Clinical trial NCT02446912
Conditions: Active Systemic Lupus Erythematosus
Keywords: Active Systemic Lupus Erythematosus
Sponsor: AstraZeneca
Start date: 2015-06-09; Completion date: 2018-07-17
Enrollment: 460 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of two doses of anifrolumab versus placebo in subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age.

Arms: arm 1: Anifrolumab arm 2: Placebo arm 3: Anifrolumab
Interventions: intervention 1: Anifrolumab intervention 2: Placebo
Intervention descriptions: intervention 1: Anifrolumab IV administration every 4 weeks from Week 0 to Week 48 for a total of 13 doses intervention 2: Placebo IV administration every 4 weeks from Week 0 to Week 48

Protocol documents:
Prot_002.pdf: 


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PROTOCOL SYNOPSIS
A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in 
Adult Subjects with Active Systemic Lupus Erythematosus
International Coordinating Investigator
Study site(s) and number of subjects planned
Approximately 450 subjects are planned at approximately 173 sites.
Study period
Phase of development
Estimated date of first subject enrolled
Q2 2015
3
Estimated date of last subject completed
Q2 2018
Study design
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab 
(150 mg or 300 mg) versus placebo in subjects with moderately to severely active, 
autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care 
(SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age.
Approximately 450 subjects receiving SOC treatment will be randomised in a 1:2:2 ratio to 
receive a fixed intravenous dose of 150 mg anifrolumab, 300 mg anifrolumab, or placebo 
every 4 weeks (Q4W) for a total of 13 doses (Week 0 to Week 48), with the primary endpoint 
evaluated at the Week 52 visit. Investigational product will be administered as an intravenous 
(IV) infusion via an infusion pump over a minimum of 30 minutes, Q4W. Subjects must be
taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial,
and/or immunosuppressants.
Randomisation will be stratified using the following factors: SLE Disease Activity Index 2000 
(SLEDAI-2K) score at screening (<10 points versus ≥10 points); Week 0 (Day 1) OCS dose 


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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(<10 mg/day versus ≥10 mg/day prednisone or equivalent); and results of a type 1 interferon 
(IFN) test (high versus low).
This study includes:

A Screening Period: Up to 30 days

Treatment Period: A 52-week double-blind treatment period with investigational
product administration Q4W from Week 0 to Week 48 for a total of 13 doses

At Week 52, subjects will have 2 options:

If eligible, enrol into the long-term extension (LTE) study
OR

Continue in the current study for another 8 weeks to complete a 12-week safety
follow-up after the last dose of investigational product (last dose of
investigational product will be given in Week 48)
Objectives
Primary Objective:
Outcome Measures:
To evaluate the effect of anifrolumab 300 mg 
compared to placebo on disease activity as 
measured by the difference in the proportion of 
subjects who achieve an SLE Responder Index 
of ≥4 (SRI[4]) at Week 52
Composite endpoint SRI(4), defined by the following 
criteria:
-
Reduction from baseline of ≥4 points in the
SLEDAI-2K and
-
No new organ system affected as defined by 1 or
more British Isles Lupus Assessment Group
(BILAG)-2004 A or 2 or more BILAG-2004 B
items compared to baseline using BILAG-2004
and
-
No worsening from baseline in subjects’ lupus
disease activity defined by an increase
≥0.30 points on a 3-point Physician’s Global
Assessment (PGA) visual analogue scale (VAS)
and
-
No discontinuation of investigational product or
use of restricted medications beyond the
protocol-allowed thresholda before assessment
Key Secondary Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab 300 mg compared to placebo on:
The proportion of subjects with SRI(4) at 
Week 52 in the IFN test-high sub-group
SRI(4) (see outcome measure for primary objective)


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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The proportion of subjects who achieve an 
OCS dose ≤7.5 mg/day at Week 40, which is 
maintained through Week 52 in the sub-group 
of subjects with baseline OCS ≥10 mg/day
Maintained OCS reduction defined by the following 
criteria: 
-
Achieve an OCS dose of ≤7.5 mg/day
prednisone or equivalent by Week 40 and
-
Maintain an OCS dose ≤7.5 mg/day prednisone
or equivalent from Week 40 to Week 52 and
-
No discontinuation of investigational product or
use of restricted medications beyond the
protocol-allowed thresholda before assessment
The proportion of subjects with a ≥50% 
reduction in Cutaneous Lupus Erythematosus 
Disease Area and Severity Index (CLASI) 
activity score at Week 12 in the sub-group of 
subjects with baseline CLASI activity score 
≥10
50% reduction in CLASI activity score compared to 
baseline defined by the following criteria:
-
Achieve ≥50% reduction of CLASI activity
score at Week 12 compared to baseline and
-
No discontinuation of investigational product or
use of restricted medications beyond the
protocol-allowed thresholda before assessment
The proportion of subjects with SRI(4) at 
Week 24
SRI(4) (see outcome measure for primary objective)
The annualised flare rate through 52 weeks
Annualised flare rate with flare defined as either 1 or 
more new BILAG-2004 A or 2 or more new 
BILAG-2004 B items compared to the previous visit
Other Secondary Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab 150 mg 
compared to placebo on disease activity as 
measured by the difference in the proportion of 
subjects who achieve SRI(4) at Week 52
SRI(4) (see endpoint for primary objective)
To assess the difference between anifrolumab 
300 mg and placebo on measures of disease 
activity including levels of SRI response other 
than 4, British Isles Lupus Assessment Group -
based Composite Lupus Assessment (BICLA), 
the individual components of SRI, and the 
number of swollen and tender joints at 
Week 52, as well as SRI and BICLA over time
SRI(4), SRI(5), SRI(6), SRI(7), SRI(8), BICLA 
response, BILAG-2004, SLEDAI-2K, PGA, Major 
Clinical Response, Partial Clinical Response, and 
joint count
To assess the difference between anifrolumab 
300 mg and placebo on measures of organ 
damage, ie, Systemic Lupus International 
Collaborating Clinics/American College of 
Rheumatology Damage Index (SDI) at 
Week 52
SDI




Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Investigational product, dosage and mode of administration
Approximately 450 subjects receiving SOC treatment will be randomised in a 1:2:2 ratio to 
receive a fixed IV dose of anifrolumab or placebo, as follows: 

Anifrolumab (MEDI-546) 150 mg IV administration Q4W OR

Anifrolumab (MEDI-546) 300 mg IV administration Q4W OR

Placebo IV administration Q4W
Statistical methods
The primary estimand of interest is the difference in change from baseline in disease activity 
between anifrolumab 300 mg and placebo, to reflect the effect of the initially assigned and 
dosed investigational product. This is measured by the primary efficacy endpoint, defined as 
the difference in the proportion of subjects achieving SRI(4) at Week 52. The full analysis set 
will be used as the primary population for reporting efficacy and safety data. The full analysis 
set is defined as subjects who are randomised and received at least 1 dose of investigational 
product (modified Intention-To-Treat).
The sample size is primarily driven by the need to acquire an adequate safety database size, as 
well as the ability to assess key secondary endpoints. The primary endpoint is the difference in 
proportions of subjects achieving SRI(4) at Week 52 comparing anifrolumab 300 mg to 
placebo. With assumed proportions of SRI(4) of 39% and 63% in the placebo and anifrolumab 
300 mg groups, respectively (based on the observed results in the interim analyses of study 
CD-IA-MEDI-546-1013), 180 subjects/arm yields more than 99% power to reject the
hypothesis of no difference using a 2-sided alpha of 0.05. The minimal detectable difference
in SRI(4) between anifrolumab 300 mg versus placebo is approximately 10% with this sample
size. With half of the sample size (ie, 90 subjects) for the anifrolumab 150 mg treatment
group, a 12.5% difference in SRI(4) between anifrolumab 150 mg versus placebo would be
associated with a nominal p-value of 0.05.
A stratified Cochran-Mantel-Haenszel test with the same stratification factors as for the 
randomisation, ie, disease activity at screening (SLEDAI-2K <10 points versus ≥10 points), 
Day 1 OCS dose (<10 mg/day versus ≥10 mg/day prednisone or equivalent), and results of the 
IFN test (high versus low) will be used for the assessment of the primary objective. 
A non-responder imputation method will be used for the handling of missing data and is 
incorporated into the definition of the primary endpoint. Subjects who discontinue from 
treatment and/or the study for any reason, as well as subjects who require restricted 
medications beyond the protocol-allowed threshold, will be imputed as failures. 
The key secondary endpoints will be analysed similarly, with the exception of the effect on 
the annualised flare rate, which will be analysed using a negative binomial regression model. 
The model will include covariates of treatment group, and the stratification factors. The 
logarithm of the follow-up time will be used as an offset variable in the model to adjust for 
subjects having different exposure times. The multiplicity of the key secondary variables will 


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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be controlled using a weighted procedure with pre-determined weights for each of the key 
secondary variables.
All safety parameters will be analysed descriptively. 


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................16
1.
INTRODUCTION .................................................................................................20
1.1
Background............................................................................................................20
1.2
Rationale for study design, doses and control groups............................................22
1.2.1
Rationale for study design .....................................................................................22
1.2.2
Rationale for primary endpoint selection...............................................................23
1.2.3
Rationale for dose selection...................................................................................23
1.2.4
Rationale for duration of infusion..........................................................................23
1.2.5
Interferon test background .....................................................................................23
1.3
Benefit/risk and ethical assessment........................................................................24
1.4
Study design...........................................................................................................29
1.4.1
Steroid burst...........................................................................................................29
1.4.2
Protocol-specified steroid tapering ........................................................................30
2.
STUDY OBJECTIVES..........................................................................................32
2.1
Primary objective...................................................................................................32
2.2
Secondary objectives .............................................................................................32
2.3
Safety objective......................................................................................................34
2.4
Exploratory objective.............................................................................................34
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION,
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................34
3.1
Inclusion criteria ....................................................................................................34
3.2
Exclusion criteria ...................................................................................................39
3.2.1
General exclusion criteria ......................................................................................39
3.2.2
Exclusion criteria related to concomitant medications ..........................................40
3.2.3
Exclusion criteria related to systemic lupus erythematosus and other 
diseases ..................................................................................................................42
3.2.4
Exclusion criteria related to infection and malignancy risk factors.......................43
3.3
Restrictions and concomitant medications.............................................................44
3.3.1
Excluded medications: Day 1 through the end of the study ..................................44
3.3.1.1
Medications that lead to immediate discontinuation of investigational 
product ...................................................................................................................44


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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3.3.1.2
Restricted medications...........................................................................................45
3.3.1.3
Other concomitant medications .............................................................................46
3.3.2
Concomitant medications for Systemic Lupus Erythematosus standard of 
care during the study..............................................................................................46
3.3.2.1
Steroid burst and taper Week 0 (Day 1) to Week 12 .............................................49
3.3.2.2
Increase in corticosteroids from Week 12 to Week 40..........................................49
3.3.2.3
Increase in oral corticosteroids after Week 40.......................................................50
3.3.2.4
Increase in oral corticosteroids for intercurrent disease or to prevent 
adrenal insufficiency..............................................................................................50
3.3.2.5
Protocol-specified steroid tapering Week 8 to Week 40........................................50
3.3.3
Other restrictions....................................................................................................51
3.3.3.1
Fasting lipid profile................................................................................................51
3.3.3.2
Perioperative management of investigational product...........................................51
3.4
Subject enrolment and randomisation....................................................................51
3.5
Methods for ensuring blinding...............................................................................52
3.6
Unblinding .............................................................................................................53
3.6.1
Unblinding for Data and Safety Monitoring Board ...............................................53
3.7
Discontinuation of investigational product............................................................53
3.7.1
Subject decision to discontinue investigational product........................................55
3.7.2
Withdrawal of the informed consent......................................................................55
3.7.3
Lost to follow-up....................................................................................................55
3.7.4
Study completion and end of study........................................................................55
3.7.5
Procedures for discontinuation of a subject from investigational product ............55
3.8
Criteria for withdrawal...........................................................................................56
3.8.1
Screen failures........................................................................................................56
3.9
Discontinuation of the study ..................................................................................56
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................57
4.1
Enrolment/Screening Period ..................................................................................66
4.1.1
Other considerations for screening ........................................................................66
4.1.1.1
Oral examination....................................................................................................66
4.1.1.2
Mammography.......................................................................................................66
4.1.2
Re-screening subjects who screen fail ...................................................................66
4.2
Treatment Period....................................................................................................67
4.2.1
Premature discontinuation of investigational product ...........................................67
4.3
Unscheduled Visit..................................................................................................68
4.4
Follow-up Period ...................................................................................................68
5.
STUDY ASSESSMENTS .....................................................................................69
5.1
Description of study procedures ............................................................................69
5.2
Efficacy assessments..............................................................................................69


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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5.2.1
Training and certification for Systemic Lupus Erythematosus assessments .........69
5.2.2
Disease Activity Adjudication Group....................................................................70
5.2.3
Systemic Lupus Erythematosus Disease Activity Index 2000...............................70
5.2.4
British Isles Lupus Assessment Group-2004.........................................................71
5.2.4.1
Protocol-specific clarification and extension of BILAG-2004 definitions............72
5.2.5
Physician Global Assessment ................................................................................72
5.2.6
Oral corticosteroid reduction .................................................................................73
5.2.7
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index................................................................................73
5.2.8
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
inflammatory disease activity ................................................................................73
5.2.9
Skin photography...................................................................................................74
5.2.10
Joint count..............................................................................................................74
5.3
Safety assessments.................................................................................................74
5.3.1
Adverse events.......................................................................................................74
5.3.2
Vital signs ..............................................................................................................75
5.3.3
Physical examination .............................................................................................75
5.3.3.1
Complete physical examination.............................................................................75
5.3.3.2
Focused physical examination ...............................................................................75
5.3.3.3
Pap smear...............................................................................................................75
5.3.3.4
Assessment of Cushingoid features .......................................................................76
5.3.4
Assessment of cardiovascular risk.........................................................................76
5.3.5
Columbia Suicide Severity Rating Scale ...............................................................76
5.3.6
Personal Health Questionnaire Depression Scale-8...............................................77
5.3.7
Electrocardiogram..................................................................................................77
5.3.8
Tuberculosis screening and monitoring.................................................................77
5.3.8.1
Screening evaluation..............................................................................................77
5.3.8.2
Tuberculosis results from screening evaluations ...................................................78
5.3.8.3
Tuberculosis monitoring during the study .............................................................78
5.3.9
Modified flare index ..............................................................................................79
5.3.10
Clinical laboratory tests .........................................................................................79
5.3.11
Laboratory assessments for cardiovascular risk assessments ................................82
5.3.11.1
Fasting lipid profile................................................................................................82
5.3.11.2
Immunology profile ...............................................................................................82
5.4
Clinical pharmacology assessments.......................................................................83
5.4.1
Pharmacokinetics ...................................................................................................83
5.4.2
Immunogenicity .....................................................................................................83
5.4.2.1
Anti-drug antibodies ..............................................................................................83
5.4.2.2
Neutralising antibodies ..........................................................................................83
5.4.3
Pharmacodynamics ................................................................................................83
5.4.4
Interferon test in whole blood................................................................................84
5.4.5
Proteomics/biomarkers ..........................................................................................84
5.4.6
Storage and destruction of biological samples.......................................................85
5.5
Quality of life/pharmacoeconomic assessments ....................................................85


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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5.5.1
Short Form 36 version 2 (acute recall) ..................................................................85
5.5.2
Functional Assessment of Chronic Illness Therapy–FATIGUE ...........................85
5.5.3
EuroQoL 5 dimensions ..........................................................................................85
5.5.4
Lupus Quality of Life.............................................................................................86
5.5.5
Patient Global Assessment.....................................................................................86
5.5.6
Work productivity and Activity Impairment .........................................................86
5.5.7
Medical Resource Use Questionnaire....................................................................86
5.5.8
Pain numerical rating scale ....................................................................................86
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................87
6.1
Definition of adverse events ..................................................................................87
6.2
Definition of serious adverse events......................................................................87
6.3
Hy’s law.................................................................................................................87
6.4
Other events of special interest..............................................................................87
6.4.1
Overdose ................................................................................................................87
6.4.2
Pregnancy...............................................................................................................88
6.4.3
Maternal exposure..................................................................................................88
6.4.4
Paternal exposure...................................................................................................88
6.5
Adverse Events of Special Interest ........................................................................89
6.5.1
Non-opportunistic serious infection.......................................................................89
6.5.2
Opportunistic infection ..........................................................................................89
6.5.3
Anaphylaxis ...........................................................................................................90
6.5.4
Malignancy ............................................................................................................90
6.5.5
Herpes zoster..........................................................................................................90
6.5.6
Tuberculosis...........................................................................................................90
6.5.7
Influenza ................................................................................................................91
6.5.8
Vasculitis (non-Systemic Lupus Erythematosus) ..................................................92
6.5.9
Major acute cardiovascular events.........................................................................92
6.6
Recording of adverse events ..................................................................................92
6.6.1
Time period for collection of adverse events.........................................................92
6.6.2
Follow-up of unresolved adverse events................................................................92
6.6.3
Variables ................................................................................................................92
6.6.4
Causality collection................................................................................................94
6.6.5
Adverse events based on signs and symptoms.......................................................94
6.6.6
Adverse events based on examinations and tests...................................................94
6.6.7
Disease progression/worsening of systemic lupus erythematosus.........................94
6.7
Reporting of serious adverse events.......................................................................95
6.8
Reporting of adverse events of special interest......................................................96
6.9
Management of investigational product-related toxicities.....................................96
6.9.1
Anaphylaxis, hypersensitivity, and infusion-related reactions ..............................96
6.9.2
Infections................................................................................................................96
6.10
Study governance and oversight ............................................................................97


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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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6.10.1
Data and Safety Monitoring Board........................................................................97
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................98
7.1
Identity of investigational products........................................................................98
7.2
Dose and treatment regimens.................................................................................98
7.2.1
Dose preparation steps ...........................................................................................98
7.2.2
Prior to administering the investigational product.................................................98
7.2.3
Investigational product administration procedures................................................99
7.2.4
Subject monitoring/procedures during and after the infusion................................99
7.2.5
Discharge .............................................................................................................100
7.2.6
Documentation of investigational product administration...................................100
7.3
Labelling ..............................................................................................................101
7.4
Storage .................................................................................................................101
7.5
Compliance ..........................................................................................................101
7.6
Accountability......................................................................................................101
7.7
Post study access to study treatment....................................................................102
8.
STATISTICAL ANALYSES ..............................................................................102
8.1
Statistical considerations......................................................................................102
8.2
Sample size estimate............................................................................................102
8.3
Definitions of analysis sets ..................................................................................103
8.3.1
All subjects analysis set .......................................................................................103
8.3.2
Full analysis set....................................................................................................103
8.3.3
Pharmacokinetic analysis set ...............................................................................103
8.4
Outcome measures for analyses...........................................................................104
8.4.1
Primary outcome variable....................................................................................104
8.4.2
Key secondary outcome variables........................................................................104
8.4.2.1
Systemic Lupus Erythematosus Responder Index of ≥4 at Week 52 in 
interferon test-high subjects.................................................................................104
8.4.2.2
Oral corticosteroid management..........................................................................104
8.4.2.3
Skin lesions ..........................................................................................................105
8.4.2.4
Systemic Lupus Erythematosus Responder Index of ≥4 at Week 24 ..................105
8.4.2.5
Flares....................................................................................................................105
8.4.3
Other secondary outcome variables.....................................................................105
8.4.3.1
Assessment of disease activity.............................................................................105
8.4.4
Subject reported outcome variables.....................................................................107
8.4.4.1
Short Form 36 version 2 (acute recall) ................................................................107
8.4.4.2
Pain Numerical Rating Scale ...............................................................................107
8.4.4.3
Functional Assessment of Chronic Illness Therapy-FATIGUE ..........................108
8.4.4.4
Patient Global Assessment...................................................................................108
8.4.4.5
LUPUS quality of life scale .................................................................................108
8.4.4.6
EuroQoL 5 dimensions ........................................................................................108


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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8.4.4.7
Work productivity and Activity Impairment - Lupus..........................................108
8.4.4.8
Medical Resource Use Questionnaire..................................................................108
8.4.5
Safety variables....................................................................................................108
8.4.5.1
Other significant adverse events ..........................................................................109
8.4.6
Immunogenicity variables....................................................................................109
8.4.7
Pharmacokinetic variables ...................................................................................109
8.4.8
Pharmacodynamic outcome variables..................................................................109
8.5
Methods for statistical analyses ...........................................................................109
8.5.1
Analysis of the primary variable..........................................................................111
8.5.2
Analysis of the secondary variables.....................................................................112
8.5.2.1
Analysis methods for key secondary efficacy variables......................................112
8.5.2.2
Analysis methods for other secondary efficacy variables....................................112
8.5.2.3
Analysis methods for safety variables .................................................................113
8.5.2.4
Analysis method for immunogenicity variables ..................................................114
8.5.2.5
Analysis methods for pharmacokinetic variables ................................................114
8.5.2.6
Analysis methods for pharmacodynamic variables .............................................114
8.5.3
Subgroup analysis ................................................................................................114
8.5.4
Interim analysis....................................................................................................114
8.5.5
Pooled analysis.....................................................................................................115
9.
STUDY AND DATA MANAGEMENT.............................................................115
9.1
Monitoring of the study .......................................................................................115
9.1.1
Source data...........................................................................................................115
9.1.2
Study agreements.................................................................................................115
9.1.3
Archiving of study documents.............................................................................116
9.2
Study timetable and end of study.........................................................................116
9.3
Data management.................................................................................................116
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................117
10.1
Ethical conduct of the study.................................................................................117
10.2
Subject data protection.........................................................................................117
10.3
Ethics and regulatory review................................................................................117
10.4
Informed consent .................................................................................................118
10.5
Changes to the protocol and informed consent form...........................................118
10.6
Audits and inspections .........................................................................................119
11.
LIST OF REFERENCES.....................................................................................119
LIST OF TABLES
Table 1
Effective methods of birth control............................................................37


Revised Clinical Study Protocol
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Table 2
Study plan detailing the procedures at screening .....................................57
Table 3
Study plan detailing the procedures during the Treatment Period 
(double-blind period)................................................................................59
Table 4
Study plan detailing the procedures during Follow-up ............................64
Table 5
Clinical laboratory tests............................................................................80
Table 6
Compatible materials of construction for IV bags..................................101
Table 7
Compatible materials of construction for ancillaries (eg, infusion 
tubing).....................................................................................................101
LIST OF FIGURES
Figure 1
Distribution of IFN transcript scores........................................................24
Figure 2
Study flow chart .......................................................................................31
Figure 3
Alpha recycling.......................................................................................110
LIST OF APPENDICES
Appendix A
Signatures (Not applicable)
Appendix B
Additional Safety Information 
Appendix C
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin – Hy’s Law
Appendix D 
American College of Rheumatology Classification Criteria
Appendix E 
Systemic Lupus Erythematosus Disease Activity Index 2000
Appendix F 
British Isles Lupus Assessment Group-2004
Appendix G 
Physician Global Assessment
Appendix H
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index
Appendix I
Cutaneous Lupus Erythematosus Disease Area and Severity Index
Appendix J
Columbia Suicide Severity Rating Scale
Appendix K
Personal Health Questionnaire Depression Scale-8


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Appendix L
Short Form 36 Version 2 (Acute Recall)
Appendix M
Functional Assessment of Chronic Illness Therapy-FATIGUE
Appendix N
EuroQoL 5 Dimensions
Appendix O
LupusQoL Questionnaire
Appendix P
Patient Global Assessment
Appendix Q
Work Productivity and Activity Impairment
Appendix R
Pain Numeric Rating Scale
Appendix S
Medical Resource Use Questionnaire
Appendix T
Vasculitic Syndromes Excluded from the Study
Appendix U
Restricted Medications
Appendix V
Oral Corticosteroid Guidance
Appendix W
General Guidance for Determination of Major Surgery
Appendix X
Guidance for Abnormal Pap Smear Results
Appendix Y
Anaphylaxis
Appendix Z 
Modified Flare Index


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ACR
American College of Rheumatology
ADA
Anti-drug antibodies
ADL
Activity of daily living
AE
Adverse event
AESI
Adverse event of special interest
AIS
Adenocarcinoma in situ 
ALT
Alanine aminotransferase
ANA
Antinuclear antibody
Anti-Sm
Anti-Smith 
Anti-RNP
Anti-Ribonucleoprotein
Anti-SSA
Anti-Sjogren’s Syndrome-related antigen A
Anti-SSB
Anti-Sjogren’s Syndrome-related antigen B
AST
Aspartate aminotransferase
β-hCG
β-human chorionic gonadotropin
BCG
Bacillus Calmette-Guerin
BICLA
British Isles Lupus Assessment Group-based Composite Lupus Assessment
BILAG
British Isles Lupus Assessment Group
BP
Blood pressure
C3
Third component of complement
C4
Fourth component of complement
CH50
Total haemolytic complement
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
CIN III
Cervical intraepithelial neoplasia grade III 
CIS
Carcinoma in situ 
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CLE
Cutaneous Lupus Erythematosus


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Abbreviation or 
special term
Explanation
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
C-SSRS
Columbia Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
Computed tomography
CV-EAC
Cardiovascular Event Adjudication Committee 
dECG
Digital electrocardiogram
DEHP
Diethylhexyl phthalate
DSMB
Data and Safety Monitoring Board
DNA
Deoxyribonucleic acid 
dsDNA
Double-stranded deoxyribonucleic acid
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
EDC
Electronic data capture 
EMA
European Medicines Agency
EQ-5D-5L
EuroQoL 5 dimensions
EudraCT
European Clinical Trials Database
EULAR
European League Against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy-FATIGUE
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV DNA
Hepatitis B virus DNA
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus


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Abbreviation or 
special term
Explanation
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive care unit
IFA
Immunofluorescent assay
IFIGx
Interferon-inducible gene expression
IFN
Interferon
Ig
Immunoglobulin
IGRA
Interferon-gamma release assay
International 
Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or 
activities internationally. 
IV
Intravenous
IXRS
Interactive voice/web response system
LLOQ
Lower limit of quantitation
LTE
Long-term extension
MACE
Major adverse cardiovascular events 
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI 
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
nAb
Neutralising antibodies 
NSAIDs
Nonsteroidal anti-inflammatory drugs
OCS
Oral corticosteroids
PD
Pharmacodynamic
PGA
Physician’s Global Assessment
PHQ-8
Personal Health Questionnaire Depression Scale-8
PI
Principal Investigator 
PIP
Proximal interphalangeal
PK
Pharmacokinetic(s)
PtGA
Patient Global Assessment
PVC
Polyvinyl chloride
Q4W
Every 4 weeks


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Abbreviation or 
special term
Explanation
QFT-G
QuantiFERON-TB Gold
QoL
Quality of life
RGQ
Rotor-Gene Q
RNA
Ribonucleic acid
RT-PCR
Reverse transcriptase polymerase chain reaction
SAE
Serious adverse event 
SAP
Statistical analysis plan
SC
Subcutaneous
SDI
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index
SF-36v2 (acute)
Short Form 36 version 2 (acute recall)
SLE
Systemic lupus erythematosus
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000
SMR
Standardised mortality ratio
SOC
Standard of care
SRI(4)
Systemic Lupus Erythematosus Responder Index of ≥4 
TB
Tuberculosis
ULN
Upper limit of normal
VAS
Visual analogue scale
WPAI
Work productivity and Activity Impairment


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1.
INTRODUCTION
1.1
Background 
Systemic lupus erythematosus (SLE) is a chronic, multisystemic, disabling autoimmune 
rheumatic disease of unknown aetiology. Systemic lupus erythematosus predominantly affects 
women of childbearing years (Cooper et al, 1998; Lahita, 1999) with a review reporting the 
female-to-male ratio in the childbearing years to be about 12:1 (Ramsey-Goldman and Manzi, 
2000). There is substantial unmet medical need in the treatment of SLE, particularly in 
subjects with moderate or severe disease. Although off-label therapy has improved 
management options in recent years, long-term prognosis remains poor for many subjects. 
Compared to the general population, the overall mortality in SLE is increased with a 
standardised mortality ratio (SMR; defined as the ratio of the number of deaths observed to 
deaths expected) of 2.4, (2.3 to 2.5 95% confidence interval [CI]) in a large international 
cohort of 9,457 subjects followed for over 70000 subject-years (Bernatsky et al, 2006).
Clinical manifestations of SLE include, but are not limited to, constitutional symptoms, 
alopecia, rashes, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, 
haemolytic anaemia, cognitive dysfunction and other nervous system involvement. These 
disease manifestations cause a significant burden of illness and can lead to reduced physical 
function, loss of employment, lower health-related quality of life (QoL), and a lifespan 
shortened by about 10 years (ACR ad hoc committee, September 1999). Increased 
hospitalisations and side effects of medications including chronic oral corticosteroids (OCS) 
and other immunosuppressive treatments add to disease burden in SLE (Doria and Briani, 
2008; Petri, 2001; Zonana-Nanach et al, 2000).
All of the therapies currently used for the treatment of SLE have well known adverse effect 
profiles and there is a medical need to identify new targeted therapies, particularly agents that 
may reduce the requirement for corticosteroids and cytotoxic agents.
There has been only 1 new treatment (belimumab) for SLE approved by the US Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) in the approximately 
50 years since hydroxychloroquine was approved for use in discoid lupus and SLE. However, 
belimumab is not approved everywhere, and the uptake has been modest. Many agents 
currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate 
mofetil/mycophenolic acid, have not been approved for the disease. Furthermore these drugs 
all have well-documented safety issues and are not effective in all patients for all 
manifestations of lupus. Antimalarial agents (eg, hydroxychloroquine) and corticosteroids 
may be used to control arthralgia, arthritis, and rashes. Other treatments include nonsteroidal 
anti-inflammatory drugs (NSAIDs); analgesics for fever, arthralgia, and arthritis; and topical 
sunscreens to minimise photosensitivity. It is often difficult to taper subjects with moderate or 
severe disease completely off corticosteroids, which cause long-term morbidity and may 
contribute to early cardiovascular mortality (Petri, 2001; Urowitz et al, 1976). Even small 
daily doses of 5 to 10 mg prednisone used long-term carry increased risks of side effects such 
as cataracts, osteoporosis, and coronary artery disease (Petri, 2001).


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


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Anifrolumab (MEDI-546) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal 
antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). It is 
composed of 2 identical light chains and 2 identical heavy chains, with an overall molecular 
weight of approximately 148 kDa. Anifrolumab inhibits binding of type I IFN to type I 
interferon receptor (IFNAR) and inhibits the biologic activity of all type I IFNs. 
1.2
Rationale for study design, doses and control groups
1.2.1
Rationale for study design
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of an intravenous (IV) treatment regimen of 
anifrolumab (150 mg or 300 mg) versus placebo in adult subjects with moderately to severely 
active, autoantibody-positive SLE while receiving standard of care (SOC) treatment. 
It is thought that neutralisation of IFN signalling through the human type I IFN receptor with 
anifrolumab will reduce the severity of disease activity in subjects with chronic, 
moderately-to-severely active SLE, and that anifrolumab will be well tolerated when given at 
the proposed doses for the duration of the study.
To ensure adequate treatment, all subjects will receive SOC treatment with at least 1 of the
following: OCS, antimalarial, or immunosuppressants, in addition to investigational product. 
This is consistent with the both the European League Against Rheumatism (EULAR) 
(Bertsias et al, 2008) and American College of Rheumatology (ACR) (ACR ad hoc 
committee, September 1999) management guidelines of moderate to severe SLE.
The study will be randomised, placebo-controlled, and double-blind to ensure a robust design 
and minimise bias. This is the preferred design as outlined in the June 2010 FDA Guidance for 
Industry Systemic Lupus Erythematosus-Developing Medical Products for Treatment and in 
the Committee for Medicinal Products for Human Use (CHMP) Guideline on clinical 
investigation of medicinal products for the treatment of SLE and lupus nephritis (CHMP, 
February 2015).
Randomisation will be stratified by Systemic Lupus Erythematosus Disease Activity Index 
2000 (SLEDAI 2K, see Appendix E) score at screening (<10 points versus ≥10 points), Day 1
OCS dose (<10 mg/day versus ≥10 mg/day of prednisone or equivalent), and the results of the 
IFN test (high versus low). Stratification is implemented in order to minimise the risk for 
baseline imbalance(s) across treatment arms on potentially confounding variables. Baseline 
imbalances of these factors could impact efficacy and/or safety assessments of anifrolumab 
versus placebo.
A treatment period of 52 weeks is an appropriate study duration to determine the 
investigational product’s long-term efficacy and safety profile.


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1.2.2
Rationale for primary endpoint selection
The primary outcome measure is the proportion of subjects who achieve Systemic Lupus 
Erythematosus Responder Index of ≥4 (SRI[4]) at Week 52. This endpoint was employed as 
the primary endpoint in both pivotal studies of a large phase 3 program (Furie et al, 2009, 
Navarra et al, 2011, Wallace et al, 2009) in SLE and provided the basis for regulatory 
approvals of belimumab. 
1.2.3
Rationale for dose selection
The selection of a dose of 300 mg anifrolumab every 4 weeks (Q4W) for this study is based 
on safety and efficacy results from the interim analysis of a Phase 2b study where 2 doses of 
anifrolumab (300 mg and 1000 mg) are evaluated relative to placebo as well as dose-response 
modelling and simulation. In the interim analysis of the Phase 2b study, clinically meaningful 
benefit was observed with the 300 mg dose, with no incremental benefit at 1000 mg, see 
Section 1.3 for details. In addition, a higher proportion of subjects reporting herpes zoster
reactivations was observed at 1000 mg compared to 300 mg. Given the comparable efficacy 
between the 300 and 1000 mg anifrolumab doses and the increased frequency of herpes zoster
events in the 1000 mg dose group relative to the 300 mg dose group, the benefit:risk profile 
appears to favour the 300 mg dose. Further, from the PK/efficacy model, minimal 
improvement in efficacy was predicted for doses higher than 300 mg, consistent with the 
observed Phase 2b study interim analysis data. The model also predicted that doses lower than 
300 mg will result in lower efficacy since trough concentrations (Ctrough) from doses lower 
than 300 mg will fall below the model-predicted concentrations corresponding to 80% of 
maximum SRI(4) efficacy. The non-linear PK properties of anifrolumab cause a large increase 
in Ctrough variability at doses below 300 mg, so as anifrolumab dose is lowered, a large 
proportion of subjects are predicted to have very rapid clearance and negligible exposure to 
anifrolumab. A dose of 150 mg is evaluated in this study to provide supportive evidence that 
300 mg is the minimum effective dose of anifrolumab.
1.2.4
Rationale for duration of infusion
In a Phase 2b study where 2 doses of anifrolumab in combination with SOC (300 mg and 
1000 mg) were compared to placebo, combined with SOC, all doses were administered over 
approximately 60 minutes. The frequency of infusion-related reactions did not differ 
substantially between the 300 mg (2.0%) and 1000 mg (3.8%) groups and both were lower 
than that observed in the placebo group (5.9%). Therefore, in this study the infusion time was 
reduced to a minimum of 30 minutes.
1.2.5
Interferon test background
Type I IFN has been considered to be important in SLE disease pathogenesis and inhibition of 
this pathway is targeted by anifrolumab. To understand the relationship between type I IFN 
expression and response to anti-IFN therapy, it is necessary to know if a subject’s disease is 
driven by type I IFN activation. However, direct measurement of the target protein remains a 
challenge. As such, a transcript-based marker was developed to evaluate the effect of over 
expression of the target protein on a specific set of mRNA markers. The expression of these 
markers is easily detected in whole blood and demonstrates a correlation with expression in 




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
Study CD-IA-MEDI-546-1013 is an ongoing Phase 2b, randomised, double-blind, 
placebo controlled study of anifrolumab (300 and 1000 mg) in adult subjects with 
moderately to severely active SLE (ongoing at the time of writing this protocol).

Study CD-IA-MEDI-546-1145 is the ongoing open-label extension (OLE) for 
subjects completing Study CD-IA-MEDI-546-1013 (ongoing at the time of writing 
this protocol).

Study D3461C00002 is an ongoing study in Japanese adult subjects with SLE 
(ongoing at the time of writing this protocol).

Study D3461C00001 is an ongoing study in adult subjects with lupus nephritis 
(ongoing at the time of amending this protocol).
Study CD-IA-MEDI-546-1013 is a Phase 2b, randomised, double-blind, placebo-controlled, 
parallel group study to evaluate the efficacy and safety of anifrolumab in adult subjects with 
chronic, moderately to severely active SLE with an inadequate response to SOC treatment for 
SLE. Subjects were randomised 1:1:1 to placebo, anifrolumab 300 mg or anifrolumab
1000 mg while continuing their SOC treatment. Enrolment in the study is complete. An 
interim analysis (including the analysis of the primary endpoint) was conducted after all 
subjects completed the Day 169 visit or discontinued from study treatment early. As of the 
data cut-off date of August 15, 2014, a total of 305 subjects had been treated with 
investigational product (2 subjects discontinued from the study prior to dosing). 
Efficacy in anifrolumab Phase 2b study
The primary efficacy endpoint of the Phase 2b study was the proportion of subjects achieving 
response in Systemic Lupus Erythematosus Responder Index (4) (SRI[4]) with sustained 
reduction of OCS (<10 mg/day and less than or equal to the dose received on Day 1 by Day 85 
and maintained between Days 85 and 169) at Day 169. There were higher proportions of 
subjects in the 300 mg (34.3%) and 1000 mg (28.8%) anifrolumab groups than in the placebo 
(17.6%) group who met the primary endpoint at Day 169. Similar results were also observed 
in the other co-primary population, the IFN test-high subjects (representing approximately 
75% of the study population) but not in the IFN test-low subjects at Day 169 (it is important to 
note that the sample size is low in this subpopulation). Further, compared to the placebo 
group, numerically higher proportions of subjects in the anifrolumab groups met the 
secondary endpoints of SRI(4) with sustained reduction of OCS (<10 mg/day and less than or 
equal to the dose received on Day 1 by Day 281 and maintained between Days 281 and 365)
at Day 365 (placebo [25.5%], 300 mg [51.5%] and 1000 mg [38.5%]) and reduction of 
background OCS dose to ≤7.5 mg/day at Day 365 in those taking ≥10 mg/day at baseline 
(placebo [26.6%], 300 mg [56.4%], and 1000 mg [31.7%]). 
The efficacy observed with the primary and secondary endpoints was supported by a wide 
range of evidence. A numerically higher proportion of subjects receiving anifrolumab met SRI 
response criteria without the OCS taper requirement at Day 169 and Day 365 compared to 
placebo. Furthermore, compared to the placebo group numerically higher proportions of 
anifrolumab treated subjects achieved SRI(5), SRI(6), SRI(7), and SRI(8) response, as well as 


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a British Isles Lupus Assessment Group (BILAG)-2004 based combined lupus assessment 
(BICLA) response.
Higher response rates were also observed in organ specific measures for anifrolumab-treated 
subjects compared with placebo. In subjects with moderate or severe skin disease (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index [CLASI] activity score ≥10) at 
baseline, a numerically higher proportion of subjects achieved at least 50% improvement from 
baseline in the CLASI activity score following anifrolumab treatment compared to subjects 
receiving placebo. In subjects with moderate or severe arthritis (≥8 swollen and tender joints) 
at baseline, a numerically higher proportion of subjects treated with 300 mg anifrolumab 
achieved at least 50% improvement in swollen and tender joint counts compared to subjects 
treated with placebo.
Amongst subjects with a dose of ≥10 mg/day oral prednisone or equivalent at baseline, a 
numerically higher proportion of subjects in the 300 mg anifrolumab group than in the 
placebo group were able to reduce OCS to ≤7.5 mg/day prednisone or equivalent by Day 169. 
Similar results were seen at Day 365. No apparent differences were seen when comparing the 
1000 mg anifrolumab and placebo groups.
Serum complement and anti-dsDNA antibody levels are often indicative of active disease in 
SLE. In subjects with detectable anti-dsDNA autoantibody levels at baseline, those treated 
with 300 mg anifrolumab demonstrated a numerically larger decrease from baseline in anti-
dsDNA antibody levels at Day 365 than those who were treated with placebo. In subjects with 
abnormal third component of complement (C3) levels at baseline, those treated with 
anifrolumab demonstrated a numerically larger increase from baseline in C3 levels at Day 169 
and 365 than those who were treated with placebo. 
Expression of type I IFN-inducible genes in whole blood using a 21-gene panel 
(pharmacodynamic [PD] marker) decreased following anifrolumab administration for all dose 
groups in subjects with a baseline positive type I IFN signature in whole blood. Both the 
300 mg and 1000 mg anifrolumab dose achieved and maintained 82 to 90% neutralisation of 
the gene signature. In the placebo group no neutralisation of the gene signature (>6%) was 
observed at any time point.
Safety experience in anifrolumab Phase 2b study through August 2014 
Although the safety profile for anifrolumab is acceptable, an imbalance was seen in the rate of 
occurrence of uncomplicated herpes zoster reactivation.
The overall number of subjects with adverse events (AEs), serious adverse events (SAEs) and 
adverse events of special interest (AESIs) (new or reactivated tuberculosis [TB], malignancy, 
infusion or hypersensitivity or anaphylactic reaction and non SLE-related vasculitis) were 
similar between the placebo and anifrolumab groups. Serious adverse events related to the 
investigational product were observed in 5.9% of the subjects in the placebo, 3.0% in the 
300 mg and 1.0% in the 1000 mg anifrolumab group. Adverse events leading to 
discontinuation of the investigational product were observed in 7.9% in the placebo, 3.0% in 


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the 300 mg and 9.5% in the 1000 mg anifrolumab group. There was 1 death in the 1000 mg 
anifrolumab group (
) and none in the other 2 treatment groups.
There was a higher number of subjects with infection-related AEs in both the 300 mg (63.6%) 
and 1000 mg (61.9%) anifrolumab groups compared with the placebo group (51.5%). This 
was due primarily to more reports of uncomplicated cases of herpes zoster in the anifrolumab 
treated subjects (300 mg: 5.1%; 1000 mg: 9.5%) compared to placebo (2.0%). Importantly, 
subjects with herpes zoster infection responded to standard antiviral treatment. One treatment-
emergent SAE of transverse myelitis with a positive varicella zoster virus polymerase chain 
reaction in cerebrospinal fluid was reported. The subject recovered following treatment with 
pulsed steroid and standard antiviral medication.
There was a higher number of subjects with infections reported as influenza in the 
anifrolumab groups (300 mg: 6.1%; 1000 mg: 7.6%) compared to placebo (2.0%); however, 
the protocol did not require objective evidence confirming the aetiology of these infections. 
Infusion-related reactions were observed in 5.9% of placebo treated subjects: 2.0% in the 
300 mg anifrolumab group and 3.8% in the 1000 mg anifrolumab group. The characteristics 
and severity of these reactions were similar in all 3 treatment groups.
Overall benefit:risk assessment 
Anifrolumab demonstrated a clinically relevant benefit in subjects with moderate to severe 
SLE treated with SOC. The efficacy was supported by a broad range of clinical measures of 
global (various levels of SRI responses, BICLA) and organ specific disease activity (CLASI, 
joint count). A clinically relevant increase in the proportion of subjects achieving 
pre-specified corticosteroid reduction in the 300 mg group was also observed compared with 
placebo, while no apparent difference was observed comparing the 1000 mg group and 
placebo. 
Anifrolumab was generally well tolerated. A dose-related increase in the number of subjects 
with uncomplicated herpes zoster infections was observed in subjects receiving anifrolumab 
compared with placebo. To date, in clinical trials of anifrolumab, hypersensitivity events or 
anaphylaxis/anaphylactoid events have not occurred more frequently in subjects who were 
treated with anifrolumab as compared to placebo, although careful monitoring for such events 
will continue.
The administration of any foreign protein may be associated with acute allergic reactions that 
may be severe, and may result in death. Acute allergic reactions may include hypotension, 
dyspnoea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, and 
unresponsiveness. Reports of infusion-related reactions from clinical trials conducted to date 
suggest that the frequency, severity and characteristics of these reactions are similar across all 
treatment groups.
Although anifrolumab is a human monoclonal antibody, subjects can develop anti-
anifrolumab antibodies that may neutralise the activity of the drug or may be associated with 


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acute or delayed hypersensitivity reactions including anaphylaxis. Subjects will be monitored 
for clinical manifestations that may be associated with the formation of specific antibodies to 
anifrolumab generated during the study, as well as for the presence of such antibodies.
In this study, anifrolumab will be administered at a fixed IV dose of 150 mg or 300 mg Q4W 
for 52 weeks. The 300 mg dose is equivalent to the lower dose in the Phase 2 study (CD-IA-
MEDI-546-1013). Anifrolumab has been generally well tolerated to date with no dose-related 
safety signal observed with the exception of an imbalance in observed events of 
uncomplicated herpes zoster infections. 
In order to minimise the risk of treatment with anifrolumab, subjects with risk factors for 
serious infection, malignancy, or immune deficiency disorders are specifically excluded from 
participation.
Serious infections, including non-opportunistic serious infections, opportunistic infections, 
anaphylaxis, malignancy, herpes zoster, TB (including latent TB), influenza, vasculitis (non 
SLE), and major adverse cardiovascular events (MACE) (including stroke, myocardial 
infarction [MI], or cardiovascular death) are designated as AESIs in this study. 
Major adverse cardiovascular events are also designated as AESIs. An external independent 
adjudication committee will assess all deaths and cardiovascular SAEs to determine if they 
meet criteria for MACE (stroke, MI, or cardiovascular death). Specific details will be 
addressed in a cardiovascular event adjudication charter. There have been no imbalances in 
reporting rates of MACE or other non-MACE cardiovascular events observed either with 
anifrolumab or other agents sharing a similar mechanism of action compared to 
controls/placebo to date. However, since accelerated coronary artery disease and 
cerebrovascular accidents are recognised complications of SLE, the adjudication process is 
put in place to support rigorous signal detection activity across treatment arms.
Compared to the general population, subjects with SLE have a higher rate of depression and 
suicide. Therefore, subjects will be screened for suicidality and those who are at high risk at 
baseline will be excluded from participation in the study.
In order to provide an independent periodic review of safety throughout the trial, in addition to 
the ongoing, blinded review provided by the Medical Monitor, an independent Data and 
Safety Monitoring Board (DSMB) will review blinded and unblinded safety data on a regular 
basis throughout the study (see Section 6.10.1).
In conclusion, AstraZeneca believes that the available nonclinical and clinical data indicate an 
acceptable safety profile for anifrolumab. The proposed dosing regimens for Protocol 
D3461C0005 are adequately justified and the management plan for potential risks associated 
with anifrolumab is appropriate. The emerging safety profile has not identified any risks that 
would preclude continued investigation of anifrolumab. AstraZeneca believes that 
anifrolumab continues to demonstrate an overall positive benefit-risk balance to support its 
further clinical evaluation in subjects with active SLE.


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Edition Number 5
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1.4
Study design 
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of an IV treatment regimen of anifrolumab (150 mg 
or 300 mg) versus placebo in adult subjects with moderately to severely active, autoantibody-
positive SLE while receiving SOC treatment. The study will be performed in adult subjects 
aged 18 to 70 years of age.
Approximately 450 subjects receiving SOC treatment will be randomised in a 1:2:2 ratio to 
receive a fixed IV dose of 150 mg anifrolumab, 300 mg anifrolumab, or placebo Q4W for a 
total of 13 doses (Week 0 to Week 48) with the primary endpoint evaluated at the Week 52 
visit. Investigational product will be administered as an IV infusion via an infusion pump over 
a minimum of 30 minutes, Q4W. 
Subjects must be taking either 1 or any combination of the following: OCS, antimalarial, or 
immunosuppressants. Specific medication restrictions are contained in the eligibility criteria 
and Section 3.3. See Figure 2 for an outline of the study design.
Randomisation will be stratified using the following factors: 

SLEDAI-2K score at screening (<10 points versus ≥10 points)

Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or
equivalent)

Results of the IFN test (high versus low)
This study includes:

A Screening Period: Up to 30 days

Treatment Period: A 52-week double-blind treatment period with investigational
product administration Q4W from Week 0 to Week 48 for a total of 13 doses

At Week 52, subjects will have 2 options:

If eligible, enrol into the long-term extension (LTE) study
OR

Continue in the current study for another 8 weeks to complete a 12-week safety
follow-up after the last dose of investigational product (last dose of
investigational product will be given in Week 48)
The total study duration could be up to approximately 64 weeks for subjects who do not enrol 
into the LTE study (including screening period) and up to approximately 56 weeks (including 
screening period) for those subjects who do enrol into the LTE study.
1.4.1
Steroid burst
Section 3.3.2 provides specific details on steroid burst and tapers. From Week 0 (Day 1) to 
Week 12, subjects may receive only 1 burst of corticosteroids for an increase in SLE disease 


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Edition Number 5
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activity or to control non-SLE related disease (eg, asthma or chronic obstructive pulmonary 
disease [COPD] exacerbation). Subjects receiving more than 1 burst during the first 12 weeks 
of treatment will be considered non-responders for subsequent assessments of disease activity, 
regardless of the reason for the burst (SLE or non-SLE activity). 
1.4.2
Protocol-specified steroid tapering
An important secondary objective in this study is assessing whether anifrolumab improves the 
ability to reduce corticosteroid dose in patients to <7.5 mg prednisone or equivalent per day. 
For this reason, steroid tapering to a target OCS dose of ≤7.5 mg/day must be attempted in all 
subjects with a baseline OCS dose ≥10.0 mg/day. This will commence at Week 8 and continue 
stepwise until the target dose is reached, unless at least 1 of the following criteria is met:

SLEDAI-2K activity which is worsened compared to baseline in major organ
systems (renal, CNS, cardiopulmonary, vasculitis, fever, thrombocytopenia, or
haemolytic anaemia, or gastrointestinal activity)

Newly-affected organ system(s) based on the SLEDAI-2K, excluding serological
abnormalities (dsDNA antibodies, hypocomplementemia)

Moderate to severe skin disease as reflected by a CLASI activity score of ≥10

Moderate to severe arthritis disease as reflected by an active joint count of ≥8 tender
and/or swollen joints
A recommended steroid-tapering regimen is provided in Appendix V, but Investigators will 
have flexibility in how the OCS dose is reduced at each visit. If steroid tapering is not 
attempted in an eligible subject, the Sponsor or Sponsor’s designee must be contacted 
immediately.
Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
7.5 mg/day up to Week 40 based on disease activity. If a subject has an increase in disease 
activity secondary to OCS tapering, they may increase the dose up to a maximum of the 
baseline OCS therapy dose from Week 8 up to Week 40 without the subject being considered 
a non-responder for subsequent assessments of disease activity. Subjects who require OCS 
dose above their baseline level may continue in the study but will be considered 
non-responders for subsequent assessments of disease activity.
Steroid tapering will not be permitted after Week 40.


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Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Figure 2
Study flow chart
IFN = interferon; IV = intravenous; N = number of subjects; OCS = oral corticosteroid; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index; 
Q4W = every 4 weeks; V = Visit; W = Week


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Edition Number 5
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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measures:
To evaluate the effect of anifrolumab 300 mg 
compared to placebo on disease activity as 
measured by the difference in the proportion 
of subjects who achieve an SLE Responder 
Index of ≥4 (SRI[4]) at Week 52
Composite endpoint SRI(4), defined by the following 
criteria:
-
Reduction from baseline of ≥4 points in the 
SLEDAI-2K and
-
No new organ system affected as defined by 1 or 
more BILAG-2004 A or 2 or more BILAG-2004 
B items compared to baseline using 
BILAG-2004 and
-
No worsening from baseline in subjects’ lupus 
disease activity defined by an increase 
≥0.30 points on a 3-point Physician’s Global 
Assessment (PGA) visual analogue scale (VAS) 
and
-
No discontinuation of investigational product or 
use of restricted medications beyond the 
protocol-allowed thresholda before assessment
a
Allowed medication is described in Section 3.3. 
2.2
Secondary objectives
Key Secondary Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab 300 mg compared to placebo on:
The proportion of subjects with SRI(4) at 
Week 52 in the IFN test-high sub-group
SRI(4) (see outcome measure for primary objective)
The proportion of subjects who achieve an 
OCS dose ≤7.5 mg/day at Week 40, which is 
maintained through Week 52 in the sub-group 
of subjects with baseline OCS ≥10 mg/day
Maintained OCS reduction defined by the following 
criteria: 
-
Achieve an OCS dose of ≤7.5 mg/day 
prednisone or equivalent by Week 40 and
-
Maintain an OCS dose ≤7.5 mg/day prednisone 
or equivalent from Week 40 to Week 52 and
-
No discontinuation of investigational product or 
use of restricted medications beyond the 
protocol-allowed thresholda before assessment


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Edition Number 5
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The proportion of subjects with a ≥50% 
reduction in CLASI activity score at Week 12 
in the sub-group of subjects with baseline 
CLASI activity score ≥10
50% reduction in CLASI activity score compared to 
baseline defined by the following criteria:
-
Achieve ≥50% reduction of CLASI activity
score at Week 12 compared to baseline and
-
No discontinuation of investigational product or
use of restricted medications beyond the
protocol-allowed thresholda before assessment
The proportion of subjects with SRI(4) at 
Week 24
SRI(4) (see outcome measure for primary objective)
The annualised flare rate through 52 weeks
Annualised flare rate with flare defined as either 1 or 
more new BILAG-2004 A or 2 or more new 
BILAG-2004 B items compared to the previous visit
Other Secondary Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab 150 mg 
compared to placebo on disease activity as 
measured by the difference in the proportion 
of subjects who achieve SRI(4) at Week 52
SRI(4) (see endpoint for primary objective)
To assess the difference between anifrolumab 
300 mg and placebo on measures of disease 
activity including levels of SRI response other 
than 4, British Isles Lupus Assessment 
Group-based Composite Lupus Assessment 
(BICLA), the individual components of SRI, 
and the number of swollen and tender joints at 
Week 52, as well as SRI and BICLA over time
SRI(4), SRI(5), SRI(6), SRI(7), SRI(8), BICLA 
response, BILAG-2004, SLEDAI-2K, PGA, Major 
Clinical Response, Partial Clinical Response, and 
joint count
To assess the difference between anifrolumab 
300 mg and placebo on measures of organ 
damage, ie, Systemic Lupus International 
Collaborating Clinics/American College of 
Rheumatology Damage Index (SDI) at 
Week 52
SDI
To assess the difference between anifrolumab 
300 mg and placebo on subject-reported health 
status, health-related QoL, and other 
subject-reported outcome measures of fatigue, 
pain, patient global assessment, and work 
productivity at Week 52
Short Form 36 version 2 (acute recall) (SF-36v2 
[acute]), Pain numeric rating scale (NRS), Functional 
Assessment of Chronic Illness Therapy-FATIGUE 
(FACIT-F), Patient Global Assessment (PtGA), 
Lupus QoL, EuroQoL 5 dimensions (EQ-5D-5L), 
Work Productivity and Activity Impairment 
(WPAI)-Lupus, and Medical Resource Use 
Questionnaire 
To evaluate the pharmacokinetics, 
immunogenicity, and pharmacodynamics of 
anifrolumab
Anifrolumab concentration and PK parameters, 
anti-drug antibodies (ADA), 21-gene type I 
interferon (IFN) gene signature, anti-dsDNA 
antibodies, C3, fourth component (C4), and total 
haemolytic (CH50) complement levels
a
Allowed medication is described in Section 3.3




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Edition Number 5
Date 18 May 2016
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6.
Diagnosis of paediatric or adult SLE with a diagnosis of SLE according to the ACR
1982 revised criteria (Tan et al, 1982) ≥24 weeks prior to signing the ICF
7.
Currently receiving at least 1 of the following*:
(a)
Where prednisone is the single standard of care medication (ie, the
subject is not concurrently receiving any medication listed in inclusion
criterion 7(c)), a dose of oral prednisone ≥7.5 mg/day but ≤40 mg/day
(or prednisone equivalent**) for a minimum of 8 weeks prior to Day 1.
In addition, the dose of oral prednisone or prednisone equivalent the
subject is taking must be stable for a minimum of 2 weeks prior to
randomisation
(b)
Where prednisone is not the single standard of care medication (ie, the
subject is concurrently receiving at least one medication listed in
inclusion criterion 7(c)), a dose of oral prednisone ≤40 mg/day (or
prednisone equivalent**) for a minimum of 2 weeks prior to signing of
the ICF. In addition, the dose of oral prednisone or prednisone
equivalent the subject is taking must be stable for a minimum of 2 weeks
prior to randomisation
(c)
Any of the following medications administered for a minimum of
12 weeks prior to signing the informed consent, and at a stable dose for
a minimum of 8 weeks prior to signing the informed consent
through Day 1:
(i)
Azathioprine ≤200 mg/day
(ii)
Antimalarial (eg, chloroquine, hydroxychloroquine,
quinacrine)
(iii)
Mycophenolate mofetil ≤2 g/day or mycophenolic acid
≤1.44 g/day
(iv)
Oral, subcutaneous (SC), or intramuscular methotrexate
≤25 mg/week
(v)
Mizoribine ≤150 mg/day
*If receiving oral prednisone (or equivalent) and an additional agent, the dose duration
and maximum allowable dosages for both (b) and (c) must be met
**See Appendix V for examples of prednisone equivalency
8.
Fulfils at least 4 of the 11 ACR modified 1982 classification criteria for SLE (see
Appendix D), at least 1 of which must be:


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Edition Number 5
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(a)
Positive antinuclear antibody (ANA) test at screening by
immunofluorescent assay (IFA) at the central laboratory with titre
≥1:80; OR
(b)
Anti-dsDNA antibodies at screening elevated to above normal
(including indeterminate), as per the central laboratory; OR
(c)
Anti-Smith (anti-Sm) antibody at screening elevated to above normal as
per the central laboratory
9.
At Screening, Disease Activity Adjudication Group confirmation of:
(a)
SLEDAI-2K Criteria: SLEDAI-2K score ≥6 points and “Clinical”
SLEDAI-2K score ≥4 points. The “Clinical” SLEDAI-2K is the
SLEDAI-2K assessment score without the inclusion of points
attributable to any urine or laboratory results including immunologic
measures:
(i)
Includes points from the following clinical components:
arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy,
pericarditis, or vasculitis
(ii)
Excludes points attributed to a fever, an SLE headache, and
organic brain syndrome
(b)
BILAG-2004 Level Criteria: At least 1 of the following:
i)
BILAG-2004 level A disease in ≥1 organ system
ii)
BILAG-2004 level B disease in ≥2 organ systems
(c)
Physician’s Global Assessment (PGA) score ≥1.0 on a 0 to 3 VAS at
screening
10.
Negative serum β-human chorionic gonadotropin (β-hCG) test at screening (females
of childbearing potential only).
11.
Females of childbearing potential must use 2 effective methods of avoiding
pregnancy, one of which is a barrier method, from Screening until 12 weeks after
the final dose of investigational product unless the subject is surgically sterile (ie,
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy), has a
sterile male partner, is 1 year postmenopausal, or practices abstinence. Cessation of
birth control after the 12-week follow up period should be discussed with a
responsible physician.


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Edition Number 5
Date 18 May 2016
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
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 an elevated follicle-stimulating hormone (FSH) level greater 
than the central laboratory value of post-menopausal at screening.
Effective methods of birth control include those listed in Table 1. 
Table 1
Effective methods of birth control
Barrier Methods
Intrauterine Device Methods
Hormonal Methods
Male condom (with
spermicide*)
Progesterone T 
Implants
Cap (with spermicide cream or 
jelly*) 
Copper T 
Hormone shot or injection
Diaphragm (with spermicide
cream or jelly*) 
Combined pill
Minipill
Patch
*where commercially available
12.
Nonsterilised males who are sexually active with a female partner of childbearing 
potential must use a condom (with spermicide where commercially available) from 
Day 1 until at least 12 weeks after receipt of the final dose of investigational 
product
13.
Females with an intact cervix must have documentation of a normal Pap smear with 
no documented malignancy (eg, cervical intraepithelial neoplasia grade III [CIN 
III], carcinoma in situ [CIS], or adenocarcinoma in situ [AIS]) within 2 years prior 
to randomisation (see Appendix X for guidance on abnormal Pap smear results)
*Any abnormal Pap smear result documented within 2 years prior to randomisation 
must be repeated to confirm patient eligibility
14.
Willing to forego other forms of experimental treatment during the study
15.
Meets all of the following TB criteria:
(a)
No history of active TB prior to any Screening visit
(b)
No history of latent TB prior to initial Screening visit, with the 
exception of latent TB with documented completion of appropriate 


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Edition Number 5
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treatment
Note: Subjects with no history of latent TB prior to the initial Screening 
visit, but who are diagnosed with latent TB during screening, may be 
considered eligible if appropriate treatment is initiated prior to 
randomisation. Such subjects may be re-screened if necessary to allow 
for local guidelines on latent TB treatment initiation.
(c)
No signs or symptoms suggestive of active TB from medical history or
physical examination
(d)
No recent contact with a person with active TB OR if there has been
such contact, referral to a physician specialising in TB to undergo
additional evaluation prior to randomisation (documented appropriately
in source), and, if warranted, receipt of appropriate treatment for latent
TB at or before the first administration of investigational product
(e)
Must meet 1 of the following criteria:
(i)
Negative QuantiFERON-TB Gold [QFT-G] test result for
TB obtained from the study Central Laboratory within
3 months prior to randomisation OR
(ii)
Positive QFT-G test result for TB obtained during the
Screening Period from the study Central Laboratory for
which active TB has been ruled out and appropriate
treatment for latent TB has been initiated prior to the first
investigational product administration OR
(iii)
Indeterminate (confirmed on retest) QFT-G test result for
TB obtained during the Screening Period from the study
Central Laboratory with ongoing QFT-G testing for TB
according to the Study Plan
(f)
A chest radiograph with no evidence of current active infection (eg, TB)
or old active TB, malignancy, or clinically significant abnormalities
(unless due to SLE) obtained during the Screening Period or anytime
within 12 weeks prior to signing of the informed consent
16.
Day 1 “Clinical” SLEDAI-2K score ≥4 points
17.
OCS dose stable for at least 2 weeks prior to randomisation
18.
Stable SLE SOC treatment (see Section 3.3.2) at the time of randomisation


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Edition Number 5
Date 18 May 2016
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19.
Women of child-bearing potential must have a negative urine pregnancy test at 
randomisation (Day 1), prior to administration of investigational product
20.
In the opinion of the Investigator, must be able to comprehend the ICF and all 
protocol related assessments, such that the patient can complete all study required 
documents, procedures, and outcome measures.
3.2
Exclusion criteria
Any of the following would exclude the subject from participation in the study:
3.2.1
General exclusion criteria
1.
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of the investigational product or interpretation of subject safety or study 
results
2.
Concurrent enrolment in another clinical study with an investigational product 
3.
Individuals involved with the conduct of the study, their employees, or immediate 
family members of such individuals
4.
Lactating or pregnant females or females who intend to become pregnant anytime 
from initiation of Screening until the 12-week safety follow-up period following 
last dose of investigational product
5.
Current alcohol, drug or chemical abuse, or a history of such abuse within 1 year 
before Week 0 (Day 1)
6.
Major surgery within 8 weeks before signing the ICF or elective major surgery 
planned during the study period (see Appendix W)
7.
Spontaneous or induced abortion, still or live birth, or pregnancy ≤4 weeks prior to 
signing the ICF
8.
At Screening (within 4 weeks before Week 0 [Day 1]), any of the following:
(a)
Aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN). 
(b)
Alanine aminotransferase (ALT) >2.0 × ULN. 
(c)
Total bilirubin >ULN (unless due to Gilbert's syndrome)
(d)
Serum creatinine >2.0 mg/dL (or >181 μmol/L)
(e)
Urine protein/creatinine ratio >2.0 mg/mg (or >226.30 mg/mmol)


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Edition Number 5
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(f)
Neutrophil count <1000/μL (or <1.0 × 109/L)
(g)
Platelet count <25000/μL (or <25 × 109/L)
(h)
Haemoglobin <8 g/dL (or <80 g/L), or <7 g/dL (or <70 g/L) if related to
subject's SLE such as in active haemolytic anaemia
(i)
Glycosylated haemoglobin (HbA1c) >8% (or >0.08) at screening
(diabetic subjects only)
Note: Abnormal screening laboratory tests may be repeated ONCE on a separate sample 
before subject is declared a screen failure.
3.2.2
Exclusion criteria related to concomitant medications
9.
Receipt of any of the following:
(a)
Where prednisone is the single standard of care medication (ie, the
subject is not concurrently receiving any medication listed in inclusion
criterion 7(c)), any addition of a new oral prednisone therapy (or
equivalent) any time in the 8 weeks prior to Day 1, OR any change in/
discontinuation of current oral prednisone dose (or equivalent) anytime
within the 2 weeks prior to randomisation (see Appendix V for examples
of prednisone equivalency)
(b)
Where prednisone is not the single standard of care medication (ie, the
subject is concurrently receiving at least one medication listed in
inclusion criterion 7(c)):
(i)
Any addition of a new oral prednisone therapy (or
equivalent) any time from 2 weeks prior to signing of the
informed consent form through Day 1, OR any change in/
discontinuation of current oral prednisone dose (or
equivalent) anytime within the 2 weeks prior to
randomisation (see Appendix V for examples of prednisone
equivalency)
(ii)
Any addition of a new dose of any of the following anytime
in the 12 weeks prior to signing of the informed consent
through Day 1, or change in/ discontinuation of current dose
anytime in the 8 weeks prior to signing of the informed
consent through Day 1: azathioprine; any antimalarial (eg,
chloroquine, hydroxychloroquine, quinacrine);
mycophenolate mofetil/mycophenolic acid; oral, SC, or
intramuscular methotrexate; mizoribine
10.
Receipt of any of the following:


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Edition Number 5
Date 18 May 2016
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(a)
Azathioprine >200 mg/day
(b)
Mycophenolate mofetil >2 g/day or mycophenolic acid >1.44 g/day
(c)
Oral, SC, or intramuscular methotrexate >25 mg/week
(d)
Mizoribine >150 mg/day
(e)
Any change in route of administration of oral, SC, or intramuscular
methotrexate anytime within the 8 weeks prior to signing of the
informed consent through Day 1
11.
Receipt of any investigational product (small molecule or biologic agent) within
4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater (see
Appendix U)
12.
Prior receipt of anifrolumab
13.
Receipt of any commercially available biologic agent within 5 half-lives (see
Appendix U) prior to signing of the ICF
14.
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab,
ofatumumab, atacicept, obinutuzumab, or rituximab)

<26 weeks prior to signing the ICF; <40 weeks for atacicept
(see Appendix U)

or if therapy was administered ≥26 weeks ago (40 weeks for atacicept),
absolute B cell less than the lower limit of normal or baseline value prior to
receipt of B cell-depleting therapy (whichever is lower)
15.
Receipt of epratuzumab or tabalumab <26 weeks prior to signing the ICF, or
belimumab <12 weeks prior to signing the ICF
16.
A known history of allergy or reaction to any component of the investigational
product formulation or history of anaphylaxis to any human gamma globulin
therapy
17.
Regular use of >1 NSAID within 2 weeks prior to Week 0 (Day 1); OR receipt of
fluctuating doses of a NSAID within 2 weeks prior to Week 0 (Day 1)
18.
Receipt of any of the following:
(a)
Intra-articular, intramuscular or IV glucocorticosteroids within 6 weeks
prior to Day 1
(b)
Any live or attenuated vaccine within 8 weeks prior to signing the ICF


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Edition Number 5
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(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)
(c)
Bacillus Calmette-Guerin (BCG) vaccine within 1 year of signing the
ICF
(d)
Any restricted medication listed in Appendix U if the washout period is
not met
(e)
Blood transfusion within 4 weeks prior to signing the ICF
3.2.3
Exclusion criteria related to systemic lupus erythematosus and other diseases
19.
History of, or current diagnosis of, a clinically significant non SLE-related
vasculitis syndrome (see Appendix T). Vasculitis due to SLE is allowed in the study
20.
History or evidence of suicidal ideation (severity of 4 [active: method and intent,
but no plan] or 5 [active: method, intent, and plan]) within the past 6 months; or any
suicidal behaviour within the past 12 months based on an assessment with the
C-SSRS at screening or at baseline
21.
Active severe or unstable neuropsychiatric SLE including, but not limited to:
aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes
(ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute
confusional state; impaired level of consciousness; psychosis; acute stroke or stroke
syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; and
mononeuritis multiplex:
(a)
That would make the subject unable to fully understand the ICF OR
(b)
Where, in the opinion of the Principal Investigator (PI), protocol
specified SOC is insufficient and utilisation of a more aggressive
therapeutic approach, such as adding IV cyclophosphamide and/or high
dose IV pulse corticosteroid therapy or other treatments not permitted in
the protocol, is indicated
22.
Active severe SLE-driven renal disease where, in the opinion of the PI, protocol
specified SOC is insufficient and utilisation of a more aggressive therapeutic
approach, such as adding IV cyclophosphamide and/or high dose IV pulse
corticosteroid therapy or other treatments not permitted in the protocol, is indicated
23.
Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or
any history of overlap syndromes of SLE and systemic sclerosis, as noted in A or B
below:


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Edition Number 5
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(a)
An overlap syndrome of SLE with myositis or rheumatoid arthritis at
screening is permitted provided the subject also meets the criteria for the
classification as SLE; or
(b)
A past history of mixed connective tissue disease, which over time has
developed into a diagnosis of SLE, is permitted provided diagnosis of
SLE has been present for at least 1 year
24.
History of or current diagnosis of catastrophic or severe anti-phospholipid
syndrome within 1 year prior to signing the ICF. Antiphospholipid syndrome
adequately controlled by anticoagulant therapy for at least 3 months is acceptable.
25.
History of, or current, inflammatory joint or skin disease other than SLE that, in the
opinion of the Investigator, could interfere with the inflammatory arthritis or skin
assessments and confound the disease activity assessments
26.
History of any non-SLE disease that has required treatment with oral or parenteral
corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to
signing the ICF
3.2.4
Exclusion criteria related to infection and malignancy risk factors
27.
Known history of a primary immunodeficiency, splenectomy, or any underlying
condition that predisposes the subject to infection, or a positive result for human
immunodeficiency virus (HIV) infection confirmed by central laboratory at
screening. Subjects refusing HIV testing during the screening period will not be
eligible for study participation
28.
Confirmed positive test for hepatitis B serology for:
(a)
Hepatitis B surface antigen (HBsAg), OR
(b)
Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA
detected above the lower limit of quantitation (LLOQ) by reflex testing
by the central laboratory at screening
Note: Subjects who are HBcAb positive at screening will be tested every 3 months for HBV 
DNA. To remain eligible for the study, the subject’s HBV DNA levels must remain below the 
LLOQ as per the central laboratory.
29.
Positive test for hepatitis C antibody as confirmed by central laboratory
30.
Any severe herpes infection at any time prior to Week 0 (Day 1), including, but not
limited to, disseminated herpes (ever), herpes encephalitis (ever), recurrent herpes
zoster (defined as 2 episodes within 2 years) or ophthalmic herpes (ever)


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31.
Any herpes zoster, cytomegalovirus (CMV) or Epstein-Barr virus infection that has
not completely resolved within 12 weeks prior to signing the ICF
32.
Opportunistic infection requiring hospitalisation or intravenous antimicrobial
treatment within 3 years of randomisation
33.
Any of the following:
(a)
Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis,
etc) within 8 weeks prior to signing the ICF (chronic nail infections are
allowed)
(b)
Any infection requiring hospitalisation or treatment with IV
anti-infectives not completed at least 4 weeks prior to signing the ICF
34.
Any infection requiring oral anti-infectives (including antivirals) within 2 weeks
prior to Day 1
35.
History of cancer, apart from:
(a)
Squamous or basal cell carcinoma of the skin treated with documented
success of curative therapy ≥3 months prior to Week 0 (Day 1)
(b)
Cervical cancer in situ treated with apparent success with curative
therapy ≥1 year prior to Week 0 (Day 1)
3.3
Restrictions and concomitant medications
3.3.1
Excluded medications: Day 1 through the end of the study
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting the Investigator.
3.3.1.1
Medications that lead to immediate discontinuation of investigational product
(a)
Cyclophosphamide
(b)
IFN therapy (alpha 2a and 2b, beta 1a and 1b, and pegylated IFNs alpha 2a and 2b)
(c)
Investigational agents
(d)
Biologic immunomodulators (including, but not limited to, belimumab, abatacept,
or rituxumab)
(e)
Live or attenuated vaccines (the Sponsor recommends that Investigators ensure all
subjects are up to date with required vaccinations prior to entry into the study)
(f)
Plasmapheresis


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Edition Number 5
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(g)
BCG vaccine
(h)
Any immunoglobulin (Ig) therapy
(i)
Intravenous corticosteroids >1 gm methylprednisolone or equivalent
(j)
Any medications listed in Appendix U (please see the sulfasalazine, danazol, and
dapsone restrictions in Section 3.3.1.2), except restrictions below.
3.3.1.2
Restricted medications 
As anifrolumab is an investigative immunomodulatory agent, non-protocol permitted changes 
to immune modifiers or immunosuppressants on study are strongly discouraged.
If a subject receives 1 of the following, the Investigator must notify the
 Medical Monitor 
immediately. The
 Medical Monitor will determine with the Sponsor if the subject may 
continue to receive investigational product, however, the subject would be considered a 
non-responder.
(a)
Sulfasalazine
(b)
Danazol
(c)
Dapsone
(d)
Azathioprine >200 mg/day or at a daily dose greater than that at Week 0 (Day 1)
(e)
Mycophenolate mofetil >2.0 g/day or mycophenolic acid >1.44 g/day or at a daily
dose greater than that at Week 0 (Day 1)
(f)
Oral, SC, or intramuscular methotrexate >25 mg/week or at a daily dose greater
than that at Week 0 (Day 1)
(g)
Mizoribine >150 mg/day or at a daily dose greater than that at Week 0 (Day 1)
(h)
Any change in route of administration of oral, SC, or intramuscular methotrexate
(i)
Intravenous corticosteroids >40 mg/day but ≤1 gm/day methylprednisolone or
equivalent
(j)
Intramuscular corticosteroids >80 mg/day methylprednisolone or equivalent
(k)
Subcutaneous or intramuscular corticosteroid precursors
(l)
Treatment with OCS >40 mg/day prednisone or equivalent
(m)
Treatment with OCS above Day 1 dose for a dosing period >14 days


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Edition Number 5
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(n)
Corticosteroids with a long biologic half-life (eg, dexamethasone, betamethasone)
(o)
Other immunosuppressants including but not limited to calcineurin inhibitors (eg,
cyclosporine, tacrolimus [including topical]) or leflunomide.
Note: Cyclosporine eye drops are acceptable for use in the study.
3.3.1.3
Other concomitant medications
Medication other than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report form (CRF).
3.3.2
Concomitant medications for Systemic Lupus Erythematosus standard of care 
during the study
Permitted medications for SOC SLE are described below. Concomitant medications should 
only be administered after all visit assessments, including investigational product 
administration and post-infusion PK blood draws (if applicable), with the exception of a 
subject with a previous infusion-related reaction who is to receive acetaminophen or 
equivalent. The acetaminophen or equivalent should be given after all visit assessments other 
than the infusion have been completed, and prior to starting the infusion.
Permitted SOC SLE
Limitations of Use
OCS
-
Oral prednisone or equivalent up to ≤40 mg/day is permitted
from at least 2 weeks prior to signing the informed consent.
The dose of oral prednisone must remain stable at least 2 weeks
prior to randomisation
-
Where prednisone is the single standard of care medication (ie,
the subject is not concurrently receiving any medication listed in
inclusion criterion 7(c)), a dose of oral prednisone ≥7.5 mg/day
but ≤40 mg/day (or prednisone equivalent) for a minimum of 8
weeks prior to Day 1 is required
-
Subjects with increased SLE disease activity may receive 1
permitted burst and taper of OCS between Day 1 and Week 12.
Additional details on burst and taper for SLE and non-SLE (eg,
asthma or COPD exacerbation) disease activity are provided in
Sections 3.3.2.1 to 3.3.2.4
Intramuscular corticosteroids
-
Subjects with increased SLE disease activity may receive 1
intramuscular injection of corticosteroids (methylprednisolone
≤80 mg or equivalent) instead of a burst and taper of OCS
described above between Day 1 and Week 12.
-
May only be administered after all assessments and
investigational product infusion have been completed at the visit
-
Additional details on burst and taper for SLE and non SLE
disease activity are provided in Sections 3.3.2.1 to 3.3.2.4


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Edition Number 5
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Permitted SOC SLE
Limitations of Use
Intra-articular/tendon 
sheath/bursal corticosteroid 
injections
-
Intra-articular/tendon sheath/bursal injection should be 
minimized. Subjects may receive a maximum of 2 injections (for 
a total dose of ≤80 mg methylprednisolone or equivalent) instead 
of a burst and taper of OCS described above, between Day 1 and 
Week 12.
-
An intra-articular/tendon sheath/bursal injection may be allowed 
for non-SLE related disorders up to Week 40 if the symptoms of 
the disorder do not interfere with the ability to assess 
SLE-related endpoints. The Investigator must contact the 
medical monitor for permission to administer an 
intra-articular/tendon sheath/bursal corticosteroid injection prior 
to administration of corticosteroids for non-SLE related 
disorders
-
If permission is given, the injection should not be administered 
until after the completion of all assessments, including 
investigational product administration and post-infusion PK 
blood draw (if applicable) 
Antimalarials and 
immunosuppressants 
(azathioprine, methotrexate, 
and mycophenolate 
mofetil/mycophenolic acid, 
and mizoribine)
-
Antimalarials and immunosuppressants (azathioprine, 
methotrexate, mycophenolate mofetil/mycophenolic acid, and 
mizoribine) are permitted, and at least 1 is required, as part of 
SLE therapy on Day 1 if the subject is not on OCS 
-
Dose regimens must remain stable from Day 1 to the completion 
of Week 52 but may be decreased for toxicity or to optimise 
management of an AE, such as infection. The toxicity/event 
must be confirmed as a documented AE. The dose can be 
returned to the Day 1 level if the toxicity/event resolves and if 
clinically indicated.
-
Antimalarials/immunosuppressants should not be changed if a 
subject has increased SLE disease activity during the OCS 
tapering period. 
Prescription NSAIDs
-
Prescription NSAIDs must remain stable from screening through 
Week 52 but can be reduced for reasons of toxicity but not 
efficacy. Prescription NSAIDs cannot be administered with 
other NSAIDs (including over-the-counter non-steroidals) 
except for low-dose aspirin
-
On a given visit day, prescription NSAIDs should not be taken 
until after all assessments have been completed and should be 
taken according to SOC


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Edition Number 5
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Permitted SOC SLE
Limitations of Use
Non-prescription NSAIDS
-
NSAIDs should not be taken on the day of a scheduled visit until 
all assessments are complete.
-
NSAIDs for analgesic purposes that never exceed 
label-approved doses of NSAIDs may be used for pain as 
required, based on Investigator judgment for up to 1 week at a 
time
-
NSAIDs cannot be used in combination with another NSAID at 
any dose, except low-dose aspirin (≤325 mg/day)
Acetaminophen or equivalent
-
Pain medications should not be used within a minimum of 6 to 
12 hours (based on known duration of effect) of a scheduled visit 
-
Normal release (not extended release) acetaminophen or 
equivalent (eg, paracetamol) may be used for pain as required
-
In a subject with a previous infusion-related reaction, 
acetaminophen or equivalent can be given after all visit 
assessments have been completed and prior to starting the 
infusion
Low-dose aspirin
-
Low-dose aspirin (maximum of 325 mg/day) for cardiovascular 
disease is permitted
Topical therapy
-
Concurrent use of topical therapy for cutaneous lupus 
erythematosus (eg, corticosteroids) is permitted. Topical 
moisturisers are also permitted
-
Topical therapy must be the same being used at signing of the 
informed consent and the dose and frequency of application 
must be stable during screening 
-
During the study, topical therapy may be reduced or 
discontinued based on clinical manifestations and Investigator 
discretion. Should cutaneous skin manifestations reoccur, the 
same topical therapy may be resumed up to the Day 1 dose.
-
It is encouraged that no new dermatologic preparations be used 
for the duration of the study. It is also recommended that 
subjects use sunscreen (list as concomitant medication for SLE) 
and avoid sun exposure during the study
NSAIDs = nonsteroidal anti-inflammatory drugs; OCS = oral corticosteroids; SLE = systemic lupus 
erythematosus; SOC = standard of care 
All permitted SOC SLE therapies received from initiation of screening through the end of the 
study will be recorded on the source document and CRF, and will include the specific 
indication for use (eg, general SLE activity, skin involvement, nephritis, pleurisy) as well as 
the dose, start and stop dates, frequency, and route of administration. In addition, any change 
in permitted SOC SLE therapy and the reason for change must be documented.


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Edition Number 5
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3.3.2.1
Steroid burst and taper Week 0 (Day 1) to Week 12
In order to allow adequate time for the investigational product to achieve significant clinical 
benefit, Investigators may administer 1 burst and taper of corticosteroids between Week 0 
(Day 1) and Week 12 for increased SLE disease activity/non-SLE activity.
A steroid burst as described below is defined as 1 of the following:

OCS increase up to a maximum daily dose of 40 mg/day prednisone (or equivalent) 
for up to a total of 14 days and that must be fully administered and tapered to less 
than or equal to the Day 1 dose by the end of the 14th day. Any course of OCS 
above the Day 1 dose must not extend beyond Week 12, regardless of when the 
course was started; 
OR

Intramuscular methylprednisone (≤80 mg) or equivalent administered as a single 
dose between Day 1 and Week 12;
OR

A maximum of 2 intra-articular/tendon sheath/bursal injections (for a total 
methylprednisolone ≤80 mg or equivalent) can be given. Subjects who receive any 
intra-articular/tendon sheath/bursal injections should not receive OCS or 
intramuscular burst between Day 1 and Week 12.
Subjects who receive more than 1 steroid burst and taper from Week 0 (Day 1) to Week 12, or 
who violate any of the criteria above, may continue in the study, but will be considered 
non-responders for subsequent assessments of disease activity, regardless of whether the OCS 
burst was administered for increased SLE activity or non-SLE causes.
3.3.2.2
Increase in corticosteroids from Week 12 to Week 40
Between Week 12 and Week 40, an increase in corticosteroid dose for increased SLE activity 
is not allowed. A subject receiving a steroid dose above his or her Week 0 (Day 1) dose may 
continue in the study, but will be considered a non-responder for subsequent assessments of 
disease activity.
An increase in OCS for non-SLE causes (eg, asthma or COPD exacerbation) is allowed 
ONCE with medical monitor approval between Week 12 and Week 40. This might include a 
non-SLE OCS up to ≤20 mg/day of prednisone (or equivalent) for up to a total of 14 days and 
must be fully administered and tapered to less than or equal to the Day 1 dose by the end of 
the 14th day and by the Week 40 visit day. This will be captured as burst and taper not 
attributable to SLE. The non-SLE indication must be clearly indicated in the source 
documents.
Subjects who receive non-SLE prednisone (or equivalent) at a total dose >20 mg/day but 
≤40 mg/day for a dosing period of greater than 14 days may continue in the study but will be 
considered non-responders for subsequent assessments of disease activity. If a subject receives 


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Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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>40 mg prednisone or equivalent) or a dose above baseline level for more than 14 days, it 
must be reported to the
 Medical Monitor. The 
 Medical Monitor will determine with 
the Sponsor if the subject may continue to receive investigational product.
3.3.2.3
Increase in oral corticosteroids after Week 40
No increase in OCS is allowed after Week 40 (except for the management of AEs or as a 
prophylaxis for adrenal insufficiency as described below). Subjects who receive an increase in 
their OCS after Week 40 will be considered non-responders for subsequent assessments of 
disease activity.
3.3.2.4
Increase in oral corticosteroids for intercurrent disease or to prevent adrenal 
insufficiency
In addition to the burst and tapers described above, subjects who are taking ≤7.5 mg/day 
prednisone or equivalent will be allowed to receive up to an additional 7.5 mg/day to a total of 
15 mg/day prednisone or equivalent for a total of up to 14 days or a single dose of IV 
hydrocortisone (≤100 mg hydrocortisone followed by half that dose for 2 days before 
returning to their usual dose) for severe illness, surgery, or symptoms of adrenal insufficiency 
or corticosteroid withdrawal if clinically warranted from Day 1 to Week 40. 
3.3.2.5
Protocol-specified steroid tapering Week 8 to Week 40
On treatment days, tapering will start after all assessments have been completed and 
investigational product has been administered. Tapering can be started on the scheduled study 
visit day (eg, Week 8 Visit) based on clinical manifestations and the laboratory values from 
the previous visit. If laboratory values of the current visit show SLE activity consistent with 
exception rule No. 1 or No. 2 below, the tapering can be reversed.
Beginning at Week 8 and continuing through Week 40, steroid tapering to an OCS dose of 
≤7.5 mg/day MUST be attempted in all subjects with OCS dose ≥10.0 mg/day at Baseline, 
unless at least 1 of the following criteria is met:

SLEDAI-2K activity which is worsened compared to baseline in major organ 
systems (renal, CNS, cardiopulmonary, vasculitis, fever, thrombocytopenia, or 
haemolytic anaemia, or gastrointestinal activity)

Newly-affected organ system(s) based on the SLEDAI-2K, excluding serological 
abnormalities (dsDNA antibodies, hypocomplementemia) 

Moderate to severe skin disease as reflected by a CLASI activity score of ≥10 

Moderate to severe arthritis disease as reflected by an active joint count of ≥8 tender 
and/or swollen joints
Steroid tapering must be started within 14 days of the visit. If steroid tapering is not attempted 
in an eligible subject, the Sponsor or Sponsor’s designee must be contacted immediately. The 
recommended steroid-tapering regimen is provided in Appendix V, but due to variability in 
subject responses to steroid treatment and tolerability of taper Investigators will have 
flexibility in how the OCS dose is reduced at each visit.


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Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
7.5 mg/day up to Week 40 based on disease activity. Steroid tapering will not be permitted 
after Week 40. 
A subject experiencing an increase in disease activity secondary to OCS tapering may increase 
the dose up to a maximum of the baseline OCS therapy dose from Week 8 up to Week 40 
without the subject being considered a non-responder for subsequent assessments of disease 
activity. Subjects who require OCS dose above their baseline level may continue in the study 
but will be considered non-responders for subsequent assessments of disease activity.
3.3.3
Other restrictions
3.3.3.1
Fasting lipid profile
Subjects will be required to fast for at least 8 hours prior to assessment of lipid profile at the 
visits described in the Treatment Period Study Plan (Table 3). If the subject has not fasted, 
they should fast before the next visit, and the test can be done at that visit.
3.3.3.2
Perioperative management of investigational product
Elective surgery should be avoided during the study if clinically feasible.
Major surgery
Pre-operative management of investigational product: if a non-urgent major surgical 
procedure becomes necessary during the study, it should be scheduled at least 4 weeks after 
the last administration of investigational product, if clinically feasible. 
Non-major surgery
The decision to withhold investigational product administration is at the Investigator’s 
discretion. 
Post-operative management of investigational product: investigational product administration 
can be resumed at the Investigator’s discretion after all of the following criteria are met:

External wound healing is complete, and 

Any postoperative antibiotic course is completed, and

All acute surgical complications have resolved
3.4
Subject enrolment and randomisation
Investigator(s) should keep a record of subjects considered for, and included in the study. The 
pre-screening/screening log will be evaluated periodically during routine monitoring visits. 
The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject before any study-specific 
procedures are performed. The subject is considered enrolled when the ICF is 


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Edition Number 5
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signed and the enrolment call is done in the interactive voice/web response system 
(IXRS).
2.
Assign potential subject a unique enrolment number, beginning with ‘
’.
3.
Determine subject eligibility. During screening, the Disease Activity Adjudication 
Group (see Section 5.2.2) will confirm eligibility criteria based on the data captured 
in the electronic data capture (EDC) system and from the Central Laboratory. Sites 
will be notified to either randomise or screen fail the subject. 
4.
On Day 1, the Investigator will confirm that all eligibility criteria still are fulfilled 
(including that the “Clinical” SLEDAI-2K score is ≥4 points [see Inclusion 
Criterion No. 9 for “Clinical SLEDAI-2K” definition], OCS dose has been stable 
for the last 2 weeks) and will then perform the randomisation transaction in the 
IXRS.
5.
At randomisation the IXRS will assign eligible subjects a unique randomisation 
code and blinded investigational product kit number(s) to the subject.
Specific information concerning the use of the IXRS will be provided in the separate user 
manual. 
Block randomisation using an IXRS will be used to randomise subjects in a 1:2:2 ratio to 
receive a fixed IV dose of 150 mg anifrolumab, 300 mg anifrolumab, or placebo. AstraZeneca 
Biostatistics group is responsible for generating the randomisation scheme for this study using 
the GRand system. 
The randomisation will be stratified using the following factors: 

SLEDAI-2K score at screening (<10 points versus ≥10 points)

Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or 
equivalent)

Results of the IFN test (high versus low)
Investigational product (anifrolumab or placebo) should, if possible, be administered the same 
day the investigational product kit number is assigned.
3.5
Methods for ensuring blinding
This is a double-blind study in which anifrolumab and placebo are distinguishable during the 
final preparation step of the investigational infusion bag. All packaging and labelling of 
investigational product is done in such way as to ensure blinding for all Sponsor and 
investigational site staff other than the unblinded investigational product manager. The kits on 
the shelf, and the infusion bags when prepared, look identical. Since anifrolumab and placebo 
can be distinguished at the preparation step, investigational product will be prepared by an 
unblinded investigational product manager at the site, who will not be involved in the 
management of study subjects. 


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Neither the subject nor any of the Investigator or Sponsor staff/designee who are involved in 
the treatment or clinical evaluation and monitoring of the subjects will be aware of the 
treatment received. In the event that the treatment allocation for a subject becomes known to 
the Investigator or other study staff involved in the management of study subjects, the 
Sponsor, or designee must be notified immediately by the Investigator.
3.6
Unblinding
In the event of a medical emergency, the Investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS manual. The investigator should 
promptly document and explain any premature unblinding to the sponsor, without revealing 
the treatment given to patient to the sponsor. In general, unblinding should only occur if 
management of the medical emergency would be different based on the subject having 
received investigational product. In the majority of cases, the management of a medical 
emergency would be the same whether or not investigational product was received by the 
subject. If this was the case, the investigational product allocation should not be unblinded.
AstraZeneca or its designee retains the right to break the code for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities. Treatment codes will not be broken for 
the planned analyses of data until all decisions on the evaluability of the data from each 
individual subject have been made and documented.
Subjects who have been unblinded by AstraZeneca Patient Safety or designee (and who have 
not been unblinded to the Investigator or Medical Monitor) will not, based on the unblinding 
alone, be discontinued from further receipt of investigational product.
3.6.1
Unblinding for Data and Safety Monitoring Board
An independent DSMB will review safety data throughout the study. The DSMB will be 
provided with partially unblinded data (data that are summarised by treatment group using 
masked treatment group labels). The DSMB may choose to unblind the data for additional 
review as specified in the DSMB charter. The Sponsor and the study team at 
 will remain 
blinded to all data transfers provided to the DSMB. Details about the DSMB will be included 
in the DSMB Charter. For further details on the DSMB, see Section 6.10.1.
3.7
Discontinuation of investigational product
Subjects may be discontinued from investigational product in the following situations:
1.
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment. The primary reason should be documented as 1 of the 
following:
(a)
Subject perceives the investigational product to be ineffective
(b)
Subject is unable to comply with protocol-specified visits and/or 


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procedures due to conflicts not related to clinical trial
(c)
Subject perceives logistics to be unacceptable
(d)
Subject wishes to participate in another clinical trial 
(e)
Subject wishes to take a treatment that is not allowed in this study
(f)
An AE or laboratory abnormality is of concern to the subject, but not 
clinically significant to physician
(g)
Other, please specify reason
2.
Lost to follow-up: must be documented by time and date of telephone calls, emails, 
text messages, numbers called, individuals spoken to if not subject, and at least 2 
attempts to contact the subject via certified letter
3.
AE that, in the opinion of the Investigator or the Sponsor/Sponsor’s delegate 
Medical Monitor, contraindicates further dosing with investigational product
4.
Severe non-compliance with the study protocol 
5.
The Investigator or Sponsor/Sponsor’s delegate Medical Monitor deems withdrawal 
as being in the subject's best interest
6.
Pregnancy, positive pregnancy test, or subject expresses an interest to become 
pregnant 
7.
Isolated HBc positivity with HBV DNA confirmed by the central laboratory
8.
Receipt of any medications identified in Section 3.3.1.1
9.
The use of restricted medications listed in Section 3.3.1.2 if the 
 Medical 
Monitor, in consultation with the Sponsor, determines the subject must be 
discontinued 
10.
A diagnosis of active TB, premature discontinuation of treatment for latent TB, or 
noncompliance with TB therapy. Note: duration of treatment for latent TB should 
follow the local practice. If local practice is not defined, then Centers for Disease 
Control guidance should be used.
Additional restrictions related to concomitant medications are discussed in Section 3.3.1.3.
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment, and will not be eligible for the LTE study.


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Edition Number 5
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3.7.1
Subject decision to discontinue investigational product 
If the subject decides to discontinue investigational product for any reason, including but not 
limited to those outlined in Section 3.7 above, the subject will not receive any further 
investigational product. The subject may also refuse to continue any further study observation. 
3.7.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) (see Section 3.7) 
and the presence of any AEs. The Investigator will follow-up AEs outside of the clinical 
study. 
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced. 
3.7.3
Lost to follow-up
Subjects will be considered lost to follow-up only if no contact has been established by the 
time the study is completed such that there is insufficient information to determine the 
subject’s status at Follow-up Visit 2. A subject is considered lost to follow up when the 
following attempts to contact the subject are unsuccessful: 

Either phone calls, faxes or emails, and 

Having sent 2 registered letters/certified mail, and

One attempt to check the status of the subject using publicly available sources, if 
allowed by local regulations
“Lost to follow-up” as a reason for study discontinuation must be documented by time and 
date of telephone calls, emails, text messages, numbers called, individuals spoken to if not 
subject, and documentation that 2 certified/registered letters were sent.
3.7.4
Study completion and end of study
An individual subject will be considered to have completed the study if the subject was 
followed up until the end of the study (Week 60, or Week 52 for those enrolling in the LTE 
study), regardless of the number of doses of investigational product that were received. The 
end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study.
3.7.5
Procedures for discontinuation of a subject from investigational product
Discontinuation of investigational product does not necessarily mean discontinuation of 
follow-up or termination of study participation. Compliant subjects who are discontinued from 
the investigational product should be encouraged to continue to undergo all study-related 
visits/procedures for the full treatment period (Table 3) in order to support the final efficacy 
and safety analysis for anifrolumab (see Section 8). The reason for premature discontinuation 


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Edition Number 5
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of investigational product will be documented in the source documents and recorded in the 
CRF.
It is essential to collect as much data as possible for all subjects throughout the study and 
especially all potential endpoint events. Complete withdrawal from the study (ie, withdrawal 
of consent) has a direct negative impact on the potential validity of all study data and should 
be avoided wherever possible. If the subject permanently discontinues investigational product 
prior to their completion of the study and wishes to continue with only selected study 
assessments; prioritized assessments are listed in Section 4.2.1.
For subjects who wish to withdraw from the study completely refer to Section 3.7.2.
3.8
Criteria for withdrawal 
3.8.1
Screen failures 
Screening failures are subjects who have provided informed consent and who subsequently do 
not fulfil the eligibility criteria for the study, and therefore must not be randomised. These 
subjects should have the reason for study withdrawal recorded as “Eligibility Criteria Not 
Fulfilled” (ie, subject does not meet the required inclusion/exclusion criteria). This reason for 
study withdrawal is only valid for screen failures (not randomised subjects). Rescreening of a 
subject will be permitted once.
3.9
Discontinuation of the study
The study may be stopped if, in the judgment of the Sponsor, trial subjects are placed at undue 
risk because of clinically significant findings that:

Meet individual stopping criteria or are otherwise considered significant (see 
Section 3.7 for reasons for discontinuation of investigational product)

Are assessed as causally related to study drug 

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for subjects at the time of 
discontinuation of follow-up must be recorded in the CRF. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.


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Edition Number 5
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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 2
Study plan detailing the procedures at screening
Study Period
Screening
Written informed consent /assignment of 
X
Medical history a
X
Physical examination, weight and height
X
Vital signs
X
ECG
X
Serum chemistry, haematology, and urinalysis
X
Urine protein/creatinine ratio
X
ANA, anti-dsDNA antibodies, anti-Sm antibody b
X
B cell count c
X
Chest x-ray (only in subjects who have not had a chest x-ray within 12 weeks 
prior to signing the ICF) d
X e
FSH in postmenopausal females
X
Serum pregnancy test in all females of childbearing potential
X
Blood test for TB f
X
Hepatitis B and C
X
HIV test g
X
IFN test b
X
Pap smear (only in females with an intact cervix who have not had a normal 
Pap smear within 2 years prior to randomisation)
X e
C3, C4, CH50 complement
X 
BILAG-2004 associated laboratory tests (anticardiolipin, lupus anticoagulant, 
haptoglobin, and Coombs h)
X
C-SSRS
X
BILAG-2004 
X i
CLASI
X i
Skin photography, if applicable j
X i
SLEDAI-2K 
X i
PGA
X i
Joint count
X i
TB questionnaire
X


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Date 18 May 2016
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Study Period
Screening
Assessment of AESIs
X
Assessment of AEs/SAEs
X
ACR classification criteria
X
Concomitant medications, including SLE medications
X
Verify eligibility criteria
X
ACR = American College of Rheumatology; AE = adverse event; AESI = adverse event of special interest; ANA 
= antinuclear antibody; BILAG = British Isles Lupus Assessment Group; C3 = third component of complement; 
C4 = fourth component of complement; CH50 = total haemolytic complement; CLASI = Cutaneous Lupus 
Erythematosus Disease Area and Severity Index; C-SSRS = Columbia Suicide Severity Rating Scale; dsDNA = 
Double stranded deoxyribonucleic acid; ECG = electrocardiogram; PGA = Physician’s Global Assessment; SAE 
= serious adverse event; SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000; TB = 
tuberculosis
a
Medical History will include details for each body system contained in the BILAG-2004 assessment 
(BILAG Related History).
b
Redraw for ANA/anti-dsDNA, or IFN test can be done within the 30-day screening window, however, 
results needed to determine eligibility and stratification must be available within the 30-day screening 
window for subjects to be randomised.
c
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab, ofatumumab, atacicept,
obinutuzumab, or rituximab) <26 weeks prior to signing the ICF (<40 weeks for atacicept [see Appendix 
U]) and if therapy was administered ≥26 weeks ago (40 weeks for atacicept), absolute B cell less than the 
lower limit of normal or baseline value prior to receipt of B cell-depleting therapy (whichever is lower).
d
Anterio-posterior and lateral images are required whenever possible, or per standard of care.
e
Assessments are allowed anytime during the screening period as long as they are completed within 30 days 
after signing the informed consent form.
f
Interferon-gamma release assay (IGRAs) using QuantiFERON®-TB Gold In-Tube Test (QFT-GIT).
g
Subjects within the treatment or follow-up period at the time of amendment 4 approval will undergo HIV 
testing at the time of amendment 4 ICF signature.
h
Coombs will be performed as applicable per BILAG assessment requirements.
i
These assessments must all be completed at the same visit (SLEDAI-2K, BILAG-2004, joint count, PGA, 
CLASI, and skin photography [if applicable]).
j
Photography will be conducted at selected sites in subjects who sign an additional optional consent, and 
have a screening CLASI score of ≥10. If no baseline skin activity or photos can be captured at the patient’s 
Screening or Day 1 visit, no further photography will be done.


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Table 3
Study plan detailing the procedures during the Treatment Period (double-blind period)
Visit Number
V1 a
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14 
(EDV) b
Study Week
W0
W4
W8 
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
Procedure/Visit 
Window
±7 D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
PtGA, FACIT-F, Pain 
NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PHQ-8
X
X
X
X
X
SF-36v2 (acute)
X
X
X
X
X
X
X
X
LupusQoL, EQ-5D-5L 
X
X
X
X
X
WPAI-Lupus
X
X
X
X
X
Medical history
X
Complete physical 
examination
X
X
X
Focused physical 
examination
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
Cushingoid features
X
X
X
ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry, 
haematology, and 
urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pap smear
X c


Revised Clinical Study Protocol
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Edition Number 5
Date 18 May 2016
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Visit Number
V1 a
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14 
(EDV) b
Study Week
W0
W4
W8 
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
Procedure/Visit 
Window
±7 D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
Urine pregnancy test d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB blood test
(QFT-GIT)
X e
X e
X e
X
HBV DNA f
X
X
X
X
Immunology profile
X
X
X
Lipid profile g
X
X
X
Cardiovascular risk 
assessment
X
X
IFN Test h
X
X
PK blood sample 
(predose)
X
X
X
X
X
X
PK blood sample 
(postdose) i
X
X
Immunogenicity blood 
sample (predose) j
X
X
X
X
X
X
Proteomics/ biomarker 
blood and urine sample
X
X
X
X
X
SLEDAI-2K associated 
laboratory tests k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Type I IFN signature 
with 21-gene signature 
(PD marker)
X
X
X
X
X


Revised Clinical Study Protocol
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Edition Number 5
Date 18 May 2016
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Visit Number
V1 a
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14 
(EDV) b
Study Week
W0
W4
W8 
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
Procedure/Visit 
Window
±7 D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BILAG-2004 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BILAG-2004 
associated laboratory 
tests l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Skin photography, if 
applicable m
X
X
X
X
X
X
X
SLEDAI-2K 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Modified flare index
X
X
X
X
X
SDI
X
X
X
PGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Joint count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protocol-specified 
steroid tapering (if 
indicated)
X
X
X
X
X
X
X
X
X
Medical Resource Use 
Questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
AEs/SAEs/AESIs
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Revised Clinical Study Protocol
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Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Visit Number
V1 a
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14 
(EDV) b
Study Week
W0
W4
W8 
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
Procedure/Visit 
Window
±7 D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
±7D
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Verify eligibility criteria
X
Randomisation
X
Investigational product 
administration n
X
X
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; BILAG = British Isles Lupus Assessment Group; CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index; C-SSRS 
= Columbia Suicide Severity Rating Scale (C-SSRS); dsDNA = double stranded deoxyribonucleic acid; ECG = electrocardiogram; EDV = Early 
Discontinuation Visit; FACIT-F = Functional Assessment of Chronic Illness Therapy-FATIGUE; IFN = interferon; NRS = numeric rating scale; PD = 
pharmacodynamic; PGA = Physician’s Global Assessment; PHQ-8: Personal Health Questionnaire Depression Scale-8; PK = pharmacokinetic; SAE = 
serious adverse event; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLEDAI-2K = 
Systemic Lupus Erythematosus Disease Activity Index 2000; TB = tuberculosis 
a
Once screening assessments are complete, all necessary laboratory results are reported, and adjudication is complete, a subject may be randomised. 
There does not need to be 30 days between screening and Week 0 (Day 1).
b
Subjects continuing in the LTE study will have all assessments, then receive investigational product as part of the LTE protocol.
c
Subjects should have a Pap smear between Week 48 and Week 52 to ensure that there is no evidence of new cervical dysplasia. Since access to a Pap 
smear may vary by country, the Sponsor recommends that local guidelines for obtaining Pap smears in subjects who have received immunomodulators 
or immunosuppressive treatment be followed.
d
Urine pregnancy test in females of childbearing potential.
e
Only done if indeterminate at screening/previous visit using the IGRAs test that was used during screening (ie, QFT-GIT).
f
Subjects who are HBcAb positive at screening will be tested every 3 months for HBV DNA. To remain eligible for the study, the subject’s HBV DNA 
levels must remain below the LLOQ as per the central laboratory.
g
Lipid profile (cardiovascular assessment) - subjects will be required to fast for at least 8 hours prior to this assessment. If a subject has not fasted, the 
assessment should be performed under fasted conditions at the next visit.
h
Whole blood will be collected in PAXgene tubes to measure the overexpression of mRNA for certain types of type I IFN-inducible genes using a 4-gene 
test. 
i
Post-dose PK samples should be drawn 15 minutes ±5 minutes after the completion of investigational product administration.


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Edition Number 5
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j
In order to help understand the potential drug-relatedness of any hypersensitivity or anaphylaxis reaction, possible additional ADA testing (if not already 
scheduled for the visit) may be done.
k
SLEDAI-2K associated laboratory tests are C3, C4, CH50 complement, anti-dsDNA antibodies, urine protein/creatinine ratio.
l
BILAG-2004 laboratory tests to include anticardiolipin, lupus anticoagulant, haptoglobin, and Coombs (Coombs will be performed as applicable per 
BILAG assessment requirements). Note: In order to avoid having to bring the subject back for a separate phlebotomy, the anticardiolipin, lupus 
anticoagulant, and haptoglobin blood specimens will be collected at all specified visits, however the blood will be stored at the central laboratory and the 
analyses performed only if the Investigator indicates that these tests need to be completed because of clinical suspicion of haemolytic anaemia or 
antiphospholipid syndrome. Direct Coombs test samples will only be collected per the investigator's opinion and applicable BILAG assessment 
requirements for determining haemolytic anaemia.
m
Photography will be conducted at selected sites in subjects who sign an additional optional consent, and have a screening CLASI score of ≥10. If no 
baseline skin activity or photos can be captured at the patient’s Screening or Day 1 visit, no further photography will be done.
n
Investigational product will be administered as an IV infusion via an infusion pump over a minimum of 30 minutes.


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Edition Number 5
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Table 4
Study plan detailing the procedures during Follow-up
Visit Number
Follow-up Visit 1 a
Follow-up Visit 2 a
Study Week
8 weeks post final dose
12 weeks post final dose
Procedure/Visit Window
EQ-5D-5L, Pain NRS,SF-36v2 (acute), FACIT-F, WPAI
X
PHQ-8
X
Physical examination, weight
X
Vital signs
X
X
Serum chemistry, haematology, and urinalysis
X
X
Urine pregnancy test in females of childbearing potential
X
X
PK blood sample
X
X
Immunogenicity blood sample
X
Proteomics/biomarkers blood and urine sample
X
TB questionnaire
X
X
Type I IFN signature with 21-gene assay (PD marker)
X
SLEDAI-2K associated laboratory tests b
X
X
BILAG-2004 associated laboratory tests c
X
X
C-SSRS
X
X
BILAG-2004 
X
X
CLASI
X
X
Skin photography, if applicable d
X
SLEDAI-2K 
X
X
PGA
X
X


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Visit Number
Follow-up Visit 1 a
Follow-up Visit 2 a
Study Week
8 weeks post final dose
12 weeks post final dose
Procedure/Visit Window
Joint count
X
X
Medical Resource Use Questionnaire
X
X
Assessment of AESIs
X
X
Assessment of AEs/SAEs
X
X
Concomitant medications
X
X
AE = adverse event; AESI = Adverse Event of Special Interest; BILAG = British Isles Lupus Assessment Group; CLASI = Cutaneous Lupus Erythematosus 
Disease Area and Severity Index; EQ-5D-5L = EuroQoL 5 dimensions; FACIT-F = Functional Assessment of Chronic Illness Therapy-FATIGUE; IFN 
= interferon; NRS = numeric rating scale; PD = pharmacodynamic; PGA = Physician’s Global Assessment; PHQ-8 = Personal Health Questionnaire 
Depression Scale-8; PK = pharmacokinetic; SAE = serious adverse event; SF-36v2 (acute) = Short Form 36 version 2 (acute recall); SLEDAI-2K = 
Systemic Lupus Erythematosus Disease Activity Index 2000; TB = tuberculosis; VAS = visual analogue scale; WPAI = Work productivity and Activity 
Impairment 
a
Follow-up assessments are to be completed when subjects complete the study (eg, early termination or after the treatment period) and are not going to 
participate in the LTE study. 
b
SLEDAI-2K associated laboratory tests are C3, C4, CH50 complement, anti-ds DNA, urine protein/creatinine ratio. If central laboratory results are not 
available for SLEDAI-2K associated samples drawn on the date of visit, labs should be redrawn one time within 14 days of the SLEDAI assessment 
date.
c
BILAG-2004 laboratory tests to include anticardiolipin, lupus anticoagulant, haptoglobin, and Coombs (Coombs will be performed as applicable per 
BILAG assessment requirements). Note: In order to avoid having to bring the subject back for a separate phlebotomy, the anticardiolipin, lupus 
anticoagulant, and haptoglobin blood specimens will be collected at all specified visits, however the blood will be stored at the central laboratory and the 
analyses performed only if the Investigator indicates that these tests need to be completed because of clinical suspicion of haemolytic anaemia or 
antiphospholipid syndrome. Direct Coombs test samples will only be collected per the investigator's opinion and applicable BILAG assessment 
requirements for determining haemolytic anaemia.
d
Photography will be conducted at selected sites in subjects who sign an additional optional consent, and have a screening CLASI score of ≥10. If no 
baseline skin activity or photos can be captured at the patient’s Screening or Day 1 visit, no further photography will be done.


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4.1
Enrolment/Screening Period
At Screening, subjects are assessed to ensure that they meet eligibility criteria. Once the 
subject signs the informed consent, they are considered enrolled in the study. Subjects who do 
not meet these criteria must not be randomised into the study.
Screening procedures will be performed according to the Screening Study Plan (Table 2), 
from Day -30 to Day -1. 
Once screening assessments are complete, all necessary laboratory results are reported, and 
adjudication is complete, a subject may be randomised. There does not need to be 30 days 
between screening and Week 0 (Day 1).
Chest x-rays and Pap smears may be completed anytime during the screening period as long 
as all results have been reviewed by the Investigator prior to randomisation. 
If a subject does not meet eligibility criteria on the basis of a laboratory value then the 
laboratory value may be repeated once within the screening period.
4.1.1
Other considerations for screening
4.1.1.1
Oral examination
In several biological programs there have been serious infections and/or death related to 
Ludwig’s angina. Although this has not been seen in the anifrolumab program, Investigators 
should check a subject’s oral cavity and review their dental health carefully during the 
screening process. While a dental examination is not required prior to enrolment in this study, 
Investigators are cautioned to consider carefully whether subjects have active caries or a 
dental infection that might impact on subject safety prior to enrolment.
4.1.1.2
Mammography
As subjects with SLE have impaired immune response, are treated with immunosuppressants, 
and are at potential risk for malignancy, it is recommended that patients enrolled into the 
study are compliant and up to date with local recommendations for mammography or other 
screening procedures for breast cancer.
4.1.2
Re-screening subjects who screen fail
If a subject fails screening for inadequate disease activity, or other reason, which, in the 
opinion of the Investigator, may change to make the subject eligible, the subject may be 
re-screened 1 time. In this case, the subject will re-sign the informed consent document. If the 
subject fails screening twice, they may not undergo further screening for this study. Initial 
screening procedures completed within the 30 days prior to subject randomisation need not be 
repeated during the re-screen visit.


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


Revised Clinical Study Protocol
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suspicion of haemolytic anaemia or antiphospholipid syndrome. Direct Coombs test 
samples will only be collected per the investigator's opinion and applicable BILAG 
assessment requirements for determining haemolytic anaemia.

CLASI

PGA (physician global assessment)

Skin photography, if indicated

Joint count
The following safety assessments will also be completed:

Serum chemistry, haematology, urinalysis

Urine for protein, creatinine and urine-protein-creatinine ratio

Lipid Profile defined in Section 5.3.11.1

Immunology Profile defined in Section 5.3.11.2

Vital signs

Physical examination, weight

Adverse events including AESIs

Cardiovascular risk assessment

TB questionnaire

Concomitant medications
If the subject does not agree to do this, they will be asked if they can be followed on a 
monthly basis via telephone calls. At these calls, they will be asked about AEs/SAEs, lupus 
symptoms, and lupus medications. Steroid bursts will also be captured. 
Adverse events will be followed up per Section 6.6.2.
4.3
Unscheduled Visit
There may be times a subject needs to have an unscheduled visit. The Investigator should 
determine the assessments to be completed based on the reason for the unscheduled visit and 
for subject safety. Concomitant medications and AEs should be completed whenever a subject 
has an unscheduled visit. 
If a subject presents for an unscheduled visit in lieu of a regularly scheduled visit (ie, the 
subject is seen for safety and efficacy assessments when a regularly scheduled dosing or 
follow-up visit is missed), the Investigator should complete all possible safety and efficacy 
assessments applicable to the missed visit. Unscheduled efficacy assessments should not be 
collected in between completed regular study visits. 
4.4
Follow-up Period
Procedures will be performed according to the Follow-up Period Study Plan (Table 4). 


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Subjects who complete the Week 52 visit may be eligible to participate in a LTE study. 
Subjects who complete the double-blind treatment period will have follow-up visits at 
Week 56 and Week 60, unless they enrol in the LTE study. Subjects who are withdrawn from 
the study, and do not agree to complete the 52-week study period, should complete the early 
discontinuation visit (Week 52 procedures) within 4 weeks of the last dose of investigational 
product, and be followed 8 and 12 weeks after the EDV visit by completing the Follow-up 
Visit 1 and 2 assessments (see Section 3.7).
5.
STUDY ASSESSMENTS 
5.1
Description of study procedures
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study.
5.2
Efficacy assessments
Efficacy measurements will be made at the times indicated in the Study Plan (see Table 2 for 
assessments to be performed at Screening, Table 3 for Treatment Period, and Table 4 for 
Follow-up). Subject-reported outcome assessments should be completed by the subject, 
unassisted by spouse, family members or friends.
5.2.1
Training and certification for Systemic Lupus Erythematosus assessments
In order to maintain consistent evaluation of SLE disease activity across study sites, training 
and certification of Investigators and designated site personnel who will be completing the 
disease evaluations listed below will be conducted.

SLEDAI-2K

BILAG-2004 

PGA

CLASI

Swollen and tender joint count evaluation
The SLEDAI-2K, BILAG-2004, PGA, and CLASI must be administered by the Investigator 
or another qualified physician, unless prior sponsor approval has been obtained for any other 
clinically trained site personnel with documentation of adequate assessment experience per the 
study central review plan. The joint count evaluation can be completed by other site personnel 
who, as per Investigator discretion, are qualified to perform the assessments and have at least 
1 year of experience administering the joint count evaluation. Training will include printed 
training materials, digital video disks (DVDs) and formal presentations, as well as web-based 
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After attending study presentations (ie, Investigator Meeting) or after completion of online 
training modules, all Investigators and designated site physicians must pass an online 
examination in order to obtain certification for all disease evaluation assessments, with the 
exception of the joint count evaluation. Investigators and designated site personnel must be 
trained and certified prior to subjects entering screening at their respective sites. All 
assessments and certifications must be renewed via the study online training website prior to 
expiration and must remain current (not expire) throughout the course of the study. If there is 
a change in site personnel over the course of the study, new Investigators or physicians must 
be certified prior to performing the SLEDAI-2K, BILAG-2004, PGA, and CLASI 
assessments.
It is expected that the Investigator will ensure all joint count assessors have adequate 
experience (minimum of 1 year) and training qualifications to perform the swollen and tender 
joint count assessment. Assessors (including any new Investigators or site personnel) must 
complete the online joint count training module and obtain certification prior to performing 
any joint assessment. 
Documentation of all training will be maintained in the site’s study file.
Over the course of the study, Investigator assessments for a given subject should be completed 
by the same trained and/or certified Investigator, designated physician, or qualified site 
personnel (as described above) whenever possible.
5.2.2
Disease Activity Adjudication Group
has a Disease Activity Adjudication Group who are medically-qualified individuals 
and/or support staff who assist in the ongoing management of this trial. The Disease Activity 
Adjudication Group will review all data necessary to characterise subject SLE in relation to 
the SLEDAI-2K, BILAG-2004, and PGA assessments (including central laboratory results); 
however, the group will remain blinded for the duration of the study. Adjudication group 
members will have access to an independent expert on SLE disease activity indices for 
unanticipated issues with regard to interpretation of these indices.
The Disease Activity Adjudication Group will be utilised to confirm eligibility during 
screening and will be utilised throughout the study to confirm SLEDAI-2K, BILAG-2004, and 
PGA scoring. The Adjudication Group will also ensure that the completion of efficacy 
assessments by Investigators is of proper quality and consistency. 
If there is inconsistency between assessments, additional clarification and training on these 
assessments will be provided through the Disease Activity Adjudication Group. 
5.2.3
Systemic Lupus Erythematosus Disease Activity Index 2000 
The SLEDAI-2K disease activity index (see Appendix E) consists of a list of organ 
manifestations, each with a definition. A certified Investigator or designated physician will 
complete the SLEDAI-2K assessment and decide whether each manifestation is “present” or 


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“absent” in the last 4 weeks. The assessment also includes the collection of blood and urine 
for assessment of the laboratory categories of the SLEDAI-2K.
The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighted instrument, in 
which descriptors are multiplied by a particular organ’s “weight”. For example, renal 
descriptors are multiplied by 4 and central nervous descriptors by 8 and these weighted organ 
manifestations are totalled into the final score. The SLEDAI-2K score range is 0 to 105 points 
with 0 indicating inactive disease. The SLEDAI-2K scores are valid, reliable, and sensitive 
clinical assessments of lupus disease activity. The SLEDAI-2K calculated using a timeframe 
of 30 days prior to a visit for clinical and laboratory values has been shown to be similar to the 
SLEDAI-2K with a 10-day window (Touma et al, 2010). A timeframe of 28 days will be used 
in this study.
The “Clinical” SLEDAI-2K score is the SLEDAI-2K assessment score without the inclusion 
of points attributable to any urine or laboratory results including immunologic measures. Its 
use may permit earlier clinical decisions to be made without waiting for immunologic 
measures (including anti-dsDNA antibodies and C3, C4, and CH50 complement levels). 
However, in any circumstance where the “Clinical” SLEDAI-2K score is used, sites must 
subsequently update the SLEDAI-2K assessment when laboratory data become available so 
that the full SLEDAI-2K score is made available to the Sponsor.
A quick Reference Guide will be provided to all study personnel, which contains detailed 
protocol-specific clarifications and extensions of SLEDAI-2K clinical parameter definitions 
and a guidance for correlating SLEDAI 2K and BILAG-2004 clinical parameters.
5.2.4
British Isles Lupus Assessment Group-2004 
The BILAG-2004 is a translational index with 9 organ systems (General, Mucocutaneous, 
Neuropsychiatric, Musculoskeletal, Cardiorespiratory, Gastrointestinal, Ophthalmic, Renal 
and Haematology) that is able to capture changing severity of clinical manifestations (see 
Appendix F). It has ordinal scales by design and does not have a global score; rather it records 
disease activity across the different organ systems at a glance by comparing the immediate 
past 4 weeks to the 4 weeks preceding them. It is based on the principle of physicians’ 
intention to treat and categorises disease activity into 5 different levels from A to E:

Grade A represents very active disease requiring immunosuppressive drugs and/or a 
prednisone dose of >20 mg/day or equivalent

Grade B represents moderate disease activity requiring a lower dose of 
corticosteroids, topical steroids, topical immunosuppressives, antimalarials, or 
NSAIDs

Grade C indicates mild stable disease

Grade D implies no disease activity but the system has previously been affected

Grade E indicates no current or previous disease activity


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Although the BILAG-2004 was developed based on the principle of intention to treat, the 
treatment has no bearing on the scoring index. Only the presence of active manifestations 
influences the scoring.
5.2.4.1
Protocol-specific clarification and extension of BILAG-2004 definitions
A quick Reference Guide will be provided to all study personnel, which contains detailed 
protocol-specific clarifications and extensions of BILAG-2004 clinical parameter definitions 
and guidance for correlating SLEDAI 2K and BILAG-2004 clinical parameters. Please refer 
to this guide when completing disease activity assessments. Important extensions of selected 
BILAG-2004 glossary definitions are included as follows:
Protocol-specific extensions of BILAG-2004 and SLEDAI-2K clinical parameter definitions:
(i)
BILAG-2004 A or B score in the musculoskeletal organ system due to active 
polyarthritis, defined as follows:

“BILAG-2004 A”: severe arthritis (BILAG-2004 #41) manifested by observed 
active synovitis in ≥2 joints with marked loss of functional range of movements 
and significant impairment of basic activities of daily living (ADL), that has 
been present on several days cumulatively over the past 4 weeks, including at 
the time of the Screening visit. Basic ADL are defined as the following 
activities which require assistance or assistive devices (at least 1 must be present 
and documented in source): ambulation, toileting, grooming including bathing, 
dressing, feeding oneself (not responsive to steroids up to 10 mg/day, 
antimalarials, NSAIDs).

“BILAG-2004 B”: moderate arthritis or tendonitis or tenosynovitis 
(BILAG-2004 #42) defined as tendonitis/tenosynovitis or active synovitis in 
≥1 joint (observed or through history) with some loss of functional range of 
movements which leads to some loss of functional range of motion as 
manifested by effects on instrumental ADLs (such as cooking, driving, using the 
telephone or computer, shopping, cleaning, etc), which has been present on 
several days over the last 4 weeks and is present at the time of the Screening 
visit.
(ii)
BILAG-2004 and SLEDAI-2K “lupus headache”: lupus headache is rare, migraine, 
tension or cluster headaches should not be recorded. Lupus headache should only be 
recorded if it is disabling, lasts at least 3 days, and does not respond to narcotics. It 
is expected that its severity would prompt formal testing (lumbar puncture, 
magnetic resonance imaging [MRI], computed tomography [CT], etc) and require 
corticosteroids and/or immunosuppressants and potentially hospitalisation for 
treatment. Lupus headache is considered a manifestation of lupus cerebritis.
5.2.5
Physician Global Assessment 
A trained and certified Investigator will complete the PGA (see Appendix G). The PGA 
represents the physician’s overall assessment of average SLE disease severity on a VAS scale 


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with 0 (no disease) to 3 (severe) disease activity over the last 4 weeks. The PGA for a given 
subject should be completed by the same physician whenever possible.
The PGA is a modification of the classic analogue scale in that it is anchored with numbers 
from 0 to 3 demarcating no, mild, moderate and severe disease. The number 3 indicates severe 
disease and is at the end of the scale. This refers to the most severe possible disease, and does 
not reflect the most severe seen in a particular subject, but the most severe disease ever seen in 
all SLE subjects. Therefore, the line made by the physician along this scale should virtually 
never get to this edge. Any disease rated greater than 2.5 is very severe. The range of 
moderate disease covers approximately 1.5 to 2.4. Mild disease falls below 1.5. The 
instrument is similar to a logarithmic scale, with greater distances or demarcations possible 
among more mild-moderate symptoms. 
When scoring the PGA, the score from the previous visit should be reviewed and the mark 
should be moved relative to the score from the previous visit. This is a global assessment, 
factoring in all aspects of the subject’s lupus disease activity. It should not reflect non-lupus 
medical conditions.
5.2.6
Oral corticosteroid reduction
Please refer to Section 3.3.2 for all information regarding steroid tapering. 
5.2.7
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index 
The SDI has been developed to assess irreversible damage in SLE subjects independently of 
its cause (SLE activity, therapy, comorbidities) but occurring after disease onset (see 
Appendix H). Damage, ie, irreversible impairment since onset of SLE is usually defined as a 
clinical feature that has to be continuously present for at least 6 months to score. In addition 
some irreversible events such as MI or a cerebrovascular accident score as damage on their 
occurrence. Briefly, damage is defined for 12 organ systems; peripheral vascular, ocular, 
neuropsychiatric, renal, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, skin, 
endocrine (diabetes), gonadal, and malignancies. Damage over time can be stable or increase, 
to a maximum of 47 points, however there should be no decrease in the number of points 
(Schwartz et al, 2009).
5.2.8
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
inflammatory disease activity 
The CLASI is a validated index used for assessing the cutaneous lesions of SLE and consists 
of 2 separate scores: the first summarises the inflammatory activity of the disease; the second 
is a measure of the damage done by the disease (see Appendix I). The activity score takes into 
account erythema, scale/hypertrophy, mucous membrane lesions, recent hair loss, and non-
scarring alopecia. The damage score represents dyspigmentation, 
scarring/atrophy/panniculitis, and scarring of the scalp. Subjects are asked if their 
dyspigmentation lasted 12 months or longer, in which case the dyspigmentation score is 
doubled. Each of the above parameters is measured in 13 different anatomical locations, 


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included specifically because they are most often involved in cutaneous lupus erythematosus 
(CLE). The most severe lesion in each area is measured.
5.2.9
Skin photography
Skin photography is an optional assessment. Subjects will sign an additional consent for 
photography if they agree to participate in these assessments. Photography will be conducted 
at selected sites in subjects who sign an additional consent, and have a screening CLASI score 
of ≥10. 
Site staff will be trained to take photographs. The person who performs the CLASI will 
identify a single, active skin lesion (the target lesion) that is suitable for being photographed, 
and is considered to be the most significant inflammatory lesion due to SLE. The same target 
lesion will be photographed throughout the study at time points specified in the Study Plan 
(Table 2, Table 3, and Table 4). If no baseline skin activity or photos can be captured at the 
patient’s Screening or Day 1 visit, no further photography will be done. In addition to the 
target lesion, photograph(s) including the anatomic area (eg, arm, back, scalp) with the target 
lesion should also be taken. If feasible, photographs of other areas with active skin disease 
should also be taken to demonstrate changes in the overall burden of cutaneous disease 
activity. Additional details about photography are provided in the photography manual. 
5.2.10
Joint count
The swollen and tender joint count is based on left and right shoulder, elbow, wrist, 
metacarpophalangeal (MCP) 1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP) 
1, PIP2, PIP3, PIP4, PIP5 joints of the upper extremities and left and right knee of the lower 
extremities. Conventionally, an active joint for the SLEDAI-2K calculation is defined as a 
joint with pain and tenderness and at least 1 of the following (warmth, erythema, swelling, or 
effusion) (Merrill, 2014). However, in this study an active joint for the joint count assessment 
is defined as a joint with tenderness and swelling only. Each of 28 joints will be then be 
evaluated separately for tenderness (by palpating the joint) and swelling. Joints with intra-
articular injection within 4 weeks are not evaluable for the assessment.
The joint count assessment will include questions regarding limitation of range of movements 
and effects of joint symptoms on basic and functional ADLs.
5.3
Safety assessments
Key safety assessments are AEs, AESIs, vital signs, physical examination, safety laboratory 
tests, and ECGs. Safety assessments will be made at the times indicated in the Study Plan (see 
Table 2 for assessments to be performed at Screening, Table 3 for Treatment Period, and 
Table 4 for Follow-up). Subject-reported outcome assessments should be completed by the 
subject, unassisted by spouse, family members or friends.
5.3.1
Adverse events
Adverse events, SAEs, and AESIs are defined in Sections 6.1, 6.2, and 6.5, respectively.


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Recording of AEs is described in Section 6.6 and reporting of SAEs in Section 6.7.
5.3.2
Vital signs
Vital signs (oral temperature, blood pressure [BP], 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).
5.3.3
Physical examination
Body height will be captured at screening only. Subjects will be weighed at each study visit. 
Medically significant changes from the Screening physical examination will be recorded as 
AEs.
5.3.3.1
Complete physical examination
A complete physical examination will be performed at the visits specified in the Study Plan 
(Table 2, Table 3, and Table 4), and will include an assessment of the following: general 
appearance, head and neck, breast, respiratory, cardiovascular, abdomen, 
musculoskeletal/extremities, neurological, skin, lymph nodes, and thyroid.
5.3.3.2
Focused physical examination
The focused physical examination will include an assessment of the organ systems required to 
complete protocol-specified assessment tools (SLEDAI-2K, BILAG-2004, joint count, and 
CLASI). Additional assessments should be done as clinically indicated. Abnormal findings 
will be recorded as part of AE, SAE, AESI, or lupus activity, as appropriate. 
5.3.3.3
Pap smear
Most cases of cervical cancer appear to be related to infection with papilloma virus. Because 
of the potential for viral reactivation due to blockade of the interferon pathway, we are 
assessing cervical dysplasia in this study, although to date there has been no signal in the 
anifrolumab studies. 
Abnormal Pap smear results received anytime within the 2 years prior to randomisation must 
be repeated to ensure subject eligibility. If a Pap smear performed within 2 years prior to 
randomisation was normal with no documented malignancy (eg, CIN III, CIS, or AIS), it does 
not need to be repeated. Subjects with abnormal Pap smear results of atypical squamous cells 
of undetermined significance (ASC-US), atypical squamous cells where high-grade squamous 
intraepithelial lesion (HSIL) cannot be ruled out (ASC-H), atypical glandular cells (AGC), or 
CIN grades I and II (CIN I and II) will be allowed to enter the study; please refer to Appendix 
X for guidance.
Subjects should have a Pap smear between Week 48 and Week 52 to ensure that there is no 
evidence of new cervical dysplasia. Since access to a Pap smear may vary by country, the 
Sponsor recommends that local guidelines for obtaining Pap smears in subjects who have 
received immunomodulators or immunosuppressive treatment be followed. If a Pap smear was 
performed between Week 48 and Week 52 and was not normal but showed no evidence of 


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malignancy (eg, CIN III, CIS, or AIS), it should be repeated as per the patient’s 
gynaecologist’s recommendations. If the patient’s gynaecologist has recommended a repeat 
Pap smear be performed at a specified interval, the Pap smear should be obtained as 
recommended and the report provided in the source document.
5.3.3.4
Assessment of Cushingoid features
Subjects will be assessed for Cushingoid features at the visits specified in the Treatment 
Period Study Plan (Table 3). Features, such as moon face, buffalo hump, purple or violaceous 
striae, central obesity, hirsutism, acne, easy bruising, and fragile skin, will be captured 
separately to evaluate whether resolution of same can occur overtime with OCS reduction.
5.3.4
Assessment of cardiovascular risk
To understand the contribution of the chronic inflammatory response in SLE to dyslipidaemia 
(as a potential risk for accelerated subclinical arteriosclerotic cardiovascular disease) and the 
potential effects of anifrolumab treatment, both lipid (including LDL and HDL, triglycerides 
[see Section 5.3.11.1]) and inflammatory profiles will be obtained during the study. Various 
risk factors for atherosclerosis will be assessed as part of the subject demographics at 
screening according to the Adult Treatment Panel (ATP) III Guidelines. Current and previous 
concomitant medications received for cardiovascular indications should be collected and 
recorded.
5.3.5
Columbia Suicide Severity Rating Scale 
The C-SSRS is a unique, simple, and short method of assessing both behaviour and ideation 
that tracks all suicidal events, and provides a summary of suicidality (Posner et al, 2007). It 
assesses the lethality of attempts and other features of ideation (frequency, duration, 
controllability, reasons for ideation, and deterrents), all of which are significantly predictive of 
completed suicide (see Appendix J). 
The C-SSRS will be administered at all study visits by a trained rater. The trained rater will 
record the clinical observation on the scale, which will be used as the source document. If at 
all possible, the same individual should perform the assessment at each visit to reduce scoring 
variability. In the event the primary rater is not available, a designated back-up rater who 
meets the same qualifications may perform the C-SSRS. An Investigator physician will review 
completed C-SSRS responses on the day of assessment and document review within the 
source. 
If a subject indicates having a rating of type 4 or 5 suicidal ideation on the C-SSRS suicidal 
ideation scale at any time since the previous visit when the C-SSRS was administered or 
indicates having had any suicidal behaviour since the previous visit, the subject should be 
referred to a mental health professional immediately. If the C-SSRS is administered by a rater 
other than the Primary Investigator, it is recommended that the Primary Investigator confirms 
suicidal ideation before making a referral to mental health services; however this should not 
delay the referral. 


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5.3.6
Personal Health Questionnaire Depression Scale-8
The PHQ-8 consists of 8 of the 9 criteria on which the DSM-IV diagnosis of depressive 
disorders is based (American Psychiatric Association, 1994, see Appendix K). It assesses 
symptoms of depression over the last 2 weeks. The PHQ-8 is completed by the subject and 
scored by the Investigator at visits specified in the Treatment and Follow-up Study Plans 
(Table 3 and Table 4). In addition to the 8 questions on depression, there is also a non-scored 
question to assess how the depressive symptoms affect the subject’s level of functioning.
5.3.7
Electrocardiogram 
Digital ECGs (dECG) for all subjects at all centres will be conducted at the centre using a 
machine provided by the central ECG vendor and will be transmitted to the central ECG 
laboratory. Digital ECGs will be performed at Screening, Randomisation, and at Visit 14 
(Week 52). Digital ECGs will be performed in triplicate at Randomisation and at Visit 14 
(Week 52). Digital ECGs will be obtained after the subject has been resting in a supine 
position for at least 10 minutes. All dECGs will be documented by recording the date, time, 
heart rate, QRS duration, PR interval, RR interval, QT, and corrected QT interval. The 
corrected QT intervals will be calculated using the Fridericia formula.
The Investigator will judge the overall interpretation as normal or abnormal. If abnormal, it 
will be decided as to whether or not the abnormality is clinically significant or not clinically 
significant and the reason for the abnormality will be recorded on the eCRF, if the Investigator 
considers it clinically significant. Abnormal values shall not be recorded as AEs unless 
deemed clinically significant.
Quality assurance of the ECG waveform and subject demographics will be conducted by a 
central ECG laboratory operator at the central ECG laboratory. Electrocardiogram reports will 
be provided to the study sites once the analysis is complete. It is the Investigator’s judgment 
whether the findings/results on the central ECG laboratory report are clinically relevant or not. 
5.3.8
Tuberculosis screening and monitoring
5.3.8.1
Screening evaluation
A blood test for TB will be done at screening using the interferon-gamma release assay 
(IGRAs) test (ie, QuantiFERON® -TB Gold In-Tube Test [QFT-GIT]). Evaluation of all 
subjects by QFT-GIT test will be performed by the central clinical laboratory, and chest x-rays 
will be completed at screening. If an adequate (anterio-posterior and lateral or per local 
standard of care) chest x-ray was performed within 12 weeks prior to signing the ICF, it does 
not need to be repeated at the Screening visit. 
Compared to culture confirmed TB, overall, 87.6% of subjects have a positive QFT-GIT result 
(Cellestis, 2005). The false negative rate in this setting appears to be over 12%. Further, the 
performance of the test in the setting of immunosuppressant drugs has not been evaluated. Nor 
has it been evaluated in individuals with medical conditions other than, or in addition to, latent 
TB or tuberculosis disease. The guide also states that “Medical treatments or conditions that 


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impair immune functions can potentially reduce IFN-γ responses and prevent detection of a
specific response to the (secretory proteins) ESAT-6 and CFP-10 (the test stimulators)”.
Given the population to be enrolled in the SLE study, false negative tests are possible, so a 
chest x-ray is a relevant technique for detecting active pulmonary disease and minimising 
potential risk to study subjects. 
5.3.8.2
Tuberculosis results from screening evaluations

If the screening QFT-G test is negative and there is no known history of recent 
exposure to individuals with active TB, and chest radiograph shows no evidence of 
active TB, the subject may be randomised without prophylaxis.

If the screening QFT-G test is newly positive and chest radiograph shows no 
evidence of active TB, and the subject has no symptoms or medical history 
consistent with active TB, the subject must have a retest, and if retest is positive, the 
subject must start on prophylaxis prior to randomisation.

If the screening QFT-G test is positive at the initial Screening visit, but the subject 
is not newly positive as of the initial Screening visit, the subject must have been 
diagnosed with latent TB and must have documentation confirming completion of 
appropriate treatment. Subjects with no history of latent TB prior to the initial 
Screening visit, but who are diagnosed with latent TB during screening, may be 
considered eligible if appropriate treatment is initiated prior to randomisation. Such 
subjects may be re-screened if necessary to allow for local guidelines on latent TB 
treatment initiation.

If the screening QFT-G test is indeterminate, the test must be repeated at least 1 
time by the central laboratory as soon as possible. 

If the result remains indeterminate, the chest radiograph shows no evidence of 
active TB, there are no signs or symptoms of active TB, no recent contact with 
anyone with active TB, and there is no history of latent (unless diagnosed with 
documentation of completion of appropriate treatment) or active TB, the subject 
may be randomised and will have additional QFT-G testing performed 
according to the Study Plan (Table 2, Table 3, and Table 4). Additionally, in the 
opinion of the Investigator and after discussion with the medical monitor, an 
expert specialising in TB may be consulted prior to randomisation. 
5.3.8.3
Tuberculosis monitoring during the study
If, during the trial a subject who had an indeterminate TB result at screening is determined to 
have a:

Positive QFT-G test result, the subject should be referred to a TB specialist. If a TB 
specialist is not available, the local country guidelines should be followed for 
further diagnostic work up and anti-TB treatment regimens. If no local guidelines 
exist for immunocompromised individuals, then USA guidelines may be followed. 
This should also be reported as an AESI.




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performed at the site using a dipstick. Abnormal safety laboratory results should be repeated 
as clinically indicated, as soon as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. 
Every attempt should be made to redraw any missing safety laboratory tests, even if the 
subject has received the investigational product. 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at the 
centre as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.6.6.
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer to 
Appendix C, ‘Actions Required in Cases of Combined Increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.
The following laboratory variables will be measured:
Table 5
Clinical laboratory tests
Screening
ANA, anti-dsDNA antibodies, anti-Sm antibody, anti-RNP, anti-Sjogren’s Syndrome-related antigen A 
[SSA], and anti-Sjogren’s Syndrome-related antigen B [SSB] 
HbA1c in diabetic subjects only
Peripheral blood B lymphocyte count (only for subjects who received B cell-depleting therapy prior to 
signing the ICF, including but not limited to ocrelizumab, ofatumumab, atacicept, obinutuzumab, or 
rituximab)
BILAG-2004 associated laboratory tests analysed for all subjects at screening (anticardiolipin, lupus 
anticoagulant, haptoglobin, and Coombs [Coombs will be performed as applicable per BILAG 
assessment requirements])*
Hepatitis B surface antigen
Hepatitis B core antibody (reflex DNA testing if isolated HBc positive)
Hepatitis C antibody 
HIV test**
CK 
C3, C4, CH50 complement
Urine protein/creatinine ratio
QFT-G test
Haematology
Haematology/Haemostasis (whole blood)


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WBC count with differential
RBC count
Haematocrit
Haemoglobin
Platelet count
MCV
MCHC
Serum Chemistry 
Calcium
Chloride
Potassium
Sodium
AST*
ALT*
ALP*
GGT
BUN
Creatinine
Total bilirubin* (reflexively fractionated if elevated)
Glucose
Albumin
CK 
*Note for serum chemistry: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and 
assessed concurrently.
Urinalysis
Colour
Appearance
Specific gravity
pH
Protein dipstick
Glucose
Ketones
Blood
Bilirubin


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Microscopy including WBC/HPF, RBC/HPF, casts
Urine creatinine and protein, urine protein/creatinine ratio
Pregnancy Test 
Serum β-hCG (at screening only)
Urine β-hCG (at every visit after screening, using a dipstick)
Serum FSH (at screening only) in postmenopausal females with menses absent for ≥1 year
Disease Evaluations
SLEDAI-2K-associated laboratory tests (C3, C4, CH50 complement, anti-ds DNA, urine 
protein/creatinine ratio)
Note: If central laboratory results are not available for SLEDAI-2K associated tests, samples should be 
redrawn one time within 14 days of the SLEDAI assessment date.
BILAG-2004 associated laboratory tests, including anticardiolipin, lupus anticoagulant, haptoglobin, 
and Coombs (as applicable). Coombs will be performed as applicable per BILAG assessment 
requirements.*
ALP = Alkaline phosphatase; ALT = alanine aminotransferase; ANA = antinuclear antibody; Anti-Sm = Anti-
Smith; AST = aspartate aminotransferase; β-hCG = β-human chorionic gonadotropin; BUN = blood urea 
nitrogen; BILAG = British Isles Lupus Assessment Group; C3 = third component of complement; C4 = fourth 
component of complement; CH50 = total haemolytic complement; CK = creatine kinase; DNA = 
Deoxyribonucleic acid; GGT = gamma glutamyl transferase; HbA1c = Glycosylated haemoglobin; HBc = 
Hepatitis B core antibody; HPF = high power field; MCHC = Mean corpuscular haemoglobin concentration; 
MCV = Mean corpuscular volume; QFT-G = QuantiFERON-TB Gold; RBC = red blood cell; SLEDAI-2K = 
Systemic Lupus Erythematosus Disease Activity Index 2000; WBC = white blood cell
*In order to avoid having to bring the subject back for a separate phlebotomy, the anticardiolipin, lupus 
anticoagulant, and haptoglobin blood specimens will be collected at all specified visits, however the blood will 
be stored at the central laboratory and the analysis performed only if the investigator indicates that these tests 
need to be completed because of clinical suspicion of haemolytic anaemia or anti phospholipid syndrome. Direct 
Coombs test samples will only be collected per the investigator's opinion and applicable BILAG assessment 
requirements for determining haemolytic anaemia.
**Subjects within the treatment or follow-up period at the time of amendment 4 approval will undergo HIV 
testing at the time of amendment 4 ICF signature.
5.3.11
Laboratory assessments for cardiovascular risk assessments
5.3.11.1
Fasting lipid profile
Subjects will have a fasting lipid profile (high density lipoprotein cholesterol, low density 
lipoprotein cholesterol, and triglycerides) completed at times indicated in the Study Plan 
(Table 2, Table 3, and Table 4). Subjects will be required to fast for at least 8 hours prior to 
this assessment (see Section 3.3.3).
5.3.11.2
Immunology profile
Subjects will have tests to determine immunology profile (ANA, anti-Sm, anti-RNP, 
anti-SSA, and anti-SSB), and quantitative immunoglobulins completed at times indicated in 
the Study Plan (Table 2, Table 3, and Table 4). 


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5.4
Clinical pharmacology assessments
Clinical pharmacology assessments will be made at the times indicated in the Study Plan 
(Table 2, Table 3, and Table 4).
5.4.1
Pharmacokinetics 
For the PK analysis it is important that the date, start and stop time for the IV infusion, and the 
sample collection time are recorded. Instructions for sample collection, processing, storage, 
and shipment can be found in the separate laboratory manual provided to the centres. Serum 
will be collected according to the Study Plan (Table 3 and Table 4). Post-dose samples should 
be collected 15 minutes ±5 minutes after completion of investigational product administration
after dosing on Week 0 (Day 1) and Week 48. Post-dose specimens should not be drawn 
through the IV line used to administer the investigational product.
Samples for determination of anifrolumab concentration in serum will be analysed by a central 
laboratory on behalf of the Sponsor, using a validated bioanalytical method. 
5.4.2
Immunogenicity
Instructions for immunogenicity (anti-drug antibodies [ADA] and neutralising antibodies 
[nAb]) sample collection, processing, storage, and shipment can be found in the separate 
laboratory manual provided to the centres.
5.4.2.1
Anti-drug antibodies 
The pre-dose serum samples to measure presence of ADA will be collected according to the 
Study Plan (Table 3 and Table 4). The presence or absence of ADA will be determined in the 
serum samples using validated bioanalytical methods. In order to help understand the potential 
drug-relatedness of any hypersensitivity or anaphylaxis reaction, possible additional ADA 
testing (if not already scheduled for a visit) may be collected and analysed.
5.4.2.2
Neutralising antibodies
Neutralising antibodies testing will only occur on samples that are ADA positive. Samples 
that are ADA negative will not be tested for nAb. The presence or absence of neutralising 
ADA will be determined using a validated bioanalytical method. 
5.4.3
Pharmacodynamics 
Type I IFN inducible signature in whole blood will be assessed by a 21-gene assay to be used 
as a PD marker to follow the biologic effect of anifrolumab on its target throughout the study. 
Whole blood will be collected for RNA isolation at the visits indicated in the Study Plan 
(Table 2, Table 3, and Table 4) in order to evaluate the mRNA expression levels of 21 type I 
IFN-inducible genes. The remaining mRNA from the PD sample may be utilised for 
additional biomarker work to further characterise the effects of anifrolumab on its target. 


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5.4.4
Interferon test in whole blood
Whole blood will be collected at screening in PAXgene tubes to measure the overexpression 
of mRNA for certain types of type I IFN-inducible genes using a 4-gene test. The IFN test and 
the data will be evaluated for development of a companion diagnostic. The IFN-4-gene testing 
will be conducted at a designated central laboratory under a separate device test site protocol 
provided by the device sponsor (QIAGEN). The QIAGEN therascreen® interferon-inducible 
gene expression (IFIGx) Rotor-Gene Q (RGQ) reverse transcriptase polymerase chain 
reaction (RT-PCR) System will be used, it comprises the following:

PAXgene™Blood RNA Tubes (sample collection)

PAXgene™Blood RNA Kit (RNA sample preparation)

Therascreen IFIGx RGQ RT-PCR Kit used with the RGQ molecular diagnostic 
Platform with bespoke IFIGx software (sample testing)
The therascreen IFIGx RGQ RT-PCR Kit will be labelled as per 21 CFR 809 .10 (c)(2)(ii), 
“For Investigational Use Only.” The performance characteristics of this product have not been 
established.
The primary intent is to prospectively identify subjects as “test-high” or “test-low” for the 
purpose of randomisation. The results of this test will be used to stratify subjects. The kit uses 
the expression of the genes IFI27, IFI44, IFI44L and RSAD2 compared with 3 reference 
genes; 18S, ACTB and GAPDH. The result is expressed as a score that is compared with a 
pre-established cut-off that classifies subjects into 2 groups with low or high levels of IFN 
inducible gene expression. The results of the test will not be used to determine eligibility and 
will not be shared with the investigative site (ie, all site personnel will remain blinded to IFN 
test results). The assay is not intended for prediction of response to anifrolumab in other 
diseases. 
5.4.5
Proteomics/biomarkers
Renal disease develops in more than half of SLE subjects. However, the onset of lupus 
nephritis is commonly insidious and thus, early diagnosis and treatment of lupus nephritis are 
difficult. Many studies have shown the presence of inflammatory proteins in the urine of lupus 
nephritis subjects and the correlation of such proteins with disease severity/activity and/or 
histological results. However, there are very few studies that have evaluated the differences in 
urine proteomics between subjects with active lupus nephritis requiring treatment and subjects 
with either minimal or inactive renal disease. Understanding how anifrolumab impacts on 
urine proteomics should expand our insights regarding the effects of anifrolumab on the 
kidney in subjects with SLE. 
Urine samples will be collected according to the time points outlined in the Study Plan (Table 
3 and Table 4). Approximately 30 to 40 mL of urine will be collected from each subject at the 
specified visits. Baseline urine samples will be used to assess differences in protein analytes 
from control healthy donor samples by a variety of technical methodologies that may include: 
immunoassays, protein arrays, and biochemical approaches. Longitudinal alterations in SLE 
dysregulated proteins will be assessed in association with clinical characteristics and/or 


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response to treatment. Additionally, the results from the proteomic analyses will be compared 
to those obtained from urine samples of lupus nephritis subjects. 
Plasma will be collected for correlative studies during visits specified in the Study Plan (Table 
3 and Table 4). These studies will include proteins, peptides and immune complexes and will 
be conducted using immunoassays, in vitro assays, and/or biochemical approaches. The data 
from these studies will be reported in separate research reports. 
5.4.6
Storage and destruction of biological samples
Samples will be stored for up to 15 years or as per local regulation from the date of the Last 
Subject’s Last Visit, after which they will be destroyed.
5.5
Quality of life/pharmacoeconomic assessments
Quality of life and pharmacoeconomic assessments will be made at the times indicated in the 
Study Plan (Table 2, Table 3, and Table 4). Subject-reported outcome assessments should be 
completed by the subject, unassisted by spouse, family members or friends.
Subjects will be completing the following subject-reported questionnaires to assess treatment 
effects.
5.5.1
Short Form 36 version 2 (acute recall) 
The SF-36-v2 (acute) is a multipurpose, 36-item survey that measures 8 domains of health: 
physical functioning, role limitations due to physical health, bodily pain, general health 
perceptions, vitality, social functioning, role limitations due to emotional problems, and 
mental health (see Appendix L). It yields scale scores for each of these 8 health domains, and 
2 summary measures of physical and mental health: the Physical Component Summary and 
Mental Component Summary.
5.5.2
Functional Assessment of Chronic Illness Therapy–FATIGUE 
The FACIT-F is a 13-item subject-completed questionnaire to assess the impact of fatigue 
over the previous 7 days (see Appendix M). The responses range from 0 (Not at All) to 4 
(Very Much). Final scores are the sum of the responses and range from 0 to 52; higher scores 
indicate better QoL (Yellen et al, 1997). Changes in scores >3 points are considered to be 
clinically meaningful (Cella et al, 2002).
5.5.3
EuroQoL 5 dimensions 
The EQ-5D-5L is comprised of the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression (EuroQoL Group, 1990, see Appendix N). 
Each dimension has 5 response options (no problems, slight problems, moderate problems, 
severe problems and unable to/extreme problems) that reflect increasing levels of difficulty. 
EQ-5D-5L health states will be converted into a single index value using values sets from the 
EQ-5D-5L Crosswalk Project. The questionnaire also includes a VAS, where the subjects are 
asked to rate their health on a scale of 0-100, with 0 being worst imaginable health state and 
100 being best imaginable health state.


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5.5.4
Lupus Quality of Life
Lupus QoL is a 34-item SLE-specific health-related QoL measure (see Appendix O). It was 
developed in the United Kingdom for use in adults with SLE (McElhone et al, 2007) and was 
further validated in the USA (Jolly et al, 2010). The instrument consists of 8 domains 
(physical health [8 items], pain [3 items], planning [3 items], intimate relationships [2 items], 
burden to others [3 items], emotional health [6 items], body image [5 items] and fatigue
[4 items]). 
5.5.5
Patient Global Assessment 
Subjects will be asked to complete the PtGA (see Appendix P). The PtGA is a single-item 
question that takes into account all the ways in which illness and health conditions may affect 
the patient at this time. The patient should consider the previous week when answering this 
question. Responses range from very well to very poor on a 100 mm VAS. The physician and 
subject must complete the PGA and PtGA, respectively, independently of each other.
5.5.6
Work productivity and Activity Impairment 
The Work Productivity and Activity Impairment (WPAI) is a validated, self-administered 
questionnaire consisting of 6 questions, assessing the impact of disease on productivity (see 
Appendix Q). The WPAI yields 4 types of scores: absenteeism (work time missed), 
presenteeism (VAS [scored from 0 to 10] rating of impairment while working), work 
productivity loss (overall work impairment /absenteeism plus presenteeism), and activity 
impairment (VAS [scored from 0 to 10] rating of daily activities, other than work at a job) 
(Reilly et al, 1993).
5.5.7
Medical Resource Use Questionnaire
Medical resource use will be determined by completing the Medical Resource Use 
Questionnaire Edition Number 3, which collects information on: 1) the number of 
unscheduled emergency department visits; 2) unscheduled hospitalisations; 3) the length of 
stay for hospitalisations; 4) the number of intensive care unit (ICU) stays and the length of 
ICU stays; 5) unscheduled medical provider visits; and 6) the cause(s) of hospitalisation over 
duration of the study (see Appendix S). 
Site personnel will administer the questionnaire by interviewing the subject at every visit. 
Further, site personnel are required to obtain source documentation (ie, medical records) for 
these visits and make the records available to the monitor. Appropriate SAE/AE forms need to 
be completed for hospitalisation and emergency department visits.
5.5.8
Pain numerical rating scale 
Overall subject-reported pain will be captured with an 11-point NRS (0 no pain; worst 
imaginable) with a 1 week recall period (see Appendix R). 


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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, ECG). In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definition of serious adverse events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent 1 of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B.
6.3
Hy’s law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with total bilirubin ≥2xULN may need to 
be reported as SAEs. Please refer to Appendix C for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.4
Other events of special interest
6.4.1
Overdose
An overdose (ie, having been administered a greater dose of study drug than specified in this 
protocol) with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modules in the CRF and in the Overdose Report.


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An overdose without associated symptoms is only reported in the Overdose Report.
If an overdose of investigational product occurs during the study, then the Investigator or 
other site personnel inform the appropriate AstraZeneca representative or designee 
immediately or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative or designee works with the Investigator to ensure 
that all relevant information is provided to the 
Safety Management data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.7. 
For other overdoses, reporting must occur within 30 days.
6.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.4.3
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative or designee works with the Investigator to ensure 
that all relevant information is provided to 
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.
6.4.4
Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
12 weeks following the last dose. 


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Pregnancy of the subject’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should if possible be followed up and documented. 
The outcome of any conception occurring from the date of the first investigational product 
administration until 12 weeks after the last investigational product administration should be 
followed up and documented. Information on the pregnancy of a subject’s partner must be 
obtained directly from the subject’s partner. Therefore, prior to obtaining information about 
the pregnancy, the Investigator must obtain the consent of the subject’s partner.
6.5
Adverse Events of Special Interest 
An AESI is an AE of scientific and medical concern specific to understanding biologics and 
requires close monitoring and rapid communication by the Investigator to the 
Sponsor/Sponsor’s delegate. An AESI may be serious or nonserious. 
Adverse Events of Special Interest in this protocol will be assessed at each visit in the CRF. 
The events of interest are serious infections, including non-opportunistic serious infections, 
opportunistic infections, anaphylaxis, malignancy, herpes zoster, TB (including latent TB), 
influenza, vasculitis (non-SLE), and MACE (including stroke, MI, or cardiovascular death). 
Lupus nephritis (associated with SLE; WHO or ISN/RPS Classification Class III, IV or V) is 
defined not as an AESI but as a new BILAG-2004 A adjudicated AE.
An AESI that meets 1 of the seriousness outcomes listed in Section 6.2 will be categorised as 
an SAE for the purposes of follow-up responsibility and safety reporting. A nonserious AESI 
will be categorised as an AE. For reporting of AESIs, see Section 6.8.
6.5.1
Non-opportunistic serious infection
A serious non-opportunistic infection is any non-opportunistic infection that meets the SAE
criteria in Section 6.2. Serious non-opportunistic infection adverse events are reported as 
SAEs and AESIs. It is expected that culture results and all diagnostic or therapeutic procedure 
results performed on a subject experiencing a serious non-opportunistic infection will be 
provided as an SAE update. Non-serious non-opportunistic infections will not be captured as 
AESIs.
6.5.2
Opportunistic infection
An opportunistic infection is an invasive infection caused by microorganisms that are 
normally non-pathogenic or rarely pathogenic in individuals with normal immune function or 
cause an infection of a type or severity not seen in the normal host. 
Examples of opportunistic infections that may occur in SLE subjects include: herpes zoster
meningoencephalitis, Salmonella bacteremia, Pneumocystis jiroveci pneumonia or progressive 
multifocal leukoencephalopathy. It is expected that culture results and all diagnostic or 
therapeutic procedure results performed on a subject experiencing a serious opportunistic 
infection will be provided as an SAE update. Since anifrolumab is an immunomodulatory 


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agent and the sponsor needs to understand the safety profile of this investigational product, 
including assessment of how anifrolumab may affect resistance to different types of 
infections, investigators are asked to undertake appropriate microbiologic identification 
including culture and report culture results for all patients who develop serious infections.
6.5.3
Anaphylaxis
Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after 
contact with an allergy-causing substance, such as investigational product. For the purposes of 
this study, the definition detailed in Appendix Y is provided as a simple and rapid means to 
make the diagnosis of anaphylaxis during infusion with investigational product. This 
definition was a product of a symposium convened by the National Institute of Allergy and 
Infectious Diseases and Food Allergy and Anaphylaxis Network (Sampson et al, 2006). 
6.5.4
Malignancy
Malignancy is a neoplasm characterised by cells with abnormal features, uncontrolled rapid 
growth with invasive and/or metastatic tendencies diagnosed based on pathologic and clinical 
standards. Understanding risk of developing different malignancies is critical to establishing 
the benefit: risk profile for anifrolumab. Investigators are therefore requested to obtain biopsy 
results and pertinent biomarker and/or genetic testing results performed and to report these for 
any malignancies reported during the study.
6.5.5
Herpes zoster
Herpes zoster is a viral infection characterized by a cutaneous vesicular eruption on an 
erythematous base presenting along dermatome(s) and usually associated with prodromal 
pain. Herpes zoster results from the reactivation of varicella-zoster virus; multiple 
dermatomes may be involved (>3 indicates disseminated disease) and organ or systemic 
infection may occur (invasive; therefore an opportunistic infection). Polymerase chain 
reaction testing of samples from vesicles, biopsy, or other specimens (for example, 
cerebrospinal fluid) may confirm the presence of varicella-zoster virus.
For additional information regarding Herpes zoster, refer to the Investigator Brochure. As this 
is an event of special interest, the Sponsor will collect information including whether or not 
subjects have received vaccination for Herpes zoster. The Herpes zoster vaccine will be 
captured in the appropriate sections of the CRF. 
6.5.6
Tuberculosis
Tuberculosis is a mycobacterial infectious disease generally presenting as cough with 
systemic symptoms of infection diagnosed by skin test (purified protein derivative), blood test 
(IFN-gamma release assay), radiographic imaging, body fluid and tissue sampling; 
presentation may include disseminated or latent disease. An infection may be new (at least 
conversion of a TB test to positive) or reactivation of dormant disease (new active disease in a 
previously TB test positive subject without prior evidence of active disease).


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
A bacteriologically confirmed TB case is a case where a biological specimen is 
positive by smear microscopy, culture or rapid diagnostic such as PCR or nucleic 
acid amplification test (Xpert MTB/RIF).

A clinically diagnosed TB case is a case where the subject does not fulfil the 
criteria for bacteriological confirmation, but has been diagnosed with active TB by 
a clinician or other medical practitioner who has decided to give the subject a full 
course of TB treatment. This definition includes cases diagnosed on the basis of 
x-ray abnormalities or suggestive histology and extra-pulmonary cases without 
laboratory confirmation. Clinically diagnosed cases subsequently found to be 
bacteriologically positive (before or after starting treatment) should be reclassified 
as bacteriologically confirmed.
Bacteriologically confirmed or clinically diagnosed cases of TB are also classified according 
to: anatomical site of disease; history of previous treatment; drug resistance; HIV status 
(World Health Organization, 2014). 
Latent TB is a mycobacterial infection without clinical, bacteriological findings, or radiologic 
findings consistent with active TB and a TB blood test such as an IGRA (QuantiFERON 
Gold) or purified protein derivative skin test that is positive both at the time of provisional 
diagnosis and on repeat assessment. 
Subjects identified with latent TB will be assessed by a local TB specialist to confirm the 
diagnosis and local SOC that will be used in treatment. Once latent TB is confirmed, treatment 
must be instituted immediately and no investigational product may be administered until 
treatment of latent TB has begun. Additionally, subjects with newly diagnosed latent TB must 
agree to complete a locally recommended course of treatment for latent TB in order to 
continue receiving IP.
6.5.7
Influenza
Influenza is a severe viral infection that includes the following symptoms: temperature greater 
than 100.8°F (38.2°C), and malaise, headache, or myalgia. It is often accompanied by nausea, 
vomiting, and diarrhoea, and at least 1 of the following respiratory symptoms: cough, sore 
throat, or shortness of breath.
Laboratory criteria for influenza include at least 1 of the following: isolation of influenza virus 
from a clinical specimen, detection of influenza virus nucleic acid in a clinical specimen, 
identification of influenza virus antigen by direct fluorescent antibody test in a clinical 
specimen, OR influenza-specific antibody response.
A confirmed case of influenza meets the clinical and laboratory criteria for the viral illness. 
Laboratory confirmation should be done using locally available, rapid, commercial tests 
approved by Regulatory Agencies and sampling respiratory specimens. 
Not all upper respiratory viral infections or gastrointestinal viral infections are influenza. In 
the case where a subject reports a viral infection severe enough to be considered, in the 
opinion of the Investigator, influenza, a viral test should be performed (if possible) to confirm 


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the diagnosis. If, in the opinion of the Investigator, the subject has had influenza (the specific 
viral infection), this should be reported as an AESI, whether or not a test to confirm the 
diagnosis has been performed. Less severe viral infection should be reported as an AE only.
6.5.8
Vasculitis (non-Systemic Lupus Erythematosus)
Vasculitis (non-SLE) is defined as an inflammatory disorder of blood vessels involving 
arteries and/or veins and characterized by characteristic clinical signs/symptoms and 
diagnosed by biopsy, imaging such as angiography or blood tests such as findings of 
antineutrophil cytoplasmic antibodies consistent with the diagnosis. Underlying causes should 
be identified, such as medications including study drug, infections or systemic inflammatory 
syndromes, wherever possible. See Appendix T for a list of vasculitic syndromes excluded 
from the study. 
6.5.9
Major acute cardiovascular events
As a measure of enhanced Pharmacovigilance, an independent Cardiovascular Event 
Adjudication Committee (CV-EAC) will review deaths (due to any cause) and all SAEs in the 
cardiovascular SOC for evaluation as to whether to classify as MACE events (stroke, MI, or 
cardiovascular death).
The CV-EAC will review cases of interest to determine if they meet accepted diagnostic 
criteria. Causality assessments will not be made by the CV-EAC, nor will the committee 
possess governance authority. The CV-EAC will be blinded regarding any information 
relating to the randomisation group.
6.6
Recording of adverse events
6.6.1
Time period for collection of adverse events
Adverse Events and SAEs will be collected from the time of signature of informed consent, 
throughout the treatment period and including the follow-up period until Follow-up Visit 2 
(12 weeks post final dose) or Week 52 for the subjects who enrol in the LTE study.
6.6.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
study staff for as long as medically indicated. The Sponsor retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
6.6.3
Variables 
The following variables will be collected for each AE;

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity


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
Whether the AE is serious or not

Investigator causality rating against the investigational product (yes or no)

Action taken with regard to investigational product

Outcome of AE 
In addition, the following variables will be collected for SAEs:

Onset Date (Date AE met criteria for serious AE)

Detection Date (Date Investigator became aware of serious AE)

AE is serious due to:
(a)
Death
-
Date of death
-
Autopsy performed
-
Primary/secondary cause of death
(b)
Life threatening
(c)
Inpatient hospitalisation or prolongation of existing hospitalisation

Date of hospitalisation

Date of discharge
(d)
Congenital abnormality or birth defect
(e)
Important medical event
(f)
Suspected transmission via a medicinal product of an infectious agent

Description of AE

Investigator causality assessment to concomitant medications

Investigator causality assessment to study procedures (yes or no)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity, whereas seriousness is defined by the criteria defined above. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. The Investigator should provide an assessment of the severity of each AE/SAE.


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6.6.4
Causality collection
The Investigator will assess causal relationship between investigational product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures 
and additional study drug (such as OCS, azathioprine, antimalarials, mycophenolate 
mofetil/mycophenolic acid, methotrexate, and mizoribine). Note that for SAEs that could be 
associated with any study procedure the causal relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
6.6.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or care provider or reported in response to the 
open question from the study personnel: ‘Have you had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded 
in the CRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.6.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR). Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs, ECGs, and other safety assessments should therefore only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator will 
use the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE (or SAE, as appropriate).
6.6.7
Disease progression/worsening of systemic lupus erythematosus
Disease progression can be considered as a worsening of a subject’s condition attributable to 
SLE. It may be an increase in the activity or severity of the existing manifestations of SLE or 




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is important that Investigators submit additional information requested by AstraZeneca or 
 as soon as it becomes available.
The reference document for definition of expectedness/listedness is the IB.
6.8
Reporting of adverse events of special interest
Adverse Events of Special Interest will be assessed by the Investigator for severity, 
relationship to the investigational product, possible aetiologies, and whether the event also 
meets criteria of an SAE. All AESIs (serious or nonserious) will be recorded on the AE CRF 
(using a recognized medical term or diagnosis that accurately reflects the event).
The reporting period for AESIs is the period immediately following the time that written 
informed consent is obtained through the end of subject participation in the study. Following 
detection of an AESI (non-serious), reporting is required within 72 hours of knowledge of the 
event, and for serious AESIs the standard 24-hour timeline for reporting to the appropriate 
AstraZeneca representative or designee applies.
6.9
Management of investigational product-related toxicities 
6.9.1
Anaphylaxis, hypersensitivity, and infusion-related reactions
Infusion-related reactions have been reported with the administration of IV Ig and monoclonal 
antibodies. As with any antibody, allergic reactions to dose administration are possible. 
Therefore, appropriate drugs and medical equipment to treat acute anaphylactic reactions must 
be immediately available, and study personnel must be trained to recognise and treat 
anaphylaxis. For a definition of anaphylaxis, hypersensitivity reactions, and infusion-related 
reactions, see Appendix Y.
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 or other investigations (eg, 
chest x-ray for pneumonia) that confirm or aid in the diagnosis or treatment should be 
obtained when indicated and results should be reported with the SAE or AESI. 
Subjects who develop a new infection while undergoing treatment with investigational 
product should receive appropriate medical therapy, as determined by local standards, and be 
monitored closely until the condition resolves. Investigational product should not be 
administered to a subject with a clinically significant, active infection as determined by the 
Investigator (see Section 3.7). For any active infection (eg, varicella zoster


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infection/chickenpox) or significant exposure to any infection (eg, varicella zoster infection in 
a naive subject, bacterial pneumonia), the Investigator should consider whether to interrupt 
investigational product administration and should notify the medical monitor. 
Similarly, if a subject presents with signs or symptoms where opportunistic infections are 
considered (eg, CNS symptoms consistent with progressive multifocal leukoencephalopathy 
or herpes encephalitis or atypical pneumonia suggesting pneumocystis jiroveci pneumonia), 
investigational product should be interrupted until the Investigator confirms the symptoms and 
signs of infection have resolved or that no active infection has developed.
If dosing is resumed after resolution of a safety concern (ie, infection or other AE) the 
investigational product must be administered within 14 days of the scheduled time of the 
missed dose. If this is not possible, dosing should be resumed at the time of the next scheduled 
dose.
6.10
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with 
 Safety Management. Issues identified 
will be addressed; for instance this could involve amendments to the study protocol and letters 
to Investigators. 
6.10.1
Data and Safety Monitoring Board 
An independent DSMB will perform evaluations of safety data at specified regular intervals 
throughout the study and make recommendations to the Sponsor regarding further conduct of 
the study. The DSMB will be provided with data that are summarised by treatment group 
using masked treatment group labels (eg, A, B, and C). After reviewing the data by masked 
treatment group, the DSMB may choose to unblind the treatment groups for additional review. 
The DSMB may also ask for unblinded efficacy data, if during the performance of a 
benefit/risk assessment the Board feels there is a potential safety issue or concern. The DSMB 
will not routinely review efficacy data (blinded or unblinded). 
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 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 Institutional Review 
Board/Independent Ethics Committee (IRBs/IECs) 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 products
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
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.
Each vial of investigational product or placebo contains 1.3 mL fill volume. Investigational 
product and placebo will be supplied to the site in cartons of 2 vials per kit. Each kit will have 
a unique number that will be printed on all labels within the kit (ie, the outer carton label and 
the label of each vial within the carton).
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 150 mg, 300 mg or placebo, will be administered via 
controlled IV infusion pump into a peripheral vein over at least 30 minutes Q4W. Each dose 
must be at least 14 days apart.
7.2.1
Dose preparation steps
From a 100 mL IV infusion bag of 0.9% normal saline, withdraw and discard a volume of 
saline equal to 2.0 mL. Then add 1.0 mL from each of the 2 vials in the kit into the infusion 
bag and mix by gentle inversion. Due to approximately 10% overfill of normal saline, the final 
volume of the dilution will be greater than 100 mL. 
7.2.2
Prior to administering the investigational product

Confirm subject was evaluated for signs and symptoms of TB

Women of childbearing potential must have a negative urine pregnancy test prior to 
receiving investigational product.


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
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 
medical monitor. 

Pre-dose blood samples will be collected

Subjects should not be premedicated unless they have had a prior infusion-related 
reaction to anifrolumab. However, if a prior infusion-related reaction has been 
documented, the Investigator may elect to administer prophylactically an 
antihistamine or acetaminophen/paracetamol for the comfort and safety of the 
subject prior to subsequent infusions. The medications should be given after visit 
assessments have been completed. Prophylactic use of glucocorticosteroids prior to 
subsequent infusions is not permitted.
7.2.3
Investigational product administration procedures

Investigational product must be administered within 4 hours after preparation and 
may be stored at room temperature until administration. Total in-use storage time 
from dilution of anifrolumab to start of administration should not exceed 4 hours at 
room temperature. If refrigerated at 2 to 8°C (36 to 46°F), storage time should not 
exceed 24 hours. If storage time exceeds these limits, a new dose must be prepared 
from new vials.

Investigational product must be administered at room temperature by controlled 
infusion via an infusion pump into a peripheral vein. A physician must be present at 
the site or immediately available to respond to emergencies during all 
administrations of investigational product.

Because compatibility of anifrolumab with IV medications and solutions other than 
0.9% sodium chloride for injection, (United States Pharmacopeia), is not known, 
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.
7.2.4
Subject monitoring/procedures during and after the infusion
Subjects will be monitored during the administration of the investigational product and for at 
least 2 hours after the first 4 infusions (Weeks 0, 4, 8, and 12). If there are no safety concerns, 
for subsequent infusions subjects will be monitored during administration of the 
investigational product and for a minimum of 1 hour after completion of the IV infusion 
thereafter (Week 16 to Week 48). 


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Monitoring will include vital signs (oral temperature, BP, pulse rate, respiratory rate) in a 
sitting position at the following times:

Shortly before the IV infusion (within 15 ±5 minutes of the beginning of the 
investigational product infusion)

Every 15 ±5 minutes during infusion

Immediately after completion of administration of investigational product, 
including post-dose saline flush (within 15 ±5 minutes after completion of 
investigational product administration)

Every 30 ±5 minutes after completion of investigational product administration (not 
including saline flush) for at least 2 hours after the first 4 doses (Week 0 [Day 1] to 
Week 12) of investigational product are administered, and for at least 1 hour, 
thereafter (Week 16 to 48)

Samples for PK laboratory assessments should be collected 15 ±5 minutes after 
completion of investigational product administration after dosing on Week 0 
(Day 1) and Week 48
Vital signs may be taken more frequently, based on Investigator judgment. 
7.2.5
Discharge
The subject should only be discharged from the site after the minimum monitoring period and 
when judged stable in the opinion of the Investigator/designee. Blood pressure and pulse rate 
will be taken prior to discharge from the site.
7.2.6
Documentation of investigational product administration
Both the duration of the investigational product infusion and the duration of investigational 
product administration will be recorded. The duration of investigational product infusion and 
duration of investigational product administration will be calculated as follows:

Duration of infusion: the amount of time elapsed from the infusion start time to the 
infusion stop time. Infusion start time is defined as the time point where 
investigational product is first infused into the subject. Infusion stop time is defined 
as the time point where the infusion pump completes infusion of the investigational 
product, not including the saline flush.
For example: an infusion with a start time of 12:00 PM would have a duration of 
infusion recorded as 30 minutes (a time between 12:00 PM and 12:30 PM).

Duration of administration: the amount of time elapsed from the infusion pump start 
time to the infusion pump stop time PLUS the time required to complete the 
additional flush of saline. The duration of administration will always be greater than 
the duration of infusion and will always include the additional flush of saline.
Initial IV bag compatibility studies demonstrate that anifrolumab is compatible with IV bags 
composed of polyolefin that is latex-free, polyvinyl chloride (PVC)-free, and diethylhexyl 
phthalate (DEHP)-free, and IV administration lines composed of PVC and polyethylene that 


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are latex free and DEHP-free. Additional studies demonstrate that anifrolumab is compatible 
with IV bags and ancillaries comprised of materials as described in Table 6 and Table 7.
Table 6
Compatible materials of construction for IV bags
IV Bag Diluent
Materials of Construction
0.9% saline
Glass
0.9% saline
Polyolefin copolymer, ethylene and propylene
0.9% saline
PVC and DEHP
0.9% saline
Polyethylene
0.9% saline
Polypropylene
0.9% saline
Ethylene polyvinyl acetate
Table 7
Compatible materials of construction for ancillaries (eg, infusion 
tubing)
Materials of Construction
Polyethylene
PVC with DEHP
PVC with 2-ethylhexyltrimellitate
Polybutadiene
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product should be stored at 2 to 8°C (36 to 46°F) and must not be frozen. 
7.5
Compliance
The administration of all study drugs (including investigational product) should be recorded in 
the appropriate sections of the CRF. The investigational product will be administered by study 
site personnel, who will monitor compliance.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.


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Edition Number 5
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The study personnel will account for all study drug administered to the subjects.
The Investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to AstraZeneca or designee. 
All unused investigational product will be returned to an AstraZeneca or designee-authorised 
depot or disposed of upon authorisation by AstraZeneca or designee or other written 
instructions provided by AstraZeneca or designee (for contact information and specific 
shipping instructions).
Details regarding supplies, dose preparation, process for reporting product complaints, and 
accountability for the investigational product will be provided to the sites.
7.7
Post study access to study treatment
Upon evaluation at Week 52, subjects will either be followed for a 12-week Follow-up Period,
or transition to an LTE study (if eligible) that will continue for approximately 3 years after the 
completion of the Week 52 visit.
8.
STATISTICAL ANALYSES 
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and identification of protocol violations. Analyses will be performed by AstraZeneca or its 
representatives. 
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to the first subject in 
to the study. Any subsequent amendments to the SAP will be documented, with final 
amendments completed prior to unblinding of the data for the analysis. Details of all analyses, 
including sensitivity analyses, will be fully documented in the SAP.
8.2
Sample size estimate
A total of 450 subjects receiving SOC treatment will be randomised 1:2:2 to treatment with 
150 mg anifrolumab, 300 mg anifrolumab, or placebo.
The sample size is primarily driven by the need to acquire an adequate safety database size, as 
well as the ability to assess key secondary endpoints. The primary endpoint is the difference in 
proportions of subjects achieving SRI(4) at Week 52 comparing anifrolumab 300 mg to 
placebo. With assumed proportions of SRI(4) of 39% and 63% in the placebo and anifrolumab 
300 mg groups, respectively, 180 subjects/arm yields more than 99% power to reject the 
hypothesis of no difference using a 2-sided alpha of 0.05. The minimal detectable difference 
in SRI(4) between anifrolumab 300 mg versus placebo is approximately 10% with this sample 
size. 


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It is not straightforward to precisely arrive at the power estimate for the assessments of key 
secondary endpoints due to the multiplicity procedure used to preserve the type I error, as well 
as uncertainties of the size of sub-groups in most assessments. Approximate estimates of 
power for 2 example endpoints are listed below. These calculations assume that the primary 
endpoint is met, and the testing of the key secondary endpoints is therefore allowed. Further, 
for these examples each endpoint is tested using a weighted Holm procedure, and the alpha 
given by the assigned weight in the first step of the algorithm: 

Difference in proportions of subjects achieving SRI(4) at Week 52 in the IFN test 
high sub group: Given 75% of subjects are IFN test-high; proportions of SRI(4) in 
the IFN test-high subgroup of 35% and 61% in the placebo and anifrolumab 
treatment groups, respectively; a 2-sided alpha of 0.04 yields 98% power.

Difference in proportion of subjects who achieve an OCS dose ≤7.5 mg/day at 
Week 40, which is maintained through Week 52 in the sub-group of subjects with 
baseline OCS ≥10 mg/day: Given 60% of subjects have an OCS dose of at least 
10 mg at baseline; proportions of subjects tapering the OCS dose of 32% and 59% 
in the placebo and anifrolumab treatment groups, respectively; a 2-sided alpha of
0.004 yields 87% power. 
The anifrolumab 150 mg treatment group will be subject to a secondary analysis to inform the 
benefit:risk profile for anifrolumab. With half of the sample size (ie, 90 subjects) for the 
anifrolumab 150 mg treatment group, a 12.5% difference in SRI(4) between anifrolumab 150 
mg versus placebo would be associated with a nominal p-value of 0.05. The evaluation of 
anifrolumab 150 mg is outside of the formal multiplicity testing strategy.
The assumptions of the effect sizes and sizes of subgroups used for the calculations above are 
based on the observed results in the interim analyses of study CD IA MEDI 546-1013. 
8.3
Definitions of analysis sets
8.3.1
All subjects analysis set
This analysis set will comprise all subjects screened for the study and will be used for 
reporting of disposition and screening failures.
8.3.2
Full analysis set
The full analysis set will be used as the primary population for reporting efficacy and safety 
data. This comprises all subjects randomised into the study who receive at least 1 dose of 
investigational product and will be analysed according to randomised treatment (modified 
Intention-To-Treat). Any major deviations from randomised treatment will be listed and 
considered when interpreting the safety data.
8.3.3
Pharmacokinetic analysis set
All subjects who received anifrolumab and who had at least 1 quantifiable serum PK 
observation post first dose, will be included in the PK analysis dataset. All PK summaries will 
be based on this analysis set.


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8.4
Outcome measures for analyses
Baseline is defined as the last measurement prior to randomisation and dose administration on 
Day 1. If the Day 1 value is missing or is invalid or is collected after administration of 
investigational product, the latest assessment prior to dose administration on Day 1 will serve 
as baseline.
When applicable, adjudicated values of BILAG-2004, SLEDAI-2K, CLASI, and PGA will be 
used for all assessments.
8.4.1
Primary outcome variable
The primary endpoint used to evaluate the effect of anifrolumab 300 mg compared to placebo 
on disease activity is the difference in proportion of subjects achieving SRI(4) at Week 52, 
where a subject achieves SRI(4) if all of the following criteria are met:

Reduction from baseline of ≥4 points in the SLEDAI-2K;

No new organ system affected as defined by 1 or more BILAG-2004 A or 2 or more 
BILAG-2004 B items compared to baseline using BILAG-2004;

No worsening from baseline in the subjects’ lupus disease activity defined by an 
increase ≥0.30 points on a 3-point PGA VAS;

No discontinuation of investigational product or use of restricted medications 
beyond the protocol-allowed threshold before assessment. Allowed medication is 
defined in Section 3.3. 
8.4.2
Key secondary outcome variables
8.4.2.1
Systemic Lupus Erythematosus Responder Index of ≥4 at Week 52 in 
interferon test-high subjects
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg compared to 
placebo on disease activity in the IFN test-high subgroup is the difference in proportions of 
subjects achieving SRI(4) at Week 52 in subjects classified as IFN test-high. SRI(4) is defined 
in Section 8.4.1.
8.4.2.2
Oral corticosteroid management
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on the ability to reduce the OCS dose in subjects with baseline OCS ≥10 mg/day prednisone 
or equivalent is the difference in proportions of subjects meeting all the following criteria: 

Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40; 

Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to 
Week 52; 

No discontinuation of investigational product or use of restricted medications 
beyond the protocol-allowed threshold before assessment (see Section 3.3).


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8.4.2.3
Skin lesions
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on inflammatory cutaneous lupus lesions in subjects with baseline CLASI activity score ≥10 is 
the difference in proportions of subjects who meet the following criteria: 

Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline; 

No discontinuation of investigational product or use of restricted medications 
beyond the protocol-allowed threshold before assessment (see Section 3.3).
8.4.2.4
Systemic Lupus Erythematosus Responder Index of ≥4 at Week 24
The key secondary endpoint used to evaluate the early effect of anifrolumab 300 mg 
compared to placebo on disease activity is the difference in proportions of subjects achieving 
SRI(4) at Week 24. SRI(4) is defined in Section 8.4.1. 
8.4.2.5
Flares 
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on flares is the annualised flare rate through Week 52. A flare is defined as either 1 or more 
new BILAG-2004 A or 2 or more new BILAG-2004 B items compared to the previous visit 
(ie, a worsening from an E, D, or C score to a B score in at least 2 organ systems or a 
worsening from an E, D, C, or B to an A score in any 1 organ system compared to the 
previous visit).
8.4.3
Other secondary outcome variables
8.4.3.1
Assessment of disease activity
SRI(4) of anifrolumab 150 mg treatment group
The effect of anifrolumab 150 mg compared to placebo on disease activity will be assessed by 
the difference in proportions of subjects achieving SRI(4) at Week 52. SRI(4) is defined in 
Section 8.4.1.
Supportive SRI endpoints
In addition to the endpoint described in Section 8.4.1, the difference between anifrolumab 
300 mg and placebo in SRI at Week 52 will be assessed using levels other than 4, ie, SRI(5), 
SRI(6), SRI(7), and SRI(8), where SRI(X) (X=5, 6, 7, or 8) is defined by the proportion of 
subjects who meet the following criteria:

Reduction from baseline of ≥X points in the SLEDAI-2K;

No new organ systems affected as defined by 1 or more BILAG-2004 A or 2 or 
more BILAG-2004 B items compared to baseline using BILAG-2004;

No worsening from baseline in the subjects’ lupus disease activity defined by an 
increase ≥0.30 points on a 3-point PGA VAS;

No discontinuation of investigational product or use of restricted medications 
beyond the protocol-allowed threshold before assessment (see Section 3.3).


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The difference between anifrolumab and placebo in the proportion of subjects achieving 
SRI(X), X=4, 5, 6, 7, or 8 will also be assessed longitudinally over time up to Week 52.
BICLA
The effect of anifrolumab 300 mg versus placebo on disease activity will also be assessed 
using the difference in proportion of subjects meeting the criteria for BICLA response at 
Week 52, where a subject is a BICLA responder if the following criteria are met:

Reduction of all baseline BILAG-2004 A to B/C/D and baseline BILAG-2004 B to 
C/D, and no BILAG-2004 worsening in other organ systems, as defined by 1 new 
BILAG-2004 A or more than 1 new BILAG-2004 B item; 

No worsening from baseline in SLEDAI-2K as defined as an increase from baseline 
of >0 points in SLEDAI-2K;

No worsening from baseline in the subjects’ lupus disease activity defined by an 
increase ≥0.30 points on a 3-point PGA VAS;

No discontinuation of investigational product or use of restricted medications 
beyond the protocol-allowed threshold before assessment (see Section 3.3).
The difference between anifrolumab 300 mg and placebo in the proportion of subjects 
achieving BICLA will also be assessed longitudinally over time up to Week 52.
Supportive outcome variables of the Individual components of SRI and BICLA
The individual components of the composite SRI and BICLA endpoints as defined in Section 
8.4.1 and above will be assessed by treatment. 
Further, the effect of anifrolumab 300 mg versus placebo on PGA will be evaluated using the 
difference in mean change in PGA from baseline longitudinally over time to Week 52. In 
addition, the effect of anifrolumab 300 mg versus placebo on Major Clinical Response and 
Partial Clinical Response will be evaluated where these endpoints are defined as: 

Difference in proportion of subjects who achieve Major Clinical Response, ie, a 
subject with BILAG-2004 C scores or better at Week 24 with no new BILAG-2004 
A or BILAG-2004 B scores and maintenance of response with no new BILAG-2004 
A or B scores between Week 24 and Week 52.

Difference in proportion of subjects who achieve Partial Clinical Response, ie, a 
subject with a maximum of 1 BILAG-2004 B score or better at Week 24 and 
maintenance of response without a new BILAG-2004 A or more than 1 new 
BILAG-2004 B item out to Week 52.
Active, swollen and tender joints
The endpoints used to evaluate the effect of anifrolumab 300 mg versus placebo on active, 
swollen, and tender joints are: 


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
Difference in change from baseline to Week 52 in the number of active, swollen, 
and tender joints; 

Difference in proportion of subjects with at least 8 swollen and at least 8 tender 
joints at baseline who achieve at least a 20% reduction from baseline in both the 
number of swollen and tender joints at Week 52;

Difference in proportion of subjects with at least 8 swollen and at least 8 tender 
joints at baseline who achieve at least a 50% reduction from baseline in both the 
number of swollen and tender joints at Week 52.
Change in SDI
The endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo on irreversible 
damage in SLE subjects is the difference in mean change in SDI global score from baseline to 
Week 52.
Supportive outcome variables for the assessment of skin lesions
In addition to the endpoint described in Section 8.4.2.3, the maintenance of effect in the 
CLASI activity score will be evaluated using the proportion of subjects with a CLASI activity 
score ≥10 at baseline who achieve at least a 50% reduction in CLASI activity score at 
Week 12 and maintain response at Week 52.
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
CLASI activity as well as CLASI damage score will be evaluated longitudinally over time up 
to Week 52.
Supportive outcome variables for the assessment of flares
In addition to the endpoint in Section 8.4.2.5, the annualised rate of flares will also be 
evaluated where a flare is defined as either 1 or more new BILAG-2004 A or 2 or more new 
BILAG-2004 B items compared to baseline. 
In addition, time to flare, ie, time from first exposure of investigational product to the first 
flare will be assessed. Both definitions of flares will be used for the assessment: either 1 or 
more new BILAG-2004 A or 2 or more new BILAG-2004 B items compared to previous visit
(as introduced in Section 8.4.2.5); and the definition described above comparing to baseline. 
8.4.4
Subject reported outcome variables
8.4.4.1
Short Form 36 version 2 (acute recall)
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
SF-36v2 (acute) Physical Component Score and Mental Component Score to Week 52 will be 
assessed. 
8.4.4.2
Pain Numerical Rating Scale 
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
pain NRS to Week 52 will be assessed.


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8.4.4.3
Functional Assessment of Chronic Illness Therapy-FATIGUE 
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
FACIT-F total score to Week 52 will be assessed. 
8.4.4.4
Patient Global Assessment 
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
PtGA (measured on a VAS ranging from 0 to 100mm) to Week 52 will be assessed.
8.4.4.5
LUPUS quality of life scale
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
LUPUS QoL score to Week 52 will be assessed.
8.4.4.6
EuroQoL 5 dimensions
The proportion of subjects in each EQ-5D-5L health state (no problems, slight problems, 
moderate problems, severe problems and unable to/extreme problems), by dimension, as well as 
the VAS Score and single summary utility index, including changes from baseline, will be 
explored over time. 
8.4.4.7
Work productivity and Activity Impairment - Lupus
The WPAI score levels (percentages) at baseline, Week 24, and Week 52 will be explored. 
8.4.4.8
Medical Resource Use Questionnaire
The following endpoints will be explored: 

Number of subjects with unscheduled health care visits; 

Number of unscheduled specialist visits;

Number of unscheduled primary care visits;

Number of subjects with unscheduled emergency department visits;

Of subjects with visits, number of unscheduled emergency department visits;

Number of subjects with hospital stays;

Of subjects with visits, number of hospital visits;

Length of hospital stay.
8.4.5
Safety variables
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, C-SSRS, PHQ-8, flares as defined by a 
modification of the SELENA Flare Index using the SLEDAI 2K, and reported AEs (including 
AEs of special interest, see Section 6.5).
Change from baseline to each post-treatment time point where scheduled assessments were 
made will be calculated for relevant measurements. The number and proportion of subjects 


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with flares as defined by a modification of the SELENA Flare Index using the SLEDAI 2K
and the number of such flares will be explored. Marked abnormal ECG values or changes 
from baseline will be identified based on pre-determined criteria. Occurrence of suicidal 
behaviour and ideation, based on the C-SSRS, from baseline up to Week 52 will be explored. 
AEs will be summarised by means of descriptive statistics and qualitative summaries. 
8.4.5.1
Other significant adverse events
During the evaluation of the AE data, a 
medically qualified expert will review the list of 
AEs that were not reported as SAEs and discontinuations due to AEs.
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Astra Zeneca Global Patient Safety Physician, be considered other 
significant AEs (OAEs) and reported as such in the CSR.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
8.4.6
Immunogenicity variables
ADA assessments will be conducted utilising a tiered approach (screen, confirm, titre). The 
presence of nAb will be tested in all ADA-positive samples time points of week 12 and later 
using a ligand binding assay.
8.4.7
Pharmacokinetic variables
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed steady-state serum trough (predose) concentrations, Ctrough. Maximum concentrations 
after the first and last dose will also be evaluated.
8.4.8
Pharmacodynamic outcome variables
The outcome variable for anti-dsDNA antibodies, C3, C4, and CH50 complement levels will 
be the mean change from baseline to Week 52 in subjects with abnormal complement level at 
baseline, or positive anti-dsDNA antibodies at baseline, defined as complement level below 
lower limit of normal. 
The outcome variable for the suppression of the IFN 21 gene PD signature is the percent 
suppression of fold change, relative to a pooled normal control, from baseline levels. 
8.5
Methods for statistical analyses
The analysis of the primary and secondary endpoints will include all data captured during the 
52-week treatment period, regardless of whether study treatment was prematurely 
discontinued, or delayed, and/or irrespective of protocol adherence. 




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
From Week 0 (Day 1) to Week 12, the study design allows for 1 burst and taper of 
OCS in order to allow adequate time for investigational product to achieve 
significant clinical benefit.

One burst of OCS to ≤20 mg/day between Week 12 and Week 40 is also allowed 
for non-SLE causes.

Subjects who require additional bursts of OCS will still be encouraged to remain in 
the study, but will be considered a non-responder for subsequent assessments of 
disease activity
Subjects who discontinue investigational product will be asked to come to each visit for the 
scheduled assessments through the Week 52 end of treatment visit. The definition of the 
primary endpoint includes a criterion that corresponds to a non-responder imputation for 
subjects who prematurely discontinue from investigational product, or who receive restricted 
medications beyond the protocol-allowed threshold. Sensitivity analyses, excluding this 
criterion from the definition of SRI-response, where missing data is handled in a different 
way, (eg, a multiple imputations method) may be carried out. Details will be pre-specified in 
the SAP. 
Presentation of Results
All data will be presented by treatment group. Descriptive statistics (number, mean, standard 
deviation [SD], median, minimum, and maximum) will be provided for continuous variables, 
and counts and percentages will be presented for categorical variables.
95% CIs will be presented for treatment comparisons. If a model is used to estimate the 
treatment difference, the corresponding CI according to the model will be presented. 
Otherwise, the unadjusted CI will be used. Nominal p-values may be presented for secondary 
endpoints not included in the strategy for preserving the type I error rate. Statistical 
significance cannot be interpreted from these p-values. 
Demography and baseline characteristics will be summarised by treatment group for the full 
analysis set. 
8.5.1
Analysis of the primary variable 
The estimand of primary interest in this study is the difference in change from baseline in 
disease activity between anifrolumab 300 mg and placebo, to reflect the effect of the initially 
assigned and dosed investigational product (full analysis set). This is measured by the primary 
efficacy endpoint, defined as the difference in the proportion of subjects achieving SRI(4) at 
Week 52 comparing the anifrolumab 300 mg to the placebo group. The null hypothesis is that 
the proportion of subjects achieving SRI(4) on anifrolumab 300 mg is equal to that of placebo. 
The alternative hypothesis is that the proportion of subjects achieving SRI(4) on anifrolumab 
300 mg is not equal to that on placebo, ie,
H0: difference in proportion achieving SRI(4) (anifrolumab vs Placebo) = 0
Ha: difference in proportion achieving SRI(4) (anifrolumab vs Placebo) ≠ 0


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The proportion of subjects achieving SRI(4) in the anifrolumab 300 mg treatment group will 
be compared to that in the placebo group using a Cochran-Mantel-Haenszel (CMH) approach 
(Cochran, 1954) stratified by: 

SLEDAI-2K score at screening (<10 points versus ≥10 points)

Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or 
equivalent)

Results of a type 1 IFN test (high versus low)
Strata with low counts will be collapsed prior to the analysis. Details for collapsing of strata 
will be pre-specified in the SAP.
The estimated treatment effect (ie, the difference in response rate for anifrolumab 300 mg 
versus placebo), corresponding 95% CI, and 2-sided p-value for the difference at Week 52 
will be presented. In addition, the response rate and the corresponding 95% CI within each 
treatment group will be presented.
Further, longitudinal presentations of results over time based on the same analysis, with the 
corresponding 95% CI, will be created. In addition, the individual components of the 
composite SRI(4) endpoints will be summarised by treatment group.
8.5.2
Analysis of the secondary variables
8.5.2.1 Analysis methods for key secondary efficacy variables
All key secondary endpoints, with the exception of the difference in annualised flare rate 
through Week 52 (which will be analysed using a negative binomial regression model), will 
be analysed and presented similarly to the primary endpoint as described in Section 8.5.1. 
Details will be described in the SAP. Non-responder imputation will be used when applicable 
to handle missing data. 
The flare rate in the anifrolumab 300 mg treatment group will be compared to the flare rate in 
the placebo group using a negative binomial model. The response variable in the model will 
be the number of flares over the 52-week treatment period. The model will include covariates 
of treatment group, and the stratification factors. The logarithm of the follow-up time will be 
used as an offset variable in the model to adjust for subjects having different exposure times. 
The estimated treatment effect and the corresponding 95% CI as well as the 2-sided p-value 
will be presented. In addition, supportive analyses only including flares while on treatment 
will be carried out.
8.5.2.2 Analysis methods for other secondary efficacy variables
The difference between anifrolumab 150 mg and placebo in the proportion of subjects who 
achieve SRI(4) at Week 52 will be assessed and presented similarly to the primary endpoint as 
described in Section 8.5.1. The difference between anifrolumab 300 mg and placebo in other 
secondary binary responder endpoints will be assessed in the same way. In addition, the 


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individual components of the composite SRI and BICLA endpoints will be summarised by 
treatment group.
The time to first flare will be analysed as a supportive analysis to the assessment of reduction 
of flares to explore the extent to which treatment with anifrolumab 300 mg delays the time to 
first flare compared with placebo. A Cox proportional hazard model will be fitted to data 
including the covariates of treatment, and the stratification factors. Details will be presented in 
the SAP.
Continuous endpoints (including SLEDAI-2K, PGA, joint counts (active, swollen and tender), 
activity and damage CLASI scores, FACIT-F, PtGA, and LUPUS QoL Scale) will be 
analysed using linear mixed effect models with fixed effects for treatment group, visit, and 
stratification factors and subject as random effect. Results will be presented in terms of the 
adjusted means for each treatment group, estimates of treatment differences, and associated 
CIs. Model assumptions will be checked and, if not met, appropriate data transformations may 
be applied or non-parametric approaches will be considered. Details will be presented in the 
SAP. 
The EQ-5D-5L health states (no problems, slight problems, moderate problems, severe 
problems and unable to/extreme problems) will be summarised by visit and treatment group 
for each dimension. The VAS Score and single summary utility index as well as their change 
from baseline will also be summarised by visit and treatment group. The WPAI scores will be 
summarised as percentages by visit and treatment. Also, the improvements in these scores 
from baseline to Week 24 and Week 52 will be summarised. The medical resource use, as 
described in Section 8.4.4.8, will be summarised by visit and treatment. 
8.5.2.3
Analysis methods for safety variables
AEs (including AESIs) will be summarised by means of counts summaries by Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term (PT) 
separately for the study periods (treatment period and follow-up period). All AEs will be 
listed. 
Laboratory data for haematology and clinical chemistry will be summarised. The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given. Shifts from normal to abnormal between baseline 
and each post-baseline time point will be evaluated for urinalysis.
The incidence of markedly abnormal values and changes from baseline in the ECG parameters 
will be summarized by treatment group.
The proportion of subjects with suicidal behaviour and suicidal ideation throughout the study 
based on the C-SSRS will be presented for each treatment group. The proportion of subjects 
within each of the 4 suicidal behaviour categories and within each of the 5 suicidal ideation 
sub-categories will also be presented for each treatment group. Descriptive statistics on the 


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total number of attempts, total number of interrupted attempts, and total number of aborted 
attempts will be summarized for each treatment group.
Other safety variables will be summarised as appropriate. Further details will be provided in 
the SAP.
8.5.2.4
Analysis method for immunogenicity variables
Anti-drug antibodies to anifrolumab will be summarised using descriptive statistics at each 
visit by treatment group. ADA titres-time profiles of anifrolumab by treatment group will be 
generated. The impact of ADA on PK and PD will be assessed. The potential association of
ADA with safety and efficacy will be explored. 
8.5.2.5
Analysis methods for pharmacokinetic variables
Anifrolumab serum concentrations will be summarised using descriptive statistics at each visit 
by treatment group. Serum concentration-time profiles of anifrolumab by treatment group will 
be generated. The potential influence of demographic covariates such as body weight, race, 
gender and age will be explored. Impact of ADA on PK will also be explored. Serum 
concentrations of anifrolumab, summary statistics, empirical covariate analysis results and PK 
profiles will be provided in the CSR or as an addendum to the CSR.
8.5.2.6
Analysis methods for pharmacodynamic variables
Pharmacodynamic variables will be summarised as appropriate.
8.5.3
Subgroup analysis 
To explore the uniformity of the detected overall treatment effect on the primary, and when 
applicable, key secondary efficacy endpoints, subgroup analyses may be performed for the 
following factors: 

SLEDAI-2K score at screening (<10 points versus ≥10 points) 

OCS dose at baseline (<10 mg/day versus ≥10 mg/day prednisone or equivalent) 

IFN test (IFN test [high versus low]) 

Gender 

Age (≥18 to 65 and ≥65 years) 

Geographic region 

Onset of disease (adult versus paediatric onset) 

BMI (≤35, >35 kg/m2) 

Race 
Full details of the subgroup analyses will be pre-specified in the SAP. 
8.5.4
Interim analysis
No interim analysis is planned.


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8.5.5
Pooled analysis
A pre-planned pooled analysis of SRI(4) at Week 52 in the IFN test-low subjects, pooling data 
from this study and its sister study, D3461C00004, will be carried out to characterise the 
disease activity in this population. 
Similarly, pre-planned pooled analyses will be carried out to further support the evaluation of 
the key secondary endpoints assessing the effect of anifrolumab 300 mg on skin lesions, 
ability to reduce the OCS dose, and flares. 
Details of these analyses will be presented in the SAP for the Integrated Summary of Efficacy.
9.
STUDY AND DATA MANAGEMENT
9.1
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 in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed

Perform source data verification (a comparison of the data in the CRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating subjects. This 
will require direct access to all original records for each subject (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the subject
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.1.1
Source data
Refer to the Clinical Study Agreement (CSA) for location of source data.
9.1.2
Study agreements
The PI at each/the 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.


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Agreements between 
 on behalf of AstraZeneca, and the PI must be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.1.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.2
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study is expected to start in Quarter 2, 2015 and to end by Quarter 2, 2018.
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow. AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with anifrolumab.
9.3
Data management
Data management will be performed by 
, according to the Clinical Informatics Plan. 
The 
system will be used for data collection and query handling. The 
Investigator will ensure that data are recorded on the CRFs as specified in the study protocol 
and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
the provision of answers to data queries according to the CSA. The Investigator will sign the 
completed CRFs. A copy of the completed CRFs will be archived at the study site.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the MedDRA. Medications will be classified according to the 
AstraZeneca Drug Dictionary. All coding will be performed by the 
coding group. Data 
queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
The data will be validated as defined in the Clinical Informatics Plan and Edit Specifications 
Document. Quality control procedures will be applied to each stage of data handling to ensure 
that all data are reliable and have been processed correctly. The Clinical Informatics Plan will 
also clarify the roles and responsibilities of the various functions and personnel involved in 
the data management process.
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked.


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Serious adverse event reconciliation
Serious adverse event reconciliation reports are produced and reconciled with the subject 
safety database and/or the investigational site. SAE reconciliation between safety data and 
clinical data will be performed by 
 The frequency depends on the expected volume of 
SAE reports and will be defined in the AE/SAE Reconciliation Plan. 
Management of external data
The data collected through third party sources will be obtained and reconciled against study 
data.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
Subject data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
10.3
Ethics and regulatory review
An EC should approve the final study protocol, including the final version of the ICF and any 
other written information and/or materials to be provided to the subjects. The Investigator will 
ensure the distribution of these documents to the applicable EC, and to the study site staff.
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to AstraZeneca or designee before enrolment of any subject into the study. 
The EC should approve all advertising used to recruit subjects for the study.
AstraZeneca or designee should approve any modifications to the ICF that are needed to meet 
local requirements.
If required by local regulations, the protocol should be re-approved by the EC annually.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca or designee will handle the distribution of any of these documents to the national 
regulatory authorities.


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


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Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the centre, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements. The Investigator will contact AstraZeneca or designee 
immediately if contacted by a regulatory agency about an inspection at the centre.
11.
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Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Edition Number 5
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Criswell LA. The genetic contribution to systemic lupus erythematosus. Bull NYU Hosp Jt 
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Doria and Briani, 2008
Doria A, Briani C. Lupus: improving long-term prognosis. Lupus. 2008;17(3):166-70.
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European Centre for Disease Prevention and Control. Influenza Case Definitions. 
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EuroQoL Group. EuroQoL- a new facility for the measurement of health-related quality of 
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Farkas et al, 2001
Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells 
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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Feng X et al, 2006
Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, et al. Association 
of increased interferon-inducible gene expression with disease activity and lupus nephritis in 
patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(9):2951-62.
Furie et al, 2009
Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, et al. Novel evidence-
based systemic lupus erythematosus responder index. Arthritis Care & Research. 
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Furie et al, 2011
Furie RA, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. A phase III, 
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2011;63:3918-3930.
Huang et al, 2008
Huang X, Yang N, Ou X, Li D, Wang Z, Xie Q, et al. Sequential activation of protein kinase 
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Jolly M, Pickard AS, Wilke C, Mikolaitis RA, Teh L-S, McElhone K, et al. Lupus-specific 
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Kirou et al, 2004
Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MG, et al. Coordinate 
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Kirou et al, 2005
Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK. Activation of the 
interferonalpha pathway identifies a subgroup of systemic lupus erythematosus patients with 
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Lahita, 1999
Lahita RG. The role of sex hormones in systemic lupus erythematosus. Curr Opin Rheumatol. 
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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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McElhone et al, 2007
McElhone K, Abbott J, Shelmerdine J, Bruce IN, Ahmad Y, Gordon, C, et al. Development 
and validation of a disease-specific health-related quality of life measure, the LupusQoL, for 
adults with systemic lupus erythematosus. Arthritis Care Res. 2007;57:972-9.
Merrill, 2014
Merrill, J.M. Guidelines for use of the SLEDAI-2K to assess disease activity (modified for 
assessment over one month). Lupus Foundation of America. Accessed 08 December 2014 at: 
http://www.lupus.org/
Navarra et al, 2011
Navarra S, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and 
safety of belimumab in patients with active systemic lupus erythematosus: a randomised, 
placebo-controlled, phase 3 trial. Lancet. 2011;377:721-31.
Okamoto et al, 2004
Okamoto H, Katsumata Y, Nishimura K, Kamatani N. Interferon-inducible protein 
10/CXCL10 is increased in cerebrospinal fluid of patients with central nervous system lupus. 
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Pascual et al, 2006
Pascual V, Farkas L, Banchereau J. Systemic lupus erythematosus: all roads lead to type I 
interferons. Curr Opin Immunol. 2006;18(6):676-82.
Petri, 2001 
Petri M. Long-term outcomes in lupus. Am J Managed Care. 2001;7(16) Suppl: S480-5.
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Rönnblom L, Alm GV. Systemic lupus erythematosus and the type I interferon system. 
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Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Study Code D3461C00005
Edition Number 5
Date 18 May 2016
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Clinical Study Protocol Appendix B
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix B
Additional Safety Information


Clinical Study Protocol Appendix B
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse.


Clinical Study Protocol Appendix B
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties?

Dechallenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility.


Clinical Study Protocol Appendix C
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix C
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin - Hy’s Law


Clinical Study Protocol Appendix C
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(6)
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.........................................................................................2
1.
INTRODUCTION ...................................................................................................3
2.
DEFINITIONS.........................................................................................................3
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES...................................3
4.
FOLLOW-UP ..........................................................................................................4
4.1
Potential Hy’s Law Criteria not met ........................................................................4
4.2
Potential Hy’s Law Criteria met ..............................................................................4
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............5
6.
REFERENCES ........................................................................................................6


Clinical Study Protocol Appendix C
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
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1.
INTRODUCTION
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with 
 clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3x upper limit of 
normal (ULN) and total bilirubin (TBL) ≥2xULN irrespective of an increase in alkaline 
phosphatase (ALP), at any point during the study following the start of study medication. The 
elevations do not have to occur at the same time or within a specified time frame.
Hy’s Law (HL)
AST or ALT ≥3x ULN and TBL ≥2xULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral 
hepatitis, another drug. The elevations do not have to occur at the same time or within a 
specified time frame.
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3xULN


Clinical Study Protocol Appendix C
Drug Substance Anifrolumab (MEDI-546)
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
AST ≥3xULN

TBL ≥2xULN
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to
 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Section 2 of this appendix 
for definition) by reviewing laboratory reports from all previous visits (including 
both central and local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Determine whether the subject meets PHL criteria (see Section 2 of this appendix 
for definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:

Immediately notify the 
 Medical Monitor representative who will then inform 
the AstraZeneca Medical and Safety Study Team within 1 business day.


Clinical Study Protocol Appendix C
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Within 1 business day, the 
 Medical Monitor contacts the Investigator, to provide 
guidance, discuss and agree an approach for the study subject’s follow-up and the continuous 
review of data. Subsequent to this initial contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the 
Medical Monitor

Complete the three Liver CRF Modules as information becomes available 

If at any time (in consultation with the 
Medical Monitor) the PHL case meets 
serious criteria, report it as an SAE using standard reporting procedures
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
The 
Medical Monitor will contact the Investigator to carry out actions as described in 
Section 4. The 
Medical Monitor should contact the Investigator within 1 business day of 
seeing the PHL laboratory criteria in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP. The 
AstraZeneca Medical Science Director and Global Safety Physician will also be involved in 
this review together with other subject matter experts as appropriate and should be notified 
within 1 business day of the
 Medical Monitor having discussed data with the 
Investigator.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:


Clinical Study Protocol Appendix C
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
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6(6)

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If the 
medical monitor cannot contact the site within 2 weeks of the PHL laboratory 
values being available to clarify details of the case, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review
6.
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


Clinical Study Protocol Appendix D
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix D
American College of Rheumatology Criteria for Systemic Lupus
Erythematosus Classification


Clinical Study Protocol Appendix D
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(3)
1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of 
Systemic Lupus Erythematosus
Item
Definition
Malar rash
Fixed erythema, flat or raised, over the malar eminences, sparing the nasolabial 
folds
Discoid rash
Erythematous, raised patches with adherent keratotic scaling and follicular 
plugging: atrophic scarring may occur in older lesions
Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient history or physician 
observation
Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by a physician
Nonerosive arthritis 
Involving 2 or more peripheral joints, characterized by tenderness, swelling, or 
effusion
Pleuritis or pericarditis
  a. Pleuritis--convincing history of pleuritic pain or rub heard by a physician or 
evidence of pleural effusion
OR
b. Pericarditis – documented by electrocardiogram or rub or evidence of 
pericardial effusion
Renal disorder
a. Persistent proteinuria > 0.5 gm per day or > 3+ if quantitation not performed
OR
b. Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed
Neurologic disorder
a. Seizures--in the absence of offending drugs or known metabolic derangement, 
eg, uremia, ketoacidosis, or electrolyte imbalance
OR
b. Psychosis--in the absence of offending drugs or known metabolic derangement, 
eg, uremia, ketoacidosis, or electrolyte imbalance
Hematologic disorder
a. Hemolytic anemia with reticulocytosis
OR
b. Leukopenia--< 4,000/mm3 on ≥ 2 occasions
OR
c. Lymphopenia--< 1,500/mm3 on ≥ 2 occasions
OR
d. Thrombocytopenia--< 100,000/mm3 in the absence of offending drugs
Immunologic disorder
a. Anti-DNA: antibody to native DNA in abnormal titer
OR
b. Anti-Sm: presence of antibody to Sm nuclear antigen
OR
c. Positive finding of antiphospholipid antibodies based on: 1) an abnormal serum 
level of IgG or IgM anticardiolipin antibodies; 2) a positive test result for lupus 
anticoagulant using a standard method; or 3) a false-positive test result for at 
least 6 months and confirmed by Treponema pallidum immobilization or 
fluorescent treponemal antibody absorption test.


Clinical Study Protocol Appendix D
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
3(3)
1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of 
Systemic Lupus Erythematosus
Item
Definition
Positive antinuclear 
antibody  
An abnormal titer of antinuclear antibody by immunofluorescence or an 
equivalent assay at any point in time in the absence of drug.


Clinical Study Protocol Appendix E
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix E
Systemic Lupus Erythematosus Disease Activity Index 2000


Clinical Study Protocol Appendix E
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)


Clinical Study Protocol Appendix F
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix F
British Isles Lupus Assessment Group-2004


Clinical Study Protocol Appendix F
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)


Revised Clinical Study Protocol Appendix G
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
3
Date
01 February 2016
Protocol Dated
01 February 2016
Appendix G
Physician Global Assessment


Revised Clinical Study Protocol Appendix G
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 3
Date 01 February 2016
2(2)


Revised Clinical Study Protocol Appendix H
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
3
Date
01 February 2016
Protocol Dated
01 February 2016
Appendix H
System Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index




Clinical Study Protocol Appendix I
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix I
Cutaneous Lupus Erythematosus Disease Area and Severity Index


Clinical Study Protocol Appendix I
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)


Clinical Study Protocol Appendix J
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix J
Columbia Suicide Severity Rating Scale




Clinical Study Protocol Appendix J
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
3(7)


Clinical Study Protocol Appendix J
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
4(7)




Clinical Study Protocol Appendix J
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
6(7)


Clinical Study Protocol Appendix J
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
7(7)


Clinical Study Protocol Appendix K
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix K
Personal Health Questionnaire Depression Scale-8


Clinical Study Protocol Appendix K
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(3)


Clinical Study Protocol Appendix K
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
3(3)


Clinical Study Protocol Appendix L
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix L
Short Form 36 Version 2 (Acute Recall)


Clinical Study Protocol Appendix L
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(5)


Clinical Study Protocol Appendix L
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
3(5)


Clinical Study Protocol Appendix L
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
4(5)


Clinical Study Protocol Appendix L
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
5(5)


Clinical Study Protocol Appendix M
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix M
Functional Assessment of Chronic Illness Therapy-FATIGUE


Clinical Study Protocol Appendix M
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)


Clinical Study Protocol Appendix N
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix N
EuroQoL 5 Dimensions


Clinical Study Protocol Appendix N
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)


Clinical Study Protocol Appendix O
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix O
LupusQoL Questionnaire






Clinical Study Protocol Appendix P
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix P
Patient Global Assessment


Clinical Study Protocol Appendix P
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)


Clinical Study Protocol Appendix Q
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix Q
Work Productivity and Activity Impairment


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
3(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
4(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
5(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
6(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
7(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
8(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
9(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
10(11)


Clinical Study Protocol Appendix Q
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
11(11)


Clinical Study Protocol Appendix R
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix R
Pain Numerical Rating Scale


Clinical Study Protocol Appendix R
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)


Revised Clinical Study Protocol Appendix S
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
3
Date
01 February 2016
Protocol Dated
01 February 2016
Appendix S
Medical Resource Use Questionnaire


Revised Clinical Study Protocol Appendix S
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 3
Date 01 February 2016
2(4)


Revised Clinical Study Protocol Appendix S
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 3
Date 01 February 2016
3(4)


Revised Clinical Study Protocol Appendix S
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 3
Date 01 February 2016
4(4)


Clinical Study Protocol Appendix T
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix T
Vasculitic Syndromes Excluded from the Study


Clinical Study Protocol Appendix T
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)
Subjects with a history or current diagnosis of the following vasculitis syndromes are 
excluded from participating in the study. Vasculitis due to SLE is allowed in the study.

Behçet’s Disease

Buerger’s Disease

Central Nervous System Vasculitis

Churg Strauss Syndrome

Cryoglobulinemia

Giant Cell Arteritis

Henoch-Schönlein Purpura

Kawasaki Disease

Microscopic Polyangiitis

Polyarteritis Nodosa

Polymyalgia Rheumatica

Takayasu’s Arteritis

Wegener’s Granulomatosis


Revised Clinical Study Protocol Appendix U
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
5
Date
18 May 2016
Protocol Dated
18 May 2016
Appendix U
Restricted Medications


Revised Clinical Study Protocol Appendix U
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 5
Date 18 May 2016
2(2)
Medications to be Discontinued Prior to signing ICF
Restricted medication
Discontinuation 
prior to signing 
ICF
Restricted medication
Discontinuation 
prior to signing 
ICF
Abatacept (CTLA 4 Ig)
24 weeks
Intravenous Globulin
4 weeks
Acthar® gel
6 weeks
Leflunomide
36 weeks
Adalimumab
12 weeks
Lenalidomide
8 weeks
Alefacept
12 weeks
Lupuzor (IPP-201101)
12 weeks
Anakinra
12 weeks
Memantine
4 weeks
Apremilast
4 weeks
Natalizumab
24 weeks
Atacicept (TACI-Ig)*
40 weeks
Obinutuzumab*
26 weeks
B cell depleter*
26 weeks
Ocrelizumab*
26 weeks
Belimumab
12 weeks
Ofatumumab*
26 weeks
Blisibimod (AMG 623)
8 weeks
Plasmapheresis
24 weeks
Certolizumab pegol
24 weeks
Retinoids
4 weeks
Cyclophosphamide
24 weeks
Rituximab*
26 weeks
Cyclosporine**
4 weeks
Sifalimumab (MEDI-545)
26 weeks
Cytokines (eg, IFN)
Washout Time
Similar to Study drug
26 weeks
Danazol
4 weeks
Sirolimus
4 weeks
Dapsone
4 weeks
Sulfasalazine
4 weeks
Eculizumab
12 weeks
Tabalumab
26 weeks
Efalizumab
12 weeks
Tacrolimus***
4 weeks
Epratuzumab
26 weeks
Thalidomide
8 weeks
Etanercept
4 weeks
Tocilizumab
12 weeks
Golimumab
12 weeks
Tofacitinib
4 weeks
Immunosuppressants
Washout Time
Topical Pimecrolimus
4 weeks
Infliximab
12 weeks
*     provided B cell count is normal at screening
**   cyclosporine eye drops are acceptable for use in the study
*** oral tacrolimus has a 4 week washout period and topical tacrolimus has a 2 week washout period


Clinical Study Protocol Appendix V
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix V
Oral Corticosteroid Guidance


Clinical Study Protocol Appendix V
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)
Examples of Equivalent Doses of Oral Prednisone
Oral Prednisone and 
Equivalents
Equivalent Dose
Oral Prednisone 
7.5 mg
10 mg
20 mg
30 mg
40 mg
Cortisone
37.5 mg
50 mg
100 mg
150 mg
200 mg
Hydrocortisone
30 mg
40 mg
80 mg
120 mg
160 mg
Methylprednisolone
6 mg
8 mg
16 mg
24 mg
32 mg
Prednisolone
7.5 mg
10 mg
20 mg
30 mg
40 mg
Triamcinolone
6 mg
8 mg
16 mg
24 mg
32 mg
Example of OCS Tapering Schedule
Time point
Initial Dose of Oral Prednisone or Equivalent
40 mg
30 mg
20 mg
10 mg*
Week 8
35 mg
27.5 mg
17.5 mg
10 mg
Week 12 
30 mg
25 mg
15 mg
10 mg
Week 16 
25 mg
20 mg
10 mg
10 mg
Week 20 
15 mg
15 mg
10 mg
7.5 mg
Week 24 
10 mg
10 mg
7.5 mg
≤7.5 mg
Week 28 
7.5 mg
7.5 mg
≤7.5 mg
≤7.5 mg
*
Note: subjects on OCS doses equivalent to 10 mg prednisone/day may tolerate tapering by 1 mg/day per 
visit rather than an abrupt drop from 10 mg/day to 7.5 mg/day. The stepwise tapering of OCS dose should 
be performed at the discretion of the Investigator.


Clinical Study Protocol Appendix W
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix W
General Guidance for Determination of Major Surgery


Clinical Study Protocol Appendix W
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)
The goal of this guidance is to maximize the benefit/risk for each subject entering this study. 
An important aspect to this goal is taking into account all relevant history, including recent 
surgeries and/or injuries that could influence the safety of the subject potentially being 
exposed to an additional immunomodulatory medication or could bias the efficacy endpoints 
of the trial.
Given the advancement and availability of surgical techniques, major surgery is in the 
judgment of the Investigator and his/her evaluation of the following criteria, regardless of the 
specific surgical procedure:
1.
Has the subject completely recovered (mentally, emotionally, and physically) from 
the surgery and is not receiving additional medications related to the prior surgery 
(ie, antibiotics)?
2.
Has the subject completed all follow-up visits related to the surgery, including 
ancillary services such as physical and/or occupational therapy?
3.
Has the subject resumed all of their prior activities?
4.
Has the subject returned to his/her baseline medications for SLE and non-SLE 
indications?


Clinical Study Protocol Appendix X
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix X
Guidance for Abnormal Pap Smear Results


Clinical Study Protocol Appendix X
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(2)
Pap Smear Result
Abbreviation
Also Known As
Suggested Action
Atypical squamous cells–
undetermined 
significance
ASC–US
—
Permitted to enter study
Atypical squamous cells–
cannot exclude HSIL
ASC–H
—
Permitted to enter study
Atypical glandular cells
AGC
—
Permitted to enter study
Low-grade squamous 
intraepithelial lesion
LSIL
Mild dysplasia
Cervical intraepithelial 
neoplasia–1 (CIN–1)
Permitted to enter study
High-grade squamous 
intraepithelial lesion
HSIL
Moderate dysplasia
CIN-2 / CIN II
Permitted to enter study
High-grade squamous 
intraepithelial lesion
HSIL
CIN–3 / CIN III
Carcinoma in situ (CIS)
Exclude/discontinue subject
Endocervical 
adenocarcinoma in situ
AIS
—
Exclude/discontinue subject


Clinical Study Protocol Appendix Y
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
2
Date
09 April 2015
Protocol Dated
09 April 2015
Appendix Y
Anaphylaxis


Clinical Study Protocol Appendix Y
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
2(6)
In adults, anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips, 
tongue and/or uvula) 
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxaemia)

Reduced BP (see number 3 below for definition) or associated symptoms of end-
organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that subject (minutes to several hours): 

Involvement of the skin-mucosal tissue (eg, generalised hives, itch, flush, swollen 
lips, tongue and/or uvula)

Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxaemia)

Reduced BP (see number 3 below for definition) or associated symptoms (eg, 
hypotonia [collapse], syncope, incontinence)

Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that subject (minutes to several 
hours); for adults a systolic BP of less than 90 mm Hg or greater than 30% decrease 
from that person’s baseline BP (taken at or immediately prior to start of the 
infusion), whichever BP is lower.
The following definitions are provided for the purposes of this study:
Hypersensitivity reaction: an acute onset of an illness with involvement of the skin, mucosal 
tissue, or both during infusion of investigational product (but does not meet the definition of 
anaphylaxis described above).
Infusion-related reaction: any other reaction occurring during infusion of investigational 
product or felt to be temporally related to the infusion within 24 hours of investigational 
product administration.
To assist with the mitigation of these AEs, see Table 1, which categorizes reactions by 
severity of symptoms, proposes severity-specific treatment and offers guidance on 
management of investigational product. Final treatment is at the discretion of the Investigator 
and should reflect local SOC.


Clinical Study Protocol Appendix Y
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
3(6)
Table 1
An approach to management of anaphylactic, hypersensitivity, and infusion-related reactions
Severity of symptoms
Treatment
Investigational product
Mild reactions (infusion and 
hypersensitivity)
Mild infusion-related reactions such 
as headache, nausea, non-pruritic 
rash, or mild hypersensitivity 
reactions including localised 
cutaneous reactions such as mild 
pruritus, flushing, rash, dizziness, 
headache, ≤20 mmHg change in 
systolic BP from pre-infusion 
measurement
Evaluate subject, including close monitoring of vital 
signs 
At the discretion of the Investigator, treat subject, for 
example, with:
-
Normal saline (~500 to 1000 mL/hour IV) 
and/or
-
Diphenhydramine 50 mg IV or equivalent and/or
-
Acetaminophen 500 to 650 mg or equivalent 
dose of paracetamol and/or
-
Topical antihistamines and/or low-potency 
topical corticosteroid preparations and/or
-
Anti-nausea medication, as needed
Stop investigational product infusion 
immediately
Option 1: do not resume investigational product 
infusion; OR at the discretion of the 
Investigator, resume current investigational 
product infusion under observation and 
complete investigational product infusion at no 
more than half the planned infusion rate
Option 2: discontinue any further 
administration of investigational product; OR at 
the discretion of the Investigator, continue 
future investigational product administrations 
and consider slowing infusion rate and 
pretreating subject 1.5 to 0.5 hours prior to 
investigational product administration, for 
example with:
-
Diphenhydramine 50 mg IV or equivalent
-
Acetaminophen 500 to 650 mg or 
equivalent dose of paracetamol
Moderate reactions (infusion)
Infusion-related reaction such as 
those listed above under mild 
reactions but excluding moderate 
hypersensitivity reactions (see 
below)
Evaluate subject, including close monitoring of vital 
signs 
Treat subject, for example, with:
-
Normal saline (~500 to 1000 mL/hour IV) 
and/or
-
Diphenhydramine 50 mg IV or equivalent and/or
-
Acetaminophen 500 to 650 mg or equivalent 
dose of paracetamol and/or
-
Anti-nausea and/or antiemetic intramuscular, as 
needed
Stop investigational product infusion 
immediately
Option 1: do not resume investigational product 
infusion; OR based on risk/benefit evaluation, 
at the discretion of the Investigator, resume 
current investigational product infusion under 
observation and at no more than half the 
planned infusion rate after treatment of current 
signs and symptoms as suggested (eg, normal 
saline and/or Tylenol and/or topical 
antihistamines)


Clinical Study Protocol Appendix Y
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
4(6)
Severity of symptoms
Treatment
Investigational product
Additional Options for Future Administration 
of investigational product
Discontinue any further administrations of 
investigational product; OR
Further investigational product infusions, at the 
discretion of the Investigator, continue 
investigational product administration and 
consider slowing infusion rate and pretreating 
subject 0.5 to 1.5 hours prior to investigational 
product administration, for example with:
-
Diphenhydramine 50 mg IV or equivalent
-
Acetaminophen 500 to 650 mg or 
equivalent dose of paracetamol
-
Anti-nausea and/or antiemetic by mouth
Prior to next administration of investigational 
product administration, consider initiating at a 
slower infusion rate and pretreating subject 0.5 
to 1.5 hours prior to next administration of 
investigational product, for example, with
-
Diphenhydramine 50 mg IV or equivalent
-
Acetaminophen 500 to 650 mg or 
equivalent dose of paracetamol
If moderate event recurs in the same subject, 
discontinue further investigational product 
administration


Clinical Study Protocol Appendix Y
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
5(6)
Severity of symptoms
Treatment
Investigational product
Moderate hypersensitivity 
reactions
Infusion related reactions which 
may include generalised rash or 
urticaria, palpitations, chest 
discomfort, shortness of breath, 
hypo- or hypertension with 
>20 mmHg change in systolic BP 
from pre-infusion measurement
Evaluate subject, including close monitoring of vital 
signs 
Treat subject, for example, with:
-
Normal saline (~500 to 1000 mL/hour IV) 
and/or
-
Diphenhydramine 50 mg IV or equivalent and/or
-
Acetaminophen 500 to 650 mg or equivalent 
dose of paracetamol and/or
-
IV corticosteroids, such as hydrocortisone 
100 mg or methylprednisolone 20 to 40 mg
Stop investigational product infusion 
immediately
DO NOT resume current infusion
Discontinue any further administrations of 
investigational product
Consider need for additional oral antihistamine 
administration or oral corticosteroid 
administration to prevent reoccurrence of 
symptoms over subsequent 2 to 3 days


Clinical Study Protocol Appendix Y
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Edition Number 2
Date 09 April 2015
6(6)
Severity of symptoms
Treatment
Investigational product
Severe
Above plus fever with rigors, hypo-
or hypertension with ≥40 mmHg 
change in systolic BP, signs of end 
organ dysfunction (eg, symptomatic 
hypotension such as hypotonia, 
syncope, incontinence, seizure) from 
pre-infusion measurement, or 
wheezing, angioedema, or stridor
OR
Life-threatening
Defined as a reaction that is 
life-threatening and requires pressor 
and/or ventilator support or shock 
associated with acidemia and 
impairing vital organ function due to 
tissue hypoperfusion
Evaluate subject, including close monitoring of vital 
signs
Maintain airway, oxygen if available
Treat subject immediately, for example with:
-
Normal saline (~500 to 1000 mL/hour IV)
-
Epinephrine for bronchospasm, hypotension 
unresponsive to IV fluids, or angioedema. Dose 
and route as per local SOC, example, 
epinephrine 1:1000, 0.5 to 1.0 mL administered 
SC for mild cases and intramuscular for more 
severe cases
-
IV corticosteroids, such as hydrocortisone 
100 mg or methylprednisolone 20 to 40 mg
-
Diphenhydramine 50 mg IV or equivalent
-
Acetaminophen 500 to 650 mg or equivalent 
dose of paracetamol
Call emergency medical transport for transport to 
emergency hospital based on judgment of the 
Investigator
Grade 3 wheezing, hypotension or angioedema is 
unresponsive to single dose of epinephrine
Grade 4 event
At the discretion of the Investigator
Stop investigational product infusion 
immediately
Do not resume current infusion 
Permanently discontinue investigational 
product administration
Consider need for additional oral antihistamine 
administration or oral corticosteroid 
administration to prevent reoccurrence of 
symptoms over subsequent 2 to 3 days


Revised Clinical Study Protocol Appendix Z
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
5
Date
18 May 2016
Protocol Dated
18 May 2016
Appendix Z
Modified Flare Index




Clinical Study Protocol Amendment
Amendment Number
04
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Date
18 May 2016
Protocol Dated
18 May 2016
A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in 
Adult Subjects with Active Systemic Lupus Erythematosus
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden
Centres affected by the Amendment:
All sites participating in the study.
Note: in addition to the changes listed below, minor text/style changes were made.
Sections of protocol affected:
3.1 Inclusion criteria; 3.3.2 Concomitant medications for Systemic Lupus Erythematosus 
standard of care during the study
Previous text:
3.1 Inclusion criteria
7.
Currently receiving at least 1 of the following*:
(a)
A dose of oral prednisone (≤40 mg/day) or prednisone equivalent dose 
for a minimum of 2 weeks prior to signing of the ICF. The dose of oral 
prednisone or prednisone equivalent the subject is taking must be stable 
for a minimum of 2 weeks prior to Week 0 (Day 1)
(b)
Any of the following medications administered for a minimum of 


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
2(17)
12 weeks prior to signing the informed consent, and at a stable dose for 
a minimum of 8 weeks prior to signing the informed consent and 
until Day 1:
(i)
Azathioprine ≤200 mg/day
(ii)
Antimalarial (eg, chloroquine, hydroxychloroquine, 
quinacrine)
(iii)
Mycophenolate mofetil ≤2 g/day or mycophenolic acid 
≤1.44 g/day
(iv)
Oral, subcutaneous (SC), or intramuscular methotrexate 
≤25 mg/week
(v)
Mizoribine ≤150 mg/day
*If receiving oral prednisone (or equivalent) and another agent, the dose duration for 
both (a) and (b) must be met
15.
Meets all of the following TB criteria:
(a)
No history of latent or active TB prior to Screening, with the exception 
of latent TB with documented completion of appropriate treatment
(b)
No signs or symptoms suggestive of active TB from medical history or 
physical examination
(c)
No recent contact with a person with active TB OR if there has been 
such contact, referral to a physician specialising in TB to undergo 
additional evaluation prior to randomisation (documented appropriately 
in source), and, if warranted, receipt of appropriate treatment for latent 
TB at or before the first administration of investigational product
(d)
Must meet 1 of the following criteria:
(i)
Negative QuantiFERON-TB Gold [QFT-G] test result for 
TB obtained from the study Central Laboratory within 
3 months prior to randomisation OR
(ii)
Positive QFT-G test result for TB obtained during the 
Screening Period from the study Central Laboratory for 
which active TB has been ruled out and appropriate 
treatment for latent TB has been initiated prior to the first 


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
3(17)
investigational product administration OR
(iii)
Indeterminate (confirmed on retest) QFT-G test result for 
TB obtained during the Screening Period from the study 
Central Laboratory with ongoing QFT-G testing for TB 
according to the Study Plan 
(e)
A chest radiograph with no evidence of current active infection (eg, TB) 
or old active TB, malignancy, or clinically significant abnormalities 
(unless due to SLE) obtained during the Screening Period or anytime 
within 12 weeks prior to signing of the informed consent
17.
OCS dose stable for at least 2 weeks at Randomisation (Day 1)
18.
Stable SLE SOC treatment at Randomisation (Day 1) (see Section 3.3.2)
3.3.2 Concomitant medications for Systemic Lupus Erythematosus standard of care during the 
study
Permitted SOC SLE
Limitations of Use
OCS
-
Oral prednisone or equivalent up to ≤40 mg/day is permitted 
from at least 2 weeks prior to signing of the informed 
consent. The dose of oral prednisone must remain stable at least 
2 weeks prior to Day 1
-
Subjects with increased SLE disease activity may receive 1 
permitted burst and taper of OCS between Day 1 and Week 12. 
Additional details on burst and taper for SLE and non-SLE (eg, 
asthma or COPD exacerbation) disease activity are provided in 
Sections 3.3.2.1 to 3.3.2.4
Revised text:
3.1 Inclusion criteria
7.
Currently receiving at least 1 of the following*:
(a)
Where prednisone is the single standard of care medication (ie, the 
subject is not concurrently receiving any medication listed in 
inclusion criterion 7(c)), a dose of oral prednisone ≥7.5 mg/day but 
≤40 mg/day (or prednisone equivalent**) for a minimum of 8 weeks 
prior to Day 1. In addition, the dose of oral prednisone or 
prednisone equivalent the subject is taking must be stable for a 
minimum of 2 weeks prior to randomisation
(b)
Where prednisone is not the single standard of care medication (ie, 


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
4(17)
the subject is concurrently receiving at least one medication listed in 
inclusion criterion 7(c)), a dose of oral prednisone ≤40 mg/day (or 
prednisone equivalent**) for a minimum of 2 weeks prior to signing of 
the ICF. In addition, the dose of oral prednisone or prednisone 
equivalent the subject is taking must be stable for a minimum of 2 weeks 
prior to randomisation
(c)
Any of the following medications administered for a minimum of 
12 weeks prior to signing the informed consent, and at a stable dose for 
a minimum of 8 weeks prior to signing the informed consent 
through Day 1:
(i)
Azathioprine ≤200 mg/day
(ii)
Antimalarial (eg, chloroquine, hydroxychloroquine, 
quinacrine)
(iii)
Mycophenolate mofetil ≤2 g/day or mycophenolic acid 
≤1.44 g/day
(iv)
Oral, subcutaneous (SC), or intramuscular methotrexate 
≤25 mg/week
(v)
Mizoribine ≤150 mg/day
*If receiving oral prednisone (or equivalent) and an additional agent, the dose 
duration and maximum allowable dosages for both (b) and (c) must be met
**See Appendix V for examples of prednisone equivalency
15.
Meets all of the following TB criteria:
(a)
No history of active TB prior to any Screening visit
(b)
No history of latent TB prior to initial Screening visit, with the 
exception of latent TB with documented completion of appropriate 
treatment
Note: Subjects with no history of latent TB prior to the initial 
Screening visit, but who are diagnosed with latent TB during 
screening, may be considered eligible if appropriate treatment is 
initiated prior to randomisation. Such subjects may be re-screened 
if necessary to allow for local guidelines on latent TB treatment 
initiation.


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
5(17)
(c)
No signs or symptoms suggestive of active TB from medical history or 
physical examination
(d)
No recent contact with a person with active TB OR if there has been 
such contact, referral to a physician specialising in TB to undergo 
additional evaluation prior to randomisation (documented appropriately 
in source), and, if warranted, receipt of appropriate treatment for latent 
TB at or before the first administration of investigational product
(e)
Must meet 1 of the following criteria:
(i)
Negative QuantiFERON-TB Gold [QFT-G] test result for 
TB obtained from the study Central Laboratory within 
3 months prior to randomisation OR
(ii)
Positive QFT-G test result for TB obtained during the 
Screening Period from the study Central Laboratory for 
which active TB has been ruled out and appropriate 
treatment for latent TB has been initiated prior to the first 
investigational product administration OR
(iii)
Indeterminate (confirmed on retest) QFT-G test result for 
TB obtained during the Screening Period from the study 
Central Laboratory with ongoing QFT-G testing for TB 
according to the Study Plan 
(f)
A chest radiograph with no evidence of current active infection (eg, TB) 
or old active TB, malignancy, or clinically significant abnormalities 
(unless due to SLE) obtained during the Screening Period or anytime 
within 12 weeks prior to signing of the informed consent
17.
OCS dose stable for at least 2 weeks prior to randomisation
18.
Stable SLE SOC treatment (see Section 3.3.2) at the time of randomisation


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
6(17)
3.3.2 Concomitant medications for Systemic Lupus Erythematosus standard of care during the 
study
Permitted SOC SLE
Limitations of Use
OCS
-
Oral prednisone or equivalent up to ≤40 mg/day is permitted 
from at least 2 weeks prior to signing the informed consent. 
The dose of oral prednisone must remain stable at least 2 weeks 
prior to randomisation
-
Where prednisone is the single standard of care medication 
(ie, the subject is not concurrently receiving any medication 
listed in inclusion criterion 7(c)), a dose of oral prednisone 
≥7.5 mg/day but ≤40 mg/day (or prednisone equivalent) for a 
minimum of 8 weeks prior to Day 1 is required
-
Subjects with increased SLE disease activity may receive 1 
permitted burst and taper of OCS between Day 1 and Week 12. 
Additional details on burst and taper for SLE and non-SLE (eg, 
asthma or COPD exacerbation) disease activity are provided in 
Sections 3.3.2.1 to 3.3.2.4
Reason for Amendment: 
The criteria for inclusion based on concomitant medication and tuberculosis status were 
clarified. These changes were made to provide further guidance to the Investigator.
Persons who initiated the Amendment:
AstraZeneca
Section of protocol affected:
3.2.2 Exclusion criteria related to concomitant medications; 3.3.1.2 Restricted medications; 4 
Study plan and timing of procedures, Table 2 Study plan detailing the procedures at screening
Previous text:
3.2.2 Exclusion criteria related to concomitant medications
9.
Receipt of any of the following:
(a)
Any new oral prednisone therapy (or equivalent) anytime from 2 weeks 
prior to signing of the ICF through Day 1 or any change in current oral 
prednisone dose (or equivalent) any time from 2 weeks prior to Day 1 
(see Appendix V for examples of prednisone equivalency) 
(b)
Any new dose of the following anytime in the 12 weeks prior to signing 
the ICF or change in the current dose anytime in the 8 weeks prior to 
signing the ICF through Day 1: azathioprine; any antimalarial (eg, 


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
7(17)
chloroquine, hydroxychloroquine, quinacrine); mycophenolate 
mofetil/mycophenolic acid; oral, SC, or intramuscular methotrexate
13.
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab, 
ofatumumab, atacicept, obinutuzumab, or rituximab) 

≤26 weeks prior to signing the ICF; ≤40 weeks for atacicept
(see Appendix U)

or if therapy was administered >26 weeks ago (40 weeks for atacicept), 
absolute B cell less than the lower limit of normal or baseline value prior to 
receipt of B cell-depleting therapy (whichever is lower) 
14.
Receipt of epratuzumab, belimumab, or tabalumab ≤12 weeks prior to signing the 
ICF
3.3.1.2 Restricted medications
(o)
Other immunosuppressants including but not limited to calcineurin inhibitors (eg, 
cyclosporine, tacrolimus [including topical]) or leflunomide. 
4 Study plan and timing of procedures, Table 2 Study plan detailing the procedures at 
screening
Footnote ‘c’:
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab, ofatumumab, 
atacicept, obinutuzumab, or rituximab) ≤26 weeks prior to signing the ICF (≤40 weeks for 
atacicept [see Appendix U]) and if therapy was administered >26 weeks ago (40 weeks for 
atacicept), absolute B cell less than the lower limit of normal or baseline value prior to receipt 
of B cell-depleting therapy (whichever is lower).
Revised text:
3.2.2 Exclusion criteria related to concomitant medications
9.
Receipt of any of the following:
(a)
Where prednisone is the single standard of care medication (ie, the 
subject is not concurrently receiving any medication listed in 
inclusion criterion 7(c)), any addition of a new oral prednisone 
therapy (or equivalent) any time in the 8 weeks prior to Day 1, OR 
any change in/ discontinuation of current oral prednisone dose (or 
equivalent) anytime within the 2 weeks prior to randomisation (see 
Appendix V for examples of prednisone equivalency)
(b)
Where prednisone is not the single standard of care medication (ie, 


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
8(17)
the subject is concurrently receiving at least one medication listed in 
inclusion criterion 7(c)): 
(i)
Any addition of a new oral prednisone therapy (or 
equivalent) any time from 2 weeks prior to signing of the 
informed consent form through Day 1, OR any change 
in/ discontinuation of current oral prednisone dose (or 
equivalent) anytime within the 2 weeks prior to 
randomisation (see Appendix V for examples of 
prednisone equivalency)
(ii)
Any addition of a new dose of any of the following 
anytime in the 12 weeks prior to signing of the informed 
consent through Day 1, or change in/ discontinuation of 
current dose anytime in the 8 weeks prior to signing of 
the informed consent through Day 1: azathioprine; any 
antimalarial (eg, chloroquine, hydroxychloroquine, 
quinacrine); mycophenolate mofetil/mycophenolic acid; 
oral, SC, or intramuscular methotrexate; mizoribine
10.
Receipt of any of the following:
(a)
Azathioprine >200 mg/day
(b)
Mycophenolate mofetil >2 g/day or mycophenolic acid >1.44 g/day
(c)
Oral, SC, or intramuscular methotrexate >25 mg/week
(d)
Mizoribine >150 mg/day
(e)
Any change in route of administration of oral, SC, or intramuscular 
methotrexate anytime within the 8 weeks prior to signing of the 
informed consent through Day 1
14.
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab, 
ofatumumab, atacicept, obinutuzumab, or rituximab) 

<26 weeks prior to signing the ICF; <40 weeks for atacicept
(see Appendix U)

or if therapy was administered ≥26 weeks ago (40 weeks for atacicept), 
absolute B cell less than the lower limit of normal or baseline value prior to 
receipt of B cell-depleting therapy (whichever is lower) 
15.
Receipt of epratuzumab or tabalumab <26 weeks prior to signing the ICF, or 
belimumab <12 weeks prior to signing the ICF


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
9(17)
3.3.1.2 Restricted medications
(o)
Other immunosuppressants including but not limited to calcineurin inhibitors (eg, 
cyclosporine, tacrolimus [including topical]) or leflunomide. 
Note: Cyclosporine eye drops are acceptable for use in the study.
4 Study plan and timing of procedures, Table 2 Study plan detailing the procedures at 
screening
Footnote ‘c’:
Receipt of B cell-depleting therapy (including but not limited to, ocrelizumab, ofatumumab, 
atacicept, obinutuzumab, or rituximab) <26 weeks prior to signing the ICF (<40 weeks for 
atacicept [see Appendix U]) and if therapy was administered ≥26 weeks ago (40 weeks for 
atacicept), absolute B cell less than the lower limit of normal or baseline value prior to receipt 
of B cell-depleting therapy (whichever is lower).
Reason for Amendment: 
The criteria for exclusion based on concomitant medications were clarified, and a minor 
addition was made allowing the concomitant use of cyclosporine eye drops (to match with 
Appendix U). These changes were made to provide further guidance to the Investigator.
Persons who initiated the Amendment:
AstraZeneca
Sections of protocol affected:
List of abbreviations and definition of terms; 3.2.4 Exclusion criteria related to infection and 
malignancy risk factors; 4 Study plan and timing of procedures, Table 2 Study plan detailing 
the procedures at screening; 4 Study plan and timing of procedures, Table 3 Study plan 
detailing the procedures during the Treatment Period (double-blind period); 5.3.10 Clinical 
laboratory tests, Table 5 Clinical laboratory tests
Previous text:
3.2.4 Exclusion criteria related to infection and malignancy risk factors
26.
Known history of a primary immunodeficiency, splenectomy, or any underlying 
condition that predisposes the subject to infection, or a positive result for human 
immunodeficiency virus (HIV) infection confirmed by central laboratory at 
screening
27.
Confirmed positive test for hepatitis B serology for:


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
10(17)
(a)
Hepatitis B surface antigen, OR 
(b)
Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA 
detected by reflex testing by the central laboratory at screening 
Note: Subjects with HBcAb positivity at screening will be tested every 3 months for HBV 
DNA. To remain eligible in the study, subject HBV DNA levels must remain below the lower 
limit of quantitation (LLOQ) as per the central laboratory.
31.
Opportunistic infection requiring hospitalisation or parenteral antimicrobial 
treatment within 3 years of randomisation 
4 Study plan and timing of procedures, Table 2 Study plan detailing the procedures at 
screening
Footnote ‘b’:
Redraw for ANA/anti-dsDNA, or IFN test can be done within the 30-day screening window, 
however, results must be available within the 30-day screening window for subjects to be 
randomised.
4 Study plan and timing of procedures, Table 3 Study plan detailing the procedures during the 
Treatment Period (double-blind period)
Footnote ‘f’:
Subjects with HBcAb positivity at screening will be tested every 3 months for HBV DNA. To 
remain eligible in the study, subject HBV DNA levels must remain below the LLOQ as per 
the central laboratory.
Revised text:
List of abbreviations and definition of terms
A new abbreviation was added:
HBsAg
Hepatitis B surface antigen
3.2.4 Exclusion criteria related to infection and malignancy risk factors
27.
Known history of a primary immunodeficiency, splenectomy, or any underlying 
condition that predisposes the subject to infection, or a positive result for human 
immunodeficiency virus (HIV) infection confirmed by central laboratory at 
screening. Subjects refusing HIV testing during the screening period will not be 
eligible for study participation
28.
Confirmed positive test for hepatitis B serology for:


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
11(17)
(a)
Hepatitis B surface antigen (HBsAg), OR 
(b)
Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA 
detected above the lower limit of quantitation (LLOQ) by reflex 
testing by the central laboratory at screening 
Note: Subjects who are HBcAb positive at screening will be tested every 3 months for HBV 
DNA. To remain eligible for the study, the subject’s HBV DNA levels must remain below 
the LLOQ as per the central laboratory.
32.
Opportunistic infection requiring hospitalisation or intravenous antimicrobial 
treatment within 3 years of randomisation
4 Study plan and timing of procedures, Table 2 Study plan detailing the procedures at 
screening
Footnote ‘b’:
Redraw for ANA/anti-dsDNA, or IFN test can be done within the 30-day screening window, 
however, results needed to determine eligibility and stratification must be available within 
the 30-day screening window for subjects to be randomised.
4 Study plan and timing of procedures, Table 2 Study plan detailing the procedures at 
screening
A new footnote ‘g’ was added:
g
Subjects within the treatment or follow-up period at the time of amendment 4 
approval will undergo HIV testing at the time of amendment 4 ICF signature.
4 Study plan and timing of procedures, Table 3 Study plan detailing the procedures during the 
Treatment Period (double-blind period)
Footnote ‘f’:
Subjects who are HBcAb positive at screening will be tested every 3 months for HBV DNA.
To remain eligible for the study, the subject’s HBV DNA levels must remain below the 
LLOQ as per the central laboratory.
5.3.10 Clinical laboratory tests, Table 5 Clinical laboratory tests
A new footnote ‘**’ was added:
**
Subjects within the treatment or follow-up period at the time of amendment 4 
approval will undergo HIV testing at the time of amendment 4 ICF signature.


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
12(17)
Reason for Amendment: 
The criteria for performing HIV testing at screening were clarified, along with exclusion 
based on antimicrobial treatment and hepatitis B serology. It was also further clarified that 
ANA/anti-dsDNA, or IFN test results needed to determine eligibility and stratification must be 
available within the 30-day screening window for subjects to be randomised. These changes
were made to provide further guidance to the Investigator.
Persons who initiated the Amendment:
AstraZeneca
Section of protocol affected:
4.4 Follow-up Period
Previous text:
Procedures will be performed according to the Follow-up Period Study Plan (Table 4). 
Subjects who complete the Week 52 visit may be eligible to participate in a LTE study. 
Subjects who complete the double-blind treatment period will have follow-up visits at Week 
56 and Week 60, unless they enrol in the LTE study. Subjects who are withdrawn from the 
study, and do not agree to complete the 52-week study period, should complete the early 
discontinuation visit (Week 52 procedures), and be followed 8 and 12 weeks after the last 
administration of investigational product by completing the Follow up Visit 1 and 2 
assessments (see Section 3.7).
Revised text:
Procedures will be performed according to the Follow-up Period Study Plan (Table 4). 
Subjects who complete the Week 52 visit may be eligible to participate in a LTE study. 
Subjects who complete the double-blind treatment period will have follow-up visits at Week 
56 and Week 60, unless they enrol in the LTE study. Subjects who are withdrawn from the 
study, and do not agree to complete the 52-week study period, should complete the early 
discontinuation visit (Week 52 procedures) within 4 weeks of the last dose of investigational 
product, and be followed 8 and 12 weeks after the EDV visit by completing the Follow up 
Visit 1 and 2 assessments (see Section 3.7).
Reason for Amendment: 
The timing of the early discontinuation visit was clarified. This change was made to provide 
further guidance to the Investigator.


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
13(17)
Persons who initiated the Amendment:
AstraZeneca
Section of protocol affected:
5.3.8.2 Tuberculosis results from screening evaluations
Previous text:

If the screening QFT-G test is positive at screening but the subject is not newly 
positive, the subject must have been diagnosed with latent TB and must have 
documentation confirming completion of appropriate treatment.
Revised text:

If the screening QFT-G test is positive at the initial Screening visit, but the subject 
is not newly positive as of the initial Screening visit, the subject must have been 
diagnosed with latent TB and must have documentation confirming completion of 
appropriate treatment. Subjects with no history of latent TB prior to the initial 
Screening visit, but who are diagnosed with latent TB during screening, may 
be considered eligible if appropriate treatment is initiated prior to 
randomisation. Such subjects may be re-screened if necessary to allow for local 
guidelines on latent TB treatment initiation.
Reason for Amendment: 
The screening requirements for a positive QFT-G test at screening were clarified. This change 
was made to provide further guidance to the Investigator.
Persons who initiated the Amendment:
AstraZeneca
Section of protocol affected:
7.7 Post study access to study treatment
Previous text:
Following evaluation at Week 52, subjects will either be followed for a 12-week Follow-up 
Period or continue in a LTE study that will continue until anifrolumab has been approved for 
use on the market or until development has been discontinued by the Sponsor.
Revised text:
Upon evaluation at Week 52, subjects will either be followed for a 12-week Follow-up 
Period, or transition to an LTE study (if eligible) that will continue for approximately 3 
years after the completion of the Week 52 visit.


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
14(17)
Reason for Amendment: 
The duration of the long-term extension (LTE) study was clarified. This change was made to
provide further guidance to the Investigator.
Persons who initiated the Amendment:
AstraZeneca


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
15(17)
Section of protocol affected:
Appendix U Restricted Medications
Previous Text:
Medications to be Discontinued Prior to signing ICF
Restricted medication
Discontinuation 
prior to signing 
ICF
Restricted medication
Discontinuation 
prior to signing 
ICF
Abatacept (CTLA 4 Ig)
24 weeks
Intravenous Globulin
4 weeks
Acthar® gel
6 weeks
Leflunomide
36 weeks
Adalimumab
12 weeks
Lenalidomide
8 weeks
Alefacept
12 weeks
Lupuzor (IPP-201101)
12 weeks
Anakinra
12 weeks
Memantine
4 weeks
Apremilast
4 weeks
Natalizumab
24 weeks
Atacicept (TACI-Ig)*
40 weeks
Obinutuzumab*
26 weeks
B cell depleter*
26 weeks
Ocrelizumab*
26 weeks
Belimumab
12 weeks
Ofatumumab*
26 weeks
Blisibimod (AMG 623)
8 weeks
Plasmapheresis
24 weeks
Certolizumab pegol
24 weeks
Retinoids
4 weeks
Cyclophosphamide
24 weeks
Rituximab*
26 weeks
Cyclosporine**
4 weeks
Sifalimumab (MEDI-545)
26 weeks
Cytokines (eg, IFN)
Washout Time
Similar to Study drug
26 weeks
Danazol
4 weeks
Sirolimus
4 weeks
Dapsone
4 weeks
Sulfasalazine
4 weeks
Eculizumab
12 weeks
Tabalumab
12 weeks
Efalizumab
12 weeks
Tacrolimus***
4 weeks
Epratuzumab
12 weeks
Thalidomide
8 weeks
Etanercept
4 weeks
Tocilizumab
12 weeks
Golimumab
12 weeks
Tofacitinib
4 weeks
Immunosuppressants
Washout Time
Topical Pimecrolimus
4 weeks
Infliximab
12 weeks
*     provided B cell count is normal at screening
**   cyclosporine eye drops are acceptable for use in the study
*** oral tacrolimus has a 4 week washout period and topical tacrolimus has a 2 week washout period


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
16(17)
Revised text:
Medications to be Discontinued Prior to signing ICF
Restricted medication
Discontinuation 
prior to signing 
ICF
Restricted medication
Discontinuation 
prior to signing 
ICF
Abatacept (CTLA 4 Ig)
24 weeks
Intravenous Globulin
4 weeks
Acthar® gel
6 weeks
Leflunomide
36 weeks
Adalimumab
12 weeks
Lenalidomide
8 weeks
Alefacept
12 weeks
Lupuzor (IPP-201101)
12 weeks
Anakinra
12 weeks
Memantine
4 weeks
Apremilast
4 weeks
Natalizumab
24 weeks
Atacicept (TACI-Ig)*
40 weeks
Obinutuzumab*
26 weeks
B cell depleter*
26 weeks
Ocrelizumab*
26 weeks
Belimumab
12 weeks
Ofatumumab*
26 weeks
Blisibimod (AMG 623)
8 weeks
Plasmapheresis
24 weeks
Certolizumab pegol
24 weeks
Retinoids
4 weeks
Cyclophosphamide
24 weeks
Rituximab*
26 weeks
Cyclosporine**
4 weeks
Sifalimumab (MEDI-545)
26 weeks
Cytokines (eg, IFN)
Washout Time
Similar to Study drug
26 weeks
Danazol
4 weeks
Sirolimus
4 weeks
Dapsone
4 weeks
Sulfasalazine
4 weeks
Eculizumab
12 weeks
Tabalumab
26 weeks
Efalizumab
12 weeks
Tacrolimus***
4 weeks
Epratuzumab
26 weeks
Thalidomide
8 weeks
Etanercept
4 weeks
Tocilizumab
12 weeks
Golimumab
12 weeks
Tofacitinib
4 weeks
Immunosuppressants
Washout Time
Topical Pimecrolimus
4 weeks
Infliximab
12 weeks
*     provided B cell count is normal at screening
**   cyclosporine eye drops are acceptable for use in the study
*** oral tacrolimus has a 4 week washout period and topical tacrolimus has a 2 week washout period


Clinical Study Protocol Amendment 04
Drug Substance Anifrolumab (MEDI-546)
Study Code D3461C00005
Date 18 May 2016
17(17)
Reason for Amendment: 
Appendix U was modified to provide further guidance to the Investigator. The washout 
periods for Epratuzumab and Tabalumab were corrected.
Persons who initiated the Amendment:
AstraZeneca
Section of protocol affected:
Appendix Z Modified Flare Index
Previous Text:
Hemolytic anemia: Hb <70g/L or decrease in Hb >30 g/L with positive Coombs AND at least 
one of the following: decreased haptoglobin, increased total bilirubin due not due to Gilbert’s 
disease, increased reticulocyte count.
Revised text:
Hemolytic anemia: Hb <70g/L or decrease in Hb >30 g/L with positive Coombs AND at least 
one of the following: decreased haptoglobin, increased total bilirubin not due to Gilbert’s 
disease, increased reticulocyte count.
Reason for Amendment: 
Incorrect text was amended.
Persons who initiated the Amendment:
AstraZeneca


Clinical Study Protocol Amendment 04 Appendix A
Drug Substance
Anifrolumab (MEDI-546)
Study Code
D3461C00005
Edition Number
5
Date
18 May 2016
Protocol Dated
18 May 2016
Appendix A
Signatures









SAP_003.pdf: 
Statistical Analysis Plan 
Study Code 
D3461C00005 
Edition Number 
3.0 
Date 
20 August 2018 
A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in 
Adult Subjects with Active Systemic Lupus Erythematosus 






Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
4
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
SIGNATURE OF 
.......................................................... 2 
SIGNATURE OF 
 3 
TABLE OF CONTENTS ......................................................................................... 4 
LIST OF ABBREVIATIONS .................................................................................. 8 
AMENDMENT HISTORY ................................................................................... 11 
1.
STUDY DETAILS ................................................................................................. 12 
1.1 
Study objectives ..................................................................................................... 12 
1.1.1 
Primary objective ................................................................................................... 12 
1.1.2 
Secondary objectives ............................................................................................. 12 
1.1.3 
Safety objective ...................................................................................................... 14 
1.1.4 
Exploratory objective ............................................................................................. 14 
1.2 
Study design ........................................................................................................... 14 
1.2.1 
Steroid burst ........................................................................................................... 15 
1.2.2 
Protocol-specified steroid tapering ........................................................................ 15 
1.3 
Number of subjects ................................................................................................ 16 
2.
ANALYSIS SETS ................................................................................................. 17 
2.1 
Definition of analysis sets ...................................................................................... 17 
2.1.1 
All subjects ............................................................................................................. 17 
2.1.2 
Full analysis set ...................................................................................................... 17 
2.1.3 
Pharmacokinetic analysis set ................................................................................. 17 
2.2 
Protocol deviations ................................................................................................. 17 
3.
PRIMARY AND SECONDARY VARIABLES ................................................... 18 
3.1 
Primary outcome variable ...................................................................................... 18 
3.2 
Key secondary outcome variables.......................................................................... 19 
3.2.1 
SRI(4) at Week 52 in IFN test-high subjects ......................................................... 19 
3.2.2 
Oral corticosteroid management ............................................................................ 19 
3.2.3 
Skin lesions ............................................................................................................ 20 
3.2.4 
SRI(4) at Week 24 ................................................................................................. 20 
3.2.5 
Flares ...................................................................................................................... 21 
3.3 
Other secondary outcome variables ....................................................................... 21 
3.3.1 
Assessment of disease activity ............................................................................... 21 
3.3.1.1 
SRI(4) of anifrolumab 150 mg treatment group .................................................... 21 
3.3.1.2 
Supportive SRI variables ....................................................................................... 21 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
5 
3.3.1.3 
BICLA .................................................................................................................... 22 
3.3.1.4 
Supportive outcome variables of the Individual components of SRI and 
BICLA .................................................................................................................... 23 
3.3.1.5 
Active, swollen and tender joints ........................................................................... 24 
3.3.1.6 
Change in SDI ........................................................................................................ 25 
3.3.1.7 
Supportive outcome variables for the assessment of OCS use .............................. 25 
3.3.1.8 
Supportive outcome variables for the assessment of skin lesions ......................... 26 
3.3.1.9 
Supportive outcome variables for the assessment of flares ................................... 26 
3.3.1.10 Lupus Low Disease Activity State ......................................................................... 26 
3.3.2 
Subject reported outcome variables ....................................................................... 28 
3.3.2.1 
Short Form 36 version 2 (acute recall) .................................................................. 28 
3.3.2.2 
Pain Numerical Rating Scale ................................................................................. 29 
3.3.2.3 
Functional Assessment of Chronic Illness Therapy-FATIGUE ............................ 29 
3.3.2.4 
Patient Global Assessment ..................................................................................... 29 
3.3.2.5 
Lupus quality of life scale ...................................................................................... 30 
3.3.2.6 
EuroQol 5 dimensions ............................................................................................ 30 
3.3.2.7 
Work productivity and Activity Impairment - Lupus ............................................ 31 
3.3.2.8 
Medical Resource Use Questionnaire .................................................................... 31 
3.4 
Assessment of study population ............................................................................. 32 
3.4.1 
Demographic and baseline characteristic variables ............................................... 32 
3.4.2 
Medical history ...................................................................................................... 32 
3.4.3 
Prior and concomitant medications ........................................................................ 32 
3.4.4 
Exposure of investigational product ...................................................................... 33 
3.5 
Safety variables ...................................................................................................... 34 
3.5.1 
Adverse events ....................................................................................................... 34 
3.5.1.1 
Other significant adverse events ............................................................................ 37 
3.5.2 
Laboratory variables .............................................................................................. 37 
3.5.3 
ECGs ...................................................................................................................... 38 
3.5.4 
Modified SELENA Flare Index based flares ......................................................... 39 
3.5.5 
Physical examination ............................................................................................. 40 
3.5.6 
Vital signs .............................................................................................................. 40 
3.5.7 
Cushingoid features ............................................................................................... 40 
3.5.8 
C-SSRS .................................................................................................................. 40 
3.5.9 
Personal Health Questionnaire Depression Scale-8 ............................................... 42 
3.6 
Pharmacokinetics, pharmacodynamics, and immunogenicity ............................... 42 
3.6.1 
Immunogenicity variables ...................................................................................... 42 
3.6.2 
Pharmacokinetic variables ..................................................................................... 43 
3.6.3 
Pharmacodynamic outcome variables .................................................................... 44 
3.7 
Exploratory variables ............................................................................................. 44 
4. 
ANALYSIS METHODS ....................................................................................... 44 
4.1 
General principles .................................................................................................. 44 
4.1.1 
Data excluded from analysis .................................................................................. 44 
4.1.2 
Database lock and unblinding ................................................................................ 45 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
6 
4.1.3 
Visit windows ........................................................................................................ 45 
4.1.4 
Presentation of results ............................................................................................ 47 
4.1.5 
Testing strategy to account for multiplicity considerations ................................... 48 
4.1.6 
Missing Data .......................................................................................................... 49 
4.1.7 
Examination of model assumptions ....................................................................... 50 
4.2 
Analysis methods ................................................................................................... 51 
4.2.1 
Analysis of the primary variable ............................................................................ 51 
4.2.2 
Key secondary outcome variables.......................................................................... 55 
4.2.2.1 
SRI(4) at Week 52 in IFN test-high subjects ......................................................... 55 
4.2.2.2 
Oral corticosteroid management ............................................................................ 56 
4.2.2.3 
Skin lesions ............................................................................................................ 56 
4.2.2.4 
SRI(4) at Week 24 ................................................................................................. 57 
4.2.2.5 
Flares ...................................................................................................................... 57 
4.2.3 
Analysis methods for other secondary efficacy variables ...................................... 59 
4.2.3.1 
Assessment of disease activity ............................................................................... 59 
4.2.3.2 
Subject reported outcome variables ....................................................................... 63 
4.2.4 
Presentation of study population ............................................................................ 64 
4.2.4.1 
Subject disposition ................................................................................................. 64 
4.2.4.2 
Demographic and baseline characteristic ............................................................... 65 
4.2.4.3 
Exposure ................................................................................................................ 65 
4.2.5 
Analysis methods for safety variables ................................................................... 66 
4.2.5.1 
Adverse events ....................................................................................................... 66 
4.2.5.2 
Laboratory variables .............................................................................................. 68 
4.2.5.3 
ECGs ...................................................................................................................... 69 
4.2.5.4 
Modified SELENA Flare Index based flares ......................................................... 69 
4.2.5.5 
Physical examination ............................................................................................. 69 
4.2.5.6 
Vital signs .............................................................................................................. 69 
4.2.5.7 
Cushingoid features ............................................................................................... 70 
4.2.5.8 
C-SSRS .................................................................................................................. 70 
4.2.5.9 
Personal Health Questionnaire Depression Scale-8 ............................................... 70 
4.2.6 
Analysis methods for pharmacokinetics, pharmacodynamics, and 
immunogenicity ..................................................................................................... 70 
4.2.6.1 
Analysis method for immunogenicity variables .................................................... 70 
4.2.6.2 
Analysis methods for pharmacokinetic variables .................................................. 71 
4.2.6.3 
Analysis methods for pharmacodynamic variables ............................................... 72 
4.2.7 
Exploratory variables ............................................................................................. 72 
4.3 
Subgroup analysis .................................................................................................. 72 
5. 
INTERIM ANALYSES ......................................................................................... 73 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL (NOT APPLICABLE) .......... 73 
7. 
REFERENCES ...................................................................................................... 74 
8. 
APPENDIX ............................................................................................................ 75 
MEDICATION BEYOND THE PROTOCOL-ALLOWED THRESHOLD ........................ 76 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
7 
DERIVATION OF PREDNISONE EQUIVALENT DAILY DOSE .................................... 77 
DERIVATION RULES FOR IMPUTATION OF PARTIAL OR MISSING DATES ......... 78 
REFERENCE RANGES AND TELVC FOR LABORATORY VALUES ........................... 79 
ECG: POTENTIALLY CLINICAL SIGNIFICANT POST BASELINE VALUES ............. 81 
REFERENCE RANGES AND TELVC FOR VITAL SIGNS .............................................. 82 
 
LIST OF TABLES 
Table 1 
Threshold values for the SF-36-v2 (acute) responder criteria .................. 28 
Table 2 
Lupus QoL domains ................................................................................. 30 
Table 3  
Data included in Week 52 lock................................................................. 45 
Table 4 
Visit windows ........................................................................................... 46 
Table 5 
Overview of subgroup analyses ................................................................ 73 
 
LIST OF FIGURES 
Figure 1 
Alpha recycling......................................................................................... 48 
 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
8 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BDR 
Blind data review 
BICLA 
British Isles Lupus Assessment Group-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BMI 
Body mass index 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
C3 
Third component of complement 
C4 
Fourth component of complement 
CH50 
Total haemolytic complement 
CI 
Confidence interval 
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
DBL 
Database lock 
dsDNA 
Double-stranded deoxyribonucleic acid 
ECG 
Electrocardiogram 
EDV 
Early Discontinuation Visit 
EQ-5D-5L 
EuroQoL 5 dimensions 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-FATIGUE 
GGT 
Gamma glutamyl transferase 
IFN 
Interferon 
IV 
Intravenous 
IXRS 
Interactive voice/web response system 
LOCF 
Last observation carried forward 
LTE 
Long-term extension 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
9 
Abbreviation or 
special term 
Explanation 
MACE 
Major adverse cardiovascular events 
MAR 
Missing at Random 
MCS 
Mental Component Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAb 
Neutralising antibodies 
NRS 
Numeric rating scale 
OCS 
Oral corticosteroids 
PCS 
Physical Component Score 
PD 
Pharmacodynamic 
PGA 
Physician’s Global Assessment 
PHQ-8 
Personal Health Questionnaire Depression Scale-8 
PK 
Pharmacokinetic(s) 
PtGA 
Patient Global Assessment 
Q 
Question 
Q-Q 
Quartile-quartile 
Q4W 
Every 4 weeks 
QoL 
Quality of life 
SAE 
Serious adverse event 
SD 
Standard deviation 
SDI 
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index 
SE 
Standard Error 
SF-36-v2 (acute) 
Short Form 36 version 2 (acute recall) 
SLE 
Systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SOC 
Standard of care 
SRI(X) 
Systemic Lupus Erythematosus Responder Index of ≥X 
TELVC 
Treatment emergent laboratory/vital signs changes 
TFL 
Tables, Figures and Listings 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WHO-DD 
World Health Organization Drug Dictionary 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
10 
Abbreviation or 
special term 
Explanation 
WPAI 
Work productivity and Activity Impairment 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
11 
AMENDMENT HISTORY 
Date 
Brief description of change 
03 May 2017 
Updates according to the changes in the table, figure and listing (TFL) shells 
after review 
Updates to provide additional details to support programming activities 
Updates to specify handling and examination of missing data (sensitivity and 
tipping point analyses) 
Updates to clarify database lock and unblinding after all subjects completed 
Week 52. 
 
 
17 August 2018 
Updates following Blind Data Review: Clarifications added, inconsistencies 
removed, additional analyses added, and minor changes to some analyses. 
Updated to clarify handling of (partially) missing AE dates 
Analysis model for longitudinal data changed to repeated measures model. 
Additional rules for pooling of strata for CMH analysis defined 
Updates to document handling of site excluded from analysis. 
Updates to further clarify week 52 lock activities. 
 
 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
12 
1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective 
Primary Objective: 
Outcome Measures: 
To evaluate the effect of anifrolumab 300 mg 
compared to placebo on disease activity as 
measured by the difference in the proportion 
of subjects who achieve a systemic lupus 
erythematosus (SLE) Responder Index of ≥4 
(SRI[4]) at Week 52 
Composite variable SRI(4), defined by the following 
criteria: 
- 
Reduction from baseline of ≥4 points in the 
Systemic Lupus Erythematosus Disease Activity 
Index 2000 (SLEDAI-2K) and 
- 
No new organ systems affected as defined by 1 
or more British Isles Lupus Assessment Group 
(BILAG-2004) A or 2 or more BILAG-2004 B 
items compared to baseline using BILAG-2004 
and 
- 
No worsening from baseline in subjects’ lupus 
disease activity defined by an increase 
≥0.30 points on a 3-point Physician’s Global 
Assessment (PGA) visual analogue scale (VAS) 
and 
- 
No discontinuation of investigational product or 
use of restricted medications beyond the 
protocol-allowed thresholda before assessment  
a 
Any medication classified as restricted medications as described in Appendix A 
 
1.1.2 
Secondary objectives 
Key Secondary Objectives: 
Outcome Measures: 
To evaluate the effect of anifrolumab 300 mg compared to placebo on: 
The proportion of subjects with SRI(4) at 
Week 52 in the interferon (IFN) test-high 
sub-group 
SRI(4) (see outcome measure for primary objective) 
The proportion of subjects who achieve an 
Oral corticosteroids (OCS) dose ≤7.5 mg/day 
at Week 40, which is maintained through 
Week 52 in the sub-group of subjects with 
baseline OCS ≥10 mg/day 
Maintained OCS reduction defined by the following 
criteria:  
- 
Achieve an OCS dose of ≤7.5 mg/day 
prednisone or equivalent by Week 40 and 
- 
Maintain an OCS dose ≤7.5 mg/day prednisone 
or equivalent from Week 40 to Week 52 and 
- 
No discontinuation of investigational product or 
use of restricted medications beyond the 
protocol-allowed thresholda before assessment 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
13 
The proportion of subjects with a ≥50% 
reduction in Cutaneous Lupus Erythematosus 
Disease Area and Severity Index (CLASI) 
activity score at Week 12 in the sub-group of 
subjects with baseline CLASI activity score 
≥10 
50% reduction in CLASI activity score compared to 
baseline defined by the following criteria: 
- 
Achieve ≥50% reduction of CLASI activity 
score at Week 12 compared to baseline and 
- 
No discontinuation of investigational product or 
use of restricted medications beyond the 
protocol-allowed thresholda before assessment  
The proportion of subjects with SRI(4) at 
Week 24  
SRI(4) (see outcome measure for primary objective) 
The annualised flare rate through 52 weeks 
Annualised flare rate with flare defined as either 1 or 
more new BILAG-2004 A or 2 or more new 
BILAG-2004 B items compared to the previous visit 
Other Secondary Objectives: 
Outcome Measures: 
To evaluate the effect of anifrolumab 150 mg 
compared to placebo on disease activity as 
measured by the difference in the proportion 
of subjects who achieve SRI(4) at Week 52 
SRI(4) (see endpoint for primary objective) 
To assess the difference between anifrolumab 
300 mg and placebo on measures of disease 
activity including levels of SRI response other 
than 4, British Isles Lupus Assessment 
Group-based Composite Lupus Assessment 
(BICLA), the individual components of SRI, 
and the number of swollen and tender joints at 
Week 52, as well as SRI and BICLA over time 
SRI(4), SRI(5), SRI(6), SRI(7), SRI(8), BICLA 
response, BILAG-2004, SLEDAI-2K, PGA, Major 
Clinical Response, Partial Clinical Response, and 
joint count 
To assess the difference between anifrolumab 
300 mg and placebo on measures of organ 
damage, ie, Systemic Lupus International 
Collaborating Clinics/American College of 
Rheumatology Damage Index (SDI) at 
Week 52 
SDI 
To assess the difference between anifrolumab 
300 mg and placebo on subject-reported health 
status, health-related quality of life, and other 
subject-reported outcome measures of fatigue, 
pain, patient global assessment, and work 
productivity at Week 52 
Short Form 36 version 2 (acute recall) (SF-36-v2 
[acute]), Pain numeric rating scale (NRS), Functional 
Assessment of Chronic Illness Therapy-FATIGUE 
(FACIT-F), Patient Global Assessment (PtGA), 
Lupus quality of life (QoL), EuroQoL 5 dimensions 
(EQ-5D-5L), Work Productivity and Activity 
Impairment (WPAI)-Lupus, and Medical Resource 
Use Questionnaire  




Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
15 
Randomisation will be stratified using the following factors:  
• 
SLEDAI-2K score at screening (<10 points versus ≥10 points) 
• 
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or 
equivalent) 
• 
Results of the IFN test (high versus low) 
This study includes: 
• 
A Screening Period: Up to 30 days  
• 
Treatment Period: A 52-week double-blind treatment period with investigational 
product administration Q4W from Week 0 to Week 48 for a total of 13 doses  
• 
At Week 52, subjects will have two options: 
- 
If eligible, enrol into the long-term extension (LTE) study in which anifrolumab 
300 mg or placebo will be administered Q4W 
OR 
- 
Continue in the current study for another 8 weeks to complete a 12-week safety 
follow-up after the last dose of investigational product (last dose of 
investigational product will be given in Week 48) 
The total study duration could be up to approximately 64 weeks for subjects who do not enrol 
into the LTE study (including screening period) and up to approximately 56 weeks (including 
screening period) for those subjects who do enrol into the LTE study. 
Database lock (DBL) and unblinding will occur after the last subject has completed Week 52 
(Visit 14/EDV). Blinding of subjects and investigators will be maintained to the greatest 
extent possible after the DBL at Week 52 until Last Subject Last Visit in the LTE study. 
1.2.1 
Steroid burst 
From Week 0 (Day 1) to Week 12, subjects may receive only 1 burst of corticosteroids for an 
increase in SLE disease activity or to control non-SLE related disease (eg, asthma or chronic 
obstructive pulmonary disease exacerbation). Subjects receiving more than 1 burst during the 
first 12 weeks of treatment will be considered non-responders for subsequent assessments of 
disease activity, regardless of the reason for the burst (SLE or non-SLE activity). More details 
are given in Sections 3.3.4 in the clinical study protocol. 
1.2.2 
Protocol-specified steroid tapering 
Steroid tapering to a target OCS dose of ≤7.5 mg/day must be attempted in all subjects with a 
baseline OCS dose ≥10.0 mg/day. This will commence at Week 8 and continue stepwise until 
the target is reached, unless at least 1 of the following criteria is met: 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
16 
• 
SLEDAI-2K activity which is worsened compared to baseline in major organ 
systems (renal, central nervous system, cardiopulmonary, vasculitis, fever, 
thrombocytopenia, or haemolytic anaemia, or gastrointestinal activity) 
• 
Newly-affected organ system(s) based on the SLEDAI-2K, excluding serological 
abnormalities (dsDNA antibodies, hypocomplementemia)  
• 
Moderate to severe skin disease as reflected by a CLASI activity score of ≥10  
• 
Moderate to severe arthritis disease as reflected by an active joint count of ≥8 tender 
and/or swollen joints 
Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
7.5 mg/day up to Week 40 based on disease activity. If a subject has an increase in disease 
activity secondary to OCS tapering, they may increase the dose up to a maximum of the 
baseline OCS therapy dose from Week 8 up to Week 40 without the subject being considered 
a non-responder for subsequent assessments of disease activity. Subjects who require OCS 
dose above their baseline level may continue in the study but will be considered 
non-responders for subsequent assessments of disease activity. 
Steroid tapering will not be permitted after Week 40. 
1.3 
Number of subjects 
A total of 450 subjects receiving SOC treatment will be randomised 1:2:2 to treatment with 
150 mg anifrolumab, 300 mg anifrolumab or placebo. 
The sample size is primarily driven by the need to acquire an adequate safety database size, as 
well as the ability to assess key secondary endpoints. The primary endpoint is the difference in 
proportion of subjects achieving SRI(4) at Week 52 comparing anifrolumab 300 mg to 
placebo. With assumed proportions of SRI(4) of 39% and 63% in the placebo and anifrolumab 
300 mg groups, respectively, 180 subjects/arm yields more than 99% power to reject the 
hypothesis of no difference using a 2-sided alpha of 0.05. The minimal detectable difference 
in SRI(4) between anifrolumab 300 mg versus placebo is approximately 10% with this sample 
size.  
Estimates of power for 2 key secondary endpoints are listed below. These calculations assume 
that the primary endpoint is met, and the testing of the key secondary endpoints is therefore 
allowed. Each endpoint is tested using a weighted Holm procedure, and the alpha given by the 
assigned weight in the first step of the algorithm:  
• 
Difference in proportion of subjects achieving SRI(4) at Week 52 in the 
IFN test-high sub group: Given 75% of subjects are IFN test-high; proportions of 
SRI(4) in the IFN test-high subgroup of 35% and 61% in the placebo and 
anifrolumab treatment groups, respectively; a 2-sided alpha of 0.04 yields 98% 
power. 


Statistical Analysis Plan  
Study Code D3461C00005 
Edition Number 3.0  
Date 20 August 2018 
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• 
Difference in proportion of subjects who achieve an OCS dose ≤7.5 mg/day at 
Week 40, which is maintained through Week 52 in the sub-group of subjects with 
baseline OCS ≥10 mg/day: Given 60% of subjects have an OCS dose of at least 
10 mg at baseline; proportions of subjects tapering the OCS dose of 32% and 59% 
in the placebo and anifrolumab treatment groups, respectively; a 2-sided alpha of 
0.004 yields 87% power.  
The assumptions of the effect sizes and sizes of subgroups used for the calculations above are 
based on the observed results in the interim analyses of study CD IA MEDI 546-1013. 
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
2.1.1 
All subjects  
This analysis set will comprise all subjects screened for the study and will be used for 
reporting of disposition and screening failures. 
2.1.2 
Full analysis set 
The full analysis set will be used as the primary population for reporting efficacy and safety 
data. This comprises all subjects randomised into the study who receive at least 1 dose of 
investigational product and will be analysed according to randomised treatment (modified 
Intention-To-Treat). Any major deviations from randomised treatment will be listed and 
considered when interpreting the safety data. 
2.1.3 
Pharmacokinetic analysis set 
All subjects who received anifrolumab and who had at least 1 quantifiable serum PK 
observation post first dose, will be included in the PK analysis dataset. All PK summaries will 
be based on this analysis set. 
2.2 
Protocol deviations 
Protocol deviations that may greatly impact the completeness, accuracy, and/or reliability of 
the study data or that may significantly affect a subject’s rights, safety, or well-being will be 
summarized. 
The final list of protocol deviations will be finalized and documented prior to unblinding the 
study data, and will be based on deviations as defined in the Protocol Deviation Guidance. 
During the blind data review (BDR) meeting, protocol deviations will be classified as 
important or other depending on the impact of the deviation to the analysis. Only important 
protocol deviations will be listed and tabulated in the Clinical Study Report (CSR). 


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3. 
PRIMARY AND SECONDARY VARIABLES 
Baseline is defined as the last measurement prior to randomisation and dose administration on 
Day 1. If the Day 1 value is missing or is invalid or is collected after administration of 
investigational product, the latest assessment prior to dose administration on Day 1 will serve 
as baseline. 
At some sites, the device to collect subject reported outcomes was not synchronized with the 
real time. Therefore, baseline for the following subject reported outcomes will be derived 
based on the date only, ignoring the time of the assessment. 
• 
Short Form 36 version 2 (acute recall) 
• 
Pain numerical rating scale 
• 
Functional Assessment of Chronic Illness Therapy – FATIGUE 
• 
Patient Global Assessment 
• 
Lupus quality of life scale 
• 
EuroQol 5 dimensions 
• 
Work productivity and Activity Impairment – Lupus 
• 
Medical Resource Questionnaire 
• 
C-SSRS 
• 
Personal Health Questionnaire Depression Scale 
If not stated otherwise, change from baseline will be calculated as value at the respective time 
point minus value at baseline. The percent change from baseline is defined as change from 
baseline divided by baseline value multiplied with 100. 
Values of BILAG-2004, SLEDAI-2K, CLASI, and PGA assessments will be adjudicated 
values. 
3.1 
Primary outcome variable 
The primary endpoint used to evaluate the effect of anifrolumab 300 mg compared to placebo 
on disease activity is the difference in proportion of subjects achieving SRI(4) at Week 52, 
where a subject achieves SRI(4) if all of the following criteria are met: 
• 
Reduction from baseline of ≥4 points in the SLEDAI-2K 
SLEDAI-2K will be derived as the sum of the scores for all items. A ≥4 points 
reduction is reached if the change from baseline is ≤-4. 
• 
No new organ systems affected as defined by 1 or more new BILAG-2004 A or 2 or 
more new BILAG-2004 B items compared to baseline 
• 
No worsening from baseline in subjects’ lupus disease activity defined by an 
increase ≥0.30 points on a 3-point PGA VAS 


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• 
No permanent premature discontinuation of investigational product (according to 
eCRF form “Discontinuation of Investigational Product”) 
• 
No use of restricted medications beyond the protocol-allowed threshold on or 
before the date of last Week 52 assessment used to derive SRI(4) 
Restricted medications are defined in Appendix A. 
If any of the criteria cannot be evaluated at Week 52 (eg, due to missing values) that criterion 
will be imputed using last observation carried forward (LOCF) and SRI(4) derived based on 
the complete data. This applies only if Week 48 data is not missing, otherwise the subject will 
be defined as not achieving SRI(4) at Week 52. 
In addition, the individual conditions of SRI(4) (SLEDAI-2K reduction ≥4 points, no new 
organ systems affected, no worsening of subjects’ lupus disease activity, no permanent 
discontinuation of investigational product, and no use of rescue medication) will be assessed 
at Week 24 and Week 52 by treatment. 
3.2 
Key secondary outcome variables 
3.2.1 
SRI(4) at Week 52 in IFN test-high subjects 
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg compared to 
placebo on disease activity in the IFN test-high subgroup is the difference in proportion of 
subjects achieving SRI(4) at Week 52 in subjects classified as IFN test-high at baseline. 
SRI(4) is defined in Section 3.1. 
3.2.2 
Oral corticosteroid management 
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on the ability to reduce the OCS dose in subjects with baseline OCS ≥10 mg/day prednisone 
or equivalent is the difference in proportion of subjects with maintained OCS reduction. A 
maintained OCS reduction is defined as meeting all the following criteria:  
• 
Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40  
The date of last assessment used for efficacy analysis (SLEDAI-2K, PGA and 
BILAG) in the time window of Week 40 (as described in Section 4.1.3) will be used 
as date of Week 40. If no such assessment falls into the respective time window, 
then the target date for the timepoint will be used instead. 
• 
Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to 
Week 52 
A maintained OCS dose is defined as no dose increase (ie, no dose greater than the 
dose at Week 40) between Week 40 and Week 52. 
The date of last assessment used for efficacy analysis  (SLEDAI-2K, PGA and 
BILAG) in the time window of Week 52 (as described in Section 4.1.3) will be used 
as date of Week 52. If no such assessment falls into the respective time window, 
then the target date for the timepoint will be used instead. 


Statistical Analysis Plan  
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• 
No permanent premature discontinuation of investigational product (according to 
eCRF form “Discontinuation of Investigational Product”) 
• 
No use of restricted medications beyond the protocol-allowed threshold on or 
before the date of Week 52 (as given above)  
Restricted medications are defined in Appendix A. 
If any of the conditions cannot be evaluated at Week 52 (eg, due to missing values) the subject 
is defined as not reaching a maintained OCS reduction. 
The derivation of the prednisone equivalent daily dose is given in Appendix B. 
3.2.3 
Skin lesions 
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on inflammatory cutaneous lupus lesions in subjects with baseline CLASI activity score ≥10 is 
the difference in proportion of subjects with an at least 50% reduction in CLASI activity score 
at Week 12. An at least 50% reduction in CLASI activity score is defined as meeting all the 
following criteria:  
• 
Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline  
The CLASI activity score will be derived as the sum of all single activity scores 
(13 locations of erythema, 13 locations of scale/hypertrophy, mucous membrane 
lesions, recent hair loss, and non-scarring alopecia). A ≥50% reduction is reached if 
the percentage change is ≤-50%. 
• 
No permanent premature discontinuation of investigational product before 
assessment (ie, duration of exposure ≥ study day of date of CLASI assessment at 
Week 12) 
• 
No use of restricted medications beyond the protocol allowed threshold on or before 
the date of CLASI assessment at Week 12 
Restricted medications are defined in Appendix A. 
If any of the criteria cannot be evaluated at Week 12 (eg, due to missing values) that criterion 
will be imputed using LOCF and an at least 50% reduction in CLASI activity score derived 
based on the complete data. This applies only if Week 8 data is not missing, otherwise the 
subject will be defined as not reaching a ≥50% reduction in CLASI activity score at Week 12. 
3.2.4 
SRI(4) at Week 24 
The key secondary endpoint used to evaluate the early effect of anifrolumab 300 mg 
compared to placebo on disease activity is the difference in proportion of subjects achieving 
SRI(4) at Week 24. SRI(4) at Week 52 is defined in Section 3.1. SRI(4) at Week 24 will be 
derived in the same way with using assessments at Week 24 instead of Week 52 (with allowed 
LOCF of Week 20 data) and no permanent premature discontinuation of investigational 
product before assessment (ie, duration of exposure ≥ study day of date of last Week 24 
assessment used to derive SRI(4)). 


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3.2.5 
Flares  
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on flares is the difference in annualized flare rate through Week 52.  
A flare is defined as either 1 or more new BILAG-2004 A or 2 or more new BILAG-2004 B 
items compared to the previous visit (ie, a worsening from an E, D, or C score to a B score in 
at least 2 organ systems or a worsening from an E, D, C, or B score to an A score in any one 
organ system compared to the previous visit).  
The occurrence of a new flare will be checked for each available visit versus the previous 
available visit up to Week 52. If no flare occurred, the number of flares will be set to 0. 
Otherwise all flares will be counted leading to a maximum number of flares of 13.  
The annualized flare rate will be calculated as the number of flares divided by the flare 
exposure time in days multiplied with 365.25. The flare exposure time is the time up to 
Week 52 (date of BILAG-2004 assessment at Week 52) or up to the date of last available 
BILAG-2004 assessment up to and including week 52 in case of premature study 
discontinuation and will be derived as date of Week 52/ date of last BILAG-2004 assessment 
minus date of first administration of investigational product + 1. 
For the sensitivity analyses of flares while on treatment, the flare exposure time is the time 
between day of first dose of investigational product and day of last dose of investigational 
product plus 28 days, both inclusive. All flares occurring within the flare exposure time will 
be considered for this analysis (even if occurring after the week 52 visit timepoint). 
3.3 
Other secondary outcome variables 
3.3.1 
Assessment of disease activity 
3.3.1.1 
SRI(4) of anifrolumab 150 mg treatment group 
The effect of anifrolumab 150 mg compared to placebo on disease activity will be assessed by 
the difference in proportions of subjects achieving SRI(4) at Week 52. SRI(4) is defined in 
Section 3.1. 
3.3.1.2 
Supportive SRI variables 
In addition to the endpoint described in Section 3.1, the difference between anifrolumab 
300 mg and placebo in SRI at Week 52 will be assessed using levels other than 4, ie, SRI(5), 
SRI(6), SRI(7), and SRI(8), where SRI(X) (X=5, 6, 7, or 8) is defined by the proportion of 
subjects who meet the following criteria: 
• 
Reduction from baseline of ≥X points in the SLEDAI-2K 
Reduction from baseline will be derived as described in Section 3.1.  
• 
No new organ systems affected as defined by 1 or more new BILAG-2004 A or 2 or 
more new BILAG-2004 B items compared to baseline 


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• 
No worsening from baseline in subjects’ lupus disease activity defined by an 
increase ≥0.30 points on a 3-point PGA VAS 
• 
No permanent premature discontinuation of investigational product (according to 
eCRF form “Discontinuation of Investigational Product”) 
• 
No use of restricted medications beyond the protocol-allowed threshold on or 
before the date of last Week 52 assessment used to derive SRI(X) 
Restricted medications are defined in Appendix A. 
If any of the criteria cannot be evaluated at Week 52 (eg, due to missing values) that criterion 
will be imputed using LOCF and SRI(X) derived based on the complete data. This applies 
only if Week 48 data is not missing, otherwise the subject will be defined as not achieving 
SRI(X) at Week 52.  
The difference between anifrolumab 300 mg and placebo in the proportion of subjects 
achieving SRI(X), X=4, 5, 6, 7, or 8 will also be assessed longitudinally over time up to 
Week 52.  
3.3.1.3 
BICLA 
The effect of anifrolumab 300 mg versus placebo on disease activity will also be assessed 
using the difference in proportion of subjects meeting the criteria for BICLA response at 
Week 52, where a subject is a BICLA responder if the following criteria are met: 
• 
Reduction of all baseline BILAG-2004  A to B/C/D and baseline BILAG-2004 B to 
C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new 
BILAG-2004 A or ≥2 new BILAG-2004 B 
• 
No worsening from baseline in SLEDAI-2K as defined as an increase from baseline 
of >0 points in SLEDAI-2K 
Increase from baseline corresponds to the change from baseline. The derivation of 
the SLEDAI-2K is described in Section 3.1.  
• 
No worsening from baseline in subjects’ lupus disease activity defined by an 
increase ≥0.30 points on a 3-point PGA VAS; 
• 
No permanent premature discontinuation of investigational product (according to 
eCRF form “Discontinuation of Investigational Product”) 
• 
No use of restricted medications beyond the protocol-allowed threshold on or 
before the date of last Week 52 assessment used to derive BICLA response 
Restricted medications are defined in Appendix A. 
If any of the criteria cannot be evaluated at Week 52 (eg, due to missing values) that criterion 
will be imputed using LOCF and BICLA response derived based on the complete data. This 
applies only if Week 48 data is not missing, otherwise the subject will be defined as a BICLA 
non-responder at Week 52.  
The difference between anifrolumab 300 mg and placebo in the proportion of subjects 
achieving BICLA will also be assessed longitudinally over time up to Week 52.  


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3.3.1.4 
Supportive outcome variables of the Individual components of SRI and BICLA 
Individual conditions 
Individual conditions of BICLA (reduction of all BILAG-2004 A and B, no worsening from 
baseline in SLEDAI-2K, no worsening in subjects’ lupus disease activity, no permanent 
discontinuation of investigational product, and no use of rescue medication) are defined in 
Section3.3.1.3. The individual conditions will be assessed at Week 24 and Week 52 by 
treatment. 
SLEDAI-2K 
SLEDAI-2K (calculated as described in Section 3.1) will be evaluated using the difference in 
mean change from baseline longitudinally over time to Week 52.  
Scores for the SLEDAI organ systems will be derived in the same way as SLEDAI-2K but 
using the scores for the respective items only. The SLEDAI organ systems are defined as 
follows: 
• 
Central nervous system: seizure, psychosis, organic brain syndrome, visual 
disturbance, cranial nerve disorder, and lupus headache  
• 
Vascular: CVA (cerebrovascular accident) and vasculitis 
• 
Musculoskeletal: arthritis and myositis 
• 
Renal: urinary casts, hematuria, proteinuria, and pyuria 
• 
Mucocutaneous: rash, alopecia, and mucosal ulcers 
• 
Cardiovascular system and respiratory: pleurisy and pericarditis 
• 
Immunology: low complement and increased DNA binding 
• 
Haematological and fever: fever, thrombocytopenia, and leukopenia 
For each SLEDAI organ system, the proportion of subjects with an improvement (ie, a 
SLEDAI organ system score less than the corresponding score at baseline) at Week 24 and 
Week 52, respectively, will be assessed for subjects with an organ system involvement at 
baseline (ie, a SLEDAI organ system score greater than 0).  
Physician’s Global Assessment  
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
PGA (measured on a VAS ranging from 0 to 3) will be assessed by visit up to Week 52. 
BILAG-2004 
BILAG-2004 grades will be presented by organ system. Furthermore, a BILAG-2004 global 
score will be derived by summing-up the numerical score equivalents for each organ system 
with the numerical score equivalents given as: A = 12, B = 8, C = 1, D = 0, and E = 0. 


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Clinical Response 
In addition, the effect of anifrolumab 300 mg versus placebo on Major Clinical Response and 
Partial Clinical Response will be evaluated where these variables are defined as:  
• 
Difference in proportion of subjects who achieve Major Clinical Response, ie, a 
subject with BILAG-2004 C scores or better at Week 24 with no new 
BILAG-2004 A or BILAG-2004 B scores and maintenance of response with no new 
BILAG-2004 A or B scores between Week 24 and Week 52. 
• 
Difference in proportion of subjects who achieve Partial Clinical Response, ie, a 
subject with a maximum of 1 BILAG-2004 B score or better at Week 24 and 
maintenance of response without a new BILAG-2004 A or more than 1 new 
BILAG-2004 B item out to Week 52. 
If BILAG-2004 grades are missing or incomplete at any relevant visit, the missing data will be 
imputed using LOCF and Major and Partial Clinical Response derived based on the complete 
data. This applies only if data of the previous visit is not missing, otherwise (ie, in case of at 
least 2 subsequent visits with missing data) the subject will be defined as non-responder. 
3.3.1.5 
Active, swollen and tender joints 
The endpoints used to evaluate the effect of anifrolumab 300 mg versus placebo on active, 
swollen, and tender joints are:  
• 
Difference in change from baseline to Week 52 in the number of active, swollen, 
and tender joints, respectively;  
• 
Difference in proportion of subjects with at least 8 swollen and at least 8 tender 
joints at baseline who achieve at least a 20% reduction from baseline in both the 
number of swollen and tender joints at Week 52; 
• 
Difference in proportion of subjects with at least 8 swollen and at least 8 tender 
joints at baseline who achieve at least a 50% reduction from baseline in both the 
number of swollen and tender joints at Week 52. 
An active joint is defined as a joint with swelling and tenderness. 
An at least 20% reduction and at least 50% reduction, respectively, is reached if the 
percentage change is ≤-20% and ≤-50%, respectively, no restricted medications beyond the 
protocol allowed threshold were used on or before the assessment, and there was no 
permanent premature discontinuation of investigational product (according to eCRF form 
“Discontinuation of Investigational Product”). To achieve at least a 20% reduction and at least 
a 50% reduction, respectively, the reduction in the number of joints needs to be reached in 
swollen and tender joints separately.  
If the change from baseline in the number of joints cannot be evaluated at Week 52 (eg, due to 
missing values) the change from baseline will be imputed using LOCF. This applies only if 


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Week 48 data is not missing, otherwise the subject will be defined as not achieving a 
reduction. 
Furthermore, the change from baseline in the number of active, swollen and tender joints, 
respectively, will be explored longitudinally up to Week 52 for all subjects. 
3.3.1.6 
Change in SDI 
The endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo on irreversible 
damage in SLE subjects is the difference in mean change in SDI global score from baseline to 
Week 52. 
The SDI is defined for 12 organ systems (possible scores): peripheral vascular (0 to 5), ocular 
(0 to 2), neuropsychiatric (0 to 6), renal (0 to 3), pulmonary (0 to 5), cardiovascular (0 to 6), 
gastrointestinal (0 to 6), musculoskeletal (0 to 7), skin (0 to 3), endocrine (diabetes) (0 to 1), 
gonadal (0 to 1) and malignancies (0 to 2). The SDI global score is the sum of the damage 
scores for all 12 organ systems. 
Furthermore, the number and percentage of subjects with changes in damage will be explored 
at Week 52. A damage according to the SDI score is defined as an SDI global score ≥1. 
Accordingly, no damage is defined as an SDI global score =0. Post-baseline categories used 
for the presentation of change in damage will be ‘no change’, ‘+ 1 point’, ‘+ 2 points’, and 
‘+ 3 or more points’.  
3.3.1.7 
Supportive outcome variables for the assessment of OCS use 
The total daily OCS dose will be assessed longitudinally over time up to Week 52. For the 
derivation of OCS dose at a specific visit, the target date for the respective visit (as described 
in Section 4.1.3) will be used. 
The standardised area under the curve (AUC) of OCS dose up to Week 52 will be calculated 
as follows: 
For each single daily dose, the duration of the single dose will be calculated as end date – start 
date + 1. If the start date is before Day 1, Day 1 will be used instead. If the end date is after 
the date of Week 52 (date of Visit 14), the date of Visit 14 will be used instead. The AUC for 
each single dose will be derived by the daily dose (mg/day) multiplied with the duration 
(days). The AUC up to Week 52 is the sum of the AUCs of the single doses. The AUC of 
OCS dose will only be calculated if all necessary data are available up to Visit 14 (ie, daily 
prednisone equivalent OCS dose can be calculated). For subjects who discontinued the study 
before Visit 14, the AUC will be calculated up to the date of study discontinuation. If a subject 
does not receive any OCS dose (ie, no corresponding medication documented) the AUC for 
this subject will be set to 0. The standardised AUC will be derived as AUC divided by the 
available days (date of Visit 14 / date of early discontinuation – date of Day 1 + 1) multiplied 
by 364 (52 weeks).  


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3.3.1.8 
Supportive outcome variables for the assessment of skin lesions 
For all subjects with a CLASI activity score ≥10 at baseline the reduction of CLASI will be 
compared between Week 12 and Week 52. An at least 50% reduction in CLASI activity score 
at Week 12 is defined in Section 3.2.3. The reduction at Week 52 is defined in the same way 
with using assessments at Week 52 (with allowed LOCF of Week 48 data) instead of Week 12 
and no permanent premature discontinuation of investigational product (according to eCRF 
form “Discontinuation of Investigational Product”). Maintenance of effect in CLASI activity 
score is defined as an at least 50% reduction in CLASI activity score at Week 12 and Week 
52. 
The difference between anifrolumab and placebo in the mean change from baseline in CLASI 
activity as well as CLASI damage score will be evaluated longitudinally over time up to 
Week 52. The CLASI damage score will be calculated as the sum of the scores for 
dyspigmentation for 13 locations, scarring/atrophy/panniculitis for 12 locations, and scarring 
of the scalp. If dyspigmentation lasts more than one year, the sum of the dyspigmentation 
scores from the 13 locations will be multiplied with 2 in the above formula. 
3.3.1.9 
Supportive outcome variables for the assessment of flares 
In addition to the variable in Section 3.2.5, the annualised rate of flares will also be evaluated 
with a supportive definition of flares. The flare rate and annualized flare rate for the following 
definition of flares will be derived similarly as described in Section 3.2.5. 
• 
Flare versus baseline:  
A flare is defined as either 1 or more new BILAG-2004 A or 2 or more new 
BILAG-2004 B compared to baseline and a change versus the previous visit. This 
implies that a new BILAG-2004 A score maintained in subsequent visits will not be 
counted as a new flare. However, a change of the situation in a subsequent visit (eg, 
one of the 2 new BILAG-2004 B scores of the previous visit improves to C but 
another worsens to B or an occurrence of a new BILAG-2004 B score in addition to 
the BILAG-2004 A score defining the previous flare) will lead to a new flare. 
In addition, time to flare for the first flare will be assessed for flares as defined in 
Section 3.2.5 and the flares versus baseline. The time to flare will be derived as date of first 
flare minus date of first administration of investigational product. If the subject did not have a 
flare, the time to flare will be censored at the end of the flare exposure time (as defined in 
Section 3.2.5). 
3.3.1.10 Lupus Low Disease Activity State 
The endpoint used to evaluate the effect of anifrolumab versus placebo on disease activity 
state is the difference in the proportion of subjects with response in Lupus Low Disease 
Activity State (LLDAS) at Week 52.  A subject will be considered to be an LLDAS responder 
at a specific visit if all the criteria below are met: 


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• SLEDAI-2K score ≤4, with no activity in major organ systems and no hemolytic anemia 
o Any subject with a SLEDAI-2K score greater than 4 won’t attain LLDAS at that 
visit. 
o Major organ activity will be assessed at each visit using the SLEDAI-2K items. 
Any subject with at least one of the following SLEDAI-2K items present (item 
score >0) at the visit won’t attain LLDAS at that visit: 
 Any in central nervous system: 
• Seizure 
• Psychosis 
• Organic brain syndrome 
• Visual disturbance 
• Cranial nerve disorder  
• Lupus headache 
 Any in vascular organ system: 
• Cerebrovascular accident(s) 
• Vasculitis 
 Any in renal organ system: 
• Urinary casts 
• Hematuria 
• Proteinuria 
• Pyuria 
 Any in cardiovascular system and respiratory: 
• Pleurisy 
• Pericarditis 
 Fever (Fever >38 degrees C [38o C], excluding infectious cause) 
o Hemolytic anemia will be assessed through BILAG-2004 evaluation at the visit. 
Any subject with present evidence of active hemolysis as assessed by BILAG-2004 
will be excluded from LLDAS at that visit. 
• No new lupus disease activity compared with the previous assessment: any patient with 
present activity (item score >0) in at least one new SLEDAI-2K item (irrespective of 
organ system) compared with the previous visit (even if the previous visit was 
unscheduled) won’t attain LLDAS.  
• PGA VAS score (scale 0–3) ≤1: any patient with PGA score greater than 1 at a study visit 
won’t attain LLDAS at that visit. 
• OCS dose ≤7.5 mg /day prednisone or equivalent: any subject on OCS treatment with a 
dose greater than 7.5 mg/day prednisone or equivalent taken on any day of the period 
starting on the day after the previous scheduled visit (if not missed) and ending on the day 
of the visit, won’t attain LLDAS at that visit.  In case the previous visit was missed, 
LLDAS won’t be attained at the visit of evaluation if OCS treatment with a dose greater 
than 7.5 mg/day prednisone or equivalent was taken at the day of the visit or any day of 
the 28-days period preceding that visit.  
• Well-tolerated standard maintenance doses of immunosuppressive drugs and approved 
biological agents as allowed and specified in the Clinical Study Protocol: no use of 
restricted medications beyond the protocol allowed threshold used on or before the 


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assessment.  It will be assumed that any discontinuation of permitted immunosuppressives 
in the period starting on the day after the previous scheduled visit (if not missed) and 
ending on the day of the visit is due to toxicity and the subject won’t attain LLDAS at that 
visit.  In case the previous visit was missed, LLDAS won’t be attained at the visit of 
evaluation if permitted immunosuppressives were discontinued at the day of the visit or 
any day of the 28-days period preceding that visit.  The Permitted (under the restrictions in 
Appendix A) immunosuppressives are: Methotrexate, Azathioprine, Mycophenolate 
mofetil, Mycophenolic acid, and Mizoribine.  
• No permanent discontinuation of IP. 
If any of the criteria for SLEDAI-2K, BILAG or PGA cannot be evaluated at particular visit 
(eg, due to missing values) that criterion will be imputed using LOCF and LLDAS derived 
based on the complete data. This applies only if the data at the previous visit is not missing, 
otherwise the subject will be defined as not achieving LLDAS at Week 52.  
Further, to define the “day of a visit” in the above, the date of the last SLEDAI-2K, BILAG 
2004 or PGA assessment used for analysis in the time window of the respective timepoint (as 
described in Section 4.1.3) will be used. If no assessment falls within a defined window, the 
corresponding visit will be considered as missing. 
The difference between anifrolumab and placebo in the proportion of LLDAS responders will 
also be assessed longitudinally over time up to Week 52. 
3.3.2 
Subject reported outcome variables 
3.3.2.1 
Short Form 36 version 2 (acute recall) 
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
SF-36-v2 (acute) domain scores (Physical Functioning, Role Physical, Bodily Pain, General 
Health, Vitality, Social Functioning, Role Emotional, and Mental Health), Physical 
Component Score (PCS) and Mental Component Score (MCS) will be assessed by visit up to 
Week 52.  
Responder criteria are defined for each of the 8 domain scores, the PCS and MCS as an 
increase from baseline to Week 52 above the following thresholds (based on US general 
population data from 2009, Maruish, 2011), no restricted medications beyond the protocol 
allowed threshold on or before the assessment, and no permanent premature discontinuation of 
investigational product (according to eCRF form “Discontinuation of Investigational 
Product”): 
Table 1 
Threshold values for the SF-36-v2 (acute) responder criteria 
Domain/Component 
Meaningful Change Threshold 
Physical Functioning 
4.3 
Role Physical 
3.4 
Bodily Pain 
6.2 


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Domain/Component 
Meaningful Change Threshold 
General Health  
7.2 
Vitality 
6.2 
Social Functioning  
6.9 
Role Emotional 
4.5 
Mental Health 
6.2 
PCS 
3.4 
MCS 
4.6 
If the change from baseline in the respective score cannot be evaluated at Week 52 (eg, due to 
missing values) the change from baseline will be imputed using LOCF. This applies only if 
Week 48 data is not missing, otherwise the subject will be defined as a non-responder. 
3.3.2.2 
Pain Numerical Rating Scale  
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
pain NRS will be assessed by visit up to Week 52. 
3.3.2.3 
Functional Assessment of Chronic Illness Therapy-FATIGUE  
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
FACIT-F total score will be assessed by visit up to Week 52. The FACIT-F total score will be 
derived using the 13 single item scores ranging from 0 (not at all) to 4 (very much). To get a 
total score for which higher values indicate better quality of life, most of the single items will 
be reversed, ie, the final item score used for the total score will be derived as 4 – documented 
item score. Item scores An5 (I have energy) and An7 (I am able to do my usual activities) will 
not be reversed, ie, the final item score is the same as the documented item score. The FACIT-
F total score will be derived as the sum of the 13 final item scores. 
A response in FACIT-F is defined as an improvement from baseline to Week 52 of >3 points 
(ie, change from baseline >3), no restricted medications beyond the protocol allowed 
threshold used on or before the assessment, and no permanent premature discontinuation of 
investigational product (according to eCRF form “Discontinuation of Investigational 
Product”). If the change from baseline cannot be evaluated at Week 52 (eg, due to missing 
values) the change from baseline will be imputed using LOCF. This applies only if Week 48 
data is not missing, otherwise the subject will be defined as a non-responder. 
3.3.2.4 
Patient Global Assessment  
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
PtGA (measured on a VAS ranging from 0 to 100 mm) will be assessed by visit up to 
Week 52. 


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3.3.2.5 
Lupus quality of life scale 
The difference between anifrolumab 300 mg and placebo in the mean change from baseline in 
lupus QoL domain scores (physical health, pain, planning, intimate relationships, burden to 
others, emotional health, body image, and fatigue) will be assessed by visit up to Week 52.  
The number of items in each domain and the item numbers that refer to that domain are 
tabulated in Table 2. 
Table 2 
Lupus QoL domains 
Domain 
Number of Items 
Item Numbers 
Physical health 
8 
1 to 8 
Pain 
3 
9 to 11 
Planning 
3 
12 to 14 
Intimate relationships 
2 
15, 16 
Burden to others 
3 
17 to 19 
Emotional health 
6 
20 to 25 
Body image 
5 
26 to 30 
Fatigue 
4 
31 to 34 
 
Each item of the lupus QoL has a five-point Likert response scale (0=all the time, 1=most of 
the time, 2=a good bit of the time, 3=occasionally, and 4=never). 
Domain scores will be derived when at least 50% of the items are answered. The mean raw 
domain score is then calculated by totalling the item response scores of the answered items 
and dividing by the number of answered items. A non-applicable response is treated as 
unanswered. The mean raw domain score will be transformed to the domain scores (ranging 
from 0 as worst QoL to 100 as best QoL) as mean raw domain score divided by 4 and 
multiplied by 100. 
3.3.2.6 
EuroQol 5 dimensions 
The EQ-5D-5L is comprised of the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. The proportion of subjects in each 
EQ-5D-5L health state (no problems, slight problems, moderate problems, severe problems 
and unable to/extreme problems), by dimension, as well as the VAS Score and single 
summary utility index, including changes from baseline, will be explored over time. 
EQ-5D-5L value sets are not available for all countries, therefore the UK value set will be 
used for all subjects in the study. By using the crosswalk link function and the individual 
responses to the EQ-5D-5L descriptive system, index values for the EQ-5D-5L will be 
calculated (Van Hout, 2012). 


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3.3.2.7 
Work productivity and Activity Impairment - Lupus 
The WPAI scores levels (percentages) and changes from baseline will be explored by visit. 
The following will be presented: 
• 
Number of subjects employed 
= number of subjects with yes in response to Question 1 (Q1) 
Percentage of all subjects employed 
• 
Number of work hours missed due to problems associated with lupus 
as responded in Q2 
• 
Absenteeism due to lupus (%) 
= [Q2 / (Q2+Q4)] x 100 
• 
Presenteeism due to lupus (%) 
= [Q5 / 10] x 100 
• 
Work Productivity Loss (%) 
= (Q2 / (Q2+Q4) + [(1 - Q2 / (Q2+Q4)) x (Q5/10)]) x 100 
• 
Activity impairment (%) 
= [Q6 / 10] x 100 
3.3.2.8 
Medical Resource Use Questionnaire 
The following variables will be explored:  
• 
Number of subjects with health care visits  
Of subjects with health care visits 
- 
Number of specialist visits 
- 
Number of primary care visits 
• 
Number of subjects with emergency department visits 
Of subjects with emergency department visits:  
- 
Number of emergency department visits 
- 
Of emergency department visits 
 Visit related to an increase in lupus related activity 
 Cause of emergency department visit 
• 
Number of subjects with hospital visits 


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Of subjects with hospital visits: 
- 
Number of hospital visits 
- 
Of hospital visits 
 Visit related to an increase in lupus related activity 
 Cause of hospitalization 
- 
Length of hospital stay 
- 
Total number of days in ICU 
For all these variables, all available data between first administration of investigational 
product and Week 52 will be summed up. 
3.4 
Assessment of study population 
3.4.1 
Demographic and baseline characteristic variables 
Demographic characteristics (including geographic region, age, sex, ethnicity and race) and 
baseline characteristics (including height, weight, body mass index [BMI] and disease 
characteristics) will be assessed. 
The clinical SLEDAI-2K score will be derived as the sum of the scores for the SLEDAI-2K 
items vasculitis, arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, and pericarditis. 
3.4.2 
Medical history 
Medical histories will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Medical history will be evaluated separately for past and 
current conditions as given in the eCRF. 
3.4.3 
Prior and concomitant medications 
Prior medications are reported according to the eCRF completion guidelines (ie, dependent of 
the relevance of the medication, the intake during the last few weeks before the first 
administration of IP, all medication taken during lifetime, or anything in-between will be 
reported). All medications will be coded using the latest version of World Health Organization 
Drug Dictionary (WHO-DD). 
Any medications taken by the subject prior to the first dose date of investigational product will 
be considered prior medication. Any medication taken by the subject at any time between the 
date of the first dose (including the date of the first dose) of investigational product up to 
Week 52 (Visit 14/EDV), inclusive, will be considered concomitant medication. Any 
medication started prior to the first dose of investigational product and ended after the first 
dose up to Week 52 (Visit 14/EDV) / was ongoing will be considered as both prior and 
concomitant medication. 
Disease related treatments at baseline are defined as all medications with therapy reason 
containing “disease under study” with an intake at the date of first dose of investigational 


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product (ie, start date on or before the date of first dose and end date on or after date of first 
dose or ongoing). The medications will be presented in the following categories: 
• 
Anti-malarial 
defined as medications with an ATC code level 4 of P01BA (aminoquinolones)  and 
P01AX (Other agents against amoebiasis and other protozoal diseases) 
• 
Any Anti-malarial 
• 
Anti-malarial Only 
• 
Anti-malarial in combination with OCS and/or immunosuppressants 
• 
Azathioprine 
defined as medications with a preferred term of azathioprine or azathioprine sodium 
• 
Methotrexate 
defined as medications with a preferred term of methotrexate or methotrexate 
sodium 
• 
Mycophenolate  
defined as medications with a preferred term of mycophenolate mofetil,  
mycophenolate sodium or mycophenolic acid 
• 
Mizoribine 
defined as medications with a preferred term of mizoribine 
• 
OCS 
• 
Any OCS 
• 
OCS only 
• 
OCS in combination with immunosuppressants and/or anti-malarial 
• 
Time on Corticosteroids up to randomization  
• 
NSAID 
defined as medication with an ATC code level 3 of M01A 
• 
Other SLE medication 
defined as SLE medications not covered within the above categories 
In case of missing or partial dates, the imputation rules as given in Appendix C will be applied 
to classify medication as prior and/or concomitant, as appropriate.  
3.4.4 
Exposure of investigational product 
The duration of exposure to the investigational product per subject is defined as the number of 
days between the start and the end dates of investigational product plus the dosing frequency 
time: 
Duration of exposure (days) = (Last dosing date + 28 days) – first dosing date + 1. 


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The total subject years of exposure is the sum of duration of exposure (days) of all subjects in 
the respective treatment group divided by 365.25 (days/year). 
The total number of infusions will be counted per subject. Furthermore, the number of 
subjects with an infusion will be assessed in 4-weekly categories (ie, 4 weeks, 8 weeks, 
12 weeks, …, 48 weeks). 
The time to discontinuation of investigational product is the same as the duration of exposure. 
However, for subjects continuing in the LTE study, the time to discontinuation will be 
censored at the last dosing date + 28 days. 
3.5 
Safety variables 
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, cushingoid features, C-SSRS, PHQ-8, modified 
SELENA Flare Index based flares, and AEs (including AESIs). 
Change from baseline to each post-treatment time point where scheduled assessments were 
made will be calculated for relevant measurements.  
If not stated otherwise, on-treatment values are defined as values with an assessment date after 
the first administration of investigational product and on or before the date of last 
administration of investigational product + 28 days. 
3.5.1 
Adverse events 
Adverse events experienced by the subjects will be collected throughout the entire study and 
will be coded using the latest version of MedDRA. 
Adverse event data will be categorized according to their onset date into the following study 
periods: 
• 
AEs occurring during screening:  
An AE during screening is defined as an AE with a date of onset ≥ date of first 
screening visit (S1) and < date of the first dose of investigational product. 
AEs occurring during screening will only be listed. 
• 
AEs occurring during treatment: 
An AE during treatment is defined as an AE with a date of onset ≥ day of first dose 
of investigational product and ≤ date of last dose of investigational product + 
28 days. 
• 
AEs occurring during follow-up: 
An AE during follow-up is defined as an AE with a date of onset > date of last dose 
of investigational product + 28 days and ≤ date of last dose of investigational 
product + 84 days. 
• 
AEs occurring during treatment and follow-up: 
The period “during treatment and follow-up” combines the periods “during 


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treatment” and “during follow-up”. An AE during treatment and follow-up is 
defined as an AE with a date of onset ≥ day of first dose of investigational product 
and ≤ date of last dose of investigational product + 84 days. 
• 
AEs occurring after follow-up: 
An AE after follow-up is defined as an AE with a date of onset > date of last dose 
of investigational product + 84 days. 
AEs occurring after follow-up will only be listed. 
If an AE has a missing onset date, then unless the stop date of the AE indicates otherwise, this 
will be considered as an AE during treatment. Similarly, if an AE has a partial onset date, then 
unless the partial onset date or the stop date indicates otherwise, this will be considered an AE 
during treatment. 
Adverse events of special interest are marked as such in the eCRF. Major acute cardiovascular 
events (MACEs) will be determined according to the assessments of the Cardiovascular Event 
Adjudication Committee. 
Adverse events with missing intensity will be assumed to be severe. Events with missing 
relationship to study medication per the investigator will be assumed to be related. If no 
information about seriousness is available, the AE will be considered serious. 
An infusion-related reaction (investigator) is defined as an AE with a preferred term of 
“Infusion related reaction”. An infection is defined as an AE within the SOC infections and 
infestations. Opportunistic infections are defined as given by the investigator and non-
opportunistic infections are all infections not marked as opportunistic by the investigator. 
Hypersensitivity is defined according to the narrow MedDRA SMQ Hypersensitivity. 
Herpes zoster is further classified according to the information given on the Herpes zoster log 
as follows: 
Category 
Rash 
[Y/N] 
Episode status of 
HZ Event 
[localized/ 
disseminated] 
Specify 
Disseminated 
[cutaneous/ 
systemic] 
Any organ 
involvement 
[Y/N] 
Cutaneous (localised) herpes zoster 
Y 
Localized 
[no rule] 
N 
Cutaneous disseminated herpes 
zoster 
Y 
Disseminated 
Cutaneous 
[no rule] 
Visceral disseminated herpes zoster 
[no rule] 
Disseminated 
Systemic  
[no rule] 
 
Adverse events during treatment will also be presented by time intervals of the first onset of 
the event. For this analysis, repeated events with the same preferred term will not be 


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considered (ie, if a subject has more than one event with the same preferred term, only the 
event with the earliest date of onset will be used). For partial or missing dates, the rules as 
described above will be used, ie. the AE will be considered as an AE during treatment unless 
the available information indicates otherwise and as occurring in the earliest possible time 
interval given the available (start and stop) date information. The following time intervals are 
defined: 
• 
Day 1 to < Week 12: 
AEs with date of onset ≥ date of first administration of investigational product and 
< date of first administration of investigational product plus 84 days 
• 
Week 12 to < Week 24: 
AEs with date of onset ≥ date of first administration of investigational product plus 
84 days and < date of first administration of investigational product plus 168 days 
• 
Week 24 to < Week 36: 
AEs with date of onset ≥ date of first administration of investigational product plus 
168 days and < date of first administration of investigational product plus 252 days 
• 
Week 36 to < Week 48: 
AEs with date of onset ≥ date of first administration of investigational product plus 
252 days and < date of first administration of investigational product plus 336 days 
• 
≥ Week 48: 
AEs with date of onset ≥ date of first administration of investigational product plus 
336 days 
The event rate per 100 subject years is defined as  
Number of subjects with an event / [sum of total exposure time in days/ (365.25*100)]. 
The exposure in a time period for each subject will be calculated as end of period – start of 
period + 1 (eg, date of last dose of investigational product + 28 days - day of first dose of 
investigational product + 1 day for summary of AEs during treatment).  If a subject 
discontinued from the study during a period, switched to the LTE study or had the last follow-
up visit earlier than expected, the date of study discontinuation/end of study will be used as 
end of the respective period. 
For herpes zoster AESI, an alternative event rate per 100 subject years will be derived as  
Number of subjects with an event / [sum of time at risk in days/ (365.25*100)]. 
The time at risk is defined as time (including start and end date) from start of period (eg, date 
of first administration of investigational product for events during treatment) to the date of 
first event, death, withdrawal of consent, or end of period, whatever comes first. If an AE has 
a (partially) missing onset date, the missing parts will be considered on treatment, unless 
available information indicates otherwise and will be imputed with the earliest possible date 
given the available information before calculating the alternative event rate. This alternative 


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event rate may also be calculated for other AESIs if suggested by data. This will be discussed 
during the BDR meeting and the decision will be made before unblinding the data. 
The time to first onset of herpes zoster during treatment will be derived as date of first onset 
of herpes zoster – date of first administration of investigational product + 1. AEs with an onset 
date before the date of first administration of investigational product and AEs with an onset 
after 28 days after the date of last administration of investigational product will not be 
considered for the time to first onset of herpes zoster during treatment. If an AE has a 
(partially) missing onset date, the missing parts will be considered on treatment, and the 
missing parts will be imputed with the earliest possible date given the available information 
before calculating time to event. If a subject has no herpes zoster during treatment, the time to 
first onset will be censored at the date of last administration of investigational product + 28 
days. 
For the by timepoint analysis of anaphylaxis, hypersensitivity, and infusion related reactions,, 
an AE at a visit is defined as an AE with a date of onset ≥ day of administration of 
investigational product at the respective visit and < date of administration of investigational 
product at the following visit (or ≤ date of last dose of investigational product + 28 days for 
the last visit with investigational product). 
3.5.1.1 
Other significant adverse events 
During the evaluation of the AE data, a medically qualified expert will review the list of AEs 
that were not reported as serious AE (SAEs) or AEs leading to discontinuation. 
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the AstraZeneca Global Patient Safety Physician, be considered other 
significant AEs and reported as such in the CSR. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment. 
3.5.2 
Laboratory variables 
The parameters haematology, serum chemistry, urinalysis (outlined in Table 5 in 
Section 5.3.10 of the clinical study protocol) and of fasting lipid profile (high density 
lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides) will be 
explored. 
Laboratory data will be reported in SI units. Changes from baseline in haematology, clinical 
chemistry and lipid profile variables will be calculated. 
Absolute values will be compared to the reference range as given in Appendix D and 
classified as low (below range), normal (within range or on limits) or high (above range). All 
values (absolute and change) falling outside the reference ranges will be flagged. 


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Treatment emergent laboratory/vital signs changes (TELVC) will be defined for post-baseline 
values according to the reference ranges given in Appendix D and Appendix F.  
Urinalysis data will be categorised as negative (0), positive (+), or strongly positive (++, +++, 
or >+++) at each time-point. Treatment-emergent changes will also be assessed. 
Treatment-emergent changes of urinalysis data are defined as  
• 
Negative/Trace/+ at baseline to ++, +++, ++++ at any on-treatment value OR  
• 
Increase of from baseline of at least ++ at any on-treatment value. 
For the liver function tests: aspartate transaminase (AST), alanine transaminase (ALT), 
Alkaline phosphatase, gamma glutamyl transferase (GGT) and total bilirubin, the multiple of 
the upper limit of the normal (ULN) range (see Appendix ) will be calculated for each data 
point. Multiple = Value / ULN, ie, if the ALT value was 72 IU/L (ULN = 36) then the 
multiple would be 2. Subjects meeting both of the following biochemical criteria for Hy’s law 
(potential Hy’s Law) at any point during the study (not necessarily at the same time) will be 
flagged: 
• 
AST ≥3x ULN and/or ALT ≥3x ULN 
• 
Total bilirubin ≥2xULN 
3.5.3 
ECGs 
The outcome of the overall evaluation of 12-lead ECG measurements by the central reading 
will be assessed as normal or abnormal. It is the investigator’s judgment whether the 
findings/results on the central ECG laboratory report are clinically relevant or not. The 
combination of both judgments leads to the following categories used for analysis: 
• 
Normal, 
• 
Abnormal, not clinically significant 
• 
Abnormal, clinically significant. 
If the overall evaluation by the investigator and the central ECG report don’t match, the 
investigator’s judgement will be used. In case of repeated measurements (triplicates) at a visit, 
the worst category at the respective visit will be used for the analysis. 
Changes from baseline of the following variables will be explored: 
• 
Heart rate (beats per minute) 
• 
QRS duration (ms) 
• 
PR interval (ms) 
• 
RR interval (ms) 
• 
QT (ms) 
• 
QTcB (ms) 




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• 
 
3.5.5 
Physical examination 
Weight (kg) will be explored using the difference in mean change from baseline longitudinally 
over time. 
3.5.6 
Vital signs 
The following variables will be explored: 
• 
Pulse (beats per minute) 
• 
Systolic blood pressure (mmHg) 
• 
Diastolic blood pressure (mmHg) 
• 
Respiration rate (breaths per minute) 
• 
Body temperature (°C) 
Changes from baseline will be calculated. 
Where applicable, absolute values will be compared to the reference ranges given in Appendix 
F and classified as low (below range), normal (within range or on limits) or high (above 
range). All values (absolute and change) falling outside the reference ranges will be flagged. 
Post-baseline values will be classified as TELVC according to reference ranges given in 
Appendix F. 
For infusion visits, only measurements before start of investigational product will be 
considered for by visit presentations. In case of multiple measurements before the start of 
investigational product, the first measurement will be used for by visit presentations but all 
measurements will be considered for the TELVC classification. 
3.5.7 
Cushingoid features 
The presence of cushingoid features (moon face, buffalo hump, purple or violaceous striae, 
central obesity, hirsutism, acne, easy bruising, and fragile skin) will be explored by visit. 
3.5.8 
C-SSRS 
The C-SSRS is an assessment tool that evaluates suicidal ideation and behaviour.  
Two different versions of the questionnaire were used: 
• 
Baseline/Screening version, assessing the last 12 months prior to the assessment 
• 
Since Last Visit Version, assessing the time since last visit. 
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale in an increasing order of severity from 
1 to 10 to facilitate the definitions of the comparative variables. 


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• 
Category 1 – Wish to be Dead 
• 
Category 2 – Non-specific Active Suicidal Thoughts 
• 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act 
• 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
• 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
• 
Category 6 – Preparatory Acts or Behaviour 
• 
Category 7 – Aborted Attempt 
• 
Category 8 – Interrupted Attempt 
• 
Category 9 – Actual Attempt (non-fatal) 
• 
Category 10 – Completed Suicide 
The Suicidal Ideation or Behaviour Score will be derived from the C-SSRS categories as the 
maximum suicidal ideation or behaviour category (1-10 on the C-SSRS) present at the 
assessment. The score will be derived at each assessment for each subject. Non-suicidal 
self-injurious behaviour will be assigned if no ideation or behaviour is present. 
Composite variables based on the above re-ordered categories are defined for assessments 
during screening, during treatment, and during follow-up, respectively as follows: 
• 
Suicidal ideation: A “yes” answer at any time in the respective study period to any 
one of the 5 (re-ordered) suicidal ideation questions (Categories 1-5) on the 
C-SSRS. 
• 
Suicidal behaviour: A “yes” answer at any time in the respective study period, to 
any one of the 5 (re-ordered) suicidal behaviour questions (Categories 6-10) on the 
C-SSRS. 
• 
No suicidal ideation or behaviour: No “yes” answer at any time in the respective 
study period to any one of the 10 (re-ordered) suicidal ideation and behaviour 
questions (Categories 1-10) on the C-SSRS. 
The total number of attempts, total number of interrupted attempts, and total number of 
aborted attempts will be derived for the different study periods by summing up all respective 
attempts during screening, during treatment and during follow-up, respectively. 
For summary of C-SSRS data, the following period definitions will be used: 
• 
Screening Period:  
Assessments with a date ≥ date of first screening visit (S1) and ≤ date of the first 
dose of investigational product. 


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• 
During treatment Period: 
Assessments with a date > date of first dose of investigational product and ≤  date of 
last dose of investigational product + 28 days. 
• 
Follow-up Period: 
Assessments with a date > date of last dose of investigational product + 28 days and 
≤ date of last dose of investigational product + 84 days. 
If the wrong questionnaire version (Baseline/Screening rather than Since last visit or vice 
versa) was used for an assessment, the assessment will be assigned to a period based on 
assessment date, regardless of the version that was completed. 
3.5.9 
Personal Health Questionnaire Depression Scale-8 
The PHQ-8 assesses symptoms of depression over the last 2 weeks. The difference between 
anifrolumab and placebo in the mean change from baseline in PHQ-8 total score will be 
assessed by visit up to Week 52. The PHQ-8 total score will be derived as the sum of the 8 
single item scores ranging from 0 (not at all) to 3 (nearly every day). 
3.6 
Pharmacokinetics, pharmacodynamics, and immunogenicity 
3.6.1 
Immunogenicity variables  
Anti-drug antibodies assessments will be conducted utilising a tiered approach (screen, 
confirm, titre).  
The following ADA results will be evaluated as proportion of subjects together with 
corresponding titre summaries. 
• 
Subjects who are ADA positive at any time (including baseline) 
Note that further use of ADA positive at any time include baseline measurements 
even if not mentioned explicitly.  
• 
Subjects who are ADA positive at baseline only  
Subjects without any post-baseline measurements are also counted in this category. 
• 
Subjects who are ADA positive at both baseline and post-baseline. 
Only subject with baseline and post-baseline measurements will be counted in this 
category. 
• 
ADA incidence, defined as ADA positive post-baseline (ADA negative at baseline) 
or a post-baseline increase in pre-existing baseline ADA titres by ≥4-fold during the 
study period (boost). 
• 
Subjects who are ADA positive post-baseline only (treatment induced ADA)  
Subjects without a baseline measurement are also counted in this category. 
• 
Subjects who are persistently positive 
Persistently positive is defined as treatment induced ADA (subject is ADA negative 
at baseline) detected at ≥ 2 post-baseline assessments with at least 16 weeks 
(112 days) between the first and last positive measurement or a treatment induced 
ADA detected at the last available assessment. 


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• 
Subjects who are transiently positive 
Transiently positive is defined as at least one treatment induced (subject is ADA 
negative at baseline) ADA positive measurement, but not fulfilling the conditions 
for persistently positive. 
• 
Subjects with an ADA positive titre ≤/> median of maximum titre 
Median of maximum titre is defined as the median of the maximum post-baseline 
titre (in subjects with treatment-induced ADA) for each subject in the treatment 
group. Baseline ADA titers are not included in this assessment. 
• 
Subjects who are ADA positive by visit 
• 
Subjects who are ADA positive at a post-baseline measurement for the first time by 
visit (Subjects that are ADA negative at baseline). 
For the presentation of ADA results at a single time point (eg, baseline or by visit summaries), 
the corresponding titre summary will be based on the titres of the positive samples for that 
particular visit. For the presentation of ADA results across visits (eg, any post-baseline), the 
corresponding titre summaries will be based on the maximum titre of all positive samples for 
each subject. Titres of positive measurements reported as ≤30 (limit of detection) will be 
imputed as 30. Titre values reported as “< 30” are negative and will not be imputed. 
The presence of neutralising antibodies (nAb) will be tested in all ADA-positive samples 
using a ligand binding assay. The following variables will be evaluated: 
• 
nAb prevalence: Proportion of subjects with ADA results available (at any time) 
who are nAb positive at any time 
• 
nAb incidence: Proportion of subjects with ADA results available at post-baseline 
timepoints who are nAb positive at post-baseline timepoints only (ie. negative at 
baseline). 
• 
nAb persistently positive: Proportion of subjects with ADA results available at post-
baseline timepoints who are nAb positive at 2 or more post-baseline assessments 
(with at least 16 weeks between first and last positive) or positive at the last post-
baseline assessment (for subjects who are nAb negative at baseline). 
• 
Proportion of subjects who are nAb positive by visit 
3.6.2 
Pharmacokinetic variables  
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed steady-state serum trough (predose) concentrations, Ctrough. Maximum concentrations 
after the first dose and the dose at Week 48 will also be evaluated. Analyses will be done by 
results of the IFN test (high versus low).  
Individual concentrations will be reviewed for exclusion from descriptive statistics by 
identifying outliers and reviewing dosing information and sample collection times. Analysis to 
determine if the identified concentrations should be excluded includes visual inspection of 




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4.1.2 
Database lock and unblinding 
Database lock at Week 52 
When the last subject reaches Week 52 visit, all data available in the database will be 
extracted and undergo through the data cleaning process. Data as detailed in Table 3 will be 
part of the database lock (hereafter referred to as Week 52 lock). Note that data for follow up 
visits and from the concomitant medication, AE, SAE and AESI log pages may not be 
completely clean at the time of the Week 52 lock.  When all relevant data have been coded, 
validated, signed, and locked, a clean file of this data will be declared. 
Once Week 52 lock is declared, the study will be un-blinded. Blinding of subjects and 
investigators will be maintained to the greatest extent possible after Week 52 lock and until 
Last Subject Last Visit in the LTE study. No changes to locked data, will be accepted after 
completion of Week 52 lock, and no analyses will be repeated for the results up to, and 
including, Week 52. 
Table 3  
Data included in Week 52 lock 
Subjects 
Week 52 lock 
Subjects who completed the study at the time 
of the week 52 lock  
All data included in week 52 lock 
Subjects who are still ongoing in follow-up at 
the time of the week 52 lock  
 
All visit data up to and including Week 52 is 
included in week 52 lock. 
Follow-up data, concomitant medications, 
AE, SAE and AESI log forms are not part of 
the lock. 
Database lock at Last Patient Last Visit  
After completion of the Last Subject Last Visit, all remaining data not locked as part of the 
Week 52 lock will undergo lock per protocol stipulated criteria. For subjects active in 
follow-up at the time of the Week 52 DBL, data from assessments after Week 52 will be listed 
separately. Database lock conducted after study Last Subject Last Visit will not include nor 
result in any changes to data locked at the Week 52 time point. 
4.1.3 
Visit windows 
For visit based analyses, the variables will be summarized based on the scheduled days with 
adjusted analysis-defined visit windows. The adjusted analysis-defined windows are 
summarized below: 


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Table 4 
Visit windows 
Adjusted Defined Windows Visit 
Scheduled Study Day 
Maximum Windows 
Baseline / Day 1 
1  
Study Day ≤1  
Week 4  
29  
2≤ Study Day ≤42  
Week 8  
57  
43≤ Study Day ≤70  
Week 12  
85  
71≤ Study Days ≤98  
Week 16  
113  
99≤ Study Day ≤126  
Week 20  
141  
127≤ Study Day ≤154  
Week 24  
169  
155≤ Study Day ≤182  
Week 28  
197  
183≤ Study Day ≤ 210  
Week 32  
225  
211≤ Study Day ≤238  
Week 36  
253  
239≤ Study Day ≤266  
Week 40  
281  
267≤ Study Day ≤294  
Week 44 
309  
295≤ Study Day ≤322  
Week 48  
337  
323≤ Study Day ≤350  
Week 52 
365 
351≤ Study Day ≤378 
Week 56 
393  
379≤ Study Day ≤406  
Week 60  
 420 
407≤ Study Day   
 
For assignment of data to time points using the visit windows, study day will be defined as 
(Date of assessment – date of first administration of investigational product) +1. Using this 
definition, the day of first dose of investigational product will be Day 1 and the scheduled visit 
date of Week 4 will be study day 29 (=28+1) for example.   
If multiple readings are recorded within a single visit window, the following rules will be 
followed.  
• 
If there are two or more observations within the same visit window, then the non-
missing one closest to the scheduled visit will be used in the analysis.  
• 
If two observations are equidistant from the scheduled visit, then the non-missing 
observation with the earlier collection date will be used in the analysis.  
• 
If two observations are collected on the same day, then the non-missing one with 
the earlier collection time will be included in the analysis.  
If a visit window does not contain any observations, then the data will remain missing.  
For the Baseline / Day 1 visit window, the visit label “Baseline” will be used for all 
measurements before the first administration of IP. If the time of measurement at Study Day 1 




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4.1.5 
Testing strategy to account for multiplicity considerations 
To account for multiplicity to test the primary and five key secondary endpoints, a testing 
strategy will be followed to control the overall type I error rate in the strong sense. The 
primary endpoint, ie, the difference in proportion of subjects achieving SRI(4) at Week 52 
comparing anifrolumab 300 mg to placebo, will be tested at an alpha level of 0.05. If the 
observed p-value is ≤0.05, a statistically significant difference in SRI(4) between the 
treatment groups at Week 52 will be concluded, and the alpha of 0.05 will be preserved for 
testing of the key secondary endpoints. If the observed p-value is >0.05, no statistically 
significant difference between treatment groups will be declared, and no formal testing of the 
key secondary endpoints will be carried out. 
Figure 1 
Alpha recycling 
 
 
If the primary endpoint is statistically significant, then the five key secondary endpoints will 
be tested and the weighted Holm procedure (Zhang, 1997 and Burman, 2009) will be used in 
order to strongly control the family-wise error rate at the 2-sided 5% level. The procedure 
applies alpha recycling according to the weights given in Figure 1. The weights were chosen 
based on a combination of estimated power for the individual key secondary endpoints and 
their relative clinical importance 
In a first step of the weighted Holm procedure, the five key secondary endpoints (SRI(4) in 
the IFN test-high subgroup, steroid reduction, CLASI reduction, SRI(4) at Week 24, and flare 
rate) will be tested at alpha levels of 0.04, 0.004, 0.004, 0.001, and 0.001, respectively. If 1 or 
2-sided α=0.05 
SRI(4) at  
Week 52 
SRI(4) 
IFN-high 
CLASI 
SRI(4) at  
Week 24 
Steroid 
reduction 
Flare 
rate 
0.8 
0.08 
0.08 
0.02 
0.02 


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more of the hypotheses will be rejected at these levels, the corresponding alpha will be 
distributed to the endpoints not rejected according to the assigned weights. As an example, the 
null hypothesis for SRI(4) for the IFN test-high sub-group will be rejected with a p-value 
≤0.04 and all other hypotheses will not be rejected due to p-values >0.004 and 0.001, 
respectively. The alpha level of 0.04 will be distributed to the remaining four key secondary 
endpoints (steroid reduction, CLASI, SRI(4) at Week 24, and flare rate) resulting in new alpha 
levels of 0.02, 0.02, 0.005, and 0.005, respectively. If any of the tests of these four endpoints 
results in a p-value smaller or equal to the corresponding new alpha level, the corresponding 
alpha level will again be distributed across the remaining endpoints. 
This corresponds to the following mathematical notation: 
We have 5 tests, and each hypothesis has a weight wi for i = 1, …, 5 with sum(wi) = 1 
Let pwi = pi/wi. Order the weighted p-values as p(w1) ≤ p(w2) ≤ ... ≤ p(w5), being H(wi) the 
hypothesis associated with p-value p(wi) and w(i) the corresponding weights.  
The weighted Holm’s method can be described as 
1. If p(w1) > α, fail to reject all 5 hypotheses  
2. If p(w1) ≤ α, reject H(w1), and move to H(w2) 
3. If p(w2) > α/(1-w(1)), fail to reject H(wi) for i ≥2 
4. If p(w2) ≤ α/(1-w(1)), reject H(w2), and move to H(w3) 
5. Proceed with all remaining hypotheses until the first j such that  
p(wj) > α/[1-sum(w(k))] for k = 1,…, j-1 
The adjusted p-values 
 corresponding to hypothesis 
 will be calculated as 
 , where 
. (Wright, 1992) If 
 its value will 
be presented as >0.999. 
4.1.6 
Missing Data 
Subjects who discontinue investigational product will be asked to come to each visit for the 
scheduled assessments through Week 52 (Visit 14/EDV). The definition of the primary 
variable includes 2 criteria that correspond to a non-responder imputation for subjects who 
prematurely discontinue from investigational product, or who receive restricted medications 
beyond the protocol-allowed threshold. This is the same for the definitions of key secondary 
binary variables. 
Based on the results from the Phase 2 study (CD IA MEDI 546-1013), the majority of missing 
data is expected to be due to permanent discontinuation of IP, which for the binary responder 
endpoints will be imputed as non-responders per the endpoint definitions. It is expected that at 
each visit between 4% and 7% of subjects will have missing data due to a reason other than 


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early discontinuation of IP (eg, missing visit [intermediate missing]), based on the results from 
the Phase 2. Given the expected small amount if intermediate missing data, it is expected to 
have a limited impact in the overall conclusions.   
For binary responder efficacy endpoints, any component with missing value will be imputed 
using last observation carried forward (LOCF) if only a single (non-consecutive) visit has 
missing data for that component. In the event of two or more consecutive visits with missing 
data for the same component, LOCF will be used for the first missing value of each sequence, 
after which the data will be imputed as non-responders for the specific responder endpoint. 
The responder endpoint is derived based on the imputed values. If a component (eg, 
SLEDAI-2K) is based on several data points, LOCF will be done for the single data points. 
To examine the impact of missing data, including the impact of non-responder imputation due 
to permanent discontinuation of IP, on the primary and key secondary endpoints tipping point 
analyses will be performed. These analyses will vary the assumptions about outcomes among 
the subsets of subjects on the treatment arms who discontinue IP early. For the primary 
endpoint an extra sensitivity analysis will be performed to examine the impact of intermediate 
missing data.   
For the derivation of the SLEDAI-2K total score, any laboratory items with missing value will 
be imputed using LOCF if only a single (non-consecutive) visit has missing data for that item. 
In the event of two or more consecutive visits with missing data for the same item, LOCF will 
be used for the first missing value of each sequence, after which the data will remain missing. 
Laboratory items of SLEDAI-2K are urinary casts, hematuria, proteinuria, pyuria, low 
complement, increased DNA Binding, thrombocytopenia, and leukopenia. 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of <x (ie, below the lower limit of quantification (LLOQ)) or >x (ie, above the upper 
limit of quantification) will be imputed as x in the calculation of summary statistics but 
displayed as <x or >x in the listings. 
Anifrolumab serum concentrations reported as below the LLOQ will be imputed with 
LLOQ/2 for analysis. Anti-dsDNA values reported as “<x” will be treated as missing values in 
summary statistics and considered as NEGATIVE results for all analyses.  
Details about imputation of partial or missing dates are given in Appendix C.  
4.1.7 
Examination of model assumptions 
Model assumptions for linear mixed effect models will be checked with graphical displays 
(plot of residuals versus predicted values, a histogram with normal density overlaid, and a 
quartile-quartile (Q-Q) plot showing the residual quantiles versus quantiles of a normal 
distribution). If the model assumptions are not met, appropriate data transformations or the use 
of non-parametric approaches will be discussed during the BDR meeting. The decision about 
an appropriate approach will be made before unblinding the data. 


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The assumption of proportionality for Cox proportional hazard models will be assessed by 
producing complementary log-log plots presenting log (-log (estimated survivor function)) 
versus log (time). (In the presence of non-proportionality, the hazard ratio will be interpreted 
as an average hazard ratio over the flare exposure time.) If these raise concerns, a time 
dependent covariate would be fitted to assess the extent to which this represents random 
variation. This will be discussed during the BDR meeting and the decision about an 
appropriate approach will be made before unblinding the data. 
4.2 
Analysis methods 
4.2.1 
Analysis of the primary variable 
The estimand of primary interest is the difference in the proportions of response between 
anifrolumab 300 mg and placebo at Week 52 in the full analysis set, where the response is 
captured with a composite binary endpoint and is defined by sufficient change from baseline 
in disease activity as measured by SLEDAI-2K, no worsening in BILAG and PGA and ability 
to adhere to the planned course of the treatment. The intercurrent events: discontinuation of IP 
and receipt of restricted medications are unfavourable outcome. Therefore, patients treated 
with restricted medications beyond protocol allowed threshold, and those who discontinued IP 
for other reasons, will be non-responders. This estimand answers a clinically relevant question 
comparing the number of patients able to both complete the study treatment and to achieve 
adequate response without further medication being required. The response is measured by the 
primary efficacy endpoint, defined as the difference in the proportion of patients who 
achieved SRI(4) at Week 52, comparing the anifrolumab 300 mg to the placebo groups.  
This is measured by the primary efficacy endpoint, defined as the difference in the proportion 
of subjects achieving SRI(4) at Week 52 comparing the anifrolumab 300 mg to the placebo 
group. The null hypothesis is that the proportion of subjects achieving SRI(4) on anifrolumab 
300 mg is equal to that on placebo. The alternative hypothesis is that the proportion of 
subjects achieving SRI(4) on anifrolumab 300 mg is not equal to that on placebo, ie,  
H0: difference in proportion achieving SRI(4) (anifrolumab 300 mg vs Placebo) = 0  
Ha: difference in proportion achieving SRI(4) (anifrolumab 300 mg vs Placebo) ≠ 0.  
The proportion of subjects achieving SRI(4) in the anifrolumab 300 mg treatment group will 
be compared to that in the placebo group using a Cochran-Mantel-Haenszel (CMH) approach 
(Stokes, 2012) stratified by:  
• 
SLEDAI-2K score at screening (<10 points versus ≥10 points)  
If different measurements are available for re-screened subjects, the value at re-
screening will be used. 
• 
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or 
equivalent)  
For the classification, the derived OCS dose rounded to 1 decimal place will be 
used. 
• 
Results of a type 1 IFN test (high versus low)  


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SLEDAI-2K score at Screening and Week 0 (Day 1) OCS strata will be derived 
programmatically from the data recorded in the database. Type 1 IFN test stratum will be 
taken as recorded at randomisation by the Interactive voice/web response system (IXRS). 
Strata with low counts will be pooled with adjacent strata prior to the analysis. If a sub-
stratum within the IFN-low stratum has less than 20 subjects (in the pooled treatment group), 
then all IFN-low sub-strata will be pooled together. If a sub-stratum within the IFN-high 
stratum has less than 20 subjects (in the pooled treatment group), then within the IFN-high 
stratum the SLEDAI-2K score <10 points sub-strata will be pooled together and the SLEDAI-
2K score ≥10 points sub-strata will be pooled together. If any of these two sub-strata within 
the IFN-high stratum still has less than 20 subjects (in the pooled treatment group), then all 
IFN-high sub-strata will be pooled together. If all IFN-low sub-strata are pooled together and 
all IFN-high sub-strata are pooled together and any of these strata has less than 20 subjects (in 
the pooled treatment group) then all strata are pooled together. 
All pooling of strata will be done separately for the anifrolumab 300 mg versus placebo 
comparison and the anifrolumab 150 mg versus placebo comparison. 
The analysis can be described as follows: 
A. 
There are nij subjects in each stratum, where i is the stratum, and j is the treatment 
group. The number of subjects achieving SRI(4) is xij. The proportion of subjects 
achieving SRI(4) is denoted as pij = xij / nij..  
B. 
For each stratum, the difference in proportion of subjects achieving SRI(4) is 
calculated as di = piA – piP, where A and P denote the different treatment groups 
(anifrolumab 300 mg and placebo, respectively).  
C. 
Weights for each stratum, wi, are calculated as niP * niA / (niA + niP). The weighted 
difference is calculated as  
 
D. 
The standard error (SE) of the weighted difference under the null hypothesis is given 
by  
 where  
 and 
 
E. 
For deriving the CI for the weighted difference in proportions, a correction will be 
applied to the variance, providing a CI with more accurate coverage. This will be 
applied to all strata, and is derived as follows. 
 with 


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The 95% CI can be generated using the weighted difference ± z0.975 * SE. 
The value of the test statistic is calculated as 
. The p-value from the two-sided test 
of no difference in treatment groups is calculated as 
, where 
Prob() is the distribution function of the standard normal distribution. 
F. 
The 95% CI for the weighted proportion (
) in a treatment group j can be 
generated using a normal approximation and assuming independence between strata, 
where pij* are used as above. 
 
, 
 
If the resulting lower or upper limit is <0% or >100%, it will be set to 0% or 100%, 
respectively. 
The estimated treatment effect (ie, the difference in response rate for anifrolumab 300 mg 
versus placebo), corresponding 95% CI, and 2-sided p-value for the difference at Week 52 
will be presented. In addition, the estimated response rate (weighted proportion) and the 
corresponding 95% CI within each treatment group (including anifrolumab 150 mg) will be 
presented.  
Longitudinal presentations of results over time (ie, for each post-baseline visit up to Week 52) 
based on the same analysis, with the corresponding 95% CI, will be created.  
A bar plot showing the estimated response rates for subjects with SRI(4) at Week 52 by 
treatment group (including CIs, number of subjects included in the analysis, and the p-value 
for the test of differences between anifrolumab 300 mg and placebo) will be provided. 
In addition, the individual conditions of SRI(4) (SLEDAI-2K reduction ≥4 points, no new 
organ systems affected, no worsening of subjects’ lupus disease activity, no permanent 
discontinuation of investigational product, and no use of rescue medication) at Week 24 and 
Week 52 will be summarised with counts and percentages by treatment group. 
All analyses on the primary variable will be conducted with the full analysis set. 
Sensitivity analysis - impact of premature discontinuation of IP 
Permanent premature discontinuation of IP is part of the SRI(4) definition. In order to 
examine the impact of different discontinuation rates between treatment groups 
(Anifrolumab 300 mg and Placebo), a tipping point analyses will be performed. This analysis 
will vary the assumptions about outcomes among the subsets of subjects on the treatment arms 
who prematurely discontinue IP and can be described as: 


Statistical Analysis Plan  
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• 
The proportions of subjects achieving SRI(4) will be analysed using a Pearson’s 
chi-squared test, thus the stratification factors that are used in the main analysis 
(CMH) will be disregarded. Since the strata will be balanced in respect of treatment 
assignment by virtue of the stratified randomisation scheme used, the only impact 
of this simplification should be that the inferences from the unstratified analysis will 
be somewhat conservative. 
• 
For the primary analysis, subjects who prematurely discontinue IP having not 
received restricted medications prior to discontinuation of IP are by definition 
imputed as non-responders. For this sensitivity analysis, these subjects will be 
altered from non-responder to responder in an iterative manner.  
• 
At each step of the analysis one of these subjects switches from not achieving 
SRI(4) to achieving SRI(4), and the Pearson’s chi-squared test is re-run. The results 
(statistical significance) are presented in a grid where the x-axis and the y-axis 
represent the number of subjects assumed to be achieving SRI(4) for placebo and 
anifrolumab 300 mg, respectively. The region where the conclusion changes, will 
be considered as the tipping point. 
• 
The grid will be divided in 3 regions, limited in the top by the expected number of 
subjects with missing values in the anifrolumab 300 mg arm which would have 
achieved SRI(4) if not prematurely discontinuing IP (based on the proportion of 
subjects achieving SRI(4) in subjects who completed IP in the anifrolumab 300 mg 
arm):  
o 
Likely – Its right limit is the expected number of subjects with missing values 
in the placebo arm which would have achieved SRI(4) if not prematurely 
discontinuing IP (based on the proportion of subjects achieving SRI(4) in 
subjects who completed IP in the placebo arm); 
o 
Uncertain – its right limit is the expected number of subjects with missing 
values in the placebo arm which would have been responders if not prematurely 
discontinuing IP (based on the proportion of subjects achieving SRI(4) in 
subjects who completed IP in the anifrolumab 300 mg arm); 
o 
Unlikely – It is the region to the right of the uncertain region. 
Sensitivity analysis – impact of intermediate missing data 
To examine the impact of intermediate missing data, the following sensitivity analysis with 
multiple imputations will be performed. Intermediate missing values for SLEDAI-2K, 
BILAG-2004, and PGA (ie, missing for other reason than early discontinuation of IP) will be 
imputed separately for each SRI(4) component.  
Intermediate missing values of SRI(4) will be imputed based on the imputed values of the 
BILAG-2004, PGA and SLEDAI-2K components. For each outcome and visit, 100 
imputations will be generated by randomised treatment group. The procedure will be initiated 
with a random seed of 12345. For analysis, each imputed dataset will be analysed separately, 
and the single estimates will be combined using PROC MIANALYZE. Each component will 
be imputed as follows: 


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• 
SLEDAI-2K total score will be imputed with PROC MI using the MCMC 
IMPUTE=FULL specification, and a VAR statement specifying the variables in 
order of visit. Specify MINIMUM=0 to ensure imputed values are non-negative. 
Specify MAXIMUM=105 to avoid imputation of values above the maximum 
possible score. 10,000 burning iterations to be used, with 100 iterations between 
each imputation. From the resulting dataset, the imputations of intermediate missing 
values only will be extracted (ie, imputations of missing values due to early 
discontinuation of IP will not be considered). 
• 
BILAG-2004 will be imputed as a binary variable reflecting the SRI(4) criterion, ie, 
“No new organ systems affected as defined by 1 or more BILAG-2004 A or 2 or 
more BILAG-2004 B items compared to baseline”. This binary BILAG variable for 
subject i at visit t will be modelled as BILAGi(t)~Binomial(πi(t)) where πi(t)= 
θ1BILAGi(t-1)+ θ0(1- BILAGi(t-1)) for t>1 and πi(t)= θ2 for t = 1 (Week 4). Independent 
Beta(1,1) priors will be specified for θ0, θ1 and θ2. 10,000 burn-in iterations will be 
used, followed by 10,000 main iterations. Imputations will then be taken from every 
100th iteration of the main chain (ie, after burn-in). From the resulting dataset, the 
imputations of intermediate missing values only will be extracted (ie, imputations of 
missing values due to early discontinuation of IP will not be considered). 
• 
PGA will be imputed in the same way as SLEDAI-2K total score, but using 
MAXIMUM=3 (instead of MAXIMUM=105). 
4.2.2 
Key secondary outcome variables 
All analyses of the key secondary outcome variables will be conducted with the full analysis 
set. 
4.2.2.1 
SRI(4) at Week 52 in IFN test-high subjects 
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg compared to 
placebo on disease activity in the IFN test-high subgroup is the difference in proportion of 
subjects achieving SRI(4) at Week 52 in subjects classified as IFN test-high.  
All analyses as described in Section 4.2.1 for the primary endpoint, except the sensitivity 
analysis with multiple imputation, will be performed for the IFN test-high subgroup. For the 
stratified CMH analyses, the stratification factors will be reduced to SLEDAI-2K score at 
screening (<10 points versus ≥10 points) and Week 0 (Day 1) OCS dose (<10 mg/day versus 
≥10 mg/day prednisone or equivalent).  
A supplemental analysis of SRI(4) in subjects classified as IFN test-low will be conducted. 
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab and placebo. The stratification 
factors will be reduced to SLEDAI-2K score at screening (<10 points versus ≥10 points) and 
Week 0 (Day 1) OCS dose (<10 mg/day versus ≥10 mg/day prednisone or equivalent). 


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4.2.2.2 
Oral corticosteroid management 
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on the ability to reduce the OCS dose in subjects with baseline OCS ≥10 mg/day prednisone 
or equivalent is the difference in proportion of subjects with maintained OCS reduction.  
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab and placebo in subjects with 
baseline OCS ≥10 mg/day prednisone or equivalent. For the stratified CMH analyses, the 
stratification factors will be reduced to SLEDAI-2K score at screening (<10 points versus 
≥10 points) and results of a type 1 IFN test (high versus low). 
A bar plot showing the estimated response rates for subjects with maintained OCS reduction 
by treatment group (including CIs, number of subjects included in the analysis, and the 
p-value for the test of differences between anifrolumab 300 mg and placebo) will be provided. 
The tipping point analysis to assess the impact of premature discontinuation of IP as described 
in Section 4.2.1, will also be performed for maintained OCS reduction.  
4.2.2.3 
Skin lesions 
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on inflammatory cutaneous lupus lesions in subjects with baseline CLASI activity score ≥10 is 
the difference in proportion of subjects with an at least 50% reduction in CLASI activity score 
at Week 12.  
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab and placebo in subjects with 
baseline CLASI activity score ≥10. Longitudinal presentations of the results over time (ie, for 
each post-baseline visit up to Week 52) based on this analysis will be created.  
A bar plot showing the estimated response rates for subjects with a ≥50% reduction in CLASI 
activity score at Week 12 by treatment group (including CIs, number of subjects included in 
the analysis, and the p-value for the test of differences between anifrolumab 300 mg and 
placebo) will be provided. 
The tipping point analysis to assess the impact of premature discontinuation of IP described in 
Section 4.2.1, will also be performed for an at least 50% reduction in CLASI activity score.  
A further sensitivity analysis will be provided if at least 10 subjects in the anifrolumab 300 mg 
or placebo treatment arm have a burst and taper of OCS or IM steroids during the first 
12 weeks of treatment. The CMH analysis will be repeated for the at least 50% reduction in 
CLASI activity score (including all criteria) at Week 12 excluding subjects administered a 
burst and taper of OCS or IM steroids during the first 12 weeks of treatment. A burst and taper 
of OCS or IM steroids is defined as an OCS increase above the daily dose at Day 1 or any IM 
steroid dose. 


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4.2.2.4 
SRI(4) at Week 24 
The key secondary endpoint used to evaluate the early effect of anifrolumab 300 mg 
compared to placebo on disease activity is the difference in proportion of subjects achieving 
SRI(4) at Week 24.  
The analysis of SRI(4) at Week 24 is covered with the longitudinal analysis described 
Section 4.2.1 for the primary variable. An additional bar plot showing the estimated response 
rates for subjects with SRI(4) at Week 24 by treatment group (including CIs, number of 
subjects included in the analysis, and the p-value for the test of differences between 
anifrolumab 300 mg and placebo) will be provided. 
The tipping point analysis to assess the impact of premature discontinuation of IP described in 
Section 4.2.1, will also be performed for SRI(4) at Week 24. 
4.2.2.5 
Flares  
The key secondary endpoint used to evaluate the effect of anifrolumab 300 mg versus placebo 
on flares is the difference in annualized flare rates through Week 52 (as defined in 
Section 3.2.5).  
The flare rate in the anifrolumab treatment group will be compared to the flare rate in the 
placebo group using a negative binomial regression model. The response variable in the model 
will be the number of flares over the 52-week treatment period (ie, up to Visit 14/EDV). The 
model will include covariates of treatment group, and the stratification factors. The logarithm 
(to base e) of the follow-up time (flare exposure time as defined in Section 3.2.5) will be used 
as an offset variable in the model to adjust for subjects having different exposure times. The 
estimated treatment effect and the corresponding 95% CI, as well as the 2-sided p-value (for 
the comparison of anifrolumab 300 mg versus placebo only) will be presented.  
A summary of the annualized flare rate by descriptive statistics as well as a summary of the 
number and percentage of subjects with no flares, at least one flare, 1 flare, 2 flares, and 3 or 
more flares, respectively, will be presented by treatment group.  
Sensitivity analysis – multiple imputation 
To examine the sensitivity of the results of the main analysis to deviations from the underlying 
assumptions, an additional analysis will be performed using the controlled multiple imputation 
method (Keene, 2014).  As with the main analysis, the sensitivity analysis includes all data 
until subjects complete the study/ withdraw from the study regardless of if they discontinue 
from randomised treatment.   
For this method, the number of flares after withdrawal from study will be imputed conditional 
upon the observed number of flares prior to the withdrawal, a post-withdrawal model 
assumption, the baseline covariates included in the main analysis model and the time the 
subject would have remained in the study if not withdrawn (ie, date of first administration of 
IP + 364 days – date of last available BILAG-2004 assessment).  


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The method involves first fitting the main analysis (ie, negative binomial regression model as 
described above) to the observed data. For each imputed dataset, first an independent sample 
is drawn from the approximate posterior distribution of the model parameters. This consists of 
sampling new regression coefficients from a multivariate normal distribution, with mean equal 
to the observed data maximum likelihood estimate, and covariance matrix corresponding to 
the maximum likelihood covariance estimate. A new (log) shape parameter is drawn from a 
normal distribution in the same way, which is exponentiated to give a draw of the shape 
parameter k. 
For each generated set of model parameters, the number of flares after withdrawal from study 
are imputed for each subject by drawing randomly from its conditional distribution given the 
subject’s number of flares before withdrawal. For a given subject let 
 and 
 denote the time 
before and after withdrawal. Let 
and 
 denote the observed number of flares before 
withdrawal and unobserved number after withdrawal, respectively, which is to be imputed. 
Let 
 and 
denote the assumed rates before and after withdrawal. Let 
 and 
. Then, using SAS’s RAND negative binomial parametrisation, the conditional 
distribution of 
 given 
 is negative binomial with ‘number of successes’ parameter 
 
and ‘probability of success’ parameter equal to  
. 
The imputed number of flares is then combined with the observed flares and data is analysed 
using the main analysis methodology. This analysis is repeated multiple times and the results 
combined using Rubin’s formulae (Fleming, 2011, Ratitch, 2013). 
Sensitivity analysis – tipping point analysis 
First a MAR analysis will be performed where for each subject the rate after withdrawal λ1 is 
assumed to be the same as their rate before withdrawal λ2, which itself is calculated based on 
their randomised treatment group and baseline covariates. 
A tipping point analysis will then be performed, where the rate after withdrawal will be 
modified to δλ2. A series of analyses will be performed with a range of increasing deltas for 
the two arms (δP and δA for placebo and anifrolumab 300 mg groups, respectively) so that one 
could assess at which point the study conclusions would change from favourable to 
unfavourable; ie, to identify a tipping point. 
In this assessment, the placebo group is assumed to improve after withdrawal and the 
anifrolumab group is assumed to worsen after withdrawal. Therefore, log(δP) will be varied 
from -1.5 to 0 in increments of 0.5 and log(δA) will be varied from 0 to 1.5 in increments of 
0.5. This corresponds to deltas between 0.22 and 1 for the placebo group and deltas between 1 
and 4.5 for the anifrolumab 300 mg group. If statistical significance is maintained among the 
matrix of possible δ combinations, the comparison is deemed robust to missing data. For a 
given comparison, if a tipping point is observed with analysis at 0.5 increments, the δ values 
will be further refined down to 0.25 increments for the relevant interval. For example if a 


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tipping point is identified when increasing log(δA) from 1 to 1.5, the matrix will be expanded 
to include also the value log(δA) = 1.25. The values for δ (and the corresponding increments) 
will be checked during the BDRM and adapted as necessary. 
Sensitivity analysis – flares while on treatment 
The flare rate in the anifrolumab treatment group will be compared to the flare rate in the 
placebo group using a negative binomial regression model. The response variable in the model 
will be the number of flares while on treatment (ie, up to last administration of investigational 
product + 28 days). The model will include covariates of treatment group, and the 
stratification factors. The logarithm (to base e) of the follow-up time (flare exposure time as 
defined in Section 3.2.5) will be used as an offset variable in the model to adjust for subjects 
having different exposure times. The estimated treatment effect and the corresponding 95% CI 
will be presented. 
4.2.3 
Analysis methods for other secondary efficacy variables 
All analyses of other secondary outcome variables will be conducted with the full analysis set. 
4.2.3.1 
Assessment of disease activity 
SRI(4) of anifrolumab 150 mg treatment group 
The effect of anifrolumab 150 mg compared to placebo on disease activity will be assessed by 
the difference in proportions of subjects achieving SRI(4) at Week 52.  
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab 150 mg and placebo and the 
corresponding response rates (weighted proportions). 
This will be included in the primary analysis table. 
Supportive SRI variables 
SRI(5), SRI(6), SRI(7), and SRI(8) will be evaluated only for subjects with baseline 
SLEDAI-2K ≥5 points, ≥6 points, ≥7 points, and ≥8 points, respectively. 
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab 300 mg and placebo as well as the 
response rates (weighted proportions) for all treatment groups. Longitudinal presentations of 
the results over time (ie, for each post-baseline visit up to Week 52) based on this analysis will 
be created. 
BICLA 
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab 300 mg and placebo as well as the 
response rates (weighted proportions) for all treatment groups for BICLA response. 
Longitudinal presentations of the results over time (ie, for each post-baseline visit up to 
Week 52) based on this analysis will be created. 


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A bar plot showing the estimated response rates for subjects with BICLA response at Week 52 
by treatment group (including Cis, and number of subjects included in the analysis) will be 
provided. 
In addition, the individual conditions of BICLA (reduction of all baseline BILAG-2004 A and 
B scores and no worsening in other organ systems, no worsening from baseline in 
SLEDAI-2K, no worsening of subjects’ lupus disease activity, no permanent discontinuation 
of investigational product, and no use of rescue medication) will be summarised with counts 
and percentages by treatment group at Week 24 and Week 52. 
Supportive outcome variables of the Individual components of SRI and BICLA 
Change from baseline in SLEDAI-2K and PGA will be analysed using repeated measures 
model with fixed effects for baseline value, treatment group, visit, treatment*visit interaction 
and stratification factors. Covariance parameters will be estimated using restricted Maximum 
Likelihood method and Kenward Rogers denominator degrees of freedom will be used for the 
tests of fixed effects. An unstructured covariance matrix will be used. In case of convergence 
issues, the following alternative structures will be used for fitting (in that order): 
Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, Homogeneous CS. Results 
will be presented for each visit in terms of the adjusted means for each treatment group, 
estimates of differences between anifrolumab 300 mg and placebo, and associated 2-sided 
CIs.  
For each SLEDAI organ system (central nervous system, vascular, musculoskeletal, renal, 
mucocutaneous, cardiovascular system and respiratory, immunology, and haematological and 
fever) the number and percentage of subjects with an improvement at Week 24 and Week 52, 
respectively, will be given for subjects with corresponding organ system involvement at 
baseline.  
For BILAG-2004, the number and percentage of subjects with a score of A, B, and C, D, or E, 
respectively, will be given by visit for the following organ systems: 
• 
General  
• 
Mucocutaneous 
• 
Neuropsychiatric  
• 
Musculoskeletal  
• 
Cardiorespiratory  
• 
Gastrointestinal  
• 
Ophthalmic  
• 
Renal  
• 
Haematology 


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For each of the organ systems, a bar plot will be provided showing the distribution of the 
scores at baseline, Week 24, and Week 52 by treatment group. The figures will include the 
percentages and number of subjects. 
Observed values and changes from baseline in BILAG-2004 global score will be presented by 
visit with descriptive statistics. 
For Major Clinical Response and Partial Clinical Response, the same CMH approach as 
described in Section 4.2.1 for the primary endpoint will be used to estimate the treatment 
difference between anifrolumab 300 mg and placebo as well as the response rates (weighted 
proportions) for all treatment groups. 
Active, swollen and tender joints 
Change from baseline in the number of active, swollen and tender joints, respectively, will be 
analysed using the same repeated measures models as described for the analysis of SLEDAI-
2K and PGA in 4.2.3.1Thereby, an unstructured covariance matrix will be used. In case of 
convergence issues, the following alternative structures will be used for fitting (in that order): 
Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, Homogeneous CS.   
For subjects with at least 8 swollen and at least 8 tender joints at baseline, the same CMH 
approach as described in Section 4.2.1 for the primary endpoint will be used to estimate the 
treatment difference between anifrolumab 300 mg and placebo in the proportions of subjects 
achieving an at least 20% and an at least 50% reduction in swollen and tender joints, 
respectively. Longitudinal presentations of the results over time (ie, for each post-baseline 
visit up to Week 52) based on this analysis will be created. 
Change in SDI 
Observed values and changes from baseline in SDI global score will be presented by visit with 
descriptive statistics. This summary will be repeated by SDI global score at baseline (0 and 
≥1). 
Additionally, a shift table presenting damage according to the SDI score at baseline versus 
damage at Week 52 will be presented according to the categories given in Section 3.3.1.6. 
Supportive outcome variables for the assessment of OCS use 
Additionally, the daily OCS dose will be displayed graphically by a longitudinal plot 
presenting the means and corresponding SDs by visit. The number of subjects will also be 
included in the graph. Subjects without an OCS dose will be included with a value of 0. The 
graphical display will be repeated for subjects with baseline OCS ≥10 mg/day only. 
A shift table will be provided for all subjects showing the daily OCS dose at baseline versus 
the daily OCS dose at Week 52. For this presentation, the daily OCS dose will be categorised 
as 0, >0 to ≤5mg, >5 to ≤7.5mg, >7.5 to ≤10mg, >10 to ≤15mg, >15 to ≤20mg, >20 to ≤30mg, 
>30 to ≤40mg, >40 mg, and missing. 


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Furthermore, the standardised AUC up to Week 52 will be summarized by treatment group for 
all subjects as well as for subjects with baseline OCS ≥10 mg/day. 
For subjects with baseline OCS ≥10 mg/day prednisone or equivalent, a shift table of reaching 
a maintained OCS reduction at Week 52 (as defined in Section 3.2.2) versus achieving SRI(4) 
at Week 52 (as defined in Section 3.1) will be provided. 
Supportive outcome variables for the assessment of skin lesions 
For subjects with baseline CLASI activity score ≥10, a shift table for an at least 50% reduction 
in CLASI activity score at Week 12 versus an at least 50% reduction at Week 52 will be 
presented to investigate the maintenance of effect in CLASI activity score. 
Change from baseline in CLASI activity score and CLASI damage score, respectively, will be 
analysed using the same repeated measures models as described for the analysis of SLEDAI-
2K and PGA in section 4.2.3.1 Thereby, an unstructured covariance matrix will be used. In 
case of convergence issues, the following alternative structures will be used for fitting (in that 
order): Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, Homogeneous CS.   
Supportive outcome variables for the assessment of flares 
The analysis of flares using a negative binomial regression model as described in 
Section 4.2.2.5 will be repeated for flares versus baseline.  
A summary of the annualized flare rate by descriptive statistics for flares versus baseline as 
well as a summary of the number and percentage of subjects with no flares, at least one flare, 
1 flare, 2 flares, and 3 or more flares, respectively, will be presented by treatment group.  
The time to first flare will be analysed as a supportive analysis to the assessment of reduction 
of flares to explore the extent to which treatment with anifrolumab 300 mg delays the time to 
first flare compared to placebo. The analyses of time to first flare will be provided for the key 
secondary outcome variable and flares versus baseline. Subjects in the anifrolumab 150 mg 
treatment group will not be included in the analyses of time to first flare. 
Cox proportional hazard models (using a profile likelihood approach with ties=Efron) 
including the covariates of treatment and the stratification factors will be used to estimate the 
treatment effect. The estimated hazard ratios and corresponding CIs will be presented for the 
effect of the treatment group.  
Furthermore, the time to first flare (key secondary outcome variable only) will be presented as 
Kaplan-Meier plot including the number of subjects at risk at each visit. 
Lupus Low Disease Activity State 
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab 300 mg and placebo as well as the 
response rates (weighted proportions) for all treatment groups for LLDA response. 


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Longitudinal presentations of the results over time (ie, for each post-baseline visit up to 
Week 52) based on this analysis will be created. 
4.2.3.2 
Subject reported outcome variables 
Short Form 36 version 2 (acute recall) 
Changes from baseline in in SF-36-v2 (acute) domain scores (Physical Functioning, Role 
Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and 
Mental Health), PCS and MCS, respectively, will be analysed using the same repeated 
measures models as described for the analysis of SLEDAI-2K and PGA in section 
4.2.3.1.Thereby, an unstructured covariance matrix will be used. In case of convergence 
issues, the following alternative structures will be used for fitting (in that order): 
Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, Homogeneous CS. 
For the responder analyses, the same CMH approach as described in Section 4.2.1 for the 
primary endpoint will be used to estimate the treatment difference between anifrolumab 
300 mg and placebo as well as the response rates for all treatment groups for each of the 8 
domain scores, PCS and MCS, respectively. Longitudinal presentations of the results over 
time (ie, for each post-baseline visit up to Week 52) based on these analyses will be created. 
Pain Numerical Rating Scale  
Change from baseline in NRS will be analysed using the same repeated measures models as 
described for the analysis of SLEDAI-2K and PGA in section 4.2.3.1.Thereby, an 
unstructured covariance matrix will be used. In case of convergence issues, the following 
alternative structures will be used for fitting (in that order): Heterogeneous Toeplitz, 
heterogeneous AR(1), Heterogeneous CS, Homogeneous CS.   
Functional Assessment of Chronic Illness Therapy-FATIGUE  
Change from baseline in FACIT-F total score will be analysed using the same repeated 
measures models as described for the analysis of SLEDAI-2K and PGA in section 4.2.3.1. 
Thereby, an unstructured covariance matrix will be used. In case of convergence issues, the 
following alternative structures will be used for fitting (in that order): Heterogeneous Toeplitz, 
heterogeneous AR(1), Heterogeneous CS, Homogeneous CS.  
The same CMH approach as described in Section 4.2.1 for the primary endpoint will be used 
to estimate the treatment difference between anifrolumab 300 mg and placebo as well as the 
response rates for all treatment groups for FACIT-F response. Longitudinal presentations of 
the results over time (ie, for each post-baseline visit up to Week 52) based on this analysis will 
be created. 
Patient Global Assessment  
Change from baseline in PtGA will be analysed using the same repeated measures model as 
described for the analysis of SLEDAI-2K and PGA in section 4.2.3.1.Thereby, an 
unstructured covariance matrix will be used. In case of convergence issues, the following 


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alternative structures will be used for fitting (in that order): Heterogeneous Toeplitz, 
heterogeneous AR(1), Heterogeneous CS, Homogeneous CS.  
Lupus quality of life scale 
Change from baseline in each of the lupus QoL domain scores (physical health, pain, 
planning, intimate relationships, burden to others, emotional health, body image, and fatigue) 
will be analysed using the same repeated measures models as described for the analysis of 
SLEDAI-2K and PGA in section 4.2.3.1.Thereby, an unstructured covariance matrix will be 
used. In case of convergence issues, the following alternative structures will be used for fitting 
(in that order): Heterogeneous Toeplitz, heterogeneous AR(1), Heterogeneous CS, 
Homogeneous CS.  
EuroQol 5 dimensions 
The 5 dimensions of EQ-5D-5L (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) will be summarized by visit as number and percentage of subjects with the 
different health states. 
Observed values and changes from baseline in VAS Score and single summary utility index, 
respectively, will be presented longitudinally with descriptive statistics. 
Work productivity and Activity Impairment - Lupus 
At each scheduled visit, the number and percentage of subjects employed will be presented.  
Observed values and changes from baseline in hours missed due to lupus and in WPAI scores 
(absenteeism, presenteeism, work productivity loss and activity impairment) will be presented 
longitudinally with descriptive statistics. 
Medical Resource Use Questionnaire 
The medical resource use, as described in Section 3.3.2.8, will be summarised by treatment. 
Results of “visit related to an increase in lupus related activity” and “cause of visit/ 
hospitalization” will be presented as number and percentage of respective visits. 
4.2.4 
Presentation of study population 
4.2.4.1 
Subject disposition 
The number and percentage of subjects completing the study and completing the study up to 
and including Week 52 (Visit 14/EDV) and the number and percentage of subjects 
withdrawing from the study including reason for withdrawal, will be summarized by treatment 
group for the full analysis set. Additionally, the number and percentage of subjects enrolled to 
the LTE study will be presented. 
The number of subjects completing treatment with investigational product up to and including 
Week 48 (ie, with last administration of investigational product at Visit 13) and the number of 
subjects permanently discontinuing the treatment with investigational product including 
reason for withdrawal, will be summarized by treatment group for the full analysis set. 


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Furthermore, the number and percentage of subjects remaining on investigational product, 
discontinued investigational product but remain on study and withdrawn from study will be 
summarized by visit up to Week 48 for the full analysis set. The number and percentage of 
subjects withdrawn from study at Week 52 and the number of subjects still in study at 
weeks 56 and 60 will also be presented. 
A summary of number and percentage of subjects in each region, each country and each site 
by treatment group and overall will be provided for the full analysis set..A summary of 
number of subjects in each population will be provided for the all subjects analysis set. 
Important protocol deviations will be summarised for the full analysis set. 
4.2.4.2 
Demographic and baseline characteristic 
Demography and baseline characteristics will be presented by descriptive statistics by 
treatment group as well as overall for the full analysis set. Additionally, the stratification 
factors (as calculated from the data for SLEDAI-2K score at screening and Week 0 [Day 1] 
OCS dose and as recorded at randomization by IXRS for the type 1 IFN test) and the 
cardiovascular risk will be presented by descriptive statistics for the full analysis set. 
An additional table will be prepared summarising miss-stratifications as per the IXRS at 
randomization for the SLEDAI-2K score at screening and Week 0 (Day 1) OCS dose. 
Past and current medical history will be summarized separately by MedDRA primary system 
organ class and preferred term. Furthermore, the number and percentage of subjects with the 
cardiovascular risk factors will be presented by risk factor. 
Prior and concomitant medications will be summarized separately by WHO-DD Anatomical 
Main Group (ATC level 1), and preferred term. Disease related treatments at baseline will be 
summarized by the categories given in Section 3.4.3. Concomitant medication beyond 
protocol allowed threshold will be summarized by preferred term. 
4.2.4.3 
Exposure 
Exposure will be summarized by treatment group for the full analysis set.  
Summary statistics will be provided for the duration of exposure. The number and percentage 
of subjects treated ≥4 weeks, ≥8 weeks, and up to ≥52 weeks in 4-weekly intervals will be 
provided. Furthermore, the total subject years of exposure will be presented. 
The number and percentage of subjects with infusions will be presented by total number of 
infusion (ie, 1, 2, …, 13) and by visit (ie, Day 1, Week 4, Week 8, Week 12, …, Week 48).  
Furthermore, the time to discontinuation of investigational product will be presented as 
Kaplan-Meier plot including the number of subjects at risk (ie, still on investigational 
product). 


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4.2.5 
Analysis methods for safety variables 
Safety variables will be summarised by treatment group for the full analysis set. 
4.2.5.1 
Adverse events 
All AE summaries will be presented for anifrolumab 150 mg, anifrolumab 300 mg, total 
anifrolumab (ie, including both anifrolumab treatment groups) and placebo. 
If not stated otherwise, all summaries described below will be presented separately for  
• 
AEs during treatment 
• 
AEs during follow-up 
• 
AEs during treatment and follow-up.  
For summaries during follow-up, only subjects with any study documentation after the date of 
last dose of investigational product + 28 days will be considered. 
An overall summary of subjects with at least one AE in the following categories will be 
presented: 
• 
Any AE 
• 
Any AE with outcome = death 
• 
Any SAE (including events with outcome = death) 
• 
Any AE leading to discontinuation of investigational product 
• 
Any AE related to investigational product 
• 
Any AE of severe intensity 
• 
Any AESI  
- 
Any AESI of non-opportunistic serious infections 
- 
Any AESI of opportunistic infections 
- 
Any AESI of anaphylaxis 
- 
Any AESI of malignancy 
- 
Any AESI of herpes zoster 
- 
Any AESI of tuberculosis 
- 
Any AESI of influenza 
- 
Any AESI of vasculitis 
- 
Any AESI of major acute cardiovascular events  
• 
Any other significant AE 
• 
The number and percentage of subjects with at least one AE (ie, multiple 
occurrences of an AE in 1 subject will only be counted once) will be summarised by 
MedDRA primary system organ class and preferred term for the following AE 
categories. These summaries will also include the event rate per 100 subject years, 


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unless otherwise specified. Event rates will generally not be included in summaries 
presented for AEs during treatment and follow-up.Any AE 
• 
Any AE above reporting threshold of 2% 
This summary will be presented by preferred term only for AEs during treatment 
only. 
• 
Any AE with outcome = death  
This summary will be presented for AEs during treatment and follow-up only. 
• 
Any SAE (including events with outcome = death)  
This summary will not be presented for AEs during follow-up. 
• 
Any AE leading to discontinuation of investigational product 
This summary will be presented for all AEs irrespective of the study period. The 
end of exposure for the calculation of event rates is defined as the maximum of date 
of last dose of investigational product + 28 days and the date of the AE leading to 
discontinuation. AEs with (partially) missing start date information will be 
considered on-treatment unless the available information indicates otherwise and 
will be imputed with the earliest on-treatment date possible given the available start 
and stop date information for this analysis. 
• 
Any AE by relationship to investigational product (yes, no) 
(multiple occurrences of an AE in 1 subject will only be counted once as related if 
at least one AE is related and as not related if all occurrences are not related) 
This summary will not be presented for AEs during treatment and follow-up. This 
summary will not include the event rate per 100 subject years. 
• 
Any AE by maximum intensity (mild, moderate, severe) 
(ie, multiple occurrences of an AE in 1 subject will only be counted once with the 
maximum intensity in this AE) 
This summary will not be presented for AEs during treatment and follow-up. This 
summary will not include the event rate per 100 subject years. 
• 
Any AESI 
This summary will not be presented by system organ class but by AESI category 
(non-opportunistic serious infections, opportunistic infections, anaphylaxis, 
malignancy, herpes zoster, tuberculosis, influenza, vasculitis, and MACEs).  
This summary will not be presented for AEs during follow-up. 
• 
Any other significant AE 
This summary will be presented for AEs during treatment and follow-up only. 
• 
Any AE by time interval for the first onset of event 
This summary will be presented for AEs during treatment only. 
Cardiovascular outcome events (during treatment and during treatment and follow-up) as 
determined by the Cardiovascular Event Adjudication Committee will be presented separately, 
summarising the number of AEs submitted for adjudication and the outcomes of the 
adjudication including MACE classification. Site reported cardiovascular AEs, cardiovascular 
SAEs and their corresponding adjudicated outcomes will be listed. 


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




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The summary statistics presented will be minimum, 1st quartile, median, 3rd quartile, 
maximum, mean, and SD. 
For each parameter with available criteria, the number and percentage of subjects with 
TELVC values will be summarized by visit. Additionally, the number and percentage of 
subjects with at least one TELVC value will be presented. Percentages will be based on 
subjects with a measurement at baseline and at least 1 subsequent measurement of the variable 
(at the respective visit). 
For each parameter, the number and percentage of subjects with values below, within or above 
the corresponding normal range will be presented as shift tables from baseline to each post-
baseline visit.  
4.2.5.7 
Cushingoid features 
The number and percentage of subjects will be explored for each feature by visit. For subjects 
with baseline OCS ≥10 mg/day prednisone or equivalent, the summary will be repeated by 
maintained OCS reduction at Week 52 (yes versus no) as defined in Section 3.2.2. 
4.2.5.8 
C-SSRS 
The number and percentage of subjects with suicidal ideation (overall and by maximum 
category), suicidal behaviour (overall and by maximum category), and no suicidal ideation or 
behaviour will be given for assessments during screening, during treatment, and during 
follow-up, respectively.  
Furthermore, descriptive statistics on the total number of attempts, total number of interrupted 
attempts, and total number of aborted attempts will be summarized for attempts during 
screening, during treatment and during follow-up, respectively. 
Subjects with a suicidal ideation or behaviour at any time will be presented in a listing. 
4.2.5.9 
Personal Health Questionnaire Depression Scale-8 
Observed values and changes from baseline in PHQ-8 total score will be presented 
longitudinally with descriptive statistics. 
4.2.6 
Analysis methods for pharmacokinetics, pharmacodynamics, and 
immunogenicity 
If not stated otherwise, all analyses of pharmacodynamics and immunogenicity will be 
performed for the full analysis set by treatment group. 
4.2.6.1 
Analysis method for immunogenicity variables 
An overall summary of ADA response will be provided by treatment group. The proportion of 
subjects with ADA results as described in Section 3.6.1 will be presented. Summary statistics 
will be provided for titer of ADA positive subjects by timepoint. Descriptive Statistics will 
include n (number of reportable titers), minimum, quartiles (1st quartile, median, 3rd quartile) 


Statistical Analysis Plan  
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and maximum. For the summary of subjects who are ADA positive by visit or at a single visit 
point, the denominator for percentages is the number of subjects with an adequate sample that 
provides a reportable result of positive or negative for the respective visit. For the summary of 
overall ADA categories (eg, ADA positive at any time), percentages will be based on subjects 
with at least one ADA result during the study. 
The percentage of subjects with positive ADA results by timepoint will be presented 
graphically in a line plot. ADA titres-time profiles (line plots of median and quartiles by time 
point) will be generated separately for each anifrolumab treatment group.  
Variables of proportions regarding neutralizing antibodies will be summarised presenting the 
number and percentage of the categories given in Section 3.6.1. 
Key subject information for subjects with an ADA positive result at any time and for subjects 
who sero-converted post-baseline and had ADA titres increase by at least 4-fold from onset to 
maximum titre will be provided. 
The analyses of impact of ADA on PK and PD endpoints are described in Sections 4.2.6.2 and 
4.2.6.3. Potential association of ADA with safety and efficacy will be explored by subgroup 
analyses. Subgroup analyses for efficacy and safety are defined in Section 4.2.7. Further 
subgroup analyses for safety will be defined in the analysis plans for the integrated summary 
of safety.  
4.2.6.2 
Analysis methods for pharmacokinetic variables 
All analyses of PK data will be performed for the PK analysis set by treatment group. 
Anifrolumab serum concentrations will be summarised using descriptive statistics by 
treatment group, visit, and time point (pre-dose/post-dose) reporting n (number of non-missing 
values), m (number of non-zero values), geometric mean, geometric CV%, arithmetic mean, 
SD, arithmetic CV%, median, minimum and maximum. If applicable, this summary will be 
repeated including individual concentrations excluded from descriptive statistics. 
Serum concentration-time profiles of anifrolumab will be generated as plots of mean values 
(including SD) by treatment group and time point in a semi-log scale and a linear scale. This 
will be presented for all values and additionally for values measured before administration 
(Ctrough). 
Individual concentrations excluded from descriptive statistics will be listed. 
The potential influence of demographic covariates such as body weight, race, sex, and age will 
be explored. Furthermore, potential correlation between anifrolumab concentrations and IFN 
21 gene PD signature will be explored. These analyses will be performed by MedImmune’s 
Clinical Pharmacology and DMPK group. 
Impact of ADA on PK will be explored. Anifrolumab serum concentration will be 
summarised by ADA result (positive at any time/negative) and treatment group.  Serum 




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• 
ADA result (positive at any time; negative; persistently positive; ADA positive with 
titre >median of maximum titre) 
Table 4 gives an overview of subgroup analyses to be performed. Where necessary (eg, for 
subgroup analysis based on stratification factors), the model factors will be reduced. If not 
stated otherwise, the subgroup analysis will be supressed if any of the sub-populations in any 
treatment group will consist of less than 25 subjects. Subjects in the anifrolumab 150 mg 
treatment group will not be included in any subgroup analysis. 
For the primary endpoint SRI(4) at Week 52, a forest plot will be used to summarise the 
estimates of the treatment effect for the applicable subgroups.  
A listing of adverse events in ADA positive (at any time) subjects will also be presented. 
Table 5 
Overview of subgroup analyses 
Analysis 
SLEDAI-2K 
OCS at baseline 
IFN test 
Sex 
Age 
Disease Onset 
BMI 
Race 
Ethnicity 
ADA result 
SRI(4) – CMH a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SRI(4) in IFN test-high – CMH 
X 
X 
 
 
 
 
 
 
 
X 
Maintained OCS reduction – CMH 
X 
 
X 
 
 
 
 
 
 
 
CLASI activity reduction – CMH  
X 
X 
X 
 
 
 
 
 
 
 
Flare rate (key efficacy) – binominal 
regression 
X 
X 
X 
 
 
 
 
 
 
 
AE overview 
 
 
 
 
 
 
 
 
 
X 
SAE Summary by SOC and PT  
 
 
 
 
 
 
 
 
 
X 
a 
Subgroup analysis will also be conducted if resulting in a sub-population of <25 subjects. 
5. 
INTERIM ANALYSES 
No interim analysis is planned for this study.  
6. 
CHANGES OF ANALYSIS FROM PROTOCOL (NOT 
APPLICABLE) 


Statistical Analysis Plan  
Study Code D3461C00005 
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Date 20 August 2018 
74 
7. 
REFERENCES 
Burman, 2009 
Burman CF, Sonesson C, Guilbaud O, 2009. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stats in Med. 2009;28:739–761. 
Fleming, 2011 
Fleming TR. Adressing Missing Data in Clinical Trials. Ann. Intern. Med. 2011. 154:113-117. 
Keene, 2014 
Keene ON, Roger JH, Hartley BF, Kenward MG, 2009. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutical Statistics. Published online 
16 June 2014 in Wiley Online Library. 
Maruish, 2011 
Maruish, M. E. (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated. 
Ratitch, 2013 
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical Statistics 2013; 12: 337-347 
Stokes, 2012 
Stokes M.E., Davis C.S., Koch G.G., 2012. Categorical Data Analysis Using SAS®, Third 
Edition. SAS Institute, 2012. 
Van Hout, 2012 
Van Hout B., Janssen M.F., Feng Y.S., Kohlmann T., Busschbach J., Golicki D., Lloyd A., 
Scalone L., Kind P., Pickard A.S. 2012. Interim scoring for the EQ-5D-5L: mapping the 
EQ-5D-5L to EQ-5D-3L value sets. Value in Health. 2012 Jul-Aug; 15(5): 708-15 
Ware, 2007 
Ware J.E., Jr., Kosinski M., Bjorner J.B., Turner-Bowker, D.M., Gandek, B. and Maruish, 
M.E., 2007. User's Manual for the SF-36v2TM Health Survey (2nd Ed). Lincoln, RI, 
QualityMetric Incorporated. 
Wright, 1992 
Wright, S. P. (1992). Adjusted P-values for simultaneous inference. Biometrics, 48, 1005–
1013. 
Zhang, 1997 
Zhang J, et. al. 1997. Some Statistical Methods for Multiple Endpoints in Clinical Trials. 
Controlled Clinical Trials 18:204-221 
 


Statistical Analysis Plan  
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8. 
APPENDIX 
Appendix A: Medication beyond the protocol-allowed threshold 
Appendix B: Derivation of prednisone equivalent daily dose 
Appendix C: Derivation rules for imputation of partial or missing dates 
Appendix D: Reference ranges and TELVC for laboratory values 
Appendix E: ECG: Potentially Clinical Significant post baseline values 
Appendix F: Reference ranges and TELVC for vital signs 


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Appendix A 
MEDICATION BEYOND THE PROTOCOL-ALLOWED THRESHOLD 
Medications beyond the protocol-allowed threshold leading to classify a subject as a 
non-responder will be identified through a medical review before unblinding the study. Details 
including programming rules are given in the document “TULIP Supplemental Process 
Description Restricted Medication”. 
 


Statistical Analysis Plan  
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Appendix B  
DERIVATION OF PREDNISONE EQUIVALENT DAILY DOSE 
The daily prednisone equivalent OCS dose will be calculated using the total daily dose in the 
Prior and Concomitant Medication/Treatment form. If the medication is taken less than daily 
the documented total daily dose reflects the dose at the day the medication is taken. To 
calculate the total daily dose to be used for statistical analyses, the documented total daily 
dose needs to be divided according to the given medication dose frequency (eg, for medication 
given every week the documented daily dose needs to be divided by 7). If the total daily dose 
is missing for a corticosteroid, the available data of this medication will be reviewed by the 
medical team. If possible, the total daily dose will be derived manually from the available 
information. OCS administered PRN are not considered in the calculation of the daily dose. 
All oral corticosteroids taken at the respective day (ie, at the date of the respective visit) will 
be considered for the derivation of the daily dose.  The identification of OCS medication is 
described in the document “TULIP Supplemental Process description OCS”. 
The following table gives examples of prednisone equivalent doses (eg, 50 mg cortisone is 
equivalent to 10 mg prednisone). A complete list is given in the document “TULIP 
Supplemental Process description OCS”. 
Conversion to prednisone equivalent dose 
Medication (preferred term) 
Equivalent dose 
Prednisone  
10 mg 
Cortisone 
50 mg 
Hydrocortisone 
40 mg 
Methylprednisolone 
8 mg 
Prednisolone 
10 mg 
Triamcinolone 
8 mg 
Betamethasone 
1.2 mg 
Dexamethasone  
1.5 mg 
Budesonide 
2.25 mg 
Deflazacort 
12 mg 
 


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


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


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


Statistical Analysis Plan  
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Date 20 August 2018 
81 
Appendix E 
ECG: POTENTIALLY CLINICAL SIGNIFICANT POST BASELINE 
VALUES 
ECG 
parameter 
Unit Low value 
Low 
decrease 
High value 
High increase 
RR interval 
ms 
<500 
NA 
>1500 
NA 
PR interval  
ms 
NA 
NA 
≥240 
NA 
QRS duration 
ms 
≤60  
NA 
≥140 
NA 
QT 
ms 
≤300 
NA 
≥500 
≥60 
QTcF  
ms 
≤300 
NA 
≥500 
≥30, ≥60 
≥500 and increase from baseline  ≥30, 
≥500 and increase from baseline  ≥60 
QTcB  
ms 
≤300 
NA 
≥500 
≥30, ≥60 
 
 
 
 
≥500 and increase from baseline  ≥30, 
≥500 and increase from baseline  ≥60 
 


Statistical Analysis Plan  
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Date 20 August 2018 
82 
Appendix F 
REFERENCE RANGES AND TELVC FOR VITAL SIGNS 
 
Parameter 
Unit 
Low value 
Low decrease 
High value 
High increase 
Pulse 
Beats 
per 
minute 
≤50 
NA 
≥120 
NA 
≤50 and decrease from BL ≥20 
≥120 and increase from BL  ≥20 
Systolic blood 
pressure 
mmHg 
≤90 
NA 
≥160 
NA 
≤90 and decrease from BL ≥20 
≥160 and increase from BL  ≥20 
Diastolic blood 
pressure 
mmHg 
≤50 
NA 
≥100 
NA 
≤50 and decrease from BL ≥10 
≥100 and increase from BL  ≥10