time to BICLA response sustained up to Week 52 will be analyzed 
using a Cox proportional hazard models (using a profile likelihood approach with ties=Efron) 
including the covariates of treatment and the stratification factors. The estimated hazard ratios 
and corresponding CIs will be presented for the effect of the treatment group. Furthermore, 
the time to BICLA response sustained up to, and including, Week 52 will be presented as 
Kaplan-Meier plot including the number of subjects at risk at each visit.
Longitudinal presentations of results over time (ie, for each post-baseline visit up to Week 52) 
based on the same analysis, with the corresponding 95% CI, will be created. 


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A bar plot showing the estimated response rates for subjects achieving BICLA response at 
Week 52 by treatment group (including CIs, number of subjects included in the analysis, and 
the p-value for the test of differences) will be provided.
In addition, the individual conditions of BICLA response (reduction of all BILAG-2004 A and 
B, no worsening from baseline in SLEDAI-2K, no worsening in subjects’ lupus disease 
activity, no permanent discontinuation of investigational product, and no use of restricted 
medication) at Week 24 and Week 52 will be summarised with counts and percentages by 
treatment group.
All analyses on the primary variable will be conducted with the full analysis set.
Sensitivity analysis - impact of premature discontinuation of IP
Permanent premature discontinuation of IP is part of the BICLA response definition. In order 
to examine the impact of different discontinuation rates between treatment groups, a tipping 
point analysis will be performed if a statistically significant result is achieved for the primary 
analysis. This analysis will vary the assumptions about outcomes among the subsets of 
subjects on the treatment arms who prematurely discontinue IP and can be described as:
!
The proportions of subjects achieving BICLA response will be analysed using a 
Pearson’s chi-squared test, thus the stratification factors that are used in the main 
analysis (CMH) will be disregarded. Since the strata will be balanced in respect of 
treatment assignment by virtue of the stratified randomisation scheme used, the only 
impact of this simplification should be that the inferences from the unstratified 
analysis will be somewhat conservative.
!
For the primary analysis, subjects who prematurely discontinue IP having not 
received restricted medications prior to discontinuation of IP are by definition 
imputed as non-responders. For this sensitivity analysis, these subjects will be 
altered from non-responder to responder in an iterative manner. 
!
At each step of the analysis one of these subjects switches from not achieving 
BICLA response to achieving BICLA response, and the Pearson’s chi-squared test 
is re-run. The results (statistical significance) are presented in a grid where the x-
axis and the y-axis represent the number of subjects assumed to be achieving 
BICLA response for placebo and anifrolumab 300 mg, respectively. The region 
where the conclusion changes, will be considered as the tipping point.
!
The grid will be divided in 3 regions, limited in the top by the expected number of 
subjects with missing values in the anifrolumab 300 mg arm which would have 
achieved BICLA response if not prematurely discontinuing IP (based on the 
proportion of subjects achieving BICLA response in subjects who completed IP in 
the anifrolumab 300 mg arm): 
o
Likely – Its right limit is the expected number of subjects with missing values 
in the placebo arm which would have achieved BICLA response if not 
prematurely discontinuing IP (based on the proportion of subjects achieving 
BICLA response in subjects who completed IP in the placebo arm);


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o
Uncertain – its right limit is the expected number of subjects with missing 
values in the placebo arm which would have been responders if not prematurely 
discontinuing IP (based on the proportion of subjects achieving BICLA 
response in subjects who completed IP in the anifrolumab 300 mg arm);
o
Unlikely – It is the region to the right of the uncertain region.
Sensitivity analysis – impact of intermediate missing data
To examine the impact of intermediate missing data, the following sensitivity analysis with 
multiple imputations will be performed. Intermediate missing values for SLEDAI-2K, 
BILAG-2004, and PGA (ie, missing for other reason than early discontinuation of IP) will be 
imputed separately for each BICLA component. 
Intermediate missing values of BICLA will be imputed based on the imputed values of the 
BILAG-2004, PGA and SLEDAI-2K components. For each outcome and visit, 100 
imputations will be generated by randomised treatment group. The procedure will be initiated 
with a random seed of 12345. For analysis, each imputed dataset will be analysed separately, 
and the single estimates will be combined using PROC MIANALYZE. Each component will 
be imputed as follows:
!
BILAG-2004 will be imputed as a binary variable reflecting the BICLA criterion, 
ie, “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”. This binary BILAG variable for 
subject i at visit t will be modelled as BILAGi(t)~Binomial(1, πi(t)) where πi(t)= 
θ1BILAGi(t-1)+ θ0(1- BILAGi(t-1)) for t>1 and πi(t)= θ2 for t = 1 (Week 4). Independent 
Beta(1,1) priors will be specified for θ0, θ1 and θ2. 10,000 burn-in iterations will be 
used, followed by 10,000 main iterations. Imputations will then be taken from every 
100th iteration of the main chain (ie, after burn-in). From the resulting dataset, the 
imputations of intermediate missing values only will be extracted (ie, imputations of 
missing values due to early discontinuation of IP will not be considered).
!
SLEDAI-2K total score will be imputed with PROC MI using the MCMC 
IMPUTE=FULL specification, and a VAR statement specifying the variables in 
order of visit. Specify MINIMUM=0 to ensure imputed values are non-negative. 
Specify MAXIMUM=105 to avoid imputation of values above the maximum 
possible score. 10,000 burning iterations to be used, with 100 iterations between 
each imputation. From the resulting dataset, the imputations of intermediate missing 
values only will be extracted (ie, imputations of missing values due to early 
discontinuation of IP will not be considered).
!
PGA will be imputed in the same way as SLEDAI-2K total score , but using 
MAXIMUM=3 (instead of MAXIMUM=105).
Sensitivity analysis – modified BILAG
A sensitivity analysis for BICLA response, as described for the primary endpoint, will be 
repeated using the modified BILAG. The modified BILAG is described in Section 3.3.2.


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Sensitivity analysis – excluding subjects with no baseline BILAG A or B or baseline PGA 
VAS > 2.7
A sensitivity analysis will be performed where subjects with no BILAG A or B at baseline, as 
well as subjects with a baseline PGA VAS score > 2.7 will be excluded from the analysis. 
Sensitivity analysis – removing the criterion of no restricted medications 
A sensitivity analysis for BICLA response, as described for the primary endpoint, will be 
repeated removing the criterion of no restricted medications beyond the protocol-allowed 
threshold. Therefore, this analysis will not count subjects as non-responders if they have used 
restricted medications beyond the protocol-allowed threshold.
4.2.2
Key secondary outcome variables
All analyses of the key secondary outcome variables will be conducted with the full analysis 
set. The intercurrent events of discontinuation of the investigational product and recipient of 
restricted medications are unfavourable outcomes. Therefore, subjects treated with restricted 
medications beyond protocol allowed threshold before the assessment, and those who 
discontinued IP for any reasons, before the assessment, will be non-responders for all key 
secondary endpoints.
4.2.2.1
BICLA at Week 52 in IFN 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 proportion of subjects 
achieving BICLA response at Week 52 in subjects classified as IFN test-high. 
All analyses as described in Section 4.2.1 for the primary endpoint, except select sensitivity 
analyses (multiple imputation, subjects with no BILAG A or B at baseline or with baseline 
PGA > 2.7, and modified BILAG), will be performed for the IFN test-high subgroup. For the 
stratified CMH analyses, the stratification factors will be reduced to SLEDAI-2K score at 
screening (<10 points versus ≥10 points) and Week 0 (Day 1) OCS dose (<10 mg/day versus 
≥10 mg/day prednisone or equivalent).
The tipping point analysis to assess the impact of premature discontinuation of IP as described 
in Section 4.2.1 will also be performed for the IFN test-high subgroup if the nominal 
unadjusted p-value is < 0.05 for the primary IFN test-high analysis.
A supplemental analysis of BICLA in subjects classified as IFN test-low will be conducted. 
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab and placebo. The stratification 
factors will be reduced to SLEDAI-2K score at screening (<10 points versus ≥10 points) and 
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or equivalent).


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4.2.2.2
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 proportion of subjects with maintained OCS reduction. 
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab and placebo in subjects with 
baseline OCS ≥10 mg/day prednisone or equivalent. For the stratified CMH analyses, the 
stratification factors will be reduced to SLEDAI-2K score at screening (<10 points versus 
≥10 points) and results of a type 1 IFN test (high versus low).
A bar plot showing the estimated response rates for subjects with maintained OCS reduction 
by treatment group (including CIs, number of subjects included in the analysis, and the 
p-value for the test of differences) will be provided.
The tipping point analysis to assess the impact of premature discontinuation of IP as described 
in Section 4.2.1 will also be performed for maintained OCS reduction if the nominal 
unadjusted p-value is < 0.05 for the primary OCS reduction analysis.
4.2.2.3
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 proportion of subjects with an at least 50% reduction in CLASI activity score 
at Week 12. 
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab and placebo in subjects with 
baseline CLASI activity score ≥10. Longitudinal presentations of the results over time (ie, for 
each post-baseline visit up to Week 52) based on this analysis will be created. 
A bar plot showing the estimated response rates for subjects with a ≥50% reduction in CLASI 
activity score at Week 12 by treatment group (including CIs, number of subjects included in 
the analysis, and the p-value for the test of differences) will be provided.
The tipping point analysis to assess the impact of premature discontinuation of IP described in 
Section 4.2.1, will also be performed for an at least 50% reduction in CLASI activity score if 
the nominal unadjusted p-value is < 0.05 for the primary CLASI analysis. 
A further sensitivity analysis will be provided if at least 10 subjects in a treatment arm have a 
burst and taper of OCS or IM steroids during the first 12 weeks of treatment. The CMH 
analysis will be repeated for the at least 50% reduction in CLASI activity score (including all 
criteria) at Week 12 excluding subjects administered a burst and taper of OCS or IM steroids 
during the first 12 weeks of treatment. A burst and taper of OCS or IM steroids is defined as 
an OCS increase above the daily dose at Day 1 or any IM steroid dose.


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4.2.2.4
Joints
The key secondary endpoint used to evaluate the effect of anifrolumab versus placebo on 
joints is the difference in proportion of subjects with at least 6 swollen and at least 6 tender 
joints at baseline who achieve an at least 50% reduction in swollen and tender joints, 
respectively, at Week 52 (as defined in Section 3.2.4).
For subjects with at least 6 swollen and at least 6 tender joints at baseline, the same CMH 
approach as described in Section 4.2.1 for the primary endpoint will be used to estimate the 
treatment difference between anifrolumab and placebo in the proportions of subjects achieving 
an at least 50% reduction in swollen and tender joints, respectively. Longitudinal 
presentations of the results over time (ie, for each post-baseline visit up to Week 52) based on 
this analysis will be created. This analysis will be repeated for subjects achieving an at least 
20% reduction in swollen and tender joints.
A bar plot showing the estimated response rates for subjects with a ≥50% reduction in swollen 
and tender joints by treatment group (including CIs, number of subjects included in the 
analysis, and the p-value for the test of differences) will be provided for subjects with at least 
6 swollen and at least 6 tender joints at baseline.
The tipping point analysis to assess the impact of premature discontinuation of IP described in 
Section 4.2.1, will also be performed for an at least 50% reduction in swollen and tender joints 
in subjects with at least 6 swollen and at least 6 tender joints at baseline, if the nominal 
unadjusted p-value is < 0.05 for the primary joints analysis.
4.2.2.5
Flares 
The key secondary endpoint used to evaluate the effect of anifrolumab versus placebo on 
flares is the difference in annualized flare rates through Week 52 (as defined in Section 5). 
The flare rate in the anifrolumab treatment group will be compared to the flare rate in the 
placebo group using a negative binomial regression model. The response variable in the model 
will be the number of flares over the 52-week treatment period (ie, up to Visit 14/EDV). The 
model will include covariates of treatment group, and the stratification factors. The logarithm 
(to base e) of the follow-up time (flare exposure time as defined in Section 5) 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 will 
be presented. 
A summary of the annualized flare rate by descriptive statistics as well as a summary of the 
number and percentage of subjects with no flares, at least one flare, 1 flare, 2 flares, and 3 or 
more flares, respectively, will be presented by treatment group. 
Sensitivity analysis – multiple imputation
To examine the sensitivity of the results of the main analysis to deviations from the underlying 
assumptions, an additional analysis will be performed using the controlled multiple imputation 
method (Keene, 2014).  As with the main analysis, the sensitivity analysis includes all data 


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until subjects complete the study/ withdraw from the study regardless of if they discontinue 
from randomised treatment.  
For this method, the number of flares after withdrawal from study will be imputed conditional 
upon the observed number of flares prior to the withdrawal, a post-withdrawal model 
assumption, the baseline covariates included in the main analysis model and the time the 
subject would have remained in the study if not withdrawn (ie, date of first administration of 
IP + 364 days – date of last available BILAG-2004 assessment). 
The method involves first fitting the main analysis (ie, negative binomial regression model as 
described above) to the observed data. For each imputed dataset, first an independent sample 
is drawn from the approximate posterior distribution of the model parameters. This consists of 
sampling new regression coefficients from a multivariate normal distribution, with mean equal 
to the observed data maximum likelihood estimate, and covariance matrix corresponding to 
the maximum likelihood covariance estimate. A new (log) shape parameter is drawn from a 
normal distribution in the same way, which is exponentiated to give a draw of the shape 
parameter k.
For each generated set of model parameters, the number of flares after withdrawal from study 
are imputed for each subject by drawing randomly from its conditional distribution given the 
subject’s number of flares before withdrawal. For a given subject let 
and 
denote the time 
before and after withdrawal. Let 
and 
denote the observed number of flares before 
withdrawal and unobserved number after withdrawal, respectively, which is to be imputed. 
Let 
and 
denote the assumed rates before and after withdrawal. Let 
and 
. Then, using SAS’s RAND negative binomial parametrisation, the conditional 
distribution of 
given 
is negative binomial with ‘number of successes’ parameter 
and ‘probability of success’ parameter equal to 
.
The imputed number of flares is then combined with the observed flares and data is analysed 
using the main analysis methodology. This analysis is repeated multiple times and the results 
combined using Rubin’s formulae (Fleming, 2011, Ratitch, 2013).
Sensitivity analysis – tipping point analysis
First a MAR analysis will be performed where for each subject the rate after withdrawal λ1 is 
assumed to be the same as their rate before withdrawal λ2, which itself is calculated based on 
their randomised treatment group and baseline covariates.
A tipping point analysis will then be performed if a nominally statistically significant (using 
the unadjusted p-value) result is achieved for the primary analysis, where the rate after 
withdrawal will be modified to δλ2. A series of analyses will be performed with a range of 
increasing deltas for the two arms (δP and δA for placebo and anifrolumab 300 mg groups, 


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respectively) so that one could assess at which point the study conclusions would change from 
favourable to unfavourable; ie, to identify a tipping point.
In this assessment, the placebo group is assumed to improve after withdrawal and the 
anifrolumab group is assumed to worsen after withdrawal. Therefore, log(δP) will be varied 
from -1.5 to 0 in increments of 0.5 and log(δA) will be varied from 0 to 1.5 in increments of 
0.5. This corresponds to deltas between 0.22 and 1 for the placebo group and deltas between 1 
and 4.5 for the anifrolumab 300 mg group. If statistical significance is maintained among the 
matrix of possible δ combinations, the comparison is deemed robust to missing data. For a 
given comparison, if a tipping point is observed with analysis at 0.5 increments, the δ values 
will be further refined down to 0.25 increments for the relevant interval. For example, if a 
tipping point is identified when increasing log(δA) from 1 to 1.5, the matrix will be expanded 
to include also the value log(δA) = 1.25. The values for δ (and the corresponding increments) 
will be checked during the BDRM and adapted as necessary.
Sensitivity analysis – flares while on treatment
The flare rate in the anifrolumab treatment group will be compared to the flare rate in the 
placebo group using a negative binomial regression model. The response variable in the model 
will be the number of flares while on treatment (ie, up to last administration of investigational 
product + 28 days). The model will include covariates of treatment group, and the 
stratification factors. The logarithm (to base e) of the follow-up time (flare exposure time as 
defined in Section 3.2.4) 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 
will be presented.
Sensitivity analysis – flares based on modified BILAG
A sensitivity analysis of annualized flare rate, as described for the key secondary flare 
endpoint, will be repeated using the modified BILAG. The modified BILAG is described in 
Section 3.3.2.
4.2.3
Analysis methods for other secondary efficacy variables
All analyses of other secondary outcome variables will be conducted with the full analysis set.
4.2.3.1
Assessment of disease activity
 
 
 
 


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Supportive outcome variables of the individual components of BICLA 
Change from baseline in SLEDAI-2K and PGA will be analysed using repeated measures 
models with fixed effects for baseline value, treatment group, visit, treatment*visit interaction 
and stratification factors. Covariance parameters will be estimated using restricted Maximum 
Likelihood method and Kenward Rogers denominator degrees of freedom will be used for the 
tests of fixed effects. An unstructured covariance matrix will be used. In case of convergence 
issues, the following alternative structures will be used for fitting (in that order): 
Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, Homogeneous CS. Results 
will be presented for each visit in terms of the adjusted means for each treatment group, 
estimates of treatment differences, and associated 2-sided CIs. 
For each SLEDAI organ system (central nervous system, vascular, musculoskeletal, renal, 
mucocutaneous, cardiovascular system and respiratory, immunology, and haematological and 
fever) the number and percentage of subjects with an improvement at Week 24 and Week 52, 
respectively, will be given for subjects with corresponding organ system involvement at 
baseline. 
For BILAG-2004, the number and percentage of subjects with a score of A, B, and C, D, or E, 
respectively, will be given by visit for the following organ systems:
!
Constitutional
!
Mucocutaneous
!
Neuropsychiatric 
!
Musculoskeletal 
!
Cardiorespiratory 
!
Gastrointestinal 
!
Ophthalmic 
!
Renal 
!
Haematology
For each of the organ systems, a bar plot will be provided showing the distribution of the 
scores at baseline, Week 24, and Week 52 by treatment group. The figures will include the 
percentages and number of subjects.
Observed values and changes from baseline in BILAG-2004 global score will be presented by 
visit with descriptive statistics. Additionally, a shift table presenting BILAG-2004 
improvement over time will be presented according to the categories given in Section 3.3.2.
 
 


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Supportive outcome variables for the assessment of OCS use
Additionally, the daily OCS dose will be displayed graphically by a longitudinal plot 
presenting the means and corresponding SDs by visit. The number of subjects will also be 
included in the graph. Subjects without an OCS dose will be included with a value of 0. The 
graphical display will be repeated for subjects with baseline OCS ≥10 mg/day only.
A shift table will be provided for all subjects showing the daily OCS dose at baseline versus 
the daily OCS dose at Week 52. For this presentation, the daily OCS dose will be categorised 
as 0, >0 to ≤5mg, >5 to ≤7.5mg, >7.5 to ≤10mg, >10 to ≤15mg, >15 to ≤20mg, >20 to ≤30mg, 
>30 to ≤40mg, >40 mg, and missing.
Furthermore, the standardised AUC up to Week 52 will be summarized by treatment group for 
all subjects as well as for subjects with baseline OCS ≥10 mg/day.
For subjects with baseline OCS ≥10 mg/day prednisone or equivalent, a shift table of reaching 
a maintained OCS reduction at Week 52 (as defined in Section 3.2.2) versus achieving BICLA 
response at Week 52 (as defined in Section 3.1) will be provided.
Supportive outcome variables for the assessment of skin lesions
For subjects with baseline CLASI activity score ≥10, a shift table for an at least 50% reduction 
in CLASI activity score at Week 12 versus an at least 50% reduction at Week 52 will be 
presented to investigate the maintenance of effect in CLASI activity score.
Change from baseline in CLASI activity score and CLASI damage score, respectively, will be 
analysed using the same repeated measures models as described for the analysis of SLEDAI-
2K and PGA in section 4.2.3.1. Thereby, an unstructured covariance matrix will be used. In 
case of convergence issues, the following alternative structures will be used for fitting (in that 
order): Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, Homogeneous CS. 
Supportive outcome variables for the assessment of joints
For subjects with at least 8 swollen and at least 8 tender joints at baseline, the same CMH 
approach as described in Section 4.2.1 for the primary endpoint will be used to estimate the 
treatment difference between anifrolumab and placebo in the proportions of subjects achieving 
an at least 20% reduction and at least 50% reduction in both swollen and tender joints, 
respectively. 


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The change from baseline in the number of active, swollen and tender joints, respectively, will 
be analysed using the same repeated measures models as described for the analysis of 
SLEDAI-2K and PGA above. Thereby, an unstructured covariance matrix will be used. In 
case of convergence issues, the following alternative structures will be used for fitting (in that 
order): Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, Homogeneous CS.
Supportive outcome variables for the assessment of flares
The analysis of flares using a negative binomial regression model as described in 
Section 4.2.2.4 will be repeated for flares versus baseline. 
A summary of the annualized flare rate by descriptive statistics for flares versus baseline as 
well as a summary of the number and percentage of subjects with no flares, at least one flare, 
1 flare, 2 flares, and 3 or more flares, respectively, will be presented by treatment group. 
The time to first flare will be analysed as a supportive analysis to the assessment of reduction 
of flares to explore the extent to which treatment with anifrolumab delays the time to first 
flare compared to placebo. The analyses of time to first flare will be provided for the key 
secondary outcome variable and flares versus baseline.
Cox proportional hazard models (using a profile likelihood approach with ties=Efron) 
including the covariates of treatment and the stratification factors will be used to estimate the 
treatment effect. The estimated hazard ratios and corresponding CIs will be presented for the 
effect of the treatment group. 
Furthermore, the time to first flare (key secondary outcome variable only) will be presented as 
Kaplan-Meier plot including the number of subjects at risk at each visit.
 
 
 
 
 
 
 
 
 
 




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4.2.4
Presentation of study population
4.2.4.1
Subject disposition
The number and percentage of subjects completing the study and completing the study up to 
and including Week 52 (Visit 14/EDV) and the number and percentage of subjects 
withdrawing from the study including reason for withdrawal, will be summarized by treatment 
group for the full analysis set. Additionally, the number and percentage of subjects enrolled to 
the LTE study will be presented.
The number of subjects completing treatment with investigational product up to and including 
Week 48 (ie, with last administration of investigational product at Visit 13) and the number of 
subjects permanently discontinuing the treatment with investigational product including 
reason for withdrawal, will be summarized by treatment group for the full analysis set.
Furthermore, the number and percentage of subjects remaining on investigational product, 
discontinued investigational product but remain on study and withdrawn from study will be 
summarized by visit up to Week 48 for the full analysis set. The number and percentage of 
subjects withdrawn from study at Week 52 and the number of subjects still in study at 
weeks 56 and 60 will also be presented.
A summary of number and percentage of subjects in each region, each country and each site 
by treatment group and overall will be provided for the full analysis set.
A summary of number of subjects in each population will be provided for each analysis set. 
Important protocol deviations will be summarised for the full analysis set.


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4.2.4.2
Demographic and baseline characteristic
Demography and baseline characteristics will be presented by descriptive statistics by 
treatment group as well as overall for the full analysis set. Additionally, the stratification 
factors (as calculated from the data for SLEDAI-2K score at screening and Week 0 [Day 1] 
OCS dose and as recorded at randomisation by IXRS for the type 1 IFN test) and the 
cardiovascular risk will be presented by descriptive statistics for the full analysis set.
An additional table will be prepared summarising miss-stratifications as per the IXRS at 
randomisation for the SLEDAI-2K score at screening and Week 0 (Day 1) OCS dose.
Past and current medical history will be summarized separately by MedDRA primary system 
organ class and preferred term. Furthermore, the number and percentage of subjects with the 
cardiovascular risk factors will be presented by risk factor.
Prior and concomitant medications will be summarized separately by WHO-DD Anatomical 
Main Group (ATC level 1), and preferred term. Disease related treatments at baseline will be 
summarized by the categories given in Section 3.4.3. 
4.2.4.3
Restricted medications
Concomitant medications beyond the protocol allowed threshold (restricted medications) that 
are considered in the evaluation of the efficacy endpoints will be summarized by preferred 
term and on-IP/off-IP and listed. On-IP/off-IP will be determined based on the medication 
start date. Subjects treated with restricted medications before the assessment of interest will be 
treated as non-responders for the primary and secondary efficacy endpoints; including 
BICLA, OCS reduction, CLASI, joints 
 in accordance with the rules defined in 
Section 1.2.1 and 
 
4.2.4.4
Exposure
Exposure will be summarized by treatment group for the full analysis set. 
Summary statistics will be provided for the duration of exposure. The number and percentage 
of subjects treated ≥4 weeks, ≥8 weeks, and up to ≥52 weeks in 4-weekly intervals will be 
provided. Furthermore, the total subject years of exposure will be presented.
The number and percentage of subjects with infusions will be presented by total number of 
infusion (ie, 1, 2, …, 13) and by visit (ie, Day 1, Week 4, Week 8, Week 12, …, Week 48). 
Furthermore, the time to discontinuation of investigational product will be presented as 
Kaplan-Meier plot including the number of subjects at risk (ie, still on investigational 
product).
4.2.5
Analysis methods for safety variables
Safety variables will be summarised by treatment group for the full analysis set.


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4.2.5.1
Adverse events
If not stated otherwise, all summaries described below will be presented separately for 
!
AEs during treatment
!
AEs during follow-up
!
AEs during treatment and follow-up. 
For summaries during follow-up, only subjects with any study documentation after the date of 
last dose of investigational product + 28 days will be considered.
An overall summary of subjects with at least one AE in the following categories will be 
presented:
!
Any AE
!
Any AE with outcome = death
!
Any SAE (including events with outcome = death)
!
Any AE leading to discontinuation of investigational product
!
Any AE related to investigational product
!
Any AE of severe intensity
!
Any AESI 
-
Any AESI of non-opportunistic serious infections
-
Any AESI of opportunistic infections
-
Any AESI of anaphylaxis
-
Any AESI of malignancy
-
Any AESI of herpes zoster
-
Any AESI of tuberculosis
-
Any AESI of influenza
-
Any AESI of vasculitis
-
Any AESI of major adverse cardiovascular events 
!
Any other significant AE
The number and percentage of subjects with at least one AE (ie, multiple occurrences of an 
AE in 1 subject will only be counted once) will be summarised by MedDRA primary system 
organ class and preferred term for the following AE categories. These summaries will also 
include the event rate per 100 subject years, unless otherwise specified. Event rates will 
generally not be included in summaries presented for AEs during treatment and follow-up.
!
Any AE
!
Any AE above reporting threshold of 2%
This summary will be presented by preferred term only for AEs during treatment 
only.


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!
Any AE with outcome = death 
This summary will be presented for AEs during treatment and follow-up only.
!
Any SAE (including events with outcome = death) 
This summary will not be presented for AEs during follow-up. This summary will 
also be presented by preferred term for SAEs during treatment only.
!
Any AE leading to discontinuation of investigational product
This summary will be presented for all AEs irrespective of the study period. The 
end of exposure for the calculation of event rates is defined as the maximum of date 
of last dose of investigational product + 28 days and the date of the AE leading to 
discontinuation. AEs with (partially) missing start date information will be 
considered on-treatment unless the available information indicates otherwise and 
will be imputed with the earliest on-treatment date possible given the available start 
and stop date information for this analysis. This summary will also be presented by 
preferred term.
!
Any AE by relationship to investigational product (yes, no)
(multiple occurrences of an AE in 1 subject will only be counted once as related if 
at least one AE is related and as not related if all occurrences are not related)
This summary will not be presented for AEs during treatment and follow-up.
This summary will not include the event rate per 100 subject years.
!
Any AE by maximum intensity (mild, moderate, severe)
(multiple occurrences of an AE in 1 subject will only be counted once with the 
maximum intensity in this AE)
This summary will not be presented for AEs during treatment and follow-up.
This summary will not include the event rate per 100 subject years.
!
Any AESI
This summary will not be presented by system organ class but by AESI category 
(non-opportunistic serious infections, opportunistic infections, anaphylaxis, 
malignancy, herpes zoster, tuberculosis, influenza, vasculitis, and MACEs). 
This summary will not be presented for AEs during follow-up.
!
Any other significant AE
This summary will be presented for AEs during treatment and follow-up only.
!
Any AE by time interval for the first onset of event
This summary will be presented for AEs during treatment only.
Cardiovascular outcome events (during treatment and during treatment and follow-up) as 
determined by the Cardiovascular Event Adjudication Committee will be presented separately, 
summarising the number of AEs submitted for adjudication and the outcomes of the 
adjudication including MACE classification. Site reported cardiovascular AEs, cardiovascular 
SAEs and their corresponding adjudicated outcomes will be listed.
The time to first onset of a non-opportunistic serious infection during treatment and time to 
first onset of herpes zoster during treatment will be presented as Kaplan-Meier plots including 
the number of subjects at risk at each visit. 


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Furthermore, the alternative event rates per 100 subject years for herpes zoster (and possible 
other AESIs) will be summarized for events during treatment and follow-up, during treatment 
(overall and by time intervals), and during follow-up. The following subcategories will also be 
considered in this summary: SAE (including events with outcome of death), AE leading to 
discontinuation of investigational product, and AE by maximum intensity (mild, moderate, 
and severe).
The number and percentage of subjects with at least one anaphylaxis, hypersensitivity, and 
infusion-related reaction (as reported by the investigator), respectively, will be summarised 
overall as well as for the following respective subcategories: SAE (including events with 
outcome of death), AE leading to discontinuation of investigational product, and AE by 
maximum intensity (mild, moderate, and severe). Furthermore, these AE categories will be 
presented graphically over time as percentage of subjects with a respective AE at a respective 
visit according to the definition as given in Section 3.5.1. 
Infections, opportunistic infections and non-opportunistic infections, will be summarised with 
the same subcategories as given above.
Key subject information for subjects with an AE with outcome of death, subjects with serious 
AEs, subjects with an AE leading to discontinuation of investigational product, subjects with 
AESIs, and subjects with a cardiovascular event, respectively, will be provided (all for AEs 
occurring during treatment and follow-up only).
4.2.5.2
Laboratory variables
Observed values and changes from baseline of laboratory data for haematology, clinical 
chemistry, continuous urinalysis, and fasting lipid profile will be summarised by visit. The 
summary statistics presented will be minimum, 1st quartile, median, 3rd quartile, maximum, 
mean, and SD.
Shift plots (scatter plots) presenting baseline values versus minimum post-baseline values 
(neutrophils, lymphocytes, monocytes and haemoglobin only) and maximum post-baseline 
values (creatinine, creatinine kinase, blood urea nitrogen, alanine aminotransferase, aspartate 
aminotransferase, bilirubin), respectively, will be provided. A diagonal line indicating no 
change and horizontal and vertical reference lines indicating the limits of the reference ranges 
will also be displayed on the shift plots.
If any laboratory variables show any unusual features (high or low values or a general shift in 
the data points) at specific visits then shift plots of these data may also be produced. This will 
be discussed and agreed upon during the BDR meeting.
For each laboratory parameter with available criteria, the number and percentage of subjects 
with TELVC values will be summarized by visit. Additionally the number and percentage of 
subjects with at least one TELVC value will be presented. Percentages will be based on 
subjects with a measurement at baseline and at least 1 subsequent measurement of the variable 
(at the respective visit).


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The number and percentage of subjects with laboratory values below, within or above the 
corresponding reference ranges (see 
will be presented as shift tables from 
baseline to maximum and minimum on-treatment value, respectively. 
Urinalysis will be summarized as shift tables from baseline to the last post-baseline value for 
each parameter. Furthermore, the number and percentage of subjects with treatment-emergent 
changes will be summarized by parameter. Percentages for the summary of treatment-
emergent changes will be based on subjects with a measurement at baseline and at least 1 
subsequent measurement of the variable (at the respective visit).
In order to identify potential Hy’s Law cases, maximum post baseline total bilirubin will be 
plotted against maximum post baseline ALT, expressed as multiples of ULN. This plot will be 
repeated to show maximum post baseline total bilirubin against maximum post baseline AST, 
expressed as multiples of ULN. These plots will be produced on a log scale and reference 
lines will be included at 2xULN for total bilirubin and at 3xULN for ALT/AST.
4.2.5.3
ECGs
The number and percentage of subjects with normal, abnormal, not clinically significant, and 
abnormal, clinically significant ECG results will be presented as a shift table from baseline to 
Week 52.
Observed values and changes from baseline of ECG values will be summarised by parameter 
and visit using descriptive statistics. The summary statistics presented will be minimum, 1st 
quartile, median, 3rd quartile, maximum, mean, and SD.
For each ECG parameter with available criteria, the number and percentage of subjects with 
Potentially Clinical Significant post-baseline values and Potentially Clinical Significant
changes from baseline, respectively, will be presented by parameter and criterion.
4.2.5.4
Modified SELENA Flare Index based flares
The number and percentage of subjects with at least one flare after Day 1 will be presented for 
mild/moderate flares, severe flares, and any flares.
4.2.5.5
Physical examination
Observed values and changes from baseline of body weight will be summarized. The 
summary statistics presented will be minimum, 1st quartile, median, 3rd quartile, maximum, 
mean, and SD.
4.2.5.6
Vital signs
Observed values and changes from baseline of pulse, systolic blood pressure, diastolic blood 
pressure, respiration rate, and body temperature, respectively, will be summarised by visit. 
The summary statistics presented will be minimum, 1st quartile, median, 3rd quartile, 
maximum, mean, and SD. 


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For each parameter with available criteria, the number and percentage of subjects with 
TELVC values will be summarized by visit. Additionally, the number and percentage of 
subjects with at least one TELVC value will be presented. Percentages will be based on 
subjects with a measurement at baseline and at least 1 subsequent measurement of the variable 
(at the respective visit).
For each parameter, the number and percentage of subjects with values below, within or above 
the corresponding normal range will be presented as shift tables from baseline to each post-
baseline visit. 
4.2.5.7
Cushingoid features
The number and percentage of subjects will be explored for each feature by visit. For subjects 
with baseline OCS ≥10 mg/day prednisone or equivalent, the summary will be repeated by 
maintained OCS reduction at Week 52 (yes versus no) as defined in Section 3.2.2).
4.2.5.8
C-SSRS
The number and percentage of subjects with suicidal ideation (overall and by maximum 
category), suicidal behaviour (overall and by maximum category), and no suicidal ideation or 
behaviour will be given for assessments during screening, during treatment, and during 
follow-up, respectively.
Furthermore, descriptive statistics on the total number of attempts, total number of interrupted 
attempts, and total number of aborted attempts will be summarized for attempts during 
screening, during treatment and during follow-up, respectively.
Subjects with a suicidal ideation or behaviour at any time will be presented in a listing.
4.2.5.9
Personal Health Questionnaire Depression Scale-8
Observed values and changes from baseline in PHQ-8 total score will be presented 
longitudinally with descriptive statistics.
 
 
 
 
 
 




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4.3
Subgroup analysis 
To explore the uniformity of the detected overall treatment effect, subgroup analyses on the 
primary, key secondary endpoints, 
will 
be performed for the following factors: 
!
SLEDAI-2K score at screening (<10 points versus ≥10 points) 
!
OCS dose at baseline (<10 mg/day versus ≥10 mg/day prednisone or equivalent) 
!
IFN test (IFN test [high versus low]) 
!
Sex (male versus female)
!
Age (≥18 to 65 versus ≥65 years) 
!
Onset of disease (adult versus paediatric onset) 
!
BMI (≤30 versus >30 kg/m2) 
!
Race (white; black or African American; Asian, native Hawaiian or other Pacific 
Islander; American Indian or Alaska native; other)
!
Ethnicity (Hispanic/Latino versus no Hispanic/Latino)
!
 
!
 
Table 5 gives an overview of subgroup analyses to be performed. Where necessary (eg, for 
subgroup analysis based on stratification factors), the model factors will be reduced. If not 
stated otherwise, the subgroup analysis will be supressed if any of the sub-populations in any 
treatment group will consist of less than 25 subjects.


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For the primary endpoint BICLA at Week 52, a forest plot will be used to summarise the 
estimates of the treatment effect for the applicable subgroups. 
A listing of adverse events in
 (at any time) subjects will also be presented.
Table 5
Overview of subgroup analyses
Analysis
SLEDAI-2K
OCS at baseline
IFN test
Sex
Age
Disease Onset
BMI
Race
Ethnicity
BICLA – CMH a
X
X
X
X
X
X
X
X
X
BICLA in IFN test-high – CMH
X
X
Maintained OCS reduction – CMH
X
X
CLASI activity reduction – CMH 
X
X
X
Flare rate – binominal regression
X
X
X
Joints reduction - CMH
X
X
X
AE overview
SAE summary by SOC and PT
a
Subgroup analysis will also be conducted if resulting in a sub-population of <25 subjects.
5.
INTERIM ANALYSES
No interim analysis is planned for this study. 
6.
CHANGES OF ANALYSIS FROM PROTOCOL 
No changes of analysis from the protocol are planned for this study.


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7.
REFERENCES
Burman, 2009
Burman CF, Sonesson C, Guilbaud O, 2009. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stats in Med. 2009;28:739–761.
Fleming, 2011
Fleming TR. Adressing Missing Data in Clinical Trials. Ann. Intern. Med. 2011. 154:113-117.
Keene, 2014
Keene ON, Roger JH, Hartley BF, Kenward MG, 2009. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutical Statistics. Published online 
16 June 2014 in Wiley Online Library.
 
Ratitch, 2013
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical Statistics 2013; 12: 337-347
Stokes, 2012
Stokes M.E., Davis C.S., Koch G.G., 2012. Categorical Data Analysis Using SAS®, Third 
Edition. SAS Institute, 2012.
 
 
 
 
Wright, 1992
Wright, S. P. (1992). Adjusted P-values for simultaneous inference. Biometrics, 48, 1005–
1013.
Zhang, 1997
Zhang J, et. al. 1997. Some Statistical Methods for Multiple Endpoints in Clinical Trials. 
Controlled Clinical Trials 18:204-221


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8.
APPENDIX
Appendix A: Supplemental Process Description: Restricted medications
Appendix B: Supplemental Process Description: Oral Corticosteroids 
Appendix C: Derivation rules for imputation of partial or missing dates
Appendix D: Reference ranges and TELVC for laboratory values
Appendix E: ECG: Potentially Clinically Significant post baseline values
Appendix F: Reference ranges and TELVC for vital signs
Appendix G Derivation of IFN21 Parameters


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Appendix A
APPENDIX A - SUPPLEMENTAL PROCESS DESCRIPTION: 
RESTRICTED MEDICATIONS


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Appendix B
APPENDIX B - SUPPLEMENTAL PROCESS DESCRIPTION: ORAL 
CORTICOSTEROIDS 


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Appendix C
APPENDIX C - DERIVATION RULES FOR IMPUTATION OF 
PARTIAL OR MISSING DATES
If any medications reported are not able to be determined as prior or concomitant due to 
missing or partial start dates and/or stop dates, the following imputation rules will be 
implemented:
!
If the year is present but the month and day are missing, then 01JAN will be 
imputed for the start date and 31DEC for the stop date.
!
If the year and month are present but the day is missing, then 01 will be imputed for 
the start date and the last day of the month for the stop date.
!
If the start date is completely missing and the end date is prior to the first dose date 
of investigational product the medication will be considered prior. 
!
If the start date is completely missing and the end date is missing or on or after the 
first dose of investigational product the medication will be considered prior and 
concomitant.
!
If the end date is completely missing and the start date is on or after the first dose of 
investigational product the medication will be treated as concomitant. 
!
If the end date is completely missing and the start date is prior to the first dose date 
of investigational product the medication will be considered prior and concomitant.


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Appendix D
APPENDIX D - REFERENCE RANGES AND TELVC FOR 
LABORATORY VALUES 
Parameter
Unit
Low value
Low decrease
High value
High increase
Haematology
Haemoglobin
g/L
≤60
NA
≥200
NA
≤70 and decrease from BL ≥15
Haematocrit
V/V
≤0.18
NA
≥0.64
NA
≤0.21 and decrease from BL 
≥15%
WBC
10E9/L
≤2, <1 
NA
≥20
NA
Neutrophils
10E9/L
<0.5
NA
≥20
NA
<1.0 and decrease from BL ≥0.5
Lymphocyte
10E9/L
≤0.5, ≤0.25
NA
≥10.0
NA
Monocytes
10E9/L
NA
NA
≥1.4, ≥5.0
NA
Eosinophils
10E9/L
NA
NA
≥1.5, ≥5.0
NA
Basophils
10E9/L
NA
NA
≥1.0, ≥2.0
NA
Platelet Count
10E9/L
≤20
≥600
NA
≤50 and decrease from BL ≥25
INR
NA
NA
≥4.5
NA
Biochemistry
ALT
IU/L
NA
NA
≥3 x ULN, 
≥5 x ULN
NA
AST
IU/L
NA
NA
≥3 x ULN, 
≥5 x ULN
NA
ALP
IU/L
NA
NA
≥3 x ULN
NA
CK
IU/L
NA
NA
≥500, ≥2000
NA
GGT
IU/L
NA
NA
≥5 x ULN
NA
Total Bilirubin
μmol/L
NA
NA
≥2 x ULN
NA


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Parameter
Unit
Low value
Low decrease
High value
High increase
Albumin
g/L
≤20
NA
≥100
NA
≤25 and decrease from BL ≥10
≥70 and increase from BL ≥10
BUN
mmol/L
NA
NA
≥18
NA
Creatinine
umol/L
NA
NA
≥140, ≥190
NA
Sodium
mmol/L
≤132
NA
≥152
NA
Potassium
mmol/L
≤3
NA
≥5.5
NA
Chloride
mmol/L
≤90
NA
≥120
NA
Fasting Glucose
mmol/L
≤2.5
NA
≥7.0, ≥11.1
NA
Total Cholesterol
mmol/L
NA
NA
≥7.25
NA
Urinalysis
Urine protein/ 
creatinine ratio
g/mmol
NA
NA
≥0.395
NA
Fasting lipid profile
HDL
mmol/L
≤0.8
NA
NA
NA
LDL
mmol/L
NA
NA
≥5.2
NA
Triglycerides
mmol/L
NA
NA
≥3.6, ≥5.4
NA


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Appendix E
APPENDIX E - ECG: POTENTIALLY CLINICALLY SIGNIFICANT 
POST BASELINE VALUES
ECG 
parameter
Unit
Low value
Low 
decrease
High value
High increase
RR interval
ms
<500
NA
>1500
NA
PR interval 
ms
NA
NA
≥240
NA
QRS duration
ms
≤60 
NA
≥140
NA
QT
ms
≤300
NA
≥500
≥60
QTcF 
ms
≤300
NA
≥500
≥30, ≥60
≥500 and increase from baseline  ≥30,
≥500 and increase from baseline  ≥60
QTcB 
ms
≤300
NA
≥500
≥30, ≥60
≥500 and increase from baseline  ≥30,
≥500 and increase from baseline  ≥60


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Appendix F
APPENDIX F - REFERENCE RANGES AND TELVC FOR VITAL 
SIGNS
Parameter
Unit
Low value
Low decrease
High value
High increase
Pulse
Beats 
per 
minute
≤50
NA
≥120
NA
≤50 and decrease from BL ≥20
≥120 and increase from BL  ≥20
Systolic blood 
pressure
mmHg
≤90
NA
≥160
NA
≤90 and decrease from BL ≥20
≥160 and increase from BL  ≥20
Diastolic blood 
pressure
mmHg
≤50
NA
≥100
NA
≤50 and decrease from BL ≥10
≥100 and increase from BL  ≥10


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Appendix G
APPENDIX G - DERIVATION OF IFN21 PARAMETERS
There are two IFN parameters to be calculated during the study; percent neutralization and the 
gene signature fold change. 
The following steps should be implemented in the derivation of these parameters.
1. Calculate the mean Ct values for each gene and the three housekeeper genes (18S, 
ATCB and GAPDH) on the ThermoFisher TLDA platform (test and normal control 
samples) within a particular subject.
2. Calculate the mean Ct value of the three housekeeper genes;
3. Calculate ∆Ct values by subtracting the mean Ct value of the three housekeeper genes 
from each test gene:
4.
Calculate the ∆Ct values for the normal control genes, as in Step 3.
5. Calculate -∆∆Ct values as:
6. Linearize the -∆∆Ct values for each gene as follows:
7. Calculate the percent neutralization values for each gene for each post-Visit 1 visit 
(Visit X) as:
The final percent neutralization score for each timepoint, for each subject, is the median of the 
individual gene % neutralization values calculated in Step 7. There will be one value per 
subject per post-Visit 1 visit:
The fold change for each timepoint and each subject is the median of the linearized values for 
each gene, calculated in Step 6:


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