A Multicentre, Randomised, Double-blind, Placebo-Controlled Phase 3 Extension Study to Characterise the Long-term Safety and Tolerability of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus.
Phase: PHASE3
Conditions: Active Systemic Lupus Erythematosus
Sponsor: AstraZeneca

Protocol Number: D3461C00009 
 
Official Title: A Multicentre, Randomised, Double-blind, Placebo-Controlled Phase 3 Extension 
Study to Characterise the Long-term Safety and Tolerability of Anifrolumab in Adult Subjects with 
Active Systemic Lupus Erythematosus 
 
NCT Number: NCT02794285 
 
Document Date: 10 August 2017 

Clinical Study Protocol 
Drug Substance
Anifrolumab (MEDI 546)
Study Code
D3461C00009
Version
3.0
Date
10 August 2017
A Multicentre, Randomised, Double-blind, Placebo-Controlled Phase 3 
Extension Study to Characterise the Long-term Safety and Tolerability of 
Anifrolumab in Adult Subjects with Active Systemic Lupus Erythematosus
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden
EudraCT number: 2016-000625-39

Clinical Study Protocol
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
Date 10 August 2017
3
order to correspond with the study schedule assessments.  (Sections affected: 
Section 3.1 Inclusion criteria – 8(d); Section 4.2.1 Premature discontinuation of the 
investigational product; Section 5.2.7.1 Tuberculosis results at time of 
randomisation/Week 52 of the Phase 3 Study D3461C00004 or D3461C00005; 
Section 5.2.7.3 Tuberculosis monitoring at Week 156).

Clarifications were made to the permitted doses of azathioprine, mycophenolate 
mofetil, mycophenolic acid, methotrexate, and mizoribine during the study.  
(Sections affected: Section 3.2.2 Exclusion criteria related to concomitant 
medications; Section 3.3.1.2 Restricted medications; Background Systemic Lupus 
Erythematosus standard of care medications (oral corticosteroids, antimalarials, and 
immunosuppressants)).

The wording of the instructions for tacrolimus monitoring during the study was 
revised to remove references to serum levels as the central laboratory requires 
plasma for tacrolimus testing.  In addition, references to absolute tacrolimus levels 
were deleted.  (Sections affected: 3.3.2.1 Background Systemic Lupus 
Erythematosus standard of care medications (oral corticosteroids, antimalarials, and 
immunosuppressants); Section 4 Study plan and timing of procedures – Table 2 
footnote o, Table 3 footnote m; Section 5.2.9 Clinical laboratory tests – Table 5).

Mizoribine was added to the list of permitted immunosuppressants.  (Section 
affected: 3.3.2.1 Background Systemic Lupus Erythematosus standard of care 
medications (oral corticosteroids, antimalarials, and immunosuppressants).

Mycophenolic acid was added to the list of permitted immunosuppressants in the 
Protocol synopsis and the dose of mycophenolic acid not to be exceeded was 
updated to >1.44 g/day.  (Sections affected: Protocol synopsis – Target subject 
population; Section 3.2.2 Exclusion criteria related to concomitant medications; 
Section 3.3.1.2 Restricted medications; Section 3.3.2.1 Background Systemic Lupus 
Erythematosus Standard of Care medications (oral corticosteroids, antimalarials, 
and immunosuppressants)).

The description of the sample size estimate was amended to ensure consistency with 
the Statistical Analysis Plan (SAP).  (Sections affected: Protocol synopsis –
Statistical methods; Section 8.2 Sample size estimate).

The range for postmenopausal follicle-stimulating hormone (FSH) levels was 
amended.  (Section affected: Section 3.1 Inclusion criteria).

The wording of the text and table describing acceptable contraception for female 
and male subjects during the study was updated.  (Section affected: Section 3.1 
Inclusion criteria – Table 1).

Instructions were added regarding safety testing requirements if the standard of care 
(SOC) is changed during the study.  (Sections affected: Section 3.3.2.1 Background 

8
PROTOCOL SYNOPSIS
A Multicentre, Randomised, Double-blind, Placebo-Controlled Phase 3 
Extension Study to Characterise the Long-term Safety and Tolerability of 
Anifrolumab in Adult Subjects with Active Systemic Lupus Erythematosus
International Coordinating Investigator
Kenneth Kalunian, MD
University of California, San Diego
9444 Medical Center Drive, Room 2-078
La Jolla, CA 92093-0943
USA
Study site(s) and number of subjects planned
Approximately 575 subjects are planned at approximately 300 sites.
Study period
Phase of development
Estimated date of first subject randomised
Q3 2016
3
Estimated date of last subject completed
Q3 2021
Study design
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled, 
extension study characterising the long-term safety and tolerability of an intravenous 
treatment regimen of anifrolumab (300 mg) versus placebo in subjects with moderately to 
severely active systemic lupus erythematosus who completed a Phase 3 study (D3461C00004 
or D3461C00005) through the 52-week double-blind treatment period.  
Approximately 575 subjects from Studies D3461C00004 or D3461C00005 who were 
previously treated with anifrolumab (150 or 300 mg) or placebo for 52 weeks while receiving 
standard of care treatment and who are willing to continue treatment may participate in the 
long-term extension study if all eligibility criteria are met.  Subjects will receive either a fixed 
intravenous dose of 300 mg anifrolumab every 4 weeks for up to 39 doses (Week 0 to 
Week 152) or placebo.  Investigational product will be administered as an intravenous 
infusion via an infusion pump over a minimum of 30 minutes, every 4 weeks.  In order to 
ensure that subjects with active systemic lupus erythematosus who enter the long-term 
extension study will have adequate treatment of their disease in this 3-year blinded, 

Clinical Study Protocol Synopsis
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
Date 10 August 2017
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placebo-controlled extension study, Investigators will be allowed to change the background 
standard of care treatment for systemic lupus erythematosus during the course of the study.
In the long-term extension study, treatment assignment will follow an Interactive Voice/Web 
Response System algorithm as follows: 

Subjects previously treated with intravenous anifrolumab 300 mg will stay on 
blinded treatment

Subjects previously treated with anifrolumab 150 mg will switch to blinded 
anifrolumab 300 mg

Subjects previously randomised to placebo will be randomised 1:1 to blinded 
anifrolumab 300 mg or placebo
Therefore, in the long-term extension study subjects will receive double-blind treatment with 
either anifrolumab 300mg or placebo in an approximate ratio of 4:1. 
Although the study will initially be completely double-blind (ie, blind for subjects, 
Investigators/site staff, and Sponsor/designated clinical research organisation), at the 
conclusion of the Phase 3 Studies D3461C00004 or D3461C00005 treatment allocation for 
most subjects will become known to the Sponsor staff and/or the designated clinical research 
organisation.  The blind will be maintained for the Investigator and investigational site staff, 
and for the subjects. 
In general, the first dose of study drug in the long-term extension study 
(Day 1/Visit 1/Week 0) should occur on the same day as the final study visit of the prior study 
(ie, Week 52); however, special circumstances may warrant a delay in subject randomisation 
of up to 30 days following the final visit of the prior study (ie, Week 52). Administration of 
study drug in the long-term extension study should not occur until all Pivotal (Visit 14/Week 
52) and LTE (Day 1/Visit 1/Week 0) evaluations are completed.
This long-term extension study includes:

Treatment Period: A 156-week treatment period with investigational product 
administered every 4 weeks from Week 0 to Week 152 for a total of 39 doses.  
During the treatment period, visits will be scheduled for each administration (every 
4 weeks).

At Week 156 (or after the last dose of investigational product) subjects will 
continue in the study for another 8 weeks to complete a 12-week safety follow-up 
period after the last dose of investigational product (last dose of investigational 
product will be given at Week 152).
An independent Data and Safety Monitoring Board 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. 

Clinical Study Protocol Synopsis
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
Date 10 August 2017
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Objectives
Primary Objective:
Outcome Measure:
To characterise the long-term safety and 
tolerability of intravenous anifrolumab 
-
Rates of adverse events of special interest and 
serious adverse events 
Target subject population
The extension study will be performed in adult subjects who completed a Phase 3 study 
(D3461C00004 or D3461C00005) through the 52-week double-blind treatment period.
Subjects may be taking any of the following: oral corticosteroids, azathioprine, antimalarials 
(eg, chloroquine, hydroxychloroquine, quinacrine), mycophenolate mofetil, mycophenolic 

Clinical Study Protocol Synopsis
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
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acid, methotrexate or mizoribine at the time they sign informed consent for this long-term 
extension study.  Subjects are not required to have a specific degree of disease activity to be 
randomised in the long-term extension study.
Duration of treatment
Investigational product or placebo will be administered every 4 weeks from Week 0 to 
Week 152 for a total of 39 doses.  The total study duration will be up to approximately 
164 weeks (including a 12-week Follow-up Period after administration of the final dose).
Investigational product, dosage and mode of administration
Subjects will receive blinded anifrolumab (MEDI-546) 300 mg or placebo every 4 weeks. 
Investigational product will be administered intravenously over a minimum of 30 minutes.
Statistical methods
No formal comparisons are planned in this study; point estimates and confidence intervals will 
be presented for each treatment group separately. The sample size is not based on statistical 
considerations, but is defined as all subjects who completed the treatment period in the 
Phase 3 pivotal Studies D3461C00004 or D3461C00005 (through Week 52) and met all study 
eligibility criteria. Assuming annual dropout rates of 30% (Randomised Placebo), 30% 
(Randomized Anifrolumab150 mg) and 20% (Randomized Anifrolumab 300 mg) , and that 
90% of the subjects completing the pivotal studies will enter the long-term extension, follow-
up times of approximately 893, 517, and 1343 patient-years for the “Randomised Anifrolumab 
300 mg,” “Randomised Placebo,” and “All Anifrolumab” treatment groups are expected. 
Given this exposure, the 95% CIs for an adverse event of special interest for which the 
observed incidence rate is 10 events in 1000 subject-years will be 5.21 to 19.21 for 
“Randomised Anifrolumab 300 mg,” and 4.24 to 23.57 for “Randomised Placebo.” For an 
adverse event of special interest for which the observed incidence rate is 1 event in 1000 
subject-years, the 95% confidence interval will be 0.18 to 5.42 for “All Anifrolumab” (0.13 to 
7.95 for “Randomised Anifrolumab 300 mg”), and 0.07 to 15.25 for “Randomised Placebo,” 
using the Rothman-Greenland Method.
All subjects enrolled in Studies D3461C00004 or D3461C00005 will be included in the main 
analysis of the long-term extension study, even if they do not enter the long-term extension
study.  Therefore, the full analysis set will consist of all subjects who were randomised and 
received at least 1 dose of investigational product in the Phase 3 pivotal Studies 
D3461C00004 or D3461C00005.
The analyses of long-term safety and tolerability will include data from randomisation in the 
Phase 3 pivotal Studies D3461C00004 or D3461C00005 until the end of the long-term 
extension study, including follow-up data.  Adverse events of special interest and serious 
adverse events will be summarised by means of descriptive statistics and qualitative 
summaries.  
Interim analyses may be performed at appropriate timepoints during the study, according to 
regulatory and other requirements. Further details of interim analyses will be provided in the 
SAP.

Clinical Study Protocol
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Study Code D3461C00009
Version 3.0
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS.....................................................................................8
TABLE OF CONTENTS................................................................................... 12
1.
INTRODUCTION ............................................................................................. 22
1.1
Background and rationale for conducting this study ........................................... 22
1.2
Rationale for study design, doses and control groups.......................................... 22
1.3
Benefit/risk and ethical assessment .................................................................... 23
1.4
Study Design...................................................................................................... 25
2.
STUDY OBJECTIVES...................................................................................... 28
2.1
Primary objective............................................................................................... 28
2.2
Secondary objectives (Not applicable)................................................................ 28
2.3
Safety objectives................................................................................................ 28
3.
SUBJECT SELECTION, RANDOMISATION, RESTRICTIONS, 
DISCONTINUATION, AND WITHDRAWAL................................................. 29
3.1
Inclusion criteria ................................................................................................ 29
3.2
Exclusion criteria ............................................................................................... 31
3.2.1
General exclusion criteria................................................................................... 32
3.2.2
Exclusion criteria related to concomitant medications ........................................ 32
3.2.3
Exclusion criteria related to systemic lupus erythematosus and other 
diseases.............................................................................................................. 32
3.2.4
Exclusion criteria related to infection and malignancy risk factors...................... 33
3.3
Restrictions and concomitant medications.......................................................... 33
3.3.1
Excluded medications: Day 1 through the end of the study................................. 33
3.3.1.1
Medications that lead to immediate discontinuation of investigational 
product............................................................................................................... 33
3.3.1.2
Restricted medications ....................................................................................... 34
3.3.1.3
Other concomitant medications .......................................................................... 35
3.3.2
Concomitant medications for Systemic Lupus Erythematosus during the 
study.................................................................................................................. 35
3.3.2.1
Background Systemic Lupus Erythematosus standard of care medications 
(oral corticosteroids, antimalarials, and immunosuppressants)............................ 35
3.3.2.2
Use of other medications for increased SLE disease activity............................... 37

Clinical Study Protocol
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Study Code D3461C00009
Version 3.0
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6.5.1.3
Influenza............................................................................................................ 72
6.5.2
Severe hypersensitivity reactions including anaphylaxis and immune 
complex disease ................................................................................................. 73
6.5.3
Malignancy........................................................................................................ 73
6.5.4
Herpes zoster reactivations (including cutaneous events).................................... 73
6.5.5
Tuberculosis....................................................................................................... 74
6.5.6
Vasculitis (non-systemic lupus erythematosus)................................................... 74
6.5.7
Major adverse cardiovascular events.................................................................. 75
6.6
Recording of adverse events............................................................................... 75
6.6.1
Time period for collection of adverse events ...................................................... 75
6.6.2
Follow-up of unresolved adverse events............................................................. 75
6.6.3
Variables............................................................................................................ 75
6.6.4
Causality collection............................................................................................ 76
6.6.5
Adverse events based on signs and symptoms.................................................... 77
6.6.6
Adverse events based on examinations and tests ................................................ 77
6.6.7
Disease progression/worsening of systemic lupus erythematosus ....................... 77
6.7
Reporting of serious adverse events ................................................................... 78
6.8
Reporting of adverse events of special interest ................................................... 79
6.9
Management of investigational product-related toxicities ................................... 79
6.9.1
Anaphylaxis, hypersensitivity, and infusion-related reactions............................. 79
6.9.2
Infections........................................................................................................... 79
6.10
Study governance and oversight......................................................................... 80
6.10.1
Data and Safety Monitoring Board..................................................................... 80
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 81
7.1
Identity of investigational product(s).................................................................. 81
7.2
Dose and treatment regimens ............................................................................. 81
7.2.1
Dose preparation steps ....................................................................................... 81
7.2.2
Prior to administering the investigational product............................................... 81
7.2.3
Investigational product administration procedures.............................................. 82
7.2.4
Subject monitoring/procedures during and after the infusion .............................. 83
7.2.5
Discharge........................................................................................................... 83
7.2.6
Documentation of investigational product administration................................... 83
7.3
Labelling............................................................................................................ 84
7.4
Storage............................................................................................................... 85
7.5
Compliance........................................................................................................ 85
7.6
Accountability.................................................................................................... 85
7.7
Concomitant and other treatments ...................................................................... 85
8.
STATISTICAL ANALYSES............................................................................. 85
8.1
Statistical considerations .................................................................................... 85

Clinical Study Protocol
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Study Code D3461C00009
Version 3.0
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10.5
Changes to the protocol and informed consent form........................................... 94
10.6
Audits and inspections ....................................................................................... 95
11.
LIST OF REFERENCES ................................................................................... 95
LIST OF TABLES
Table 1
Highly effective intrauterine device and hormonal methods and 
effective barrier methods of birth control (2 methods are required, 
one being a barrier method and one being a intrauterine 
device/hormonal method)......................................................................30
Table 2
Study plan detailing the procedures during the Treatment Period 
Year 1...................................................................................................45
Table 3
Study plan detailing the procedures during the Treatment Period 
Year 2 through Year 3 or End of Study .................................................49
Table 4
Study plan detailing the procedures during Follow-up...........................54
Table 5
Clinical laboratory test ..........................................................................64
Table 6
Compatible materials of construction for IV bags..................................84
Table 7
Compatible materials of construction for ancillaries (eg, infusion 
tubing) ..................................................................................................84
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................27

Clinical Study Protocol
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
Date 10 August 2016
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Clinical Study Protocol
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
Date 10 August 2016
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest 
AGC
Atypical glandular cells
AIS
Adenocarcinoma in situ 
ALT
Alanine aminotransferase 
ASC-H
Atypical squamous cells where HSIL cannot be ruled out
AST
Aspartate aminotransferase 
 
anti-RNP
Anti-ribonucleoprotein 
CI
Confidence interval
CIN I, II, or III
Cervical intraepithelial neoplasia grade I, II, or III 
CIS
Carcinoma in situ 
CNS
Central nervous system 
CRF
Case Report Form (electronic/paper)
CRO 
Clinical Research Organisation
CSA
Clinical Study Agreement
CV-EAC
Cardiovascular Event Adjudication Committee 
DEHP
Diethylhexyl phthalate
DILI
Drug Induced Liver Injury 
DMARD
Disease-modifying antirheumatic drugs
DNA
Deoxyribonucleic acid 
DSMB
Data and Safety Monitoring Board 

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Study Code D3461C00009
Version 3.0
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Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
EDV
Early Discontinuation Visit
FSH
Follicle-stimulating hormone 
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice 
HbA1c
Glycosylated haemoglobin 
HBcAb
Hepatitis B core antibody 
HBV
Hepatitis B virus 
HIV
Human immunodeficiency virus 
HL
Hy’s Law
HSIL
High-grade squamous intraepithelial lesion
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive care unit
IFN
Interferon
IFNAR
Interferon receptor
Ig
Immunoglobulin(s)
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
mAb
Monoclonal antibody(ies)
MACE
Major adverse cardiovascular events 
MedDRA
Medical Dictionary for Regulatory Activities 

Clinical Study Protocol
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Study Code D3461C00009
Version 3.0
Date 10 August 2016
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Systemic lupus erythematosus (SLE) is a chronic, multisystemic, disabling autoimmune 
rheumatic disease of unknown aetiology. 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. 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 a 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 (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).
All of the therapies currently used for the treatment of SLE have well known adverse effects 
and there is a medical need to identify new targeted therapies, particularly agents that may 
reduce the requirement for corticosteroids and cytotoxic agents.
Multiple lines of evidence indicate a role of type I interferons (IFNs) in the pathogenesis of 
SLE (Hylton et al, 1986; Bengtsson et al, 2000; Baechler et al, 2003; Bennett et al, 2003; 
Crow and Wohlgemuth, 2003; Kirou et al, 2004; Okamoto et al, 2004; Dall’era et al, 2005; 
Kirou et al, 2005; Feng et al, 2006; Criswell, 2008; Huang et al, 2008; Sigurdsson, Göring et 
al, 2008; Sigurdsson, Nordmark et al, 2008; Yao et al, 2010).
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 
represent a novel, effective therapy for the treatment of SLE and its significant unmet medical 
need.
Anifrolumab (MEDI-546) is a human immunoglobulin (Ig) G1 kappa 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 IFNAR and 
inhibits the biologic activity of all type I IFNs.
1.2
Rationale for study design, doses and control groups
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled, 
long-term extension (LTE) study to characterise the long-term safety and tolerability of an 
intravenous (IV) treatment regimen of anifrolumab (300 mg) versus placebo in adult subjects 

Clinical Study Protocol
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Study Code D3461C00009
Version 3.0
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who completed a Phase 3 study (D3461C00004 or D3461C00005) through the 52-week 
double-blind treatment period.  
The LTE will allow subjects to continue with treatment for an extended period of up to 3 
years. Subjects who received anifrolumab (150 or 300 mg) in the Phase 3 Pivotal studies will 
receive anifrolumab (300 mg) and subjects who received placebo in the Phase 3 Pivotal 
studies will be randomised to receive anifrolumab (300 mg) or placebo in a 1:1 ratio. The 
expected ratio of subjects receiving anifrolumab (300 mg) vs placebo in the LTE study will 
be approximately 4:1. Subjects randomised to placebo in the LTE study serve as comparators 
to support interpretability of the data collected for subjects randomised to anifrolumab. 
Subjects who were receiving anifrolumab 150 mg in the Phase 3 Pivotal study will switch to
300 mg in the LTE to provide long-term safety data on the higher study dose. This study 
allows for the addition of new oral immunosuppressants or changing doses of background 
immunosuppressants, as well as for flexible oral corticosteroids (OCS) use in order for 
subjects to achieve adequate control of their disease throughout the study. 
Although the study will initially be completely double-blind, (ie, blind for subjects, 
Investigators/site staff, and Sponsor/designated clinical research organisation [CRO]), at the 
conclusion of the Phase 3 Studies D3461C00004 or D3461C00005 treatment allocation for 
most subjects will become known to some Sponsor staff and/or designated CRO. The blind 
will be maintained for the Investigator, investigational site staff, and for the subjects.
A treatment period of 156 weeks is an appropriate study duration to characterise the 
investigational product’s long-term safety profile.
The primary outcome measure is the assessment of adverse events of special interest (AESIs), 
and serious adverse events (SAEs) to characterise safety profile.
The selection of a dose of 300 mg anifrolumab every 4 weeks (Q4W) is based on safety and 
efficacy results from the analysis of a Phase 2b study where 2 doses of anifrolumab (300 mg 
and 1000 mg) were evaluated relative to placebo, as well as dose-response modelling and 
simulation that were performed.
1.3
Benefit/risk and ethical assessment
A detailed assessment of the data supporting the overall risk/benefit of anifrolumab is 
discussed in the Investigator’s Brochure (IB).
There is a 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 that 
targets type I IFN receptors, such as anifrolumab, may be beneficial in the treatment of these 
subjects.
Anifrolumab demonstrated a clinically relevant benefit in subjects with moderate to severe 
SLE treated with standard of care (SOC).  The efficacy was supported by a broad range of 
clinical measures of global (various levels of SLE Responder Index responses, British Isles 

Clinical Study Protocol
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
Date 10 August 2016
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Lupus Assessment Group-based Composite Lupus Assessment) and organ-specific disease 
activity (Cutaneous Lupus Erythematosus Disease Area and Severity Index, 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. 
In this study, anifrolumab will be administered at a fixed IV dose of 300 mg Q4W for 
156 weeks (the last dose of investigational product will be given at Week 152), equivalent to 
the lower dose in the Phase 2 study (CD-IA-MEDI-546-1013).  
Anifrolumab was generally well tolerated.  A dose-related increase in the reporting rate of 
herpes zoster reactivation with cutaneous presentation was observed in patients receiving 
anifrolumab compared with placebo.  Herpes zoster reactivation with cutaneous presentation 
is an identified risk for anifrolumab.  No other infectious risks have been identified; however, 
this continues to be closely monitored.  Although anifrolumab is a human mAb, patients can 
develop anti-drug antibodies (ADAs) that may neutralize the activity of the drug or may be 
associated with acute or delayed hypersensitivity reactions, including anaphylaxis.  
Furthermore, the administration of any foreign protein may be associated with acute allergic 
or hypersensitivity reactions that may be severe and may result in death.  Patients will be 
monitored for the presence of and the clinical manifestations associated with the formation of 
specific antibodies to anifrolumab.
As of 18 January 2017, a total of 2 severe hypersensitivity events have occurred in clinical 
studies of anifrolumab, although these events remain blinded.  Careful monitoring for such 
events will continue.
In addition to the ongoing, blinded review provided by the PRA Medical Monitor, an 
independent Data and Safety Monitoring Board (DSMB) reviews safety data on a regular 
basis throughout the study (see Section 6.10.1).
AstraZeneca considers that the available non-clinical and clinical data indicate an acceptable 
safety profile for anifrolumab.  Protocol-defined exclusions are in place to prevent enrolment
of patients with infection and malignancy risks that might compromise their safety.  AESIs, 
such as herpes zoster reactivation with cutaneous presentation, as well as other herpes zoster-
associated adverse events (AEs), anaphylaxis, opportunistic infections, serious infections, 
influenza, TB (including latent TB), malignancies, major adverse cardiovascular events 
(MACE), and vasculitis (non-SLE), are being closely monitored in clinical studies.  
The proposed dosing regimens for the Phase 3 studies are supported by positive Phase 2 
efficacy data and an acceptable safety profile.  The management plan for identified, potential, 
and important potential risks associated with anifrolumab is designed to minimize risk to 
patients, and the emerging safety profile supports continued investigations.  AstraZeneca 
considers that anifrolumab continues to demonstrate an overall positive benefit risk balance to 
support its further clinical evaluation.

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1.4
Study Design 
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled 
extension study characterising the long-term safety and tolerability of an IV treatment regimen 
of anifrolumab (300 mg) versus placebo in subjects with moderately to severely active SLE 
who completed a Phase 3 study (D3461C00004 or D3461C00005) through the 52-week 
double-blind treatment period.  
Approximately 575 subjects from Studies D3461C00004 or D3461C00005 who were 
previously treated with anifrolumab (150 or 300 mg) or placebo for 52 weeks while receiving 
standard of care (SOC) treatment and who are willing to continue treatment may participate in 
the long-term extension (LTE) study if all eligibility criteria are met.  Subjects will receive 
either a fixed IV dose of 300 mg anifrolumab Q4W for up to 39 doses (Week 0 to Week 152) 
or placebo.  Investigational product will be administered as an IV infusion via an infusion 
pump over a minimum of 30 minutes, Q4W.  
In order to ensure that subjects with active SLE who enter the LTE will have adequate 
treatment of their disease in this 3-year blinded, placebo-controlled extension study, 
Investigators will be allowed to change the background SOC treatment for SLE during the 
course of the study. This study allows for the addition of new oral immunosuppressants or 
changing doses of background immunosuppressants, as well as for flexible OCS use, so that 
subjects may achieve adequate control of their disease on study. However, it is recommended 
that subjects receive the lowest possible corticosteroid dose. Concomitant medications for 
SLE during the study are detailed in Section 3.3.2. 
In the LTE study, treatment assignment will follow an Interactive Voice/Web Response 
System (IXRS) algorithm as follows: 

Subjects previously treated with anifrolumab 300 mg IV will stay on blinded 
treatment

Subjects previously treated with anifrolumab 150 mg will switch to blinded 
anifrolumab 300 mg

Subjects previously randomised to placebo will be randomised 1:1 to blinded 
anifrolumab 300 mg or placebo
Therefore, in the LTE study subjects will receive double-blind treatment with either 
anifrolumab or placebo in an approximate ratio of 4:1.  
Although the study will initially be completely double-blind (ie, blind for subjects, 
Investigators/site staff, and Sponsor/designated CRO), at the conclusion of the Phase 3 Studies 
D3461C00004 or D3461C00005 treatment allocation for most subjects will become known to 
the Sponsor staff and/or designated CRO. The blind will be maintained for the Investigator, 
investigational site staff, and for the subjects.

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In general, the first dose of study drug in the LTE study (Day 1/Visit 1/Week 0) should occur 
on the same day as the final study visit of the prior study (ie, Week 52); however, special 
circumstances may warrant a delay in subject randomisation of up to 30 days following the 
final visit of the prior study (ie, Week 52). Administration of study drug in the LTE long-term 
extension study should not occur until all Pivotal (Visit 14/Week 52) and LTE (Day 1/Visit 
1/Week 0) evaluations are completed.
This LTE study includes:

Treatment Period: A 156-week treatment period with investigational product 
administered Q4W from Week 0 to Week 152 for a total of 39 doses.  During the 
treatment period, visits will be scheduled for each Q4W administration.    

At Week 156 (or after the last dose of investigational product) subjects will 
continue in the 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 at Week 152).
The total study duration will be up to approximately 164 weeks (including a 12-week 
Follow-up Period after administration of the final dose).  
Once subjects have completed Studies D3461C00004 or D3461C00005 (through Week 52), 
signed the informed consent form (ICF), and met all study eligibility criteria, they may be 
included in the LTE study. 
In the event a site has not obtained the required approval (eg, regulatory authority, local ethics 
committee [EC]) by the time a subject is eligible to be randomised in the LTE study, the site 
may be allowed the time to obtain the approval(s).  
If due to regulatory delays or other exceptional circumstances it is likely that 
Day 1/Visit 1/Week 0 will occur greater than 30 days after the final visit of the prior study, the 
PRA Medical Monitor must be contacted to confirm that the subject will be permitted to be 
randomised.  The rationale for the delayed start, date of last dose of study drug, and subject 
compliance in the prior study will be reviewed to determine whether the subject will be 
permitted to be randomised.  In addition, all Day 1/Visit 1/Week 0 visit procedures listed in 
Table 2 must be performed.
If dosing occurs on the same day of the final visit of the prior study, it should occur after all 
Day 1/Visit 1/Week 0 assessments have been completed, the Investigator has determined that 
the subject can continue dosing, and the subject has been randomised.
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.  
See Figure 1 for an outline of the study design.

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Study Code D3461C00009
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Figure 1
Study flow chart

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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To characterise the long-term safety and 
tolerability of intravenous anifrolumab 
-
Rates of AESIs and SAEs 
2.2
Secondary objectives (Not applicable)
2.3
Safety objectives
See Section 2.1 Primary objective.
  

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3.
SUBJECT SELECTION, RANDOMISATION, RESTRICTIONS, 
DISCONTINUATION, AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1.
Subjects who have qualified for and received investigational product (anifrolumab 
or placebo) and completed the treatment period in Studies D3461C00004 or 
D3461C00005 (through Week 52)
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 Day 1 evaluations
3.
Adequate peripheral venous access
4.
Females of childbearing potential must use 2 effective methods (Table 1) of 
avoiding pregnancy, only 1 of which is a barrier method and the other is a highly 
effective intrauterine device or hormonal method described in Table 1 below, from 
Day 1/Visit 1 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 sustained 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.

Postmenopausal is defined as at least 1 year since last menses and the 
subject has a follicle-stimulating hormone (FSH) level within 
postmenopausal range according to central laboratory testing at 
Day 1/Visit 1.
Effective methods of birth control include those listed in Table 1. 

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Table 1
Highly effective intrauterine device and hormonal methods and 
effective barrier methods of birth control (2 methods are required, one 
being an intrauterine device/hormonal method and the other a barrier 
method ) 
Contraceptive methods
Barrier Methods
(choose only one)
Intrauterine Device/Hormonal Methods
(choose only one)
Intrauterine Device Methods
Hormonal Methods
Male condom
(with spermicide*)
Progesterone T 
Contraceptive implants
Cap (with spermicide cream or 
jelly*)
Copper T
Hormone shot or injection
Diaphragm (with spermicide 
cream or jelly*)
Combined pill (progesterone 
and estrogen)
Minipill (progesterone only)
Contraceptive patch
*where commercially available
5.
All males (sterilised or non-sterilised) who are sexually active must use a condom 
(with spermicide where commercially available) for contraception with a woman of 
child bearing potential from Day 1 until at least 12 weeks after receipt of the final 
dose of investigational product.  It is strongly recommended that female partners of 
child bearing potential of male subjects use a highly effective method of birth 
control from Table 1 (other than a barrier method) throughout this period.
6.
Females with an intact cervix must have a Pap smear completed and without 
documented malignancy (eg. no signs of CIN grade III, CIS, or AIS) within 90 days 
prior to randomization or up until 30 days post-randomization, ie, before IP dosing 
at V2.
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
.
7.
Willing to forego other forms of experimental treatment during the study
8.
Meets the following TB criteria:

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(a)
Negative QuantiFERON®-TB Gold [QFT-G] test result for TB obtained 
from the study central laboratory at Week 52 of Studies D3461C00004 
or D3461C00005 
OR
(b)
Newly positive QFT-G test result for TB obtained at Week 52 of 
Studies D3461C00004 or D3461C00005 from the study central 
laboratory.  A chest x-ray must be performed.  If the chest x-ray 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.  If the 
retest is positive, the subject must initiate treatment for latent TB within 
30 days of randomisation, but prior to the second dose of investigational 
product administration (Visit 2/Week 4). This should be reported as an 
AESI. 
OR
(c)
Positive but not newly positive QFT-G test at Week 52 of Studies 
D3461C00004 or D3461C00005 from the study central laboratory.  The 
subject must have been diagnosed with latent TB and must have 
documentation confirming completion of appropriate treatment OR 
initiate treatment for latent TB within 30 days of randomisation, but 
prior to the second dose of investigational product administration 
(Visit 2/Week 4) 
OR
(d)
Newly indeterminate (as confirmed on retest unless prior positive 
QFT-G was documented, along with completed treatment for latent TB) 
or indeterminate but not newly indeterminate QFT-G test result at 
Week 52 of Studies D3461C00004 or D3461C00005 from the study 
central laboratory with ongoing QFT-G testing for TB according to the 
Study Plan
The QFT-G test results obtained at Week 52 of Studies D3461C00004 or 
D3461C00005 should be available within 30 days of randomisation, but prior to the 
second dose of investigational product administration (Visit 2/Week 4).  The PRA 
Medical Monitor may be contacted for questions.
9.
In the opinion of the Investigator, subject must be able to comprehend the ICF and 
all protocol-related assessments, and be able to complete all study-required 
documents, procedures, and outcome measures
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

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3.2.1
General exclusion criteria
1.
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of the investigational product or interpretation of subject safety or study 
results
2.
Concurrent enrolment in another clinical study (except studies D3461C00004 and 
D3461C00005) with an investigational product
3.
Pregnant females or females who intend to become pregnant anytime from 
randomisation until the end of the 12-week safety Follow-up Period following last 
dose of investigational product
4.
Current alcohol, drug, or chemical abuse
3.2.2
Exclusion criteria related to concomitant medications
5.
Receipt of any of the following within the last 60 days prior to Day 1/Visit 1:
(a)
Azathioprine >200 mg/day
(b)
Mycophenolate mofetil >2.0 g/day /mycophenolic acid >1.44 g/day
(c)
Oral, subcutaneous, or intramuscular methotrexate >25 mg/week
(d)
Mizoribine >150 mg/day
6.
Receipt of any investigational product (small molecule or biologic agent other than 
anifrolumab) within 4 weeks or 5 half-lives prior to Day 1/Visit 1, whichever is 
greater 
7.
Receipt of any commercially available biologic agent within 5 half-lives prior to 
Day 1/Visit 1
8.
Receipt of any of the following:
(a)
Any live or attenuated vaccine within 8 weeks prior to Day 1/Visit 1 
(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)
(b)
Bacillus Calmette-Guerin (BCG) vaccine between the end of Studies 
D3461C00004 or D3461C00005 and Day 1/Visit 1
3.2.3
Exclusion criteria related to systemic lupus erythematosus and other diseases
9.
Active severe SLE-driven renal or neuropsychiatric disease where, in the opinion of 
the Principal Investigator, protocol-specified SOC is insufficient and utilisation of a 

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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
3.2.4
Exclusion criteria related to infection and malignancy risk factors
10.
Any underlying condition that predisposes the subject to infection, including history 
of/current human immunodeficiency virus (HIV) infection 
An HIV test confirmed by the central laboratory must be performed if not done in 
Studies D3461C00004 or D3461C00005.  The result should be available within 
30 days of randomisation, but prior to the second dose of investigational product 
administration (Visit 2/Week 4).  
11.
Subjects with Hepatitis B core antibody (HBcAb) positivity at enrolment of Studies 
D3461C00004 or D3461C00005 will be tested every 3 months for Hepatitis B virus 
(HBV) deoxyribonucleic acid (DNA).  To remain eligible in the LTE study, subject 
HBV DNA levels must remain below the lower limit of quantitation (LLOQ) as per 
the central laboratory.
12.
Opportunistic infection requiring hospitalisation or parenteral antimicrobial 
treatment within 3 years of Day 1/Visit 1
13.
Any of the following:
(a)
Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis, 
etc) within 8 weeks prior to Day 1/Visit 1 (chronic nail infections  not 
causing open skin lesions are allowed)
(b)
Any infection requiring hospitalisation or treatment with IV 
anti-infectives not completed at least 4 weeks prior to Day 1/Visit 1 
14.
Any infection requiring IV or oral anti-infectives (including antivirals) within 
2 weeks prior to Day 1/Visit 1
Procedures for withdrawal of incorrectly randomised subjects see Section 3.5.
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 
and/or herbal products, without first consulting the Investigator.
3.3.1.1
Medications that lead to immediate discontinuation of investigational product
(a)
Cyclophosphamide
(b)
Baricitinib, tofacitinib or other Janus kinase inhibitors

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(l)
Corticosteroids with a long biologic half-life (eg, dexamethasone, betamethasone)
(m)
Other immunosuppressants including but not limited to calcineurin inhibitors (eg,
cyclosporine) or leflunomide, except for tacrolimus (see Section 3.3.2.1)
If a subject receives any of the above listed medications, the Investigator will use his/her 
judgment to consider if the subject may continue to receive investigational product.  The 
Investigator may contact the PRA Medical Monitor to discuss the case.  
3.3.1.3
Other concomitant medications
Medications, other than those described above, which are 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 during the study
Concomitant medications should only be administered after all visit assessments, including 
investigational product administration 
, 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 have been completed, and prior to starting the infusion.
3.3.2.1
Background Systemic Lupus Erythematosus standard of care medications 
(oral corticosteroids, antimalarials, and immunosuppressants)
Permitted SOC medications for SLE during the LTE study include OCS (up to 40 mg/day of 
prednisone or equivalent
), antimalarials, and immunosuppressants 
(methotrexate, mycophenolate mofetil/mycophenolic acid, mizoribine, azathioprine, and 
tacrolimus). 
Investigators should apply local practices for safety monitoring, eg, by serum chemistry tests, 
in case SOC dose is changed, eg, increased, and/or new disease-modifying antirheumatic drug 
(DMARD) is added.
Subjects may undergo changes in their background SOC medication for SLE (OCS, 
antimalarials, or immunosuppressants) doses, based on the opinion of the Investigator.  On 
treatment days, changes in doses will commence after all assessments have been completed 
and the investigational product has been administered.  There is no minimum dose 
requirement for background SOC medications for SLE, and subjects may taper off as 
permitted by disease activity.  Due to variability in subject responses to background SOC
medications for SLE and tolerability of taper, Investigators are asked to use their clinical 
judgment with respect to the taper schedule.  If the subject experiences an increase in SLE 
disease activity, SOC medications for SLE may be adjusted according to the Investigator’s 
clinical judgment, but may not exceed maximally permitted doses as defined by exclusionary 
criteria.

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All permitted SOC SLE therapies received from randomisation 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.
Immunosuppressants
Subjects may change from the immunosuppressant on which they entered the LTE study to 
another permitted immunosuppressant (methotrexate, mycophenolate mofetil/mycophenolic 
acid, mizoribine, azathioprine, or tacrolimus) at the discretion of the Investigator.  Subjects 
who were not taking an immunosuppressant at the time they enter the LTE study may add 1 of 
the permitted immunosuppressants and be escalated up to the protocol-defined doses.  
Combination therapy of tacrolimus and a second immunosuppressant is not permitted during 
the study and would lead to discontinuation of the investigational product.  Doses of any new 
immunosuppressants will be limited to the doses defined below.  It is recommended that 
immunosuppressants not be changed more frequently than every 4 months, unless for 
intolerability reasons. 
If subjects are on immunosuppressants, dosing must not exceed the following:

Azathioprine >200 mg/day

Mycophenolate mofetil >2.0 g/day or mycophenolic acid >1.44 g/day

Oral, subcutaneous, or intramuscular methotrexate >25 mg/week

Mizoribine >150 mg/day

Tacrolimus >0.2 mg/kg/day (tacrolimus at a starting dose of 0.05 mg/kg/day to be 
escalated to ≤0.2 mg/kg/day.  Subjects must maintain tacrolimus trough levels 
below the central laboratory upper limit of the therapeutic range based on monthly 
measurements.)
If the subject plans to use tacrolimus during the study, the subject must not have a history of 
intolerance to tacrolimus or a past history of reversible posterior leukoencephalopathy, other 
severe central nervous system (CNS) disorders, past history of renal impairment, or 
microangiopathic disorders in association with a calcineurin inhibitor, including tacrolimus.
Corticosteroids
Subjects with increased SLE disease activity may receive 1 steroid burst within the first 
12 weeks of the LTE study.  Subsequently, 1 burst every 6 months is allowed.  If additional 
bursts are needed, the Investigator should contact the PRA Medical Monitor to discuss 
subject’s management.  Additionally, subjects may have their background OCS dose titrated 

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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 2 and 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
Surgery should be avoided during the study if clinically feasible, but is permitted.  If a surgery 
becomes necessary during the study, it should be scheduled at least 4 weeks after the previous 
administration of investigational product. 
For non-major surgery, the decision to withhold investigational product administration is at 
the Investigator’s discretion. 
For major surgery, 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.
3.3.3.3
Blood and sperm donations
Subjects should not donate whole blood, blood components or sperm until the completion of 
the follow-up period or 90 days after the last dose.
3.4
Subject randomisation
Investigator(s) should keep a record of subjects considered for randomisation in the LTE study 
(ie, those who completed a Phase 3 study [D3461C00004 or D3461C00005] through the 
52-week double-blind treatment period and consented, but were not randomised) and those 
randomised in the study.  
The same subject identifier (E-code) used in the Phase 3 study (ie, D3461C00004 or 
D3461C00005) will be used in the LTE study.
Subjects will be randomised in the LTE and stratified by Phase 3 study (ie, D3461C00004 and 
D3461C00005) according to the algorithm described in Section 3.6.  
A similar pseudo-randomisation will be done for all subjects randomised in the previous 
Phase 3 Studies (D3461C00004 or D3461C00005) but not randomised in the LTE study, ie, a 
pseudo-treatment (treatment that would have been administered if the subject would have 
continued in the LTE study) will be assigned to each of these subjects. The pseudo-treatment 
will be used for analysis purposes only.

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The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject before any study-specific 
procedures are performed.
2.
Determine subject eligibility for the LTE study.
3.
On Day 1, the Investigator will perform an IXRS transaction for all subjects who 
sign the ICF.  The IXRS will assign blinded investigational product kit number(s) to 
randomised subjects.
Specific information concerning the use of the IXRS will be provided in the separate user 
manual. 
3.5
Procedures for handling incorrectly randomised subjects
Where a subject does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should immediately inform the PRA Medical 
Monitor, who will discuss with AstraZeneca study physician, whether the subject should 
continue or discontinue from treatment.  The PRA Medical Monitor must ensure all decisions 
are appropriately documented.
3.6
Methods for assigning treatment groups
Treatment assignment will follow an IXRS algorithm as follows: 

Subjects previously treated with anifrolumab 300 mg IV will stay on blinded 
treatment

Subjects previously treated with anifrolumab 150 mg will switch to blinded 
anifrolumab 300 mg

Subjects previously randomised to placebo will be randomised 1:1 to anifrolumab 
300 mg or placebo
In general, the first dose of study drug in the LTE study (Day 1/Visit 1/Week 0) should occur 
the same day as the final study visit of the prior study (ie, Week 52); however, special 
circumstances may warrant a delay in subject randomisation of up to 30 days following the 
final visit of the prior study (ie, Week 52).  Administration of study drug should not occur 
until all Pivotal (Visit 14/Week/52) and LTE (Day 1/Visit 1/Week 0 evaluations are 
completed.
3.7
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 a way as to ensure blinding for all Sponsor and 
investigational site staff other than the unblinded investigational product manager.  The kits 

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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 the Investigator or site staff 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.
3.8
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
subject, will be available to the Investigator(s) or pharmacists from the IXRS.  Routines for 
this will be described in the IXRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation.  The 
Investigator should promptly document and explain any premature unblinding to the Sponsor, 
without revealing the treatment given to subject.  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 the PRA Medical Monitor) will not, based on the 
unblinding alone, be discontinued from further receipt of investigational product.
Although the study will initially be completely double-blind (ie, blind for subjects, 
Investigators/site staff, and Sponsor/designated CRO), at the conclusion of the Phase 3 Studies 
D3461C00004 or D3461C00005 treatment allocation for most subjects will become known to 
the Sponsor staff and/or designated CRO. The blind will be maintained for the Investigator,
investigational site staff, and for the subject.

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3.9
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 study treatment, 
without prejudice to further disease 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 needs to take a treatment that is not allowed in this study
(f)
An adverse event (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.
An AE that, in the opinion of the Investigator or the Sponsor/PRA Medical 
Monitor, contraindicates further dosing with investigational product
4.
Severe non-compliance with the study protocol 
5.
The Investigator or Sponsor/PRA 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 HBcAb 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 Investigator 
determines the subject should be discontinued 
10.
A diagnosis of active TB, premature discontinuation of treatment for latent TB, or 
non-compliance with TB therapy.  Note: duration of treatment for latent TB should 

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follow the local practice.  If local practice is not defined, then US 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 (due to an AE, or other), will be identified as having permanently 
discontinued treatment.
3.9.1
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 3.9 above, the subject will not receive any further 
investigational product.  The subject may also refuse to continue any further study 
observation.
3.9.2
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 3.9) 
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 randomisation code cannot 
be reused.  Withdrawn subjects will not be replaced.
3.9.3
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.

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3.9.4
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 (Follow-up Visit 2), 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.
3.9.5
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 2 and Table 3) in order to support the 
final analysis for anifrolumab (see Section 8).  The reason for premature discontinuation of 
investigational product will be documented in the source documents and recorded on 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 3.9.2.
3.10
Criteria for withdrawal 
3.10.1
Ineligible subjects who sign informed consent 
Subjects who have provided informed consent and who subsequently do not fulfil eligibility 
criteria for the study must not be included in the study.  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 
subjects who were never randomised.  
3.10.2
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) and the presence of any AE.  The Investigator will follow 
up AEs outside of the clinical study. 

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3.11
Discontinuation of the study
The study may be stopped if, in the judgment of the Sponsor or the DSMB, trial subjects are 
placed at undue risk because of clinically significant findings that:

Meet individual stopping criteria or are otherwise considered significant (see 
Section 3.9 for reasons for discontinuation of investigational product)

Are assessed as causally related to the investigational product

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded on the CRF.
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 

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4.1
Randomisation
Before randomisation (Day 1/Visit 1/Week 0), subjects will be assessed to ensure that they 
have signed the ICF and meet eligibility criteria.  Once the subject is randomised, relevant 
data must be captured in the appropriate LTE system.  Events that occur prior to 
randomisation in the LTE study should be reported in Studies D3461C0004 or D3461C00005.  
Subjects who do not sign the ICF and/or who do not meet the eligibility criteria must not be 
randomised into the LTE study.
The Week 52 assessments of the Phase 3 Studies D3461C00004 or D3461C00005 will serve 
as Day 1/Visit 1/Week 0 assessments of the LTE study; additional procedures that are part of 
the LTE study will also be performed.  If Day 1/Visit 1/Week 0 occurs more than 30 days 
after the Week 52 final visit of the Phase 3 Studies D3461C00004 or D3461C00005, the PRA 
Medical Monitor must be contacted.  In case the Day 1/Visit 1/Week 0 occurs >60 days after 
the Week 52 final visit of the pivotal studies, additional safety laboratory tests, eg,
haematology, liver function tests, and serum creatinine, might be required as judged by the 
PRA/AZ medical monitor.  The rationale for delayed start, date of last dose of study drug, and 
subject compliance in the prior study will be reviewed.  In addition, all procedures for 
Day 1/Visit 1/Week 0 must be completed. 
4.1.1
Other considerations for randomisation
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.  While a dental 
examination is not required prior to randomisation in this study, Investigators are cautioned to 
consider carefully whether subjects have active caries or a dental infection prior to 
randomisation that might impact subject safety.
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 subjects randomised into the 
LTE study are compliant and up to date with local recommendations for mammography or 
other screening procedures for breast cancer.
4.2
Treatment period
During the treatment period, visits will be scheduled for each Q4W administration.  
Procedures during the Treatment Period Year 1 will be performed according to the Study Plan 
detailing the procedures (Table 2).  Procedures during the Treatment Period Year 2 through 
Year 3 will be performed according to the Treatment Period Study Plan detailing the 
procedures (Table 3).  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.

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5.2.2
Vital signs
Vital signs (oral temperature, blood pressure, pulse rate, and respiratory rate) will be obtained 
at each visit.  Specific information on vital signs surrounding the infusion is included in 
Section 7.2.4 (Subject monitoring/procedures during and after infusions).
5.2.3
Physical examination 
A 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.  Body height will be captured at randomisation 
only.  Subjects will be weighed at each study visit.  Medically significant changes from 
randomisation in the LTE study on physical examination will be recorded as AEs.
5.2.4
Pap smear
Most cases of cervical cancer appear to be related to papilloma virus infection. Because of the 
potential for viral reactivation due to blockade of the Type 1 IFN pathway, we are assessing 
cervical dysplasia in this study, although to date there has been no signal in the anifrolumab 
studies. Females with an intact cervix must have a Pap smear completed and without 
documented malignancy (eg. no signs of CIN grade III, CIS, or AIS) within 90 days before 
Day 1 or up until 30 days after randomization, ie before dosing at V2. Pap smears should 
thereafter be performed yearly and all female subjects with an intact cervix should have a Pap 
smear performed within 3 months of the last IP dose, eg, at the end of study or at the early 
discontinuation visit.
Subjects with abnormal Pap smear results of atypical squamous cells of undetermined 
significance, 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;
. If the subject’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. Since access to a Pap smear may vary by country, the Sponsor recommends that 
local guidelines are used for obtaining routine follow-up Pap smears in females who have 
received immunomodulators or immunosuppressive treatment.
5.2.5
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 low- and high-density 
lipoproteins and triglycerides [see Section 5.2.9]) and inflammatory profiles will be obtained 
during the study.  Concomitant medications received for cardiovascular indications should be 
collected and recorded.

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5.2.6
Electrocardiogram 
Digital ECGs 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 the visits specified in the Study Plan (Table 2 and Table 3).  
Digital ECGs will be obtained after the subject has been resting in a supine position for at 
least 10 minutes.  All digital ECGs 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 or qualified designee 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 CRF, if the Investigator considers it clinically significant.  Abnormal values shall not be 
recorded as AEs unless deemed clinically significant.
5.2.7
Tuberculosis monitoring
Blood testing for TB will be done using the interferon-gamma release assay (IGRA) test (ie, 
QTF-G In-Tube Test).  Evaluation of all subjects by QFT-G In-Tube Test will be performed 
by the central clinical laboratory according to the Study Plan (Table 2 and Table 3).  Annual 
QFT-G testing is required for all study subjects.
Compared to culture-confirmed TB, overall, 87.6% of subjects have a positive QFT-G 
In-Tube Test result (Cellestis, 2005).  The false negative rate in this setting appears to be over 
12%.  Further, the performance of the test in the setting of immunosuppressant drugs has not 
been evaluated.  Nor has it been evaluated in individuals with medical conditions other than, 
or in addition to, latent TB, or TB disease.  The guide also states that “Medical treatments or 
conditions that impair immune functions can potentially reduce IFN-γ responses and prevent 
detection of a specific response to the (secretory proteins) ESAT-6 and CFP-10 (the test 
stimulators).”
5.2.7.1
Tuberculosis results at time of randomisation/Week 52 of the Phase 3 Study 
D3461C00004 or D3461C00005

If the QFT-G test result was negative and there is no known history of recent 
exposure to individuals with active TB, the subject may be randomised.  

If the QFT-G test result was newly positive, a chest x-ray must be performed.  If 
the chest x-ray 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.  If the 
retest is positive, the subject must start on prophylaxis within 30 days of 
randomisation, but prior to the second dose (Visit 2/Week 4) in the LTE study.  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 
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individuals, then USA guidelines may be followed.  This should be reported as an 
AESI.  The QFT-G test must be repeated annually.

If the QFT-G test was positive but not newly positive, the subject must have been 
diagnosed with latent TB and must have documentation confirming completion of 
appropriate OR initiate treatment for latent TB within 30 days of randomisation, but 
prior to the second dose (Visit 2/Week 4).

If the QFT-G test result was newly indeterminate (as confirmed on retest unless 
prior positive QFT-G was documented, along with completed treatment for latent 
TB) or indeterminate but not newly indeterminate, further QFT-G testing will be 
done according to the Study Plan (Table 2 and Table 3).  
QFT-G testing is performed at least annually and in some cases more often, depending on the 
result.  Refer to the Study Plan (Table 2 and Table 3).
5.2.7.2
Tuberculosis monitoring during the study
At every visit, sites should ensure that the subject has 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 initiation of appropriate treatment) or active TB. 
If during the trial a subject is determined to have a:

Negative QFT-G test result, only the annual TB testing is required.

Newly positive QFT-G test result, a chest x-ray has to be performed, and 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 be reported as an 
AESI.  The QFT-G test must be repeated annually.

For indeterminate QFT-G test result, refer to Section 5.2.7.1.
QFT-G testing is performed at least annually and in some cases more often, depending on the 
result.  Refer to the Study Plan (Table 2 and Table 3).
5.2.7.3
Tuberculosis monitoring at Week 156

Negative QFT-G test result:  No further testing is required.

Newly positive QFT-G test result at Week 156 or later:  Follow prior 
recommendations for newly positive QFT-G result during study. 

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
Newly indeterminate QTF-G test result (as confirmed on retest unless prior
positive QFT-G was documented, along with completed treatment for latent TB):
Repeat at Follow-up Visit 1 (8 weeks post-final dose).

If negative, no further testing

If indeterminate, repeat again at Follow-up Visit 2 (12 weeks post-final dose).
5.2.8
Modified Flare Index
A modified SELENA flare index, using the SLEDAI-2K instead of the SELENA SLEDAI, 
will be completed at the times indicated in the Study Plan (Table 2 and Table 3) to 
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 that, in the opinion 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.
5.2.9
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). 
Urine pregnancy tests will be performed at the site using a dipstick.  A serum FSH will be 
performed at randomisation at the central laboratory in newly postmenopausal females with 
menses absent for ≥1 year.
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 test samples, 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 
site as source data for laboratory variables.  For information on how AEs based on laboratory 
tests should be recorded and reported, see Section 6.6.
In case a subject shows an aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) ≥3 × upper limit of normal (ULN) and total bilirubin (TBL) ≥2 × ULN 
 
‘Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of 
Hy’s Law’ for further instructions.

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The following laboratory variables in Table 5 will be measured:
Table 5
Clinical laboratory test
Randomisation
 
HbA1c in diabetic subjects only
HBV DNA (testing every 3 months for subjects with HBcAb positivity at enrolment of Studies 
D3461C00004 or D3461C00005.  To remain eligible in the LTE study, subject HBV DNA levels must 
remain below the LLOQ as per the central laboratory.)
HIV test (only in subjects not tested in Studies D3461C00004 or D3461C00005)
CK 
 
Urine protein/creatinine ratio
QFT-G
Haematology
Haematology/Haemostasis (whole blood)
WBC count with differential
RBC count
Haematocrit
Haemoglobin
Platelet count
MCV
MCHC
Serum Chemistry 
Calcium
Chloride
Potassium
Sodium
AST*
ALT*
ALP*
GGT
BUN
Creatinine
TBL* (reflexively fractionated if elevated)

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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 after 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.
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.
6.4.2.2
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 on the CRF. 
The events of interest are medically significant infections (non-opportunistic serious 
infections and opportunistic infections including viral infection/reactivation), severe 
hypersensitivity reactions including anaphylaxis and immune complex disease, malignancy, 
herpes zoster with cutaneous presentation, TB (including latent TB), influenza, vasculitis (non 
SLE), and MACE (including stroke, myocardial infarction, or cardiovascular death). Lupus 
nephritis (associated with SLE; WHO or ISN/RPS Classification Class III, IV or V) is defined 

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not as an AESI but as a new SLEDAI AE, and diagnosis will be supported with laboratory 
results.
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
Medically significant infections (including viral 
infection/reactivation/opportunistic infections)
Medically significant infections are an important potential risk based on the mechanism of 
action of anifrolumab.  For safety reporting purposes, in this study, infections are classified as 
either serious non-opportunistic infections or opportunistic infections as described here.
6.5.1.1
Serious non-opportunistic infection
A serious non-opportunistic infection is any non-opportunistic infection that meets the SAE 
criteria in Section 6.2.  Serious non-opportunistic infection AEs 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.  Nonserious non-opportunistic infections will not be captured as AESIs.
6.5.1.2
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 bacteraemia, Pneumocystis jirovecii 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 subjects who develop serious 
infections.
6.5.1.3
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, 

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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.
6.5.2
Severe hypersensitivity reactions including anaphylaxis and immune complex 
disease 
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 
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). 
6.5.3
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.
6.5.4
Herpes zoster reactivations (including cutaneous events)
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 (eg, cerebrospinal fluid) 
may confirm the presence of varicella zoster virus.  Herpes Zoster reactivation with cutaneous 
presentation is an identified risk.
. Systemic infections or other medically significant herpes zoster infections are considered 
important potential risks and classified as medically significant infections for adverse event 
reporting in this study unexpected for regulatory reporting purposes. For additional 
information regarding herpes zoster, refer to the IB. As all herpes zoster events are 
considered to be an AESI, the Sponsor will collect information including whether or not 

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subjects have received vaccination for herpes zoster. The herpes zoster vaccine medical 
history data will be captured in the appropriate sections of the CRF.
6.5.5
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 
(IGRA), 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 polymerase chain 
reaction 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 
(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 (QFT-G) or purified 
protein derivative skin test that is positive both at the time of provisional diagnosis and on 
repeat assessment. 
Subjects identified with latent TB will be assessed by a local TB specialist to confirm the 
diagnosis and local SOC that will be used in treatment.  Once latent TB is confirmed, 
treatment must be instituted immediately and no investigational product may be administered 
until treatment of latent TB has begun.  Additionally, subjects with newly diagnosed latent TB 
must agree to complete a locally recommended course of treatment for latent TB to continue 
to receive investigational product.
6.5.6
  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 

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be identified, such as medications including study drug, infections, or systemic inflammatory 
syndromes, wherever possible.  
6.5.7
Major adverse 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 System Organ Classes for evaluation as to whether to classify as MACE events 
(stroke, myocardial infarction, 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.
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 randomisation, throughout the 
treatment period, and including the follow-up period until Follow-up Visit 2 (12 weeks 
post-final dose).  Events that occur prior to randomisation in the LTE study should be reported 
in Studies D3461C0004 or D3461C00005.  
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 

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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)
In-patient hospitalisation or prolongation of existing hospitalisation

Date of hospitalisation

Date of discharge
(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 an 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 
an 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?’

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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 randomisation through 
the end of subject participation in the study.  Adverse events of special interest that occur prior 
to randomisation in the LTE study should be reported in Studies D3461C0004 or 
D3461C00005.  Following detection of an AESI (nonserious), 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. Nonserious 
non-opportunistic infections will not be captured as AESIs.
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 mAb.  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,
 
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 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 tests 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.  
Failure to obtain this information will impair the Sponsor’s ability to characterise the 
benefit:risk profile of anifrolumab.
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 3.9).  For any active infection (eg, varicella zoster
infection/chickenpox) or significant exposure to any infection (eg, varicella zoster infection in 

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a naive subject, bacterial pneumonia), the Investigator should consider whether to interrupt 
investigational product administration and should notify the PRA 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 P jirovecii 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 after 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.  After reviewing the data, the DSMB may choose to unblind the treatment groups 
for additional review.  The DSMB will not routinely review efficacy data.
At any time during the study, as well as on an ad hoc basis, the DSMB will also review any 
safety data assessed by the PRA Medical Monitor as medically relevant.  Additional 
information, including frequency of DSMB review, can be found in the DSMB charter. 
If any event(s) occur that, in the opinion of the DSMB, contraindicates further dosing of 
additional subjects, the Sponsor will conduct a prompt cumulative review of safety data and 
the circumstances of the event in question to determine whether dosing and study 
randomisation should be stopped, whether the protocol will be modified, or whether the study 
will be discontinued permanently.  Review by the DSMB and Sponsor decision to resume 
(with or without modifications) is required for resumption of the study in the event the study 
is interrupted.  Where applicable, the regulatory authorities and ECs will be notified of any 
actions taken with the study.

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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s) 
Investigational product
Dosage form and strength
Manufacturer
Anifrolumab (MEDI-546)
150 mg/mL solution of 
anifrolumab (clear colourless to 
slightly yellow) intended for 
IV administration following 
dilution into 0.9% saline
MedImmune, LLC
Placebo
Solution (clear) intended for 
IV administration following 
dilution into 0.9% saline
MedImmune, LLC
IV = intravenous
Excipients include 25 mM histidine/histidine-HCl, 50 mM lysine-HC1, 130 mM trehalose 
dihydrate, 0.05% (w/v) plant-derived polysorbate 80, pH 5.9.
Investigational product and placebo will be provided in vials within cartons.  Each kit will 
contain 2 mL nominal volume.  Every kit will have a unique number that will be printed on all 
the labels within the kit (ie, the outer carton label and the vial label).
Preparation of investigational product and placebo must be performed by an unblinded 
qualified person (eg, pharmacist or study nurse) at the site.  When diluted as directed in the 
investigational product study manual provided by the Sponsor, placebo and investigational 
drug appear identical.  See Section 7.2 below for diluent and infusion vessel and tubing 
specifications.
7.2
Dose and treatment regimens
The investigational product, anifrolumab (MEDI-546) 300 mg or placebo, will be 
administered via controlled IV infusion pump into a peripheral vein over a minimum of 
30 minutes Q4W.  Each dose must be at least 14 days apart, ie, the next infusion can be 
scheduled on Day 15 or later.
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 2.0 mL from the kit into the infusion 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.

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
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 or 24 hours at 2 to 8°C (36 to 46°F).  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, the 
investigational product solution should not be infused through an IV line in which 
other solutions or medications are being administered.

Investigational product should be administered over a minimum of 30 minutes. 

Immediately following the initial dosing, up to an additional 25 mL of saline will 
be given via infusion pump at the same pump speed utilised at the completion of the 
initial dosing.

An emergency cart should be available in the infusion suite.

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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 comprising 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
DEHP = diethylhexyl phthalate; IV = intravenous; PVC = polyvinyl chloride
Table 7
Compatible materials of construction for ancillaries (eg, infusion 
tubing)
Materials of Construction
Polyethylene
PVC with DEHP
PVC with 2-ethylhexyltrimellitate
Polybutadiene
DEHP = diethylhexyl phthalate; PVC = polyvinyl chloride
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 products) 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
Concomitant and other treatments 
See Section 3.3.
8.
STATISTICAL ANALYSES
8.1
Statistical considerations
Analyses will be performed by AstraZeneca or its representatives.
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to the first subject 
included into 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.
8.2
Sample size estimate
No formal comparisons are planned in this study; point estimates and CIs will be presented for 
each treatment group separately. The sample size is not based on statistical considerations, 
but is defined as all subjects who completed the treatment period in the Phase 3 pivotal 

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Supportive:

Placebo Feeder + Placebo LTE:  Subjects randomised to placebo in Studies 
D3461C00004 or D3461C00005 and re-randomised to placebo in LTE using all 
data from randomisation to end of LTE.  Data from subjects discontinuing from the 
investigational product in Studies D3461C00004 or D3461C00005, or who elect not 
to participate in the LTE, but who would have been re-randomised to placebo are 
included in this treatment group up to withdrawal. 

All Anifrolumab:  Subjects randomised to anifrolumab in studies D3461C00004 or 
D3461C00005, regardless of dose, and subjects randomised to placebo in studies 
D3461C00004 or D3461C00005 and then re-randomised to anifrolumab 300 mg in 
LTE, using all data from randomisation or switch to anifrolumab, respectively, to 
end of LTE.
Additional supportive:

Placebo Feeder + Placebo LTE:  As described above but using data collected 
during the LTE study only, ie, reduced to subjects enrolled in the LTE study.

Placebo Feeder + Anifrolumab 300 mg LTE:  Subjects randomised to placebo in 
studies D3461C00004 or D3461C00005 and then re-randomised to anifrolumab 
300 mg in LTE using data from switch to end of LTE.

Anifrolumab 150 mg Feeder + Anifrolumab 300 mg:  Subjects randomised to 
anifrolumab 150 mg in Study D3461C00005 and then switched to anifrolumab 
300 mg in LTE using data from switch to end of LTE.
In addition, supplemental summaries with the data collected in the LTE only (excluding the 
feeder studies) will be provided.
8.4
Outcome measures for analyses
8.4.1
  Primary outcome variables: Safety variables
The following primary safety data will be collected: AESIs (see Section 6.5) and SAEs.
Other safety variables include AEs, vital signs, physical examination, ECGs, flares as defined 
by a modification of the SELENA Flare Index using the SLEDAI-2K, haematology, clinical 
chemistry, and urinalysis.
Adverse events, AESIs, and SAEs will be summarised by means of descriptive statistics and 
qualitative summaries.
8.4.1.1
Other significant adverse events
During the evaluation of the AE data, a PRA medically qualified expert will review the list of 
AEs that were not reported as SAEs and discontinuations due to AEs.

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8.5.3
Interim analysis
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 as described in Section 6.10.1.  Interim analyses may be performed at appropriate 
timepoints during the study, according to regulatory and other requirements. Further details of 
interim analyses will be provided in the SAP.  
9.
STUDY AND DATA MANAGEMENT 
9.1
Training of study site personnel
Before the first subject is randomised into the study, an AstraZeneca representative will 
review and discuss the requirements of the Clinical Study Protocol and related documents 
with the investigational staff and also train them in any study-specific procedures and 
system(s) utilised (see Section 5.1.1).
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca or designee representative will have regular contacts with 
the study site, including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded on the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed

Perform source data verification (a comparison of the data in the CRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating subjects. This 
will require direct access to all original records for each subject (eg, clinic charts)

Ensure that withdrawal of informed consent to the use of the subject’s biological 
samples is reported, and that biological samples are identified and disposed 

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of/destroyed accordingly, and that the action is documented and reported to the 
subject.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for location of source data.
9.2.2
Study agreements
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the CSA, the terms of the Clinical Study Protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of subjects, the terms of the CSA 
shall prevail.
Agreements between PRA, on behalf of AstraZeneca, and the Principal Investigator must be 
in place before any study-related procedures can take place, or subjects are randomised.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The study is expected to start in Quarter 3, 2016, and to end by Quarter 3, 2021.
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.
9.4
Data management 
Data management will be performed by PRA, according to the Data Management Plan.  The 
PRA Datalabs system will be used for data collection and query handling.  
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the Medical Dictionary for Regulatory Activities (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 Data Management Plan and Edit Check Plan.  
Quality control procedures will be applied to each stage of data handling to ensure that all data 

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are reliable and have been processed correctly.  The Data Management Plan will also clarify 
the roles and responsibilities of the various functions and personnel involved in the data 
management process.
When all data have been coded, validated, signed, and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious adverse event reconciliation
Serious adverse event reconciliation reports are produced and reconciled with the subject 
safety database and/or the investigational site.  Serious adverse event 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 before randomisation 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.

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Before randomisation 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 will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, ECs and Principal Investigators with safety 
updates/reports according to local requirements.
Each Principal Investigator 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 Principal Investigator 
so that he/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure that each subject is given full and adequate oral and written information 
about the nature, purpose, possible risk and benefit of the study

Ensure that 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 that each subject provides signed and dated informed consent before 
conducting any procedure specifically for the study

Ensure that the original, signed ICF(s) is/are stored in the Investigator’s Study File

Ensure that a copy of the signed ICF is 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 that is 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 changes to the study protocol, then these changes will be documented in a new 
version of the study protocol.

Clinical Study Protocol
Drug Substance Anifrolumab (MEDI 546)
Study Code D3461C00009
Version 3.0
Date 10 August 2017
95
If applicable, the new version of the protocol is to be approved by the relevant EC and 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 Principal Investigator(s).  For distribution to 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.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements.  The Investigator will contact AstraZeneca or 
designee immediately if contacted by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
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Baechler 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.
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 erythematosus blood. J Exp Med 
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.