Conditions: Lupus Nephritis
Keywords: lupus, nephritis, randomized, placebo, anifrolumab, safety, efficacy, adult
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 147
Healthy volunteers: no

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 active proliferative lupus nephritis (LN).

Detailed description:
This is a Phase 2, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of two intravenous (IV) treatment regimens of anifrolumab versus placebo while taking standard of care (SOC) treatment with mycophenolate mofetil (MMF) and corticosteroids in adult subjects with active proliferative lupus nephritis (LN).

Arms:
arm 1: Anifrolumab - Lower Dose arm 2: Anifrolumab - Higher Dose arm 3: Placebo IV Q4W plus SOC

Interventions: intervention 1: Anifrolumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administration every 4 week from Week 0 to Week 100 in addition to SOC which will continue until Week 112 intervention 2: Administration every 4 week from Week 0 to Week 100 in addition to SOC which will continue until Week 112

Protocol document:
Prot_000.pdf: 
• Protocol number: D3461C00007 
• Document title: A Multicentre, Randomised, Double-blind, Placebo controlled, 
Phase 2 Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects with 
Active Proliferative Lupus Nephritis 
• NCT number: NCT02547922 
• Version number:  4.0 
• Date of the document: 13 December 2017 


Clinical Study Protocol 
Drug Substance 
Anifrolumab 
Study Code 
D3461C00007 
Version 
4.0 
Date 
13 December 2017 
A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 2 
Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects 
with Active Proliferative Lupus Nephritis 
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
2 (231) 
VERSION HISTORY 
Version 4.0, 13 December 2017 
Changes to the protocol are summarised below. 
The renal function and proteinuria components of renal response criteria will be 
modified by changing the estimated glomerular filtration rate (eGFR) and 24-hour urine 
protein to creatinine ratio (UPCR) cut-off values. 
For complete renal response (CRR), the alternative complete renal response (aCRR), the 
partial renal response (PRR), graded CRR, and graded aCRR, the cut-off values for the renal 
function (eGFR) will be changed to:  
• 
eGFR to ≥60 mL/min/1.73m2 or no confirmed decrease of eGFR from 
baseline of ≥20%  
For CRR and aCRR, the cut-off value for proteinuria (24-hour UPCR) will be changed to: 
• 
24-hour UPCR to ≤0.7 mg/mg  
For graded CRR and graded aCRR, the cut-off values for proteinuria will be changed to: 
• 
For subjects with baseline 24-hour UPCR of >3 mg/mg 24-hour UPCR 
cut-off will be changed to ≤1 mg/mg 
• 
For subjects with baseline 24-hour UPCR of ≤3 mg/mg 24-hour UPCR 
cut-off will be changed to ≤0.7 mg/mg 
The flare definition for proteinuria (UPCR) will be changed to >1.5 mg/mg. 
Changes to objectives 
aCRR and 24-hour UPCR will be added as exploratory objectives at Week 104.  
It will be clarified that the proportion of subjects achieving PRR or CRR at Week 104 will be 
used to evaluate the effect of anifrolumab on lupus nephritis (LN) at this timepoint. 
Clarification will be added that International Society of Nephrology (ISN)/Renal Pathology 
Society (RPS) classification and National Institute of Health (NIH) indices will also be 
summarised based on CRR and PRR at Week 104. 
Interim analysis 
Text will be added that an interim analysis may be performed after approximately 50% of 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
3 (231) 
subjects have completed Week 52 visit.  
 
The statistical analysis plan (SAP) v1.0 was completed and the last 
SAP amendment will be completed prior to unblinding of data.
 
 
 
Changes to statistical analysis 
Text will be added in Section 8.6 that strong control of the familywise error rate will be 
performed for the primary and secondary endpoints for the pooled anifrolumab group 
compared with placebo as well as the respective tests for the individual anifrolumab regimens 
and the testing strategy to account for multiplicity considerations will be described. The power 
and minimal detectable difference will be updated based on primary endpoint for the pooled 
anifrolumab group compared with placebo in Section 8.2. The sample size will provide 
approximately 86% power with a 2-sided alpha of 0.049. 
Relevant sections in the protocol will be updated to be consistent with the SAP. 
• 
Text will be added that the primary and secondary endpoints will be 
based on the pooled anifrolumab group compared with the placebo group. 
• 
Three additional subgroups; ADA (positive at any time, negative), eGFR 
at baseline (<60 mL/min/1.73m2, ≥60 mL/min/1.73m2) and oral 
corticosteroids (OCS) dose at baseline (≤20 mg/day, >20 mg/day) will be 
added to Section 8.5.10. The geographic region subgroup will be 
renamed placebo response region. 
• 
The age subgroups in Section 8.5.10 will be changed to ≥18 to 64 and 
≥65 years. 
• 
In Section 8.1 it will be clarified that all personnel involved in the 
conduct of the study would remain blinded until database soft lock. 
• 
In Section 8.5 it will be clarified that nominal p-values could be 
presented for endpoints not included in the strategy for preserving type 1 
error rate. 
Other changes 
In Section 3.2.1, the exclusion criteria for aspratate transaminase (AST) and alanine 
transaminase (ALT) were changed to >2.5x upper limit of normal (ULN). 
It will be clarified that no increase in oral corticosteroids (OCS), or the use of intravenous (IV) 
intra-articular, tendon sheath or bursal injections is allowed from Week 40 until Week 52 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
4 (231) 
assessment. 
Exclusion criterion No.3 will be updated that subjects concurrently enrolled in another clinical 
study with an IP within 4 weeks prior to ICF signing will be excluded. 
Text for unblinding plan for anti-drug antibodies (ADA) and pharmacokinetic (PK) analysis 
will be added. 
Criteria for discontinuing investigational product (IP) at Week 52, Week 56 or Week 60 will 
be included. 
Pap smear will be clarified as follows: 
• 
In Section 4.2.1.2 that Pap smear results must be found to meet eligibility 
requirements for Pap smears as defined in Appendix K. Table 2 footnote 
h will be corrected to state that Pap smear results must be obtained after 
Week 48 and must be found to meet eligibility requirements for Pap 
smears as defined in Appendix K and available by Week 60 or IP will be 
discontinued.  
• 
Text on Pap smear access varying by country and recommendation that 
local guidelines for obtaining Pap smears in subjects who have received 
immunomodulators or immunosuppressive treatment be followed will be 
removed from Section 5.2.3.3 and footnote h in Table 2.  
• 
In Section 5.2.3.3 that the Pap smear will be repeated in female subjects 
with an intact cervix between Week 48 and Week 52 and Week 100 and 
Week 104 to ensure there is no evidence of new cervical dysplasia. 
Text in Section 4.2.1.1 will be edited to clarify that all Week 52 laboratory samples (blood and 
urine, including 24-hour UPCR sample) should be collected between Week 50 to Week 52, to 
allow assessment of PRR requirement for the second year and reference to Table 2 footnote 1 
included. Table 2 footnote 1 will be edited to be consistent with new text and footnote 2 
deleted. 
It will be clarified that Columbia-Suicide Severity Rating Scale (C-SSRS) is only collected 
until Week 52. It will be clarified that tuberculosis questionnaire, assessment of Cushingoid 
features, and assessment of cardiovascular risk (fasting lipid profile) will be analysed for 
safety. 
It will be clarified that only Ctrough will be assessed in the second year. 
It will be clarified that subjects would be randomised at approximately 95 sites and estimated 
date of last subject completed would be Q3 2020. 
Reference to UPCR will be removed from renal discontinuation at Week 52 as re-test applies 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
5 (231) 
to all PRR related laboratory tests not to UPCR only. 
In Section 3.9.9 it will be clarified that subjects who discontinue IP earlier than 12 weeks and 
before Week 52 will be followed until Week 52. 
Text in Section 4.2.1.3 on 24-hour UPCR and laboratory assessments will be removed as this 
was not needed for Week 104. 
In Section 4.2.2 it will be clarified that assessment for 24-hour UPCR should be completed for 
subjects who discontinue IP. 
In Section 5.1 it will be clarified that 24-hour UPCR will be used to derive CRR at Week 104. 
In Section 5.4.2 it will be clarified that drug concentration determination would be in serum 
not plasma. 
It will be clarified in Section 7.7.4.3 and Table 2 footnote v that randomised subjects who 
receive anti-malarial therapy within 12 months prior to signing ICF must have an eye exam by 
a qualified professional within 12 months prior to signing the ICF and that subjects starting 
anti-malarial therapy during the Screening Period must have an eye exam within 12 weeks 
after signing the ICF. 
In Section 7.2.4, it will be clarified that monitoring which include vital signs will be up to 
20 minutes before IP infusion starts and also within 20 minutes after completion of post-dose 
saline flush. 
Text on efficacy in anifrolumab Phase 2b study and safety experience in anifrolumab Phase 2b 
study through November 2015 in Section 1.3 will be deleted as information is already 
available in Investigator’s Brochure (IB). The overall benefit/risk assessment for study 
D3461C00007 section will be updated to be consistent with the current IB. 
Text on the objective of the Lupus Nephritis Steering Committee will be added to Section 9.4. 
It will be clarified that the World Health Organisation (WHO) Drug Dictionary not 
AstraZeneca Drug Dictionary will be used to classify medications. 
Typographical and grammatical errors and administrative changes will be corrected as needed 
throughout the protocol. 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
6 (231) 
Version 3.0, 3rd September 2016 
Changes to the protocol are summarised below. 
Text was added to clarify the study design of the second year extension period. Eligible 
subjects enrolled in the original Phase 2 study will continue in their randomised treatment 
groups. The treatment groups will continue to receive IP infusions (anifrolumab 300 mg or 
placebo) every 4 weeks (Q4W) starting at Week 52 for an additional 48 weeks in addition to 
standard of care (SOC) until Week 100. Final efficacy assessment will be made at Week 104. 
Safety follow-up will continue every 4 weeks until Week 112. 
Criteria for discontinuation of IP at Week 52 were added. 
Subjects not meeting the criteria to continue for the second year extension period will not 
receive any IP at Week 52 and will complete the study after completing the required follow-up 
visits. 
Subjects meeting the following criteria may continue to receive blinded IP between Weeks 52 
and 100. 
(i) 
Meeting all of the following criteria based on the renal portion of the PRR 
definition: 
• 
eGFR is: 
− 
≥80 mL/min/1.73 m2, if baseline eGFR was ≥90 mL/min/1.73 m2 or 
− 
>85% of baseline eGFR, if baseline eGFR was <90 mL/min/1.73 m2 
• 
Improvement in 24-hour UPCR: 
− 
For subjects with a baseline UPCR ≤3 gm/gm: <1.0 gm/gm 
− 
For subjects with a baseline UPCR >3 gm/gm: >50% improvement 
from baseline and ≤3.0 gm/gm 
Renal discontinuation criteria must be confirmed in two separate samples. The second UPCR 
measurement should be at least 1 week after the first measurement. 
(ii) 
No discontinuation of IP 
(iii) 
Negative human immunodeficiency virus (HIV) test after signing the Main 
informed consent form (ICF) 
Criteria for discontinuation of IP during the second year extension period were added: 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
7 (231) 
• 
Week 56: 
− 
Abnormal Pap smear or failure to obtain a Pap smear after Week 48  
− 
Failure to obtain Week 52 QuantiFERON test result by Week 56 
• 
At Week 60 and later 
− 
OCS >7.5 mg/d (except one OCS burst and taper) 
− 
Mycophenolate mofetil (MMF) >2 gm/day or >Week 52 dose, 
whichever is lower 
The following flow of activities related to the transitioning to the second year extension was 
added: 
• 
All Week 52 efficacy assessments must be completed prior to initiation 
of second year extension period dosing 
• 
First dose in second year extension period must be between Week 52 
(+14 days) and Week 60 
• 
At Week 52, the 24-hour UPCR may be collected between Weeks 50 and 
52 to assess response and eligibility for participation in the second year 
extension period 
• 
The eGFR measured between Week 50 and Week 52 will be used to 
assess eligibility for participation in the second year extension period 
• 
Safety assessments: 
The electrocardiogram (ECG) at Week 52 has to be done prior to dosing 
of IP. Pap smear, hepatitis B virus (HBV), QuantiFERON-tuberculosis 
(TB) are to be performed as per protocol. Results must be available prior 
to the Week 56 dosing of IP. The Week 56 dose (or the Week 60 dose if 
that is the first in the extension) cannot be administered without the 
results of the Pap smear, HBV and TB assessments 
Text was added to explain the treatments during the second year extension period: 
Blinded IP administration every 4 weeks (last dose at Week 100) 
MMF: 
− 
MMF ≤2 gm/day and ≤Week 52 dose, whichever is lower 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
8 (231) 
− 
If >2gm at Week 52, taper to ≤2 gm/day required by Week 60. Failure 
to do so will lead to withdrawal from IP 
− 
Decrease in MMF dose or discontinuation of MMF allowed at 
investigators discretion between Week 52 to Week 92; no minimum 
dose during second year 
− 
If MMF is tapered, return to ≤2 gm/day but not exceeding Week 52 
dose is allowed 
− 
No change in MMF dose from Week 92 to Week 104 
OCS: 
− 
If OCS >7.5 mg/day at Week 52, taper to ≤7.5 mg/day required by 
Week 60. Failure to do so will lead to withdrawal from IP 
− 
OCS tapering goal ≤5 mg/day at Week 80. Tapering below 5 mg/day 
allowed until Week 92 
− 
No change in OCS dose from Week 92 to Week 104 
− 
1 burst and taper allowed between Week 52 and Week 92 
Efficacy and safety assessments in the second year extension period were added to Tables 4 
and 5 to clarify the time points of the assessments. 
Schedule of samplings was added to Tables 4 and 5 to clarify the time points of sampling. 
 
 
 
 
 
 
 The 
database will be locked and the primary analysis will be performed once all subjects complete 
Week 52 or discontinue the study prior to Week 52. The Sponsor and Sponsor's delegates will 
be unblinded to treatment assignments at the time of the primary analysis.  
Investigators and subjects who continue in the second year extension phase will continue to be 
blinded to their treatment. The database will be locked for the final analysis of the second year 
extension period once the last subject in the second year extension period completes 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
9 (231) 
Week 112, or discontinues the second year extension period prior to Week 112. 
 
Version 2.0, 28th April 2016 
Changes to the protocol are summarised below. 
Text was added to clarify that stratification sample for 24- hour UPCR can be obtained within 
14 days prior to the expected date of randomisation. Without the results of this second 
(stratification) sample, subjects cannot be randomised. Turn-around time for results from 
central laboratory is up to 7 days. On rare occasion an extension of the 30-day screening 
window is allowed if the re collection of the sample is necessary or the results needed for 
randomisation are delayed. 
An error noted in relation to the duration of administration (first "12 weeks" instead of first "3 
doses of the IP") has been corrected throughout the protocol. 
Unit of UPCR has been corrected from "gm/gm" to "mg/mg" throughout the protocol. 
The abbreviation "SFI" has been deleted throughout the protocol and in Appendix L. The term 
SFI has been replaced by the term " Systemic Lupus Erythematosus Disease Activity Index 
2000 (SLEDAI-2K) based Flare Assessment Instrument" 
The outcome measure to evaluate the safety and tolerability of anifrolumab has been updated 
as "extra-renal flares using SLEDAI-2K based Flare Assessment Instrument". 
For the exploratory objectives, the criteria to determine improvement in 24-hour UPCR for 
subjects with a baseline UPCR >3 mg/mg has been updated as >50% improvement from 
baseline and ≥3.0 mg/mg (previously <3.0). 
A note has been added to clarify that MMF will be supplied by the Sponsor to the subjects 
from the day of randomisation onwards until the end of subject's participation in the study. 
MMF has been updated as "Sponsor provided MMF" in relevant sections of the protocol. 
The criteria for discontinuing IP at any time have been updated to include:  the receipt of 
methylprednisolone pulse, discontinuation of MMF and initiation of another 
immunosuppressant.  In addition, text was added to clarify that decrease is eGFR is to be 
based on two independent samples. 
The criteria for discontinuing IP at Week 12 and Week 24 have been revised to clarify the 
wording on OCS that decrease is eGFR is to be based on two independent samples. Cut-off 
values for nephrotic range UPCR have been aligned with that of UPCR values for 
stratification. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
10 (231) 
The term "patients" has been replaced with "subjects" where relevant. 
Section 1.3 has been updated based on the safety data from the new Investigator's Brochure 
(version 9.0, dated 18 November 2015). 
The minimum dose of MMF has been updated from ≤1.5 gm/day to ≤1.0 gm/day.  
Day 1 has been replaced by "the day of randomisation" for clarity in Section 1.4.1.2 and other 
applicable sections of the protocol, including the inclusion/exclusion criteria. 
Section 1.4.1.2 has been updated to clarify that methylprednisolone pulse can be administered 
on two consecutive days but the cumulative dose must not exceed 500 mg and that OCS burst 
and taper means one burst and taper of corticosteroids between Week 8 and Week 40 for 
increased extra renal systemic lupus erythematosus (SLE) disease activity or for non-SLE 
activity is allowed from randomisation to Week 40. 
Inclusion criterion No. 4(b) has been reworded to address indeterminate values and reference 
to the Laboratory Manual for specifics has been added. 
Inclusion criterion No. 7 has been updated to add System International (SI) values of urine 
protein to creatinine ratio and to clarify that the stratification sample  for UPCR can be 
collected within 14 days of expected date of randomisation. 
Inclusion criterion No. 9 has been updated to include a note on "borderline" pregnancy test 
result. 
Inclusion criteria No. 10, 11, 12, and 13 have been updated to be in line with the MMF 
product information. 
Table 1 under inclusion criterion No. 11 has been updated to remove mention of "plus condom 
or spermicide" and updated to state that one of the two effective methods of avoiding 
pregnancy should be the barrier method. 
Inclusion criterion No. 12 has been updated to provide clarity on the acceptable contraceptive 
methods. "MMF" has been added to clarify that contraception requirements are applicable for 
both IP and MMF. "MMF" has also been added in exclusion criterion No. 6, Section 5.4, 
Section 6.4.3, and Section 6.4.4. 
Text has been added in inclusion criterion No. 14 to provide examples of the types of 
malignancy that should not be noted at screening and to provide clarity on the timing of Pap 
smear at screening. Reference to exclusion criterion No. 36(b) has been added for clarity. 
Exclusion criterion No. 2 was revised to align with the change in the minimum dose of MMF 
(from ≤1.5 gm/day to ≤1.0 gm/day. 
Exclusion criterion No. 6 has been updated to add that the restriction could be 6 weeks after 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
11 (231) 
the last dose of MMF if it is later than 12 weeks after last dose of IP. 
Exclusion criterion No. 13(b) has been updated as "Oral or IV pulse methylprednisolone 
(cumulative dose)" for clarity. For exclusion criterion No. 13(d), equivalent dose of 
mycophenolate sodium has been added. 
Exclusion criterion No. 14(g) has been updated to simplify the haemoglobin eligibility 
requirements. 
Exclusion criterion No. 15 has been updated to include the term 'the subject' for clarity. 
Exclusion criterion No. 17 has been updated to clarify the washout period for specific 
concomitant medications. 
Exclusion criterion No. 19 has been updated for clarity. 
Exclusion criterion No. 26 has been updated to provide clarity on the criteria related to 
infection and malignancy risk factors. 
Exclusion criterion No. 27 has been updated to clarify that the subject's HBV DNA levels 
should be "below the lower limit of quantitation (LLOQ)" as per central laboratory to remain 
eligible for the study. Reference to HBV DNA level of >20 IU/mL has been deleted.  
Exclusion criterion No. 32 has been updated to remove the word "systemic" from "systemic 
opportunistic infection". Text has been added to clarify that vaginal, oral, and skin candidiasis 
is not an exclusion criterion. Definition of serious non opportunistic infection and reporting 
procedure in Section 6.5.2 has been updated and reference to Section 6.5.2 has been added in 
exclusion criterion No. 32. 
Exclusion criterion No. 36 has been updated to be consistent with the corresponding footnote 
in Table 2. 
Section 3.3.2.1 heading has been updated to clarify that the exclusionary timeframe for these 
medications is upon signing of ICF. The bullet point on "corticosteroid pulse" has been 
updated for clarity. 
Danazol, dapsone, sulfasalazine, and prednisolone have been removed from the list of 
restricted medications in Section 3.3.2.2. Cholestryramine has been added to the list. 
Reference to these medications in Section 3.3.2.1 has been deleted. Appendix G has been 
updated to reflect these changes. In Section 3.3.2.2, the term "burst and taper" has been 
deleted from the last bullet point and text has been added to cross refer to Section 3.3.2.1 for 
any increase in methylprednisolone pulses for clarity. 
Section 3.3.3.1 has been updated to provide clarity to the investigators whether reaching the 
target MMF dose of 2 gm/day was mandatory or just recommended. Texts have been added to 
clarify that the requirements for MMF dose escalation have to be met only once and re-testing 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
12 (231) 
is not required. Several other edits have also been made in Section 3.3.3.1 for clarity. 
Several edits have been in Section 3.3.3.2 for clarity.  
Text in Section 3.3.4.1 has been updated to simplify the protocol. 
Text in Section 3.3.4.2 has been updated to clarify that the use of Angiotensin Converting 
Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Blockers (ARB) was allowed if they 
were started 10 days prior to the second screening 24- hour UPCR. 
Text in Section 3.3.4.3 has been updated to provide clarity on the acceptable timeframe of 
documented ophthalmologic examination in subjects who have been taking anti-malarials for 
more than 12 months at the time of signing the ICF or, have initiated anti-malarials within 12 
months prior to signing the ICF. 
In Section 3.3.4.4, the term "enrolment" has been replaced by "signing ICF" to provide clarity 
on the timeframe. 
Section 3.3.4.5: The text has been moved up to the start of Section 3.3 and has been reworded 
for clarity. 
Section 3.4 has been updated to add additional information about instructions for subjects who 
were enrolled incorrectly.  
A new subsection (Section 3.7.3) on "blood donation" has been added to inform restriction on 
blood donation from date of randomisation until 6 weeks after the last dose of Sponsor 
provided MMF. 
In Section 3.8.2, bullet No. 11 which was erroneously included has been deleted. 
In Section 3.9, the heading name "Criteria for withdrawal" was replaced with "Screen 
failures". A sentence has been added to Section 3.9 to state that rescreening of a subject is 
permitted once. 
The term "study drug" has been replaced by "IP" in Section 3.10 for clarity. Similar changes 
have been made in all the applicable sections of the protocol. 
Following changes have been made in Table 2: 
• 
American College of Rheumatology (ACR) classification criteria at Visit 
1 has been unchecked. 
• 
QuantiFERON-TB Gold (QFT-G) test is checked at Visit 14 
• 
New rows for Sponsor-provided MMF and oral corticosteroids have been 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
13 (231) 
added 
• 
Footnotes have been added for Table 2 and the original foot-notes have 
been edited for better guidance and consistency. 
In Table 3, physical examination (PE) has been checked for Visit 15 and "urine pregnancy 
tests (using dipstick)" has been added for Visit 15 and Visit 16. 
Text in Section 4.1.1 has been reworded for clarity. 
Text in Section 4.1.3 has been updated to include the exception (minor dose adjustments done 
>3 months prior to the ICF signature date) to document prescription medications the subject 
has ever taken for SLE and LN. 
Subsections in Section 4.2 have been updated as: Section 4.2.1 End of treatment visit (Week 
52) and Section 4.2.2 Follow-up visits after premature discontinuation of IP. Edits have been 
made throughout this section for clarity and to simplify protocol. 
Text in Section 4.4 has been updated for clarity on the follow-up requirements in subjects who 
discontinue the IP but continue the study schedule and, other early discontinuation subjects. 
The term "unless otherwise specified" has been added in parenthesis in Section 5.1 for clarity 
Edits have been made throughout Section 5.2 for clarity and to simplify protocol. 
In section 5.3.2, text has been added to state that temperature should be measured by the same 
methodology for a subject throughout the study. 
In Section 5.3.3.3, the text on the requirement of Pap smear at screening in women who have 
not had their cervix surgically removed has been deleted. The text on the requirement of 
repetition of Pap smear if performed within 2 years prior to screening has been reworded for 
clarity. 
Text in Section 5.3.4 has been updated to provide clarity on the assessment of cardiovascular 
risk. 
Definition of extra-renal flares in Section 5.3.7 has been updated for clarity to clarify the 
timeframe for assessments related to the SLEDAI 2K. Section 5.3.7 heading has also been 
updated for clarity. 
Text in Section 5.3.9.1 has been reworded to provide clarity on the criteria for the screening 
QFT-G test and chest X-rays. 
Text in Section 5.3.9.3 has been updated to provide clarity around positive QTF-G test result. 
Text in Section 5.4 has been reworded to provide clarity on the urine pregnancy tests that are 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
14 (231) 
performed after the screening visit. 
Table 4 in Section 5.4 has been updated to reflect the changes made to the other relevant 
sections of the protocol. Activated partial thromboplastin time and prothrombin time have 
been grouped under a new subheading "Coagulation panel". International normalised ratio 
(INR) has been under this subheading as INR is part of the routine coagulation panel as per 
central laboratory specifications. A note has been added under Table 4 to state that 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. 
Cholesterol has been added as part of the fasting lipid profile in Section 5.4.1 as cholesterol is 
part of the routine lipid profile as per central laboratory specifications. 
Text has been added in Section 5.4.3 to state that the dose of MMF should be withheld until 
samples for the Mycophenolic acid (MPA) blood draw test has been collected on that visit 
day. Corresponding footnote has been added in Table 2. 
Text on how long the samples will be stored has been added in Section 5.4.4 and Section 
5.4.5. 
In Section 5.4.5.4, text has been reworded to clarify that pharmacogenomics is not considered 
a sub-study but an optional component of the protocol. 
Text in Section 5.4.5.5 has been reworded for clarify. 
In Section 5.5, text has been added to explain how the samples will be analysed for 
determination of drug concentration in plasma. 
Section 5.6 has been reworded to clarify the period of patient global assessment (PtGA).  
Section 6.4.1 have been updated to add the term 'or designee' due to the change in 
responsibility of unblinding and overdose reporting, respectively. Similar change has also 
been made in other applicable section of the protocol. 
Subsections on Maternal Exposure and Paternal Exposure have been added under Section 
6.4.2 (previously labelled as Section 6.4.3 and Section 6.4.4). Text has been updated to clarify 
that any subject or subject's partner who becomes pregnant during the course of the study 
should be followed up for pregnancy until the outcome of the pregnancy is known. Texts have 
also been updated to clarify the timeframe for collection of pregnancy data for both the IP and 
MMF.  
Text in Section 6.5.1 has been reworded to amend the definition of "serious non opportunistic" 
infection. 
Texts in Section 6.5.2, Section 6.5.4, Section 6.5.5, Section 6.5.6, Section 6.9.2, and Section 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
15 (231) 
6.9.3 have been updated to be in line with the Phase 3 SLE protocol. 
Text in Section 6.5.9 has been updated to provide further information regarding the criteria for 
review of events by an independent Cardiovascular Event Adjudication Committee (CV-
EAC). 
Text in Section 6.6.1 has been updated to provide clarity on the timeframe for collection of 
adverse events and serious adverse events (SAEs). Text has been added to clarify the 
timeframe for following up on SAEs and pregnancies occurring within the 12-week post final 
dose period. 
Text in Section 6.6.3 has been updated to be in line with the causality assessment in the 
Electronic Case Record Form (eCRF). 
Text in Section 6.6.4 has been updated to provide clarity that SAEs causal relationship will be 
assessed for "any" medication. 
Section 6.9 heading has been updated to include "MMF-related warnings and precautions". A 
new subsection (Section 6.9.3) on MMF-related warnings and precautions has been added. 
A sentence has been added to Section 7.1: "Study drug" refers to any medication mandated by 
the protocol. 
Text in Section 7.2.3 has been updated for clarity and to make the description of storage 
conditions in the protocol consistent with the updated Investigator's Brochure. Reference to 
Appendix K has been added in this section. 
Text in Section 7.2.4 has been updated to clarify the monitoring requirements applicable for 
the first 3 infusions and also to and to make distinction between infusion (not including saline 
flush) and administration (including saline flush). 
Section 7.2.6, Table 5, and Table 6 have been updated to ensure consistency between text and 
information presented in the tables. 
Text has been added in Section 8.2 to clarify that formal hypothesis testing will not be 
performed. 
The ≤ has been corrected to < in the second sub bullet point in Section 8.4.3.2 and Section 
8.4.3.3. 
Typographical error in the abbreviation PtGA in Section 8.4.4 has been corrected. 
Text in Section 8.5.1 and Section 8.5.10 have been updated to ensure consistency of the 
protocol with the SAP. 
Text on evaluation of change from baseline in spot UPCR has been added in Section 8.5.3 to 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
16 (231) 
align the protocol with the SAP. 
Text on training of study site personnel has been added in Section 9.1. 
Text has been added in Section 10.3 to clarify that the Investigatory should submit the written 
approval to AstraZeneca or designee before consenting of any subject into the study. 
Appendix E, Appendix G, Appendix J, Appendix L, Appendix M, and Appendix P have been 
updated in line with the updates made to the protocol. 
 
Version 1.0, 22nd May 2015 
Initial creation. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
17 (231) 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 


18 (231) 
CLINICAL STUDY PROTOCOL SYNOPSIS 
 
A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 2 
Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects 
with Active Proliferative Lupus Nephritis 
 
 
International Coordinating Investigator 
 
Cambridge CB2 20Q 
United Kingdom 
Study site(s) and number of subjects planned 
Approximately a total of 150 subjects are planned to be randomised at approximately 95 sites. 
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
Q3 2015 
2 
Estimated date of last subject completed 
Q3 2020 
 
 
Study design 
This is a Phase 2, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of two intravenous (IV) treatment regimens of 
anifrolumab versus placebo while taking protocol-specified standard of care (SOC) treatment 
with mycophenolate mofetil (MMF) and corticosteroids (see Section 7.7.3 for details) in adult 
subjects with active proliferative lupus nephritis (LN). The study will be performed in adult 
subjects, 18 to 70 years of age. 
PPD


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
19 (231) 
Approximately 150 subjects will be randomised in a 1:1:1 ratio to receive one of two IV 
dosing regimens of anifrolumab or placebo every 4 weeks (Q4W) for 48 weeks in addition to 
SOC which will continue until Week 52. After the primary objective time point at Week 52, 
eligible subjects will continue with randomised treatment (anifrolumab 300 mg or placebo IV 
Q4W) until Week 104. Those subjects not eligible to continue with treatment based on the 
Week 52 assessments will complete the 8 weeks of additional safety follow-up to complete 
involvement in the study. The regimens for anifrolumab are as follows: 
• 
Basic Regimen: Anifrolumab 300 mg IV Q4W (13 doses) plus SOC 
• 
Intensified Regimen: Anifrolumab 900 mg IV Q4W for the first 3 doses 
followed by 300 mg IV Q4W for an additional 10 doses plus SOC 
Subjects who meet the criteria at Week 52 (as defined in Section 3.9) to continue in the 
second year extension will continue to receive blinded IP (anifrolumab 300 mg or placebo IV 
Q4W) for an additional 13 doses plus SOC for another 52 weeks (second year extension 
period). 
The primary objective in the study is to evaluate the efficacy of anifrolumab plus SOC 
compared with placebo plus SOC in subjects with active proliferative LN measured by the 
relative difference in change from baseline to Week 52 in 24-hour urine protein to creatinine 
ratio (UPCR), comparing the pooled anifrolumab group (Basic and Intensified) to the placebo 
group. 
After all randomised subjects have completed the 52-week double-blind period, the data base 
will be soft-locked, and the primary analysis will be performed, including the assessment of 
the primary, secondary, and safety objectives. This analysis will also encompass available data 
collected after the 52 week time point and details will be provided in the Statistical Analysis 
Plan (SAP). At this stage the Sponsor and Sponsor’s delegate who are not directly involved in 
the management of sites will be unblinded to randomised treatment, but the subjects and 
Investigators will remain blinded (single-blind). The end of study analysis will be performed 
after all subjects have completed the second year extension period. One interim analysis may 
be conducted after approximately 50% of subjects have completed the Week 52 visit.
 
 
 
Investigational product (IP) will be administered as an IV infusion via an infusion pump over 
no less than 60 minutes for the first 3 doses of IP (Visits 1, 2, and 3). Starting with Visit 4, IP 
can be administered as an IV infusion via an infusion pump over no less than 30 minutes. 
Randomisation will be stratified using two factors: 
• 
Results of Type I interferon (IFN) test using a 4-gene type I IFN test (IFN 
test-high versus IFN test-low) at screening  
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
20 (231) 
• 
24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg (based on 24-hour UPCR 
performed on a sample obtained within 14 days prior to the expected date 
of randomisation). Without the results of the second (stratification) 
sample, subjects cannot be randomised. Turn-around time for results 
from central laboratory is up to 7 days.  
On rare occasions an extension of the 30-day screening window may be allowed if the 
re-collection of the 24-hour UPCR or other required samples is necessary or if the results 
needed for randomisation are delayed. Renal biopsy performed within 12 weeks prior to 
signing informed consent form (ICF) or during the screening period will be considered as the 
screening biopsy. Biopsies will be evaluated locally and the local classification will be used to 
confirm the eligibility criteria. The biopsy must reveal Class III (±Class V) or Class IV 
(±Class V) LN according to the World Health Organisation (WHO) or 2003 International 
Society of Nephrology/Renal Pathology Society ISN/RPS classification. An external renal 
biopsy adjudication group will adjudicate renal biopsies post-randomisation. 
The overall study duration is approximately 116 weeks: 
• 
A Screening Period: Up to 30 days  
• 
Treatment Period:  
The total treatment period is up to 100 weeks (26 doses administered 
every 4 weeks). 
− 
52 week double-blind treatment period: IP will be administered 
every 4 weeks from Week 0 to Week 48 for a total of 13 doses. The 
primary endpoint will be evaluated at Week 52. 
− 
Second year extension period: At Week 52, eligible subjects will 
continue treatment with IP (anifrolumab 300 mg or placebo) 
administration Q4W from Week 52 to Week 100 for a total of 13 
doses. The last efficacy assessments will be performed at Week 104. 
• 
Follow-up: After the completion of the last IP treatment (Week 48 for 
subjects who are not participating in the second year extension period and 
Week 100 for subjects who participate in the second year extension 
period) subjects will continue in the study for another 12 weeks of safety 
follow-up after the last administration of IP. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
21 (231) 
Objectives 
Primary Objective: 
Outcome Measure: 
To evaluate the efficacy of anifrolumab plus 
SOCa compared with placebo plus SOCa in 
subjects with active proliferative LN measured 
by the relative difference in change from 
baseline to Week 52 in 24-hour urine protein to 
creatinine ratio (UPCR) 
24-hour UPCR 
a Required SOC is described in Section 7.7.3. 
Secondary Objective: 
Outcome Measures: 
To evaluate the effect of anifrolumab plus 
SOCa compared with placebo plus SOCa on the 
proportion of subjects achieving Complete 
Renal Response (CRR) at Week 52 
CRR is defined as meeting all of the following: 
• 
Estimated glomerular filtration rate (eGFR) is 
­ 
≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20%  
• 
24-hour UPCR ≤0.7 mg/mg  
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
eGFR is based on Modification of Diet in Renal 
Disease (MDRD) formula 
a Required SOC is described in Section 7.7.3. 
b Allowed medication is described in Section 7.7. 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
22 (231) 
Safety Objective: 
Outcome Measures: 
To characterise the safety and tolerability of 
anifrolumab 
Adverse events (AEs) (including AEs of special 
interest [AESIs]), vital signs, physical examination, 
baseline and End of Treatment 12-lead 
electrocardiograms (ECG), and clinical laboratory 
tests (haematology, clinical chemistry, urinalysis), 
Columbia-Suicide Severity Rating Scale (C-SSRS), 
Personal Health Questionnaire Depression Scale-8, 
extra-renal flares using Systemic Lupus 
Erythematosus Disease Activity Index 2000 
(SLEDAI 2K) based Flare Assessment Instrument 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
23 (231) 
Exploratory Objective: 
Outcome Measures: 
To evaluate the effect of anifrolumab plus SOCa 
compared with placebo plus SOCa on: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
24 (231) 
Exploratory Objective: 
Outcome Measures: 
Proportion of subjects achieving alternative 
CRR (aCRR) at Week 52 (and Week 104) 
 
The difference between the CRR and the 
aCRR is the addition of a criterion regarding 
“inactive urine sediment” 
aCRR is defined as meeting all of the following: 
• 
eGFR is 
≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20% 
• 
24-hour UPCR ≤0.7 mg/mg  
• 
Inactive urine sediment (defined as <10 red 
blood cells [RBC]/hpf) 
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
eGFR is based on MDRD formula 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
25 (231) 
Exploratory Objective: 
Outcome Measures: 
Proportion of subjects meeting Graded aCRR 
at Week 52 (and Week 104) 
Graded aCRR is defined as meeting both the 24-hour 
UPCR and eGFR criteria: 
• 
A decrease in 24-hour UPCR: 
­ 
For subjects with baseline UPCR >3 mg/mg: 
UPCR ≤1 mg/mg 
­ 
For subjects with baseline UPCR ≤3 mg/mg: 
UPCR ≤0.7 mg/mg 
• 
eGFR: 
≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20% 
• 
Inactive urine sediment defined as <10 RBC/hpf 
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
Proportion of subjects able to achieve 
sustained reduction in oral corticosteroids 
(OCS) dose at Week 52 or Week 104 
Sustained reduction of OCS dose: 
• 
Week 52: Prednisone-equivalent dose 
≤7.5 mg/day by Week 24 and not exceeding this 
dose through Week 52 
• 
Week 104: Prednisone-equivalent dose 
≤5.0 mg/day by Week 80 and not exceeding this 
dose through Week 104  
and 
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
Proportion of subjects achieving CRR at 
Week 52 or Week 104 and achieving sustained 
reduction of OCS dose 
CRR (see definition of CRR above) 
Sustained reduction of OCS dose (see definition 
above) 
 
 
 
 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
26 (231) 
Exploratory Objective: 
Outcome Measures: 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
27 (231) 
Exploratory Objective: 
Outcome Measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean change in scores for overall disease 
activity from baseline to Week 52 (and to 
Week 104) 
SLEDAI-2K 
Mean change in score measures of non-renal 
disease activity from baseline to Week 52 (and 
to Week 104) 
Non-renal components of SLEDAI-2K 
Mean change in scores for overall disease 
activity from baseline to Week 52 (and to 
Week 104) 
Physician’s Global Assessment (PGA) 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
28 (231) 
Exploratory Objective: 
Outcome Measures: 
Mean change in the Systemic Lupus 
International Collaborating Clinics/American 
College of Rheumatology (SLICC/ACR) 
Damage Index (SDI) score from baseline to 
Week 52 (and to Week 104) 
SDI 
Mean change in scores for patient-reported 
health status from baseline to Week 52 (and to 
Week 104) 
Patient Global Assessment (PtGA) 
To evaluate the immunogenicity of 
anifrolumab, pharmacokinetics (PK), 
pharmacodynamics (the PK and 
immunogenicity results will be reported in the 
clinical study report) 
Anti-drug antibodies (ADA), anifrolumab 
concentration and PK parameters, 21 gene type I IFN 
gene signature 
To evaluate the pharmacokinetics of 
mycophenolic acid (MPA) 
MPA concentration and PK parameters (if applicable) 
Mean change in lupus serology from baseline 
to Week 52 (and to Week 104) 
Anti-dsDNA antibodies, C3 and C4 complement 
levels 
 
 
 
 
 
a 
 Required SOC is described in Section 7.7.3.  
b 
Allowed medication is described in Section 7.7. 
c 
Note: Spot UPCR will be used instead of 24-hour UPCR for the PRR and CRR classification, when 
evaluating time to renal response modified to include OCS tapering requirement as well as for the PRR and 
CRR classification for flare assessment. 
Target subject population 
The study will be performed in adult subjects, 18 to 70 years of age with documented active 
proliferative LN. 
Duration of treatment 
The overall study duration is approximately 116 weeks. The total treatment period is 
approximately 100 weeks (26 doses administered every 4 weeks): 
• 
52 week double-blind treatment period: IP will be administered every 
4 weeks from Week 0 to Week 48 for a total of 13 doses. 
• 
Second year extension period: IP will be administered every 4 weeks 
from Week 52 to Week 100 for a total of 13 doses plus SOC. 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
29 (231) 
Investigational product, dosage and mode of administration 
Approximately 150 subjects will be randomised in a 1:1:1 ratio to receive one of the two IV 
anifrolumab dosing regimens or placebo, as follows: 
• 
Basic Regimen: Anifrolumab 300 mg IV Q4W (13 doses) plus SOC or 
• 
Intensified Regimen: Anifrolumab 900 mg IV Q4W for the first 3 doses 
followed by 300 mg IV Q4W for an additional 10 doses plus SOC or 
• 
Placebo: IV Q4W plus SOC 
Subjects eligible for the second year extension will continue to receive blinded IP (in the 
treatment arm they were randomised to on Day 1) for another 13 doses plus SOC.  
Criteria for discontinuing investigational product for worsening of LN or SLE: 
At any time: 
• 
>30% decrease in eGFR compared to baseline due to LN and eGFR 
<60 mL/min/1.73 m2 (on two independent samples) or 
• 
Increase in renal or extra-renal lupus activity requiring prohibited 
systemic immunosuppressive treatment (eg, cyclophosphamide, 
rituximab, belimumab) 
• 
Receipt of >1 methylprednisolone pulse after the day of randomisation 
• 
Receipt of any methylprednisolone pulse after Week 8 
• 
The IP will be discontinued if MMF is discontinued and another 
immunosuppressant is initiated 
At Week 12 and Week 24: 
• 
eGFR <75% of baseline and <60 mL/min/1.73 m2 (on two independent 
samples) or 
• 
Nephrotic range UPCR (confirmed by a second measurement at least two 
weeks after the first measurement): 
− 
Subjects with 24-hour UPCR ≤3 mg/mg at baseline will be withdrawn 
if 24-hour UPCR increases by >50% from baseline to >3.5 mg/mg 
− 
Subjects with 24-hour UPCR >3 mg/mg at baseline will be withdrawn 
if 24-hour UPCR at Week 24 >3.5 mg/mg and there is <60% 
improvement from baseline or 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
30 (231) 
• 
Inability to adhere to corticosteroids requirements:  
− 
Inability to reduce OCS to ≤15 mg/day prednisone-equivalent at 
Week 12 
− 
Inability to reduce OCS to ˂15 mg/day by Week 24 
Subjects who exceed the maximum daily OCS dose at the Week 12 or Week 24 visits may 
continue to receive IP if the current dose is part of a temporary increase in OCS dose (eg, 
protocol-allowed burst and taper). Subjects who cannot be returned to their pre-increase dose 
within 14 days from the start of increase will have their IP discontinued at the next visit. 
Subjects who discontinue the IP before Week 48 will be followed until Week 52 (or for a 
minimum of 12 weeks after last dose of IP for subjects for whom IP was discontinued within 
12 weeks of Week 52). 
Criteria for discontinuing investigational product at Week 52: 
Subjects not meeting the criteria to continue in the second year extension period will not 
receive any IP at Week 52 and will complete the study after completing the required follow-up 
visits. 
Subjects meeting the following criteria may continue to receive blinded IP between Weeks 52 
and 100. 
(i) 
Meeting all of the following criteria based on the renal portion of the PRR 
definition: 
• 
eGFR is: 
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline 
of ≥20% 
• 
Improvement in 24-hour UPCR: 
− 
For subjects with a baseline UPCR ≤3 mg/mg: <1.0 mg/mg 
− 
For subjects with a baseline UPCR >3 mg/mg: >50% improvement 
from baseline and ≤3.0 mg/mg 
Renal discontinuation criteria must be confirmed in two separate samples. The 
second UPCR measurement should be at least 1 week after the first measurement. 
(ii) 
No discontinuation of IP 
(iii) 
Negative human immunodeficiency virus (HIV) test after signing the Main ICF 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
31 (231) 
The study Medical Monitor/Designee will confirm eligibility criteria based on electronic data 
capture (EDC) system, and from the central laboratory.  
Criteria for discontinuing investigational product at Week 52, Week 56 or Week 60: 
• 
Failure to obtain pap smear after Week 48 with result available at 
Week 60 at latest 
• 
Pap smear result not meeting the eligibility criteria (see Appendix K) at 
Week 52, 56, or 60 of a Pap smear obtained after Week 48 
• 
Failure to obtain Week 52 QuantiFERON test result by Week 56 
Criteria for discontinuing investigational product at Week 60 and later: 
• 
OCS >7.5 mg/day (except one OCS burst and taper) 
• 
MMF >2 gm/day or >Week 52 dose, whichever is lower 
Subjects who discontinue the IP during the second year extension period will be followed 
until Week 104 (or for a minimum of 12 weeks after last dose of IP for subjects for whom IP 
was discontinued within 12 weeks of Week 104). 
Statistical methods 
The primary estimand is evaluating the efficacy on disease activity of anifrolumab relative to 
placebo in subjects with active proliferative LN. This is measured by the relative difference in 
change from baseline to Week 52 in 24-hour UPCR. The full analysis set, defined as subjects 
who are randomised and received at least 1 dose of IP (modified Intention-To-Treat) will be 
used, in order to reflect the effect of the initially assigned and dosed IP. 
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 IP 
and will be analysed according to randomised treatment (modified Intention-To-Treat 
principle). Any major deviations from randomised treatment will be listed and considered 
when interpreting the safety data. 
Analysis method for primary endpoint 
The analysis will be performed using a mixed model repeated measures fitted to log-
transformed data comparing the pooled anifrolumab group (Basic and Intensified) with the 
placebo group, with fixed effects for treatment group, visit, stratification factors and log-
transformed 24 hour UPCR at baseline.  An interaction term for visit and treatment will also 
be included in the model to allow the relationship to differ across treatment groups. Note that 
visit will be fitted as a repeated variable in the model. Model assumptions will be checked 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
32 (231) 
and, if not met, appropriate data transformations may be applied or non-parametric approaches 
will be considered. 
Analysis method for safety endpoints 
All safety variables will be analysed descriptively. The safety analysis will be based on the 
full analysis set.  
Interim analysis 
One interim analysis may be conducted after approximately 50% of subjects have completed 
the Week 52 visit. 
 
Sample size calculations 
A total of 150 subjects will be randomised in a 1:1:1 ratio to receive one of the two IV 
anifrolumab dosing regimens (Basic Regimen or Intensified Regimen) or placebo. 
The sample size is based on the following assumptions: 
• 
Reductions from baseline to Week 52 in 24-hour UPCR of 65% and 46% 
for the anifrolumab and placebo arms, respectively (ie, ratios of 24-hours 
UPCR from Week 52 to baseline of 0.35 and 0.54, respectively), based 
on data presented in Furie et al, 20141.  
• 
The log-transformed 24-hour UPCR values follow a normal distribution 
with a standard deviation (SD) of 0.8, based on data from the anifrolumab 
Phase 2b study (CD1013). 
Based on these assumptions, a sample size of 50 subjects per arm would result in an observed 
relative difference in the change from baseline to Week 52 in 24-hour UPCR of 0.65 (here 
expressed as the ratio, comparing anifrolumab to placebo), and a corresponding 95% 
confidence interval (CI) of (0.50, 0.85) comparing the pooled anifrolumab group (Basic and 
Intensified) with the placebo group. If the interim analysis is performed, a 0.001 two-sided 
alpha will be spent, and the final analysis will based on a 2-sided alpha of 0.049 (East Version 
6.4). This sample size provides approximately 86% power with a 2-sided alpha of 0.049 to 
reject the hypothesis of no effect (relative difference =1) for comparing the pooled 
anifrolumab treatment group with placebo. The minimal detectable relative difference in the 
change from baseline to Week 52 in 24-hour UPCR between the pooled anifrolumab treatment 
group versus placebo is approximately 0.76, corresponding to a reduction from baseline to 
Week 52 in 24-hour UPCR of 59% in the pooled anifrolumab group (ratio of 24-hour UPCR 
from Week 52 to baseline of 0.41).
                                                 
1 Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL, et al. Efficacy and safety of abatacept 
in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol. 2014;66(2):379-839. 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
33 (231) 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
CLINICAL STUDY PROTOCOL SYNOPSIS ..................................................... 18 
TABLE OF CONTENTS ....................................................................................... 33 
1. 
INTRODUCTION ................................................................................................. 48 
1.1 
Background and rationale for conducting this study ............................................. 48 
1.2 
Rationale for study design, doses and control groups ............................................ 51 
1.2.1 
Rationale for study design ..................................................................................... 51 
1.2.2 
Rationale for primary endpoint selection ............................................................... 52 
1.2.3 
Rationale for duration of treatment ........................................................................ 53 
1.2.4 
Rationale for dose selection ................................................................................... 53 
1.2.5 
Rationale for duration of infusion .......................................................................... 54 
1.2.6 
Interferon test background ..................................................................................... 54 
1.3 
Benefit/risk and ethical assessment........................................................................ 55 
1.4 
Study Design .......................................................................................................... 57 
1.5 
Study governance and oversight ............................................................................ 63 
1.5.1 
Data and Safety Monitoring Board ........................................................................ 63 
1.5.2 
Lupus Nephritis Steering Committee ..................................................................... 63 
2. 
STUDY OBJECTIVES .......................................................................................... 63 
2.1 
Primary objective ................................................................................................... 63 
2.2 
Secondary objectives ............................................................................................. 64 
2.3 
Safety objectives .................................................................................................... 64 
2.4 
Exploratory objectives ........................................................................................... 65 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 70 
3.1 
Inclusion criteria .................................................................................................... 71 
3.2 
Exclusion criteria ................................................................................................... 74 
3.2.1 
General exclusion criteria ...................................................................................... 75 
3.2.2 
Exclusion criteria related to concomitant medications .......................................... 76 
3.2.3 
Exclusion criteria related to systemic lupus erythematosus and other 
diseases .................................................................................................................. 78 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
34 (231) 
3.2.4 
Exclusion criteria related to infection and malignancy risk factors ....................... 79 
3.3 
Subject enrolment and randomisation .................................................................... 80 
3.4 
Procedures for handling incorrectly enrolled or randomised subjects ................... 81 
3.5 
Methods for assigning treatment groups ................................................................ 82 
3.6 
Methods for ensuring blinding ............................................................................... 82 
3.7 
Methods for unblinding .......................................................................................... 82 
3.7.1 
Unblinding for Data and Safety Monitoring Board ............................................... 84 
3.8 
Restrictions ............................................................................................................ 84 
3.8.1 
Fasting lipid profile ................................................................................................ 84 
3.8.2 
Perioperative management of investigational product ........................................... 84 
3.8.2.1 
Major surgeries ...................................................................................................... 84 
3.8.2.2 
Non-major surgeries ............................................................................................... 84 
3.8.3 
Blood donation ....................................................................................................... 85 
3.9 
Discontinuation of investigational product ............................................................ 85 
3.9.1 
Criteria for discontinuation of investigational product due to worsening LN 
or SLE (at any time) ............................................................................................... 85 
3.9.2 
Criteria for discontinuation of investigational product for worsening of LN 
or SLE at Week 12 and Week 24 ........................................................................... 85 
3.9.3 
Criteria for discontinuation of investigational product during the second 
year extension period: ............................................................................................ 86 
3.9.4 
Criteria for discontinuation of investigational product for reasons other 
than lack of efficacy at any time during the study ................................................. 87 
3.9.5 
Subject decision to discontinue investigational product ........................................ 89 
3.9.6 
Withdrawal of the informed consent ...................................................................... 89 
3.9.7 
Lost to follow-up .................................................................................................... 89 
3.9.8 
Study completion and end of study ........................................................................ 89 
3.9.9 
Procedures for discontinuation of a subject from investigational product ............ 90 
3.10 
Criteria for withdrawal ........................................................................................... 90 
3.11 
Discontinuation of the study .................................................................................. 91 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 91 
4.1 
Screening/Enrolment period ................................................................................ 109 
4.1.1 
Re-screening subjects who screen fail ................................................................. 109 
4.1.2 
Medical history .................................................................................................... 109 
4.1.3 
SLE and LN medication history .......................................................................... 110 
4.2 
Treatment period .................................................................................................. 110 
4.2.1 
Week 52 visit ....................................................................................................... 110 
4.2.1.1 
Assessment criteria for participation in the second year extension period 
(Week 52) ............................................................................................................. 111 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
35 (231) 
4.2.1.2 
Initiation of dosing in the second year extension period (Week 52 to Week 
60) ........................................................................................................................ 111 
4.2.1.3 
Week 104 visit ..................................................................................................... 111 
4.2.2 
Follow-up visits after premature discontinuation of investigational product ...... 111 
4.3 
Unscheduled visit ................................................................................................. 112 
4.4 
Follow-up period .................................................................................................. 113 
5. 
STUDY ASSESSMENTS ................................................................................... 113 
5.1 
Efficacy assessments ............................................................................................ 113 
5.1.1 
Renal biopsy ......................................................................................................... 115 
5.1.2 
Systemic Lupus Erythematosus Disease Activity Index 2000............................. 116 
5.1.3 
Systemic Lupus International Collaborating Clinics/American College 
Rheumatology damage index ............................................................................... 116 
5.1.4 
Physician’s Global Assessment ........................................................................... 116 
5.1.5 
Oral corticosteroid reduction ............................................................................... 117 
5.2 
Safety assessments ............................................................................................... 117 
5.2.1 
Adverse events ..................................................................................................... 117 
5.2.2 
Vital signs ............................................................................................................ 118 
5.2.3 
Physical examination ........................................................................................... 118 
5.2.3.1 
Complete physical examination ........................................................................... 118 
5.2.3.2 
Focused physical examination ............................................................................. 118 
5.2.3.3 
Pap smear ............................................................................................................. 118 
5.2.3.4 
Assessment of Cushingoid features ..................................................................... 119 
5.2.4 
Electrocardiogram ................................................................................................ 119 
5.2.5 
Assessment of cardiovascular risk ....................................................................... 119 
5.2.6 
Columbia-Suicide Severity Rating Scale ............................................................. 119 
5.2.7 
Personal Health Questionnaire Depression Scale–8 ............................................ 120 
5.2.8 
SLEDAI-2K based Flare Assessment Instrument ................................................ 120 
5.2.9 
Tuberculosis screening and monitoring ............................................................... 120 
5.2.9.1 
Screening evaluation ............................................................................................ 120 
5.2.9.2 
Tuberculosis results from screening evaluations ................................................. 121 
5.2.9.3 
Tuberculosis monitoring during the study ........................................................... 122 
5.2.10 
Safety laboratory tests .......................................................................................... 124 
5.2.10.1 Laboratory assessments for cardiovascular risk assessments .............................. 127 
5.2.11 
Immunological tests ............................................................................................. 127 
5.2.11.1 Immunology profile ............................................................................................. 127 
5.2.11.2 Lupus serology ..................................................................................................... 127 
5.2.11.3 Anti-drug antibodies ............................................................................................ 128 
5.2.11.4 Neutralising antibodies ........................................................................................ 128 
5.2.12 
Mycophenolic acid levels .................................................................................... 128 
5.3 
Other assessments ................................................................................................ 128 
5.3.1 
Quality of life/pharmacoeconomic assessments .................................................. 128 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
36 (231) 
5.3.1.1 
Patient Global Assessment ................................................................................... 128 
5.4 
Pharmacokinetics ................................................................................................. 128 
5.4.1 
Collection of samples ........................................................................................... 128 
5.4.2 
Determination of drug concentration ................................................................... 129 
5.4.3 
Storage and destruction of pharmacokinetic samples .......................................... 129 
5.5 
Pharmacodynamics .............................................................................................. 129 
5.5.1 
Collection of samples ........................................................................................... 129 
5.5.2 
Storage, re-use and destruction of pharmacodynamic samples ........................... 129 
5.6 
Genetics ................................................................................................................ 129 
5.6.1 
Pharmacogenomics (optional).............................................................................. 129 
5.7 
Biomarker analysis ............................................................................................... 130 
5.7.1 
Serum and plasma biomarkers ............................................................................. 130 
5.7.2 
Urine biomarkers ................................................................................................. 130 
5.7.3 
RNA transcript profiling ...................................................................................... 130 
5.7.4 
Interferon test in whole blood .............................................................................. 131 
5.7.5 
Tissue biomarkers: immunostaining, epigenetic and gene expression 
studies on renal biopsies (optional) ...................................................................... 131 
5.7.6 
Storage, re-use and destruction of biological samples ......................................... 131 
5.7.7 
Labelling and shipment of biological samples ..................................................... 131 
5.7.8 
Chain of custody of biological samples ............................................................... 131 
5.7.9 
Withdrawal of Informed Consent for donated biological samples ...................... 132 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT ............................ 133 
6.1 
Definition of adverse events ................................................................................ 133 
6.2 
Definitions of serious adverse event .................................................................... 133 
6.3 
Hy’s Law .............................................................................................................. 134 
6.4 
Definition of Adverse Event of Special Interest .................................................. 134 
6.4.1 
Non-opportunistic serious infection ..................................................................... 134 
6.4.2 
Opportunistic infection ........................................................................................ 134 
6.4.3 
Anaphylaxis ......................................................................................................... 135 
6.4.4 
Malignancy .......................................................................................................... 135 
6.4.5 
Herpes zoster ........................................................................................................ 135 
6.4.6 
Tuberculosis ......................................................................................................... 135 
6.4.7 
Influenza .............................................................................................................. 136 
6.4.8 
Vasculitis (non-systemic lupus erythematosus) ................................................... 137 
6.4.9 
Major acute cardiovascular events ....................................................................... 137 
6.5 
Recording of adverse events ................................................................................ 137 
6.5.1 
Time period for collection of adverse events ....................................................... 137 
6.5.2 
Follow-up of unresolved adverse events .............................................................. 138 
6.5.3 
Variables .............................................................................................................. 138 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
37 (231) 
6.5.4 
Causality collection .............................................................................................. 140 
6.5.5 
Adverse events based on signs and symptoms..................................................... 140 
6.5.6 
Adverse events based on examinations and tests ................................................. 140 
6.5.7 
Disease progression/worsening of systemic lupus erythematosus and lupus 
nephritis ................................................................................................................ 141 
6.6 
Reporting of serious adverse events..................................................................... 141 
6.7 
Reporting of adverse events of special interest .................................................... 142 
6.8 
Overdose .............................................................................................................. 142 
6.9 
Pregnancy ............................................................................................................. 142 
6.9.1 
Maternal exposure ................................................................................................ 143 
6.9.2 
Paternal exposure ................................................................................................. 144 
6.10 
Medication Error .................................................................................................. 144 
6.11 
Management of investigational product-related toxicities and MMF-related 
warnings and precautions ..................................................................................... 145 
6.11.1 
Anaphylaxis, hypersensitivity, and infusion-related reactions ............................ 145 
6.11.2 
Infections .............................................................................................................. 145 
6.11.3 
MMF-related warnings and precautions .............................................................. 146 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................. 147 
7.1 
Identity of investigational product(s) ................................................................... 147 
7.2 
Dose and treatment regimens ............................................................................... 148 
7.2.1 
Dose preparation steps ......................................................................................... 148 
7.2.2 
Prior to administering the investigational product ............................................... 148 
7.2.3 
Investigational product administration procedures .............................................. 148 
7.2.4 
Subject monitoring/procedures during and after the infusion .............................. 149 
7.2.5 
Discharge ............................................................................................................. 150 
7.2.6 
Documentation of investigational product administration ................................... 150 
7.3 
Labelling .............................................................................................................. 151 
7.4 
Storage ................................................................................................................. 152 
7.5 
Compliance .......................................................................................................... 152 
7.6 
Accountability ...................................................................................................... 152 
7.7 
Concomitant and other treatments ....................................................................... 152 
7.7.1 
Anti-hypertensive agents and statins ................................................................... 153 
7.7.2 
Excluded medications .......................................................................................... 153 
7.7.2.1 
Medications that are excluded after signing the ICF ........................................... 153 
7.7.2.2 
Restricted medications ......................................................................................... 154 
7.7.3 
Standard of care immunosuppressive treatment during the study ....................... 154 
7.7.3.1 
Mycophenolate mofetil ........................................................................................ 154 
7.7.3.2 
Corticosteroids ..................................................................................................... 157 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
38 (231) 
7.7.4 
Other concomitant medications ........................................................................... 159 
7.7.4.1 
Topical therapy .................................................................................................... 159 
7.7.4.2 
Anti-proteinuric agents (ACEI or ARB) .............................................................. 160 
7.7.4.3 
Anti-malarials ...................................................................................................... 160 
7.7.4.4 
Non-steroidal anti-inflammatory drugs ................................................................ 160 
7.7.4.5 
Acetaminophen (Paracetamol): ............................................................................ 161 
7.7.4.6 
Narcotic analgesics .............................................................................................. 161 
7.8 
Post Study Access to Study Treatment ................................................................ 161 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA .......................................... 161 
8.1 
Statistical considerations ...................................................................................... 161 
8.2 
Sample size estimate ............................................................................................ 162 
8.3 
Definitions of analysis sets .................................................................................. 162 
8.3.1 
All subjects analysis set ....................................................................................... 162 
8.3.2 
Full analysis set .................................................................................................... 163 
8.3.3 
Pharmacokinetic analysis set ............................................................................... 163 
8.4 
Outcome measures for analyses ........................................................................... 163 
8.4.1 
Primary outcome variable .................................................................................... 163 
8.4.2 
Secondary outcome variables............................................................................... 163 
8.4.2.1 
Complete renal response ...................................................................................... 163 
8.4.3 
Exploratory outcome variables ............................................................................ 164 
8.4.3.1 
24-hour UPCR ..................................................................................................... 164 
8.4.3.2 
At least partial renal response .............................................................................. 164 
8.4.3.3 
Complete renal response in second year extension period .................................. 164 
8.4.3.4 
Graded complete renal response .......................................................................... 164 
8.4.3.5 
Alternative Complete renal response ................................................................... 165 
8.4.3.6 
Graded alternative complete renal response ........................................................ 165 
8.4.3.7 
Sustained reduction of oral corticosteroid dose ................................................... 166 
8.4.3.8 
Renal response modified to include oral corticosteroid tapering 
requirement .......................................................................................................... 166 
8.4.3.9 
Estimated glomerular filtration rate ..................................................................... 167 
8.4.3.10 Time to achieve renal response modified to include oral corticosteroid 
tapering requirement ............................................................................................ 167 
8.4.3.11 Time to renal flare ................................................................................................ 168 
8.4.3.12 Renal biopsy: ISN/RPS classification and NIH activity and chronicity 
indices .................................................................................................................. 168 
8.4.3.13 Other exploratory endpoints ................................................................................ 169 
8.4.4 
Patient-reported outcome variables ...................................................................... 169 
8.4.5 
Safety variables .................................................................................................... 169 
8.4.5.1 
Other significant adverse events .......................................................................... 170 
8.4.6 
Immunogenicity variables .................................................................................... 170 
8.4.7 
Pharmacokinetic variables ................................................................................... 170 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
39 (231) 
8.4.8 
Lupus serology variables ..................................................................................... 170 
8.4.9 
Pharmacodynamic outcome variables .................................................................. 171 
8.5 
Methods for statistical analyses ........................................................................... 171 
8.5.1 
Analysis of the primary variable .......................................................................... 172 
8.5.2 
Analysis of the secondary variable ...................................................................... 173 
8.5.3 
Analysis of exploratory variables ........................................................................ 174 
8.5.4 
Analysis of safety variables ................................................................................. 175 
8.5.5 
Renal biopsy: ISN/RPS classification, NIH activity and chronicity indices ....... 175 
8.5.6 
Analysis of immunogenicity variables ................................................................. 175 
8.5.7 
Analysis of pharmacokinetic variables ................................................................ 176 
8.5.8 
Analysis of pharmacodynamic variables ............................................................. 176 
8.5.9 
Analysis of lupus serology variables ................................................................... 176 
8.5.10 
Subgroup analysis ................................................................................................ 176 
8.5.11 
Interim analysis .................................................................................................... 177 
8.6 
Testing strategy to account for multiplicity considerations ................................. 177 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ........................ 179 
9.1 
Training of study site staff ................................................................................... 179 
9.1.1 
Training and certification for systemic lupus erythematosus assessments .......... 179 
9.2 
Monitoring of the study ....................................................................................... 180 
9.2.1 
Source data ........................................................................................................... 181 
9.2.2 
Study agreements ................................................................................................. 181 
9.2.3 
Archiving of study documents ............................................................................. 181 
9.2.4 
SLE Data Medical Review Team ........................................................................ 181 
9.3 
Study timetable and end of study ......................................................................... 181 
9.4 
Data management ................................................................................................. 182 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 183 
10.1 
Ethical conduct of the study ................................................................................. 183 
10.2 
Subject data protection ......................................................................................... 183 
10.3 
Ethics and regulatory review................................................................................ 183 
10.4 
Informed consent ................................................................................................. 184 
10.5 
Changes to the Clinical Study Protocol and Informed Consent Form ................. 185 
10.6 
Audits and inspections ......................................................................................... 185 
11. 
LIST OF REFERENCES ..................................................................................... 185 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
40 (231) 
LIST OF TABLES 
Table 1 
Effective methods of birth control (2 Required) ...................................... 73 
Table 2 
Study plan detailing the procedures from screening through Week 
52 treatment period (double-blind period)................................................ 92 
Table 3 
Study plan detailing the procedures during follow-up (for subjects 
not participating in the second year extension period) ............................. 99 
Table 4 
Study plan detailing the procedures from Week 56 to Week 104 
during the second year extension period ................................................ 102 
Table 5 
Study plan detailing the procedures during follow-up (second year 
extension period) .................................................................................... 106 
Table 6 
Clinical laboratory tests .......................................................................... 125 
Table 7 
Compatible materials of construction for IV bags.................................. 151 
Table 8 
Compatible materials of construction for ancillaries (eg, infusion 
tubing) ..................................................................................................... 151 
 
LIST OF FIGURES 
Figure 1 
Distribution of IFN transcript scores ........................................................ 55 
Figure 2 
Study flow chart (52 week double-blind treatment period) ...................... 61 
Figure 3 
Multiplicity correction at final analysis .................................................. 178 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
41 (231) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
42 (231) 
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 
ACEI 
Angiotensin-Converting-Enzyme Inhibitor 
ACR 
American College of Rheumatology 
aCRR 
Alternative complete renal response 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIS 
Adenocarcinoma in situ  
ALP 
Alkaline Phosphatase 
ALT 
Alanine transaminase 
ANA 
Antinuclear antibody 
Anti-dsDNA 
Anti-double stranded deoxyribonucleic acid 
Anti-RNP 
Anti-ribonucleoprotein  
APS 
Anti-phospholipid syndrome  
ARB 
Angiotensin II Receptor Blocker 
AST 
Aspartate transaminase 
β-hCG 
β human chorionic gonadotropin 
BCG 
Bacillus Calmette-Guérin 
BICLA 
BILAG-based Combined Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
Blood pressure 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
43 (231) 
Abbreviation or 
special term 
Explanation 
BUN 
Blood Urea Nitrogen 
C3 
Third component of complement 
C4 
Fourth component of complement 
CDC 
Centers for Disease Control and Prevention  
CHMP 
Committee for Medicinal Products for Human Use  
CI 
Confidence interval 
CIN III 
Cervical intraepithelial neoplasia grade III  
CIS 
Carcinoma in situ  
CK 
Creatine Phosphokinase 
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
CRF 
Case Report Form (electronic/paper) 
CRR 
Complete renal response  
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CV-EAC 
Cardiovascular Event Adjudication Committee 
DEHP 
Diethylhexyl phthalate 
DNA 
Deoxyribonucleic acid  
dsDNA 
Double stranded deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee, synonymous with Institutional Review Board 
(IRB) and Independent Ethics Committee (IEC) 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
44 (231) 
Abbreviation or 
special term 
Explanation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form  
EDC 
Electronic data capture  
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of Treatment  
EU 
European Union  
EULAR 
European League Against Rheumatism  
FDA 
Food and Drug Administration 
FWER 
Familywise error rate 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP 
Good Manufacturing Practice 
HbA1C 
Glycosylated Haemoglobin 
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 
hpf 
High power field 
HPV 
Human papilloma virus  
HSIL 
High-grade squamous intraepithelial lesion  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
45 (231) 
Abbreviation or 
special term 
Explanation 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IFN 
Interferon 
IFNAR 
Type I Interferon receptor  
Ig 
Immunoglobulin 
IGRA 
Interferon-gamma release assay 
ICI 
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  
ISN/RPS 
International Society of Nephrology (ISN)/Renal Pathology Society 
(RPS) 
IV 
Intravenous 
IXRS 
Interactive voice/web response system 
KDIGO 
Kidney Disease Improving Global Outcomes  
LN 
Lupus nephritis 
LLOQ 
Lower limit of quantitation 
LSLV 
Last Subject’s Last Visit 
MACE 
Major adverse cardiovascular events 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
46 (231) 
Abbreviation or 
special term 
Explanation 
MMF 
Mycophenolate mofetil 
MMRM 
Mixed model repeated measures 
MPA 
Mycophenolic acid  
MR Team 
SLE Data Medical Review Team  
mRNA 
Messenger ribonucleic acid 
nAb 
Neutralising antibodies 
NIH 
National Institutes of Health 
NSAIDs 
Non-steroidal anti-inflammatory drugs  
OCS 
Oral corticosteroids 
PD 
Pharmacodynamic 
PGA 
Physician’s Global Assessment 
PHQ-8 
Personal Health Questionnaire Depression Scale 
PK 
Pharmacokinetic(s) 
PRR 
Partial renal response 
PtGA 
Patient Global Assessment 
PVC 
Polyvinyl chloride 
Q4W 
Every 4 weeks 
QFT-G 
QuantiFERON-TB Gold 
RBC 
Red Blood Cell 
RNA 
Ribonucleic acid 
RNP 
Ribonucleoprotein  
SAE 
Serious adverse event  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
47 (231) 
Abbreviation or 
special term 
Explanation 
SAP 
Statistical analysis plan 
SD 
Standard deviation  
SDI 
Systemic Lupus International Collaborating Clinics/American 
College of Rheumatology (SLICC/ACR) Damage index  
SLE 
Systemic lupus erythematosus 
SLEDAI 2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SOC 
Standard of care 
SRI (4) 
Systemic Lupus Erythematosus Responder Index of ≥4 
SSc 
Systemic sclerosis 
TB 
Tuberculosis 
ULN 
Upper limit of normal 
UPCR 
Urine protein to creatinine ratio 
US 
United States 
VAS 
Visual Analogue Scale  
WBC 
White blood cell 
WHO 
World Health Organisation 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
48 (231) 
1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
Anifrolumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody 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 interferon (IFN) to IFNAR1 and inhibits the 
biologic activity of all type I IFN.  
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of unknown 
aetiologies. Lupus nephritis (LN) is the most common major organ manifestation of SLE. It 
affects approximately 35-60% of lupus patients and is more prevalent in certain ethnic groups, 
such as African Americans, Asians, and Hispanics (Borchers et al, 2010). Although renal 
outcome has improved with the introduction of immunosuppressive treatment, LN still 
represents a major risk factor for the long-term outcome of patients with SLE and adversely 
affects the prognosis, as measured by patient and renal survival rates as well as quality of life 
and work disability (Furst et al, 2013; Li et al, 2009; Mok et al, 2013; Pelletier et al, 2009). 
Renal survival rates in recent studies ranged from 83% to 92% at 5 years of follow-up and 
from 74% to 84% at 10 years of follow-up (summarised in Mok et al, 2013). The risk of 
end-stage renal disease is particularly high in patients with diffuse proliferative 
glomerulonephritis (reviewed in Mok et al, 2013). Several studies have shown that the 
standardised mortality ratio of patients with LN is 6-9 fold higher compared to the general 
population and about 3 fold higher compared to patients with non-renal SLE (reviewed in 
Mok et al, 2013). The mortality rate increases with accumulation of renal damage and is 
highest in LN patients with end-stage renal disease. The life expectancy of SLE patients with 
renal disease and those with renal damage is reduced by approximately 15 years and 23 years, 
respectively, compared to the general population (Mok et al, 2013). Lupus nephritis is also a 
major factor contributing to SLE-related hospitalisations and overall health care costs (Furst et 
al, 2013; Li et al, 2009; Pelletier et al, 2009).  
There is substantial unmet medical need in the treatment of LN, particularly for patients with 
proliferative LN. There is no approved treatment for LN, but various treatment regimens are 
widely used as local standards of care. The standard treatment for proliferative LN consists of 
6 to 12 months of intensive immunosuppressive therapy (usually cyclophosphamide or 
mycophenolate mofetil [MMF] with high-dose corticosteroids) followed by a longer period of 
less intensive maintenance therapy (Bertsias et al, 2012; Hahn et al, 2012). Corticosteroid 
dosing frequently includes pulse intravenous (IV) methylprednisolone (500 mg to 
1,000 mg/day) followed by daily oral glucocorticoids (0.5 to 1 mg/kg/day of prednisone-
equivalent) with a goal of reducing the dose to around 10 mg/day of prednisone-equivalent at 
6 months. Mycophenolate mofetil is the recommended agent by American College of 
Rheumatology (ACR) (Hahn et al, 2012) and the European League Against Rheumatism 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
49 (231) 
(EULAR) (Bertsias et al, 2012) with a total daily dose of 2 to 3 gm orally for 6 months, 
followed by an extended period of treatment with lower doses of MMF.  
Two regimens of IV cyclophosphamide are recommended as alternatives: 1) low-dose 
“Euro-Lupus” cyclophosphamide (500 mg IV once every 2 weeks×3 months), followed by 
maintenance therapy with daily oral azathioprine or daily oral MMF or 2) high-dose 
cyclophosphamide (500 to 1000 mg/m2 IV once a month×6 months), followed by maintenance 
treatment with MMF or azathioprine. 
Maintenance therapy is recommended for a minimum of 12 months with lower intensity 
immunosuppression with or without low-dose steroids (≤7.5 mg/day). Mycophenolate mofetil 
(≤2 gm/day) or azathioprine are the most commonly used agents for maintenance (Bertsias et 
al, 2012; Hahn et al, 2012; Radhakrishnan et al, 2012). 
Mycophenolate mofetil was chosen over cyclophosphamide in this study as standard of care 
(SOC), because the response rates are similar in all races and ethnicities, whereas African 
Americans and Hispanics respond less well to IV cyclophosphamide than Whites and Asians 
(Isenberg et al, 2010). The target dose of MMF recommended by various management 
guidelines (ACR, EULAR, and KDIGO) is 2 to 3 gm/day orally for 6 months, followed by an 
extended period of treatment with lower doses of MMF. Several studies in Asian and 
Caucasian LN populations, have shown doses ≤2 gm/day lead to similar renal responses but 
lower frequency of adverse events (AEs) compared to doses of 3 gm/day (Chan, 2012; Li et 
al, 2012; Mulic-Bacic et al, 2008; Ong et al, 2005). Consistent with these observations, the 
ACR guidelines recommend to target 2 gm/day for induction in Caucasian patients with LN 
(Hahn et al, 2012), which is also the higher end of the range used for induction in Asian 
countries. Although a higher target dose is frequently used in patients of African descent, 
there is no evidence to support this distinction. 
Multiple lines of evidence indicate a role of type I IFN in the pathogenesis of SLE and LN. 
For example, overexpression of type I IFN and proteins induced by type I IFN (the “type I 
IFN signature”) have been associated with greater disease activity and organ system 
involvement in SLE (Dall’Era et al, 2005; Bengtsson et al, 2000). High serum levels of type I 
IFN have been associated with high anti-double stranded deoxyribonucleic acid (anti-dsDNA) 
antibody titres, LN, and progressive skin rashes (Bengtsson et al, 2000). 
The disease pathogenesis of SLE includes activation of innate immunity, with increased 
production of type I IFN, including IFN-α, and increased number of plasmacytoid dendritic 
cells and myeloid dendritic cells in involved tissue (Baechler et al, 2003; Crow and 
Wohlgemuth, 2003; Baechler et al, 2004; Banchereau et al, 2004; Bengtsson et al, 2000; 
Crow, 2010; Dall’Era et al, 2005; Rönnblom and Alm, 2003). Specific humoral and cellular 
immune systems are activated. Autoantibodies are universally present and may precede 
development of clinically apparent disease by many years (Arbuckle et al, 2003). Systemic 
lupus erythematosus-associated autoantibodies include anti-dsDNA, anti-nucleosomes, 
anti-ribonucleoprotein (anti-RNP) complex, and anti-Smith antibodies (Rahman and Isenberg, 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
50 (231) 
2008). Immune complexes containing anti-dsDNA or anti-RNP antibodies can activate type I 
IFN production by plasmacytoid dendritic cells (Bengtsson et al, 2000; Rönnblom and Alm, 
2003). 
A potential role of IFN in the pathogenesis of LN has been suggested by both animal and 
human data. 
Animal models: 
• 
Interferon-α can induce glomerulonephritis in normal mice and 
accelerates the onset of the spontaneous autoimmune disease of NZB/W 
mice (Mathian et al, 2005). 
• 
A murine model of SLE, treated with a synthetic double stranded RNA 
ligand that induces type I IFN response, showed high titres of anti-
dsDNA antibodies, increased immune complex deposition, and increased 
metalloproteinase activity, which led to accelerated LN and death 
(Triantafyllopoulou et al, 2010). 
• 
Overexpression of systemic IFN-α accelerated LN in several murine 
models of LN (Fairhurst et al 2008, Liu et al, 2011). Signalling blocked 
by deleting the type I IFN receptor (Jørgensen et al, 2007; Nacionales et 
al, 2007; Santiago-Raber et al, 2003) or an anti-IFN-α antibody (Baccala 
et al, 2012) prevented or ameliorated LN. 
Human data: 
A role for IFN-α in the initiation of the autoimmune disease process is suggested more 
directly by the observation that patients with non-autoimmune disorders who are treated with 
IFN-α can develop antinuclear antibodies, anti-dsDNA antibodies, and occasionally also SLE 
(Rönnblom and Alm, 2003). 
Although no direct causal evidence has been established for type I IFN in human LN, several 
observations suggest that IFNs have an important role in the pathogenesis of this disease: 
• 
The formation of endothelial cell tubuloreticular inclusions found in LN 
is thought to be driven by type I IFN, and other than in LN, they can only 
be seen in viral and IFN-induced nephropathies (Anders et al, 2014). 
• 
Plasmacytoid dendritic cells, which are the main producers of type I IFN 
in SLE, are increased in number in the kidneys of LN patients (Tucci et 
al, 2008). 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
51 (231) 
• 
Type I gene signature is increased in the glomeruli of a subset of LN 
patients (Peterson et al, 2004). 
• 
Some cross-sectional studies showed a positive correlation between the 
blood IFN signature and active LN or a higher risk of renal flare (Feng et 
al, 2006; Landolt-Marticorena et al, 2009), whereas other studies showed 
an association between the blood IFN signature and the presence or 
history of LN (Baechler et al, 2003; Kirou et al, 2005). 
• 
A strong correlation between type I IFN-induced chemokine and LN was 
demonstrated in several studies (Bauer et al, 2009; Manoharan et al, 
2010). Elevated serum IFN-induced chemokine levels were strongly 
associated with the risk of renal flare (Bauer et al, 2009), whereas urine 
chemokine levels were proposed as biomarkers for active LN 
(Manoharan et al, 2010). 
Together, these pre-clinical and clinical data strongly support the hypothesis that type I IFN is 
involved in the immunopathogenesis of LN and therefore suppressing signalling through the 
type I IFN receptor may have clinical benefit in active LN. 
With the growing evidence that type I IFNs play an important role in autoimmune diseases 
such as SLE and LN, inhibition of the biological activity of type I IFNs with anifrolumab 
may, therefore, be a novel efficacious therapy for the treatment of LN and its significant 
unmet medical need. 
1.2 
Rationale for study design, doses and control groups 
1.2.1 
Rationale for study design 
This is a Phase 2, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of two IV treatment regimens of anifrolumab versus 
placebo in adult subjects with active, proliferative LN proven with biopsy while concurrently 
taking SOC treatment with MMF and corticosteroids. 
It is hypothesised that treatment with anifrolumab will neutralise the type I IFN signalling 
through the human IFNAR that is driving disease activity and thereby will reduce the severity 
of disease in patients with proliferative LN, and that anifrolumab will be well tolerated when 
given at the proposed dose for the duration of the study. 
To ensure adequate treatment, all subjects will receive SOC treatment with MMF and 
corticosteroids. This is consistent with both the EULAR (Bertsias et al, 2012) and ACR (Hahn 
et al, 2012) management guidelines and kidney disease improving global outcomes (KDIGO) 
recommendations (Radhakrishnan et al, 2012) for the management of proliferative LN.  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
52 (231) 
The study will be randomised, placebo-controlled, and double-blind prior to the primary 
analysis to ensure a robust design and minimise bias. This is the preferred design as outlined 
in the United States Food and Drug Administration (US FDA) Guidance for Industry Systemic 
Lupus Erythematosus-Developing Medical Products for Treatment (US FDA, June 2010) and 
in the Committee for Medicinal Products for Human Use (CHMP) Guideline on clinical 
investigation of medicinal products for the treatment of SLE and LN (CHMP, February 2015). 
After the last subject completes the Week 52 visit, the primary analysis will be conducted, 
after which the Sponsor and Sponsor’s delegates will be unblinded. Site investigators and 
subjects will remain blinded to treatment assignment throughout the study. 
Randomisation will be stratified using two factors: 
• 
Results of IFN test at screening using a 4-gene type I IFN test (IFN 
test-high versus IFN test-low) 
• 
24-hour Urine protein to creatinine ratio (UPCR) ≤3.0 mg/mg versus 
>3.0 mg/mg (based on 24-hour UPCR performed on a sample obtained 
within 14 days prior to the expected date of randomisation). Without the 
results of the second (stratification) sample, subjects cannot be 
randomised. Turn-around time for results from central laboratory is up to 
7 days.  
On rare occasion an extension of the 30-day screening window may be allowed if the re-
collection of the 24-hour UPCR or other required samples is necessary or if the results needed 
for randomisation are delayed.  
Stratification is implemented in order to minimise the risk of 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. 
The duration of renal responses will be assessed in a second year extension period where 
eligible subjects will continue in their randomised treatment groups. Treatment assignment 
will remain blinded for the Investigators and subjects. At the time of primary analysis, after 
the last subject has completed the Week 52 visit, the Sponsor and Sponsor’s delegates will be 
unblinded to treatment assignment. 
1.2.2 
Rationale for primary endpoint selection 
The primary objective is to evaluate the efficacy of anifrolumab plus SOC compared to 
placebo plus SOC in subjects with active proliferative LN measured by the relative difference 
in change from baseline to Week 52 in 24-hour UPCR. 
The treatment goal in LN is preservation of renal function. With current SOC, end-stage renal 
disease occurs late and with a relatively low frequency which makes it impractical for use as 
endpoint in clinical studies. Recent studies used various composite endpoints for renal 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
53 (231) 
response. The core elements of all these criteria are stable or improving renal function and a 
decrease in or normalisation of proteinuria. Improvement in proteinuria reflects control of 
inflammation and the subsequent repair of the kidney. Although the ultimate goal is to 
eliminate proteinuria, several studies have shown that reducing proteinuria (which in itself is 
toxic to the kidney) during the first year of treatment is associated with good long-term renal 
prognosis even if the proteinuria cannot be eliminated (Korbet et al, 2013; Dall’Era et al, 
2011; Dall’Era et al, 2015) Therefore, showing a benefit in decreasing proteinuria at Week 52 
represents a clinically meaningful endpoint for an exploratory proof of concept study. 
Furthermore, maintaining renal function while decreasing oral corticosteroid (OCS) dose 
(worsening of renal function or not meeting clinically meaningful decreases in OCS doses are 
withdrawal criteria in the study) will provide supportive evidence for potential long-term 
efficacy in LN patients. 
1.2.3 
Rationale for duration of treatment 
Treatment guidelines for proliferative lupus nephritis recommend maintenance therapy for a 
minimum of 12 months for patients with adequate response to initial immunosuppressive 
therapy. The 52 week double-blind randomised period will allow the evaluation of the primary 
endpoint whereas the second year extension will provide additional data to evaluate the 
exploratory endpoint assessing the duration of renal responses in patients who achieved 
clinically important improvements in proteinuria, maintained renal function and decreased the 
dose of corticosteroids during the first year of treatment.  
1.2.4 
Rationale for dose selection 
The study is evaluating the safety and efficacy of anifrolumab across 2 dosing regimens: the 
Basic Regimen will test 300 mg throughout the treatment period whereas the Intensified 
Regimen will test a higher dose of 900 mg for the first 3 doses followed by 300 mg for the rest 
of the treatment period. 
The selection of doses of 300 mg and 900 mg anifrolumab every 4 weeks (Q4W) is based on 
safety and efficacy results from the interim analysis of a Phase 2b study in extra-renal SLE 
where 2 doses of anifrolumab (300 mg and 1000 mg) were evaluated relative to placebo. At 
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. Based on these data, the 300 mg dose was identified as the dose to test 
in a Phase 3 study for extra-renal SLE.  
For this study, the rationale for selection of the 300 mg dose-level for evaluation in LN 
subjects is to replicate the dose identified in the Phase 2b study in subjects with extra-renal 
SLE. 
A higher dose of 900 mg will be given at the first 3 doses (Visits 1, 2, and 3) in LN subjects to 
account for potential IFN overexpression in the kidneys and potential loss of anifrolumab 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
54 (231) 
concentration due to proteinuria. Based on observations in the extra-renal SLE Phase 2b study, 
faster IFN signature suppression is expected at the 900 mg dose in LN subjects with potential 
clinical benefit. The dose of 900 mg will only be given for the first 3 doses of treatment 
(starting with the fourth dose all subjects will be switched to a dose of 300 mg) in order to 
limit the incidence of potential AEs related to anifrolumab. The 900 mg dose was chosen over 
1000 mg for ease of administration (anifrolumab is supplied in 150 mg vials). For these 
reasons, the selection of doses of 900 mg and 300 mg anifrolumab are justified for this study. 
1.2.5 
Rationale for duration of infusion 
In a Phase 2b study where two doses of anifrolumab (300 mg and 1000 mg) in combination 
with SOC were compared to placebo combined with SOC, all doses were administered over 
approximately 60 minutes. Based on the interim analysis, the frequency of infusion-related 
reactions did not differ substantially between the 300 mg (2.0%) and 1000 mg (3.8%) groups 
and 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 for the visits (starting with Visit 4), 
where all the subjects receive 300 mg anifrolumab or placebo. For the first 3 visits (Visits 1 to 
3), the time of infusion will be no less than 60 minutes. 
1.2.6 
Interferon test background 
Type I IFN has long been considered to be important in the pathogenesis of SLE and 
inhibition of this pathway is an attractive goal, targeted by anifrolumab. To understand the 
relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to 
know if a specific patient’s disease is driven by type I activation. Direct measurement of the 
IFN is challenging, so a transcript based marker, measuring the effect of IFN, was developed 
to evaluate the effect of overexpression of the target protein on a specific set of messenger 
ribonucleic acid (mRNA) markers. The expression of these markers is easily detected in 
whole blood and demonstrates a correlation with expression in diseased tissue, such as skin, in 
SLE. The bimodal distribution of the transcript scores for SLE patients, as shown in the 
Figure 1 below, supports defining an IFN test-high and IFN test-low subpopulation. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
55 (231) 
Figure 1 
Distribution of IFN transcript scores 
 
1.3 
Benefit/risk and ethical assessment 
A detailed assessment of the overall benefit/risk of anifrolumab is discussed in the 
Investigator’s Brochure. 
There is significant unmet medical need for the treatment of patients with active proliferative 
LN. Since type I IFNs seem likely to have a role in SLE and LN, a therapy such as 
anifrolumab, that targets type I IFN receptors, may be beneficial. 
Overall benefit/risk assessment for Study D3461C00007 
Clinically relevant benefit has been recognized in subjects with moderately to severely active 
SLE treated with anifrolumab on a background of SOC. The benefit of anifrolumab was 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
56 (231) 
suggested over a range of efficacy endpoints in a Phase 2b study in SLE, when compared to 
placebo. The findings included 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 (Week 12) and 
maintained between Days 85 and 169 (Week 24)) at Day 169, and the proportions of subjects 
achieving 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 [Week 40] and 365 
[Week 52]) at Day 365.  
The efficacy observed with the primary and secondary endpoints was supported by a wide 
range of evidence. A higher proportion of subjects receiving anifrolumab met SRI (4) 
response criteria without the OCS taper requirement at Day 169 and Day 365, compared to 
placebo. Additionally, compared to the placebo group, a numerically higher proportion of 
anifrolumab treated subjects achieved SRI(5), SRI(6), SRI(7), and SRI(8) response, as well as 
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.   
Anifrolumab was generally well tolerated. Herpes zoster reactivation with cutaneous 
presentation has been determined to be an identified risk for anifrolumab. No other infectious 
risks have been established; however, this continues to be closely monitored. 
SLE and lupus nephritis are thought to impair elements of the human immune system that 
contribute to the latency of herpes zoster (HZ) virus and prevent reactivation. The addition of 
a potent immunosuppressant like mycophenolate mofetil (MMF) as standard of care may also 
diminish the immunologic forces that keep HZV latent, further increasing the likelihood of 
reactivation. Evidence to date from completed and ongoing studies that included 
administration of MMF as SOC suggest that HZ reactivations are mostly cutaneous, self-
limited and responsive to antiviral medications. Sequelae, such as post-herpetic neuralgia, 
have been reported infrequently. Overall, risk associated with HZ reactivations in the LN 
population is anticipated to be acceptable and similar to that reported in the SLE program. 
Compared to the general population, patients with SLE and LN have a higher rate of 
infections including serious and opportunistic infections. In the presence of 
immunosuppression with MMF and potentially also at the doses of anifrolumab administered 
in the Basic or Intensified Regimens Q4W in addition to SOC, there is a further theoretically 
increased likelihood of infections.  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
57 (231) 
Patients receiving immunosuppressants, including MMF are at increased risk of developing 
bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic 
infections. These infections may lead to serious, including fatal outcomes. 
Immune surveillance related to development and progression of malignancy may be 
suppressed by standard of care such as MMF, potentially increasing the risk of malignancy, 
specifically lymphoma. However, at this time, no signal for malignancy risk has been 
recognized for anifrolumab. 
Risk associated with hypersensitivity reactions, including anaphylaxis and development of 
anti-drug antibodies (ADA) are expected to be unchanged in the LN study. Theoretically, the 
immunosuppressive effect of MMF may diminish adverse immune responses to anifrolumab.  
In order to minimise the risk associated with anifrolumab treatment, subjects with risk factors 
for serious infection, recurrent herpes zoster, malignancy, or immune deficiency disorders are 
specifically excluded from participation. 
Serious infections including non-opportunistic serious infections, opportunistic infections, 
anaphylaxis, malignancy, herpes zoster, TB (including latent TB), influenza, and vasculitis 
(non-SLE) are designated as AESIs in this study so they are reported and assessed promptly. 
Careful systematic monitoring and ongoing blinded surveillance for all such events continues. 
In order to provide an independent periodic review of safety throughout the study, in addition 
to the ongoing, blinded review provided by the Sponsor/Designee Medical Monitor for 
detection of any potential safety signals, an independent Data and Safety Monitoring Board 
(DSMB) will review blinded and, if needed, unblinded safety data on a regular basis 
throughout the study (see Section 1.5.1). 
In conclusion, AstraZeneca believes there is an unmet medical need in the treatment of LN. 
Phase 2 clinical findings suggest substantial efficacy in SLE. Available non-clinical and 
clinical data indicate an acceptable safety profile for anifrolumab for treatment of SLE with 
some data on ongoing MMF standard of care. Immunosuppression may lead to increased 
susceptibility to infection MMF treatment has been associated with development of 
lymphoma. The proposed dosing regimens for Protocol D3461C00007 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 considers that anifrolumab in combination with 
SOC continues to demonstrate an overall positive benefit/risk balance to support its clinical 
evaluation in subjects with active proliferative LN. 
1.4 
Study Design  
This is a Phase 2, multicentre, multinational, randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of two IV treatment regimens of anifrolumab versus 
placebo, while taking protocol-specified SOC treatment with MMF and corticosteroids (see 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
58 (231) 
Section 7.7.3 for details), in adult subjects with active biopsy-proven proliferative LN. The 
study will be performed in adult subjects, 18 to 70 years of age. The study duration is 
approximately 116 weeks for those subjects who meet the criteria for the second year 
extension period and approximately 64 weeks for those subjects who do not meet the criteria 
for the second year extension period. 
In this study, approximately 150 subjects will be randomised in a 1:1:1 ratio to receive one of 
the two IV anifrolumab dosing regimens or placebo, which will continue until Week 52, as 
follows: 
• 
Basic Regimen: Anifrolumab 300 mg IV Q4W for 13 doses plus SOC or 
• 
Intensified Regimen: Anifrolumab 900 mg IV Q4W for the first 3 doses 
followed by 300 mg IV Q4W for 10 doses plus SOC or 
• 
Placebo: IV Q4W plus SOC 
The primary objective will be evaluated at Week 52. After Week 52, eligible subjects will 
continue with randomised treatment plus SOC until Week 104. Those subjects not eligible to 
continue with treatment based on the Week 52 assessments will complete the 8 weeks of 
additional safety follow-up to complete involvement in the study. 
After all randomised subjects have completed the 52 week double-blind period the data base 
will be soft-locked, and the primary analysis will be performed, including the assessment of 
the primary, secondary, and safety objectives. This analysis will also encompass available data 
collected after the 52 week time point and details will be provided in the SAP. At this stage 
the Sponsor and Sponsor’s delegate who are not directly involved in the management of sites 
will be unblinded to randomised treatment, but the subjects and investigators will remain 
blinded (single-blind). The end of study analysis will be performed after all subjects have 
completed the second year extension period. One interim analysis may be conducted after 
approximately 50% of subjects have completed the Week 52 visit
 
 
 
IP will be administered as an IV infusion via an infusion pump over no less than 60 minutes 
for the first 3 doses (Visits 1, 2, and 3). Starting with Visit 4, IP can be administered as an IV 
infusion via an infusion pump over no less than 30 minutes.  
Randomisation will be stratified using two factors: 
• 
Results of IFN test at screening using a 4-gene type I IFN test (IFN test-
high versus IFN test-low) 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
59 (231) 
• 
24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg (based on 24-hour UPCR 
performed on a sample obtained within 14 days prior to the expected date 
of randomisation). Without the results of the second (stratification) 
sample, subjects cannot be randomised. Turn-around time for results 
from central laboratory is up to 7 days.  
On rare occasions, an extension of the 30-day screening window may be allowed if the 
re-collection of the 24-hour UPCR or other required samples is necessary or if the results 
needed for randomisation are delayed.  
Renal biopsy performed within 12 weeks prior to signing ICF or during the screening period 
will be considered as the screening biopsy. Biopsies will be evaluated locally and the local 
classification will be used to confirm the eligibility criteria. The biopsy must reveal Class III 
(±Class V) or Class IV (±Class V) LN according to the World Health Organisation (WHO) or 
2003 International Society of Nephrology/Renal Pathology Society ISN/RPS classification. 
An external renal biopsy adjudication group will adjudicate renal biopsies post-randomisation. 
The overall study duration is approximately 116 weeks: 
• 
A Screening Period: Up to 30 days  
• 
Treatment Period:  
The total treatment period is up to 100 weeks (26 doses administered 
every 4 weeks). 
− 
52 week double-blind treatment period: IP will be administered 
every 4 weeks from Week 0 to Week 48 for a total of 13 doses. The 
primary endpoint will be evaluated at Week 52. 
− 
Second year extension period: At Week 52, eligible subjects will 
continue treatment with IP (anifrolumab 300 mg or placebo IV Q4W) 
administration Q4W from Week 52 to Week 100 for a total of 13 
doses. The last efficacy assessments will be performed at Week 104. 
• 
Follow-up: After the completion of the last IP treatment (Week 48 for 
subjects who are not participating in the second year extension period and 
Week 100 for subjects who participate in the second year extension 
period) subjects will continue in the study for another 12 weeks of safety 
follow-up after the last administration of IP.  
At Week 52, eligible subjects will continue in their randomised treatment group for a second 
year of IP administration. The treatment groups will continue to receive IP infusions 
(anifrolumab 300 mg or placebo) Q4W starting at Week 52 for an additional 48 weeks in 
addition to SOC until Week 100. Final assessments will be performed at Week 104. After 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
60 (231) 
completion of Week 104, subjects will continue for another 8 weeks until Week 112 to 
complete safety follow-up (every 4 weeks) after the last administration of IP.  
See Figure 2 for an outline of the study design. Required SOC specific medication restrictions 
are contained in the eligibility criteria and Section 7.7. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
61 (231) 
Figure 2 
Study flow chart (52 week double-blind treatment period) 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
62 (231) 
Study flow chart (second year extension period) 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
63 (231) 
1.5 
Study governance and oversight 
1.5.1 
Data and Safety Monitoring Board  
An independent DSMB will perform evaluations of safety data at specified regular intervals 
throughout the study and make recommendations to the Sponsor regarding further conduct of 
the study. The DSMB will be provided with data that are summarised by treatment group 
using masked treatment group labels (eg, A and B). After reviewing the data by masked 
treatment group, the DSMB may choose to unblind the treatment groups for additional review. 
The DSMB may also ask for unblinded efficacy data, if during the performance of a 
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 /Designee 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. 
1.5.2 
Lupus Nephritis Steering Committee 
A Lupus Nephritis Steering Committee will ensure the validity and integrity of all of the data 
(efficacy and safety) as well as the conduct of the trial according to GCP guidelines and to 
provide guidance for program progression. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To evaluate the efficacy of anifrolumab plus 
SOCa compared with placebo plus SOCa in 
subjects with active proliferative LN measured 
by the relative difference in change from 
baseline to Week 52 in 24-hour urine protein to 
creatinine ratio (UPCR) 
24-hour UPCR 
a Required SOC is described in Section 7.7.3. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
64 (231) 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure : 
To evaluate the effect of anifrolumab plus 
SOCa compared with placebo plus SOCa on the 
proportion of subjects achieving Complete 
Renal Response (CRR) at Week 52 
CRR is defined as meeting all of the following: 
• 
Estimated glomerular filtration rate (eGFR) is 
≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20% 
• 
24-hour UPCR ≤0.7 mg/mg  
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
eGFR is based on Modification of Diet in Renal 
Disease (MDRD) formula 
a Required SOC is described in Section 7.7.3. 
 
b Allowed medication is described in Section 7.7. 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measure : 
To characterise the safety and tolerability of 
anifrolumab 
Adverse events (AEs) (including AEs of special 
interest [AESIs]), vital signs, physical examination, 
baseline and End of Treatment 12-lead 
electrocardiograms (ECG), and clinical laboratory 
tests (haematology, clinical chemistry, urinalysis), 
Columbia-Suicide Severity Rating Scale (C-SSRS), 
Personal Health Questionnaire Depression Scale-8, 
extra-renal flares using Systemic Lupus 
Erythematosus Disease Activity Index 2000 
(SLEDAI 2K) based Flare Assessment Instrument 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
65 (231) 
2.4 
Exploratory objectives 
Exploratory Objective: 
Outcome Measure : 
To evaluate the effect of anifrolumab plus SOCa 
compared with placebo plus SOCa on: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
66 (231) 
Exploratory Objective: 
Outcome Measure : 
Proportion of subjects achieving alternative 
CRR (aCRR) at Week 52 (and Week 104) 
 
The difference between the CRR and the 
aCRR is the addition of a criterion regarding 
“inactive urine sediment” 
 
aCRR is defined as meeting all of the following: 
• 
eGFR is 
≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20% 
• 
24-hour UPCR ≤0.7 mg/mg 
• 
Inactive urine sediment (defined as <10 red 
blood cells [RBC]/hpf) 
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
eGFR is based on MDRD formula 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
67 (231) 
Exploratory Objective: 
Outcome Measure : 
Proportion of subjects meeting Graded aCRR 
at Week 52 (and Week 104) 
Graded aCRR is defined as meeting both the 24-hour 
UPCR and eGFR criteria: 
• 
A decrease in 24-hour UPCR: 
­ 
For subjects with baseline UPCR >3 mg/mg: 
UPCR ≤1 mg/mg 
­ 
For subjects with baseline UPCR ≤3 mg/mg: 
UPCR ≤0.7 mg/mg 
• 
eGFR: 
≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20% 
• 
Inactive urine sediment defined as <10 RBC/hpf 
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
Proportion of subjects able to achieve 
sustained reduction in oral corticosteroids 
(OCS) dose at Week 52 or Week 104 
Sustained reduction of OCS dose: 
• 
Week 52: Prednisone-equivalent dose 
≤7.5 mg/day by Week 24 and not exceeding this 
dose through Week 52 
• 
Week 104: Prednisone-equivalent dose 
≤5.0 mg/day by Week 80 and not exceeding this 
dose through Week 104  
and 
• 
No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
Proportion of subjects achieving CRR at 
Week 52 or Week 104 and achieving sustained 
reduction of OCS dose 
CRR (see definition of CRR above) 
Sustained reduction of OCS dose (see definition 
above) 
 
 
 
 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
68 (231) 
Exploratory Objective: 
Outcome Measure : 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
69 (231) 
Exploratory Objective: 
Outcome Measure : 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean change in scores for overall disease 
activity from baseline to Week 52 (and to 
Week 104) 
SLEDAI-2K 
Mean change in score measures of non-renal 
disease activity from baseline to Week 52 (and 
to Week 104) 
Non-renal components of SLEDAI-2K 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
70 (231) 
Exploratory Objective: 
Outcome Measure : 
Mean change in scores for overall disease 
activity from baseline to Week 52 (and to 
Week 104) 
Physician’s Global Assessment (PGA) 
Mean change in the Systemic Lupus 
International Collaborating Clinics/American 
College of Rheumatology (SLICC/ACR) 
Damage Index (SDI) score from baseline to 
Week 52 (and to Week 104) 
SDI 
Mean change in scores for patient-reported 
health status from baseline to Week 52 (and to 
Week 104) 
Patient Global Assessment (PtGA) 
To evaluate the immunogenicity of 
anifrolumab, pharmacokinetics (PK), 
pharmacodynamics (the PK and 
immunogenicity results will be reported in the 
clinical study report) 
Anti-drug antibodies (ADA), anifrolumab 
concentration and PK parameters, 21 gene type I IFN 
gene signature 
To evaluate the pharmacokinetics of 
mycophenolic acid (MPA) 
MPA concentration and PK parameters (if applicable) 
Mean change in lupus serology from baseline 
to Week 52 (and to Week 104) 
Anti-dsDNA antibodies, C3 and C4 complement 
levels 
 
 
 
 
a 
Required SOC is described in Section 7.7.3. 
b 
Allowed medication is described in Section 7.7. 
c 
Note: Spot UPCR will be used instead of 24-hour UPCR for the PRR and CRR classification, when 
evaluating time to achieve renal response modified to include OCS tapering requirement as well as for the 
PRR and CRR classification for flare assessment. 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. If a subject does not meet 
eligibility criteria on the basis of a laboratory value, then the laboratory parameter may be 
repeated once within the screening period; this will be re-testing so that re-screening is not 
required. Please refer Section 4.1.1 for details on re-screening and re-testing. 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
71 (231) 
Note: From the day of randomisation onwards until the end of subject’s participation in the 
study, MMF will be supplied by the Sponsor to the subjects. 
3.1 
Inclusion criteria 
For inclusion in the study subjects should fulfil the following criteria: 
1. 
In the opinion of the investigator, must be able to understand the informed consent 
form (ICF), and all protocol-related subject assessments 
2. 
Men and women, age 18 through 70 years at the time of screening 
3. 
Written informed consent and any locally required authorisation (eg, Health 
Insurance Portability and Accountability Act [HIPAA] in the US, Data Privacy 
Directive in the European Union [EU]) obtained from the subject prior to 
performing any protocol-related procedures, including screening evaluations 
4. 
Fulfils at least 4 of the 11 ACR classification criteria for SLE (see Appendix E), one 
of which must be: 
(a) 
Positive antinuclear antibody (ANA) test (1:40 or higher) at screening 
by immunofluorescence assay at central laboratory; or 
(b) 
Elevated anti-dsDNA antibodies at screening (reported as equivocal or 
positive results), as per the central laboratory; or 
(c) 
Anti-Smith antibody at screening elevated to above normal (ie, positive 
or equivocal results) as per the central laboratory 
Clinical criteria may be present by history if documented in the medical record. 
Historical laboratory values can be counted for SLE criteria but at least one of the 
values specified above must be met at screening for eligibility. 
5. 
Weigh ≥40.0 kg at screening 
6. 
Diagnosis of proliferative LN based on a renal biopsy obtained within 12 weeks 
prior to signing the ICF or during the screening period: 
− 
Class III (±Class V) or Class IV (±Class V) LN according to the 
World Health Organisation (WHO) or 2003 ISN/RPS classification 
(based on local evaluation of renal biopsy) 
7. 
Urine protein to creatinine ratio >1 mg/mg (113.17 mg/mmol), obtained on a 
24-hour urine collection at both: 
− 
The start of screening and 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
72 (231) 
− 
Within 14 days prior to the expected date of randomisation. Without 
the results of the second (stratification) sample, subjects cannot be 
randomised. Turn-around time for results from central laboratory is up 
to 7 days.  
8. 
Estimated glomerular filtration rate (as calculated by the MDRD formula, with 
screening laboratory results for serum creatinine value) ≥35 mL/min/1.73 m2  
9. 
Negative serum β-human chorionic gonadotropin (β-hCG) test at screening (females 
of childbearing potential only)  
Note: If the result of the serum β human chorionic gonadotropin (β-hCG) test is 
borderline or thought to be false positive the test can be repeated during the 
screening. The subject can continue if the repeat test is negative. 
10. 
Women of childbearing potential must have a negative urine pregnancy test prior to 
administration of IP and prior to the first dose of Sponsor-provided MMF 
11. 
Females of childbearing potential must use 2 effective methods (Table 1) of 
avoiding pregnancy, only one of which is a barrier method, from Screening until 12 
weeks after the final dose of IP and from the first dose of Sponsor-provided MMF 
until 6 weeks after the last dose of Sponsor-provided MMF unless the subject is 
surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy), has a sterile male partner, is 1 year post-menopausal, or practices 
sustained abstinence. Cessation of birth control after the specified period for IP or 
Sponsor-provided MMF should be discussed with a responsible physician. 
• 
Sustained abstinence is an acceptable practice; however, periodic 
abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. 
• 
Post-menopausal is defined as at least 1 year since last menses and the 
subject has an elevated follicle-stimulating hormone (FSH) central 
laboratory value within the post-menopausal range. 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
73 (231) 
Effective methods of birth control include those listed in Table 1.  
Table 1 
Effective methods of birth control (2 Required) 
Barrier Methods (Choose 1) 
Intrauterine Device/Hormonal Methods (Choose 1) 
 
Intrauterine Device Methods 
Hormonal Methods 
Male condom (with 
spermicidea) 
Progesterone T 
Implants 
Cap (with spermicide cream or 
jellya) 
Copper T 
Hormone shot or injection 
Diaphragm (with spermicide 
cream or jelly*) 
 
Combined pill 
 
 
Minipill 
a where commercially available 
 
Patch 
12. 
All males (sterilised or non-sterilised) who are sexually active must use condom 
(with spermicide where commercially available for contraception) from Day 1 until 
at least 12 weeks after receipt of the final dose of IP and until at least 90 days after 
the last dose of Sponsor- provided MMF (whichever is later). It is strongly 
recommended for the female partner of a male subject to also use an effective 
method of contraception from Table 1 (other than a barrier method) throughout this 
period. 
13. 
Male subjects must not donate sperm during the course of the study and for 12 
weeks after the last dose of the IP and 90 days after the last dose of Sponsor-
provided MMF (whichever is later) 
14. 
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 signing the ICF (see Appendix K for guidance on abnormal Pap smear results).  
Note: Any abnormal Pap smear result documented within 2 years prior to signing 
the ICF must be repeated to confirm subject eligibility. Refer to exclusion criterion 
No. 36(b). 
15. 
Willing to forego other forms of experimental treatment during the study. 
16. 
Meets all of the following TB criteria: 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
74 (231) 
(a) 
No history of latent or active TB prior to screening, with the exception 
of latent TB with documented completion of appropriate treatment or 
currently receiving prophylactic treatment for latent TB and the subject 
commits to completing the full duration of prophylaxis 
(b) 
No signs or symptoms suggestive of active TB from medical history or 
physical examination 
(c) 
No recent close contact with a person with active TB or if there has been 
such contact, referral to a physician specialising in TB to undergo 
additional evaluation prior to randomisation (documented appropriately 
in source), and, if warranted, receipt of appropriate treatment for latent 
TB at or before the first administration of IP 
(d) 
Must meet one of the following criteria: 
 
(i) 
Negative QuantiFERON-TB Gold [QFT-G] test result for TB 
obtained from central laboratory within 12 weeks prior to 
randomisation or 
 
(ii) 
Positive QFT-G test result for TB obtained during the 
screening period from central laboratory for which active TB 
has been ruled out and appropriate treatment for latent TB 
has been initiated prior to the first IP administration and the 
subject commits to completing the full duration of 
prophylaxis, which may mean completing prophylaxis during 
the study or 
 
(iii) 
Indeterminate (confirmed as indeterminate on retest during 
screening) QFT-G test for TB obtained during the screening 
period from central laboratory with ongoing QFT-G testing 
for TB to the Study Plan (Table 2) 
(e) 
A chest radiograph with no evidence of current active TB or other 
infection, or old active TB, malignancy, or clinically significant 
abnormalities (unless due to SLE) obtained during the screening period 
or anytime within 12 weeks prior to signing of the ICF 
17. 
Adequate peripheral venous access 
3.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
75 (231) 
3.2.1 
General exclusion criteria 
 
1. 
Any condition that, in the opinion of the Investigator, would interfer with evaluation 
of the IP or interpretation of subject safety or study results  
2. 
Known intolerance to ≤1.0 gm/day of MMF  
3. 
Concurrent enrolment in another clinical study with an IP within 4 weeks prior to 
ICF signing or within 5 half-lives of the IP used in that clinical study, whichever is 
longer 
4. 
Prior participation in an anifrolumab clinical study 
5. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and staff at the study site and their immediate family members) 
6. 
Lactating or pregnant females or females who intend to become pregnant or begin 
breastfeeding anytime from initiation of screening through the 12 week safety 
follow-up period following last dose of IP and 6 weeks after the last dose of 
Sponsor-provided MMF (whichever is later) 
7. 
Current alcohol, drug or chemical abuse, or a recent history of such abuse within 1 
year before Day 1 (Week 0 visit) 
8. 
Major surgery within 8 weeks before signing the ICF or major surgery planned 
during the study period (see Appendix J for guidance on major surgery) 
9. 
Spontaneous or induced abortion, still or live birth, or pregnancy ≤4 weeks prior to 
signing the ICF 
10. 
A diagnosis of pure Class V membranous LN. This will be based on the renal 
biopsy obtained within 12 weeks prior to signing ICF or during the screening period 
11. 
History of dialysis within 12 months prior to signing the ICF or expected need for 
renal replacement therapy (dialysis or renal transplant) within a 6 month period 
after enrolment 
12. 
History of, or current renal diseases (other than LN) that in the opinion of the 
Investigator could interfere with the LN assessment and confound the disease 
activity assessment (eg, diabetic nephropathy) 
13. 
Subjects, who at the time of signing the ICF, received any of the following 
immunosuppressive therapies after their qualifying biopsy: 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
76 (231) 
(a) 
Oral corticosteroids >0.5 mg/kg/day for more than 8 weeks or 
(b) 
Oral or IV pulse methylprednisolone >3.0 gm (cumulative dose) or 
(c) 
IV cyclophosphamide >2 pulses of high-dose (≥0.5 gm/m2) or >4 doses 
of low-dose (500 mg every 2 weeks) or 
(d) 
Average MMF >2.5 gm/day (or >1800 mg/day of enteric coated 
mycophenolate sodium) for more than 8 weeks or 
(e) 
Tacrolimus >4 mg/day for more than 8 weeks 
Note: Any combination of treatments with these therapeutic agents is allowed if 
none of the components exceeds the above limits 
14. 
During screening (within 30 days before Day 1 [Week 0 visit]), any of the 
following: 
(a) 
Aspartate transaminase (AST) >2.5×upper limit of normal (ULN) 
(b) 
Alanine transaminase (ALT) >2.5×ULN 
(c) 
Total bilirubin >ULN (unless due to Gilbert's syndrome [based on 
Investigator’s judgement]) 
(d) 
Glycosylated haemoglobin (HbA1c) >8% (or >0.08) at screening 
(diabetic subjects only) 
(e) 
Neutrophil count <1x103/μL (or <1.0 GI/L) 
(f) 
Platelet count <25x103/μL (or <25 GI/L) 
(g) 
Haemoglobin <8 g/dL (or <80 g/L) 
15. 
Abnormal ECG findings that in the opinion of the investigator would put the subject 
at risk, if the subject participated in this study 
3.2.2 
Exclusion criteria related to concomitant medications 
16. 
Receipt of any experimental agent (small molecule or biologic) or commercially 
available biologic agent within four weeks or 5 half-lives, whichever is greater (see 
Appendix H) prior to ICF signing  
17. 
B cell targeted therapy restrictions: 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
77 (231) 
(a) 
Receipt of epratuzumab, belimumab, or tabalumab ≤12 weeks prior to 
signing the ICF and atacicept ≤40 weeks prior to signing the ICF 
(b) 
Receipt of B cell-depleting therapy (including but not limited to 
ocrelizumab, ofatumumab, obinutuzumab, or rituximab) ≤26 weeks 
prior to signing the ICF. If B cell-depleting therapy was administered 
>26 weeks ago, an absolute B cell count (CD19+ cells) less than the 
lower limit of normal or less than baseline value prior to receipt of B 
cell-depleting therapy (whichever is lower) will be exclusionary 
(determined during screening by the central laboratory) 
18. 
A known history of allergy or reaction to any component of the IP formulation or 
history of anaphylaxis to any human gamma globulin therapy 
19. 
Receipt of any of the following: 
(a) 
Any live or attenuated vaccine within 8 weeks prior to signing the ICF 
(administration of killed vaccines is acceptable, the Sponsor 
recommends Investigators ensure all subjects are up to date on required 
vaccinations prior to study entry) or an anticipated requirement for live 
vaccine during the treatment period and for 12 weeks following the last 
dose of the IP 
(b) 
Bacillus of Calmette-Guérin (BCG) vaccine within 1 year (12 months) 
prior to signing the ICF 
(c) 
Any excluded medication or treatment modality listed in Appendix H 
(d) 
Blood transfusion within 4 weeks prior to signing the ICF 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
78 (231) 
(e) 
The following medications must be discontinued prior to the day of 
randomisation (because of potential interaction with MMF):  
− 
Methotrexate 
− 
Azathioprine 
− 
Leflunomide 
− 
Tacrolimus 
− 
Cyclosporine 
− 
Mizoribine 
− 
Cholestyramine 
 
3.2.3 
Exclusion criteria related to systemic lupus erythematosus and other diseases 
20. 
History of, or current diagnosis of, a clinically significant non-SLE-related 
vasculitis syndrome (see Appendix G). Subjects who have experienced vasculitis as 
a feature of their SLE can be recruited to the study 
21. 
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 
Columbia-Suicide Severity Rating Scale (C-SSRS) at screening or at baseline 
22. 
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 might cause the subject to be unable to fully understand the ICF or 
(b) 
In the opinion of the Investigator, protocol-specified SOC is insufficient 
to control neurologic features of SLE 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 or anticipated 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
79 (231) 
23. 
Documented history of systemic sclerosis or diagnosis of SLE with overlap 
systemic sclerosis 
24. 
History of, or current diagnosis of, catastrophic anti-phospholipid syndrome (APS), 
see Appendix P) or APS-related thromboembolic event or pregnancy loss within 1 
year prior to signing the ICF. Subjects with APS adequately controlled by 
anticoagulants or aspirin for at least 12 weeks can be recruited to the study 
25. 
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 
26. 
Known history of a primary immunodeficiency (eg, common variable 
immunodeficiency syndrome), 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: 
(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 monthly for 
HBV DNA. To remain eligible for the study, the subject’s HBV DNA levels must 
remain below the LLOQ as per central laboratory. 
A reflex test is a test that must be performed based on the results of a prior test 
(pre-set criteria). 
28. 
Positive test for hepatitis C antibody 
29. 
Any severe herpes infection at any time prior to randomisation (Week 0 visit), 
including but not limited to, disseminated herpes, herpes encephalitis, or ophthalmic 
herpes 
30. 
Recurrent herpes zoster (defined as 2 episodes within 2 years) within 5 years prior 
to randomisation 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
80 (231) 
31. 
Any herpes zoster infection that has not completely resolved within 12 weeks prior 
to signing the ICF 
32. 
History of opportunistic infection (see Section 6.4.2 for definition) requiring 
hospitalisation or parenteral anti-infective treatment with in 3 years prior to 
randomisation (vaginal, oral and skin candidiasis is not an exclusion reason) 
33. 
Cytomegalovirus and/or Epstein–Barr virus infection that has not been completely 
resolved within the 12 weeks prior to signing the ICF 
34. 
Either of the following: 
(a) 
Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis, 
etc.) which is not resolved 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 8 weeks prior to randomisation 
35. 
Any infection requiring oral anti-infectives (including antivirals) within 2 weeks 
prior to randomisation, except chronic suppressive antiviral treatment for herpes 
simplex virus in the absence of active lesions within 2 weeks prior to randomisation 
36. 
History of cancer, apart from: 
(a) 
Squamous or basal cell carcinoma of the skin treated with documented 
success of curative therapy ≥12 weeks prior to randomisation (Week 0 
visit) 
(b) 
High-grade squamous intraepithelial lesion (CIN III, CIS) treated with 
apparent success with curative therapy ≥1 year prior to randomisation 
(Week 0 visit) 
For procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4. 
3.3 
Subject enrolment and randomisation 
Investigator(s) should keep a record of subjects considered for, and included in the study. The 
pre-screening/screening log will be evaluated periodically during routine monitoring visits. 
The Investigator(s) will: 
1. 
Obtain signed informed consent from the potential subject before any study specific 
procedures are performed. The subject is considered enrolled when the ICF is 
signed and the enrolment call is done in the interactive voice/web response system 
(IXRS). 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
81 (231) 
2. 
IXRS will assign the subject with a unique enrolment number. The subject ID will 
be pre-fixed with ‘E’ in IXRS reports and on the screen (sites will have to enter the 
7 digit subject ID into the IXRS to retrieve subject data) 
3. 
Determine subject eligibility. During the screening period, the study Medical 
Monitor/Designee 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 the subject or to consider the subject as screen failed, 
prior to the planned randomisation date. 
4. 
On Day 1, the Investigator will confirm that all eligibility criteria are still fulfilled 
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 IP kit number(s) to the subject. 
See additional information in Section 3.5. 
Randomisation will be stratified using two factors:  
• 
Results of IFN test at screening using a 4-gene type I IFN test (IFN 
test-high versus IFN test-low) 
• 
24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg (within 14 days prior to 
the expected date of randomisation). Without the second (stratification) 
sample, subjects cannot be randomised. Turn-around time for results 
from central laboratory is up to 7 days. On rare occasion an extension of 
the 30-day screening window may be allowed if the re-collection of the 
24-hour UPCR or other required samples is necessary or if the results 
needed for randomisation are delayed. 
IP (anifrolumab or placebo) should, if possible, be administered the same day the IP kit 
number is assigned. 
3.4 
Procedures for handling incorrectly enrolled or randomised 
subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive IP and Sponsor-provided MMF.  There can be no exceptions to this rule.  
Subjects who are enrolled, but subsequently found not to meet all the eligibility criteria must 
not be randomised or initiated on treatment, and must be withdrawn from the study. 
Where a subject does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Principal Investigator should inform the 
Sponsor/Designee Medical Monitor immediately, and a discussion should occur between the 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
82 (231) 
Sponsor/Designee Medical Monitor and the Principal Investigator regarding whether to 
continue or discontinue the subject from treatment. The Sponsor/Designee must ensure all 
decisions are appropriately documented. 
3.5 
Methods for assigning treatment groups 
On Day 1, the Investigator will confirm that all eligibility criteria and will then perform the 
randomisation transaction in the IXRS. The IXRS will assign eligible subjects a unique 
randomisation code and blinded IP kit number(s). 
Specific information concerning the use of the IXRS will be provided in the separate user 
manual.  
Block randomisation using an IXRS will be used to randomise subjects in a 1:1:1 ratio to 
receive one of the two IV dosing regimens of anifrolumab (Basic Regimen/Intensified 
Regimen) or placebo. AstraZeneca Biostatistics group is responsible for generating the 
randomisation scheme for this study using the GRand system. 
3.6 
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. Hence, the IP will be prepared by a 
trained unblinded team member at the site, who will not be involved in the management of 
study subjects.  
To ensure blinding of the anifrolumab regimens, the duration of infusion is no less than 
60 minutes for the first 3 doses of IP (Visits 1, 2, and 3) for all three arms. 
All packaging and labelling of IP is done in such way as to ensure blinding for all 
Sponsor/Designee and investigational site staff, other than the unblinded team member who is 
assigned to prepare the IP. The kits on the shelf, and the infusion bags when prepared, look 
identical. Neither the subject nor any of the Investigators or Sponsor/Designees 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/Designee must be notified immediately by the Investigator. 
Investigators and subjects who continue in the second year extension period will continue to 
be blinded to their treatment. However, the Sponsor and Sponsor’s delegates who are not 
directly involved in the management of sites will be unblinded at the time of the primary 
analysis at Week 52. 
3.7 
Methods for unblinding  
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation. The 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
83 (231) 
Investigator must document and report the action to AstraZeneca or designee, without 
revealing the treatment given to subject to the AstraZeneca staff or the designee. Instructions 
for unblinding an individual subject’s IP allocation are contained in the IXRS manual. In 
general, unblinding should only occur if management of the medical emergency would be 
different based on the subject having received IP. In the majority of cases, the management of 
a medical emergency would be the same whether or not IP was received by the subject. If this 
was the case, the IP allocation should not be unblinded. Subjects who have been unblinded by 
the Investigator must be discontinued from IP. 
One interim analysis may be conducted after approximately 50% of subjects have completed 
the Week 52 visit. 
 
 
 
 
 
 
 
 Details of the interim analysis including a description of who will be 
unblinded will be specified in the interim analysis and communication plans prior to 
unblinding. 
After all randomised subjects have completed the 52 week double-blind period the data base 
will be soft-locked, and the primary analysis will be performed, including the assessment of 
the primary, secondary, and safety objectives. This analysis will also encompass available data 
collected after the 52 week time point and details will be provided in the SAP. At this stage 
the Sponsor and Sponsor’s delegate who are not directly involved in the management of sites 
will be unblinded to randomised treatment, but the subjects and investigators will remain 
blinded (single-blind). The end of study analysis will be performed after all subjects have 
completed the second year extension period. 
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 IP and that potentially require expedited 
reporting to regulatory authorities. Treatment codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual subject 
have been made and documented. 
Subjects who have been unblinded by AstraZeneca Patient Safety or designee (and who have 
not been unblinded to the Principal Investigator or Sponsor/Designee Medical Monitor) will 
not, based on the unblinding alone, be discontinued from further receipt of IP. 
Individual treatment codes, indicating the treatment randomisation for each randomised 
subject, will be available to the Investigator(s) or pharmacists at the study site. 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
84 (231) 
Live unblinded randomisation data will be periodically released to an independent PK analyst 
and an independent immunogenicity samples analyst from PPD, in order to allow them to 
perform laboratory PK and immunogenicity analysis.  The unblinded randomisation data will 
be only released to specific named personnel for this purpose and will not be made available 
to any staff from AstraZeneca or Sponsor’s delegate.   
3.7.1 
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/Sponsor’s delegate study team 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 1.5.1. 
3.8 
Restrictions 
3.8.1 
Fasting lipid profile 
Subjects will be required to fast for at least 8 hours prior to assessment of lipid profile at the 
visits described in the Treatment Period Study Plan (Table 2 and Table 4). If the subject has 
not fasted, he/she should fast before the next visit, and the test can be done at that visit. 
3.8.2 
Perioperative management of investigational product 
Planned surgeries should be avoided during the study if clinically feasible. 
3.8.2.1 
Major surgeries 
Pre-operative management of IP: If a non-urgent major surgery becomes necessary during the 
study, it should be scheduled at least 4 weeks after the last administration of IP, if clinically 
feasible. The determination of whether or not a surgery is “urgent” will be at the discretion of 
the investigator, preferably in consultation with the Sponsor/Designee Medical Monitor. 
3.8.2.2 
Non-major surgeries 
The decision to withhold IP administration is at the Investigator’s discretion.  
Post-operative management of IP: IP administration can be resumed at the Investigator’s 
discretion after all of the following criteria are met: 
• 
External wound healing is complete and  
• 
Any post-operative antibiotic course is completed and 
• 
All acute surgical complications have resolved 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
85 (231) 
3.8.3 
Blood donation 
Subjects must not donate blood from date of randomisation until 6 weeks after the last dose of 
Sponsor-provided MMF and within 12 weeks after the last IP dose. 
3.9 
Discontinuation of investigational product 
3.9.1 
Criteria for discontinuation of investigational product due to worsening LN or 
SLE (at any time) 
Blinded IP will be discontinued in subjects who meet pre-defined criteria for worsening LN or 
SLE. Subjects may receive rescue treatment as clinically indicated. Subjects who had their IP 
discontinued will be followed according to the study schedule. These subjects will be 
followed until Week 52 (or for a minimum of 12 weeks after last dose of IP for subjects for 
whom IP was discontinued within 12 weeks prior to Week 52). If discontinuation occurs 
during the second year extension period, subjects will be followed until Week 104 (or for a 
minimum of 12 weeks after last dose of IP for subjects for whom IP was discontinued within 
12 weeks prior to Week 104). 
• 
>30% decrease in eGFR compared to baseline due to LN and eGFR 
<60 mL/min/1.73 m2 (on two independent samples) or 
• 
Increase in renal or extra-renal lupus activity requiring prohibited 
systemic immunosuppressive treatment (eg, cyclophosphamide, 
rituximab, belimumab) 
• 
Receipt of >1 methylprednisolone pulse after the day of randomisation 
• 
Receipt of any methylprednisolone pulse after Week 8 
• 
The IP will be discontinued if MMF is discontinued and another 
immunosuppressant is initiated 
3.9.2 
Criteria for discontinuation of investigational product for worsening of LN or 
SLE at Week 12 and Week 24 
• 
eGFR <75% of baseline and <60 mL/min/1.73 m2 (on two independent 
samples) or 
• 
Nephrotic range UPCR (confirmed by a second measurement at least two 
weeks after the first measurement): 
− 
Subjects with 24-hour UPCR ≤3 mg/mg at baseline will be withdrawn 
if 24-hour UPCR increases by >50% from baseline to >3.5 mg/mg 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
86 (231) 
− 
Subjects with 24-hour UPCR >3 mg/mg at baseline will be withdrawn 
if 24-hour UPCR at Week 24 >3.5 mg/mg and there is <60% 
improvement from baseline or 
• 
Inability to adhere to corticosteroids requirements:  
− 
Inability to reduce OCS to ≤15 mg/day prednisone-equivalent at 
Week 12 
− 
Inability to reduce OCS to <15 mg/day by Week 24 
Subjects who exceed the maximum daily OCS dose at the Week 12 or Week 24 visits may 
continue to receive IP if the current dose is part of a temporary increase in OCS dose (eg, 
protocol-allowed burst and taper). Subjects who cannot be returned to their pre-increase dose 
within 14 days from the start of the increase will have their IP discontinued at the next visit. 
3.9.3 
Criteria for discontinuation of investigational product during the second year 
extension period: 
Criteria for discontinuing investigational product at Week 52: 
Subjects not meeting the criteria to continue in the second year extension will not receive any 
IP at Week 52 and will complete the study after completing the required follow-up visits. 
Subjects meeting the following criteria may continue to receive blinded IP between Weeks 52 
and 100. 
(i) 
Meeting all of the following criteria based on the renal portion of the PRR 
definition: 
• 
eGFR is: 
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline 
of ≥20% 
• 
Improvement in 24-hour UPCR: 
− 
For subjects with a baseline UPCR ≤3 mg/mg: <1.0 mg/mg 
− 
For subjects with a baseline UPCR >3 mg/mg: >50% improvement 
from baseline and ≤3.0 mg/mg 
Renal discontinuation criteria must be confirmed in two separate samples. 
The second measurement should be at least 1 week after the first 
measurement.  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
87 (231) 
(ii) 
No discontinuation of IP 
(iii) 
Negative HIV test after signing the Main ICF 
Criteria for discontinuing investigational product at Week 52, Week 56 or Week 60 
• 
Failure to obtain Pap smear after Week 48 with result available at 
Week 60 at latest 
• 
Pap smear result not meeting the eligibility criteria (see Appendix K) at 
Week 52, 56, or 60 of a Pap smear obtained after Week 48 
• 
Failure to obtain Week 52 QuantiFERON test result by Week 56 
Criteria for discontinuing investigational product at Week 60 and later 
• 
OCS >7.5 mg/day (except one OCS burst and taper) 
• 
MMF >2 gm/day or >Week 52 dose, if Week 52 dose <2 gm/day 
Subjects who discontinue the IP during the second year extension period will be followed 
until Week 104 (or for a minimum of 12 weeks after last dose of IP for subjects for whom IP 
was discontinued within 12 weeks of Week 104). 
3.9.4 
Criteria for discontinuation of investigational product for reasons other than 
lack of efficacy at any time during the study 
Subjects may be discontinued from IP 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 one of 
the following: 
(a) 
Subject is unable to comply with protocol-specified visits and/or 
procedures due to conflicts not related to clinical study 
(b) 
An AE or laboratory abnormality is of concern to the subject, but not 
clinically significant to physician 
(c) 
The subject is concerned about possibility of receiving placebo or 
ineffective treatment 
(d) 
Subject wishes to participate in another clinical study 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
88 (231) 
(e) 
Subject is interested in taking a treatment that is not allowed in this 
study 
(f) 
Subject perceives logistics at the clinical site to be unacceptable 
(g) 
Other reason 
2. 
Lost to follow-up: must be documented by time and date of telephone calls, e-mails, 
text messages, numbers called, individuals spoken to if not subject, and at least 2 
attempts to contact the subject via certified letter (see Section 3.9.7) 
3. 
Adverse event that, in the opinion of the Investigator or the Sponsor/Designee 
Medical Monitor, contraindicates further dosing with IP 
4. 
Severe non-compliance with the study protocol 
5. 
The Investigator or Sponsor/Designee Medical Monitor deems withdrawal as being 
in the subject's best interest 
6. 
Pregnancy, positive pregnancy test, or subject expresses an interest in becoming 
pregnant  
7. 
Isolated HBcAb positivity with HBV DNA above the LLOQ confirmed by the 
central laboratory 
8. 
Positive HIV test 
9. 
Receipt of any medications identified in Section 7.7.2.1 
10. 
The use of restricted medications listed in Section 7.7.2.2 if the Sponsor/Designee 
Medical Monitor, in consultation with the Sponsor, determines the subject must be 
discontinued  
11. 
A diagnosis of active TB, premature discontinuation of treatment for latent TB, or 
non-compliance with latent 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 and Prevention (CDC) guidance for immunocompromised patients 
should be used. 
12. 
Subject is unblinded by the Investigator 
Additional restrictions related to concomitant medications are discussed in Section 7.7. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
89 (231) 
3.9.5 
Subject decision to discontinue investigational product  
If the subject decides to discontinue IP for any reason including but not limited to those 
outlined in Section 3.9 above, the subject will not receive any further IP. Subjects who 
discontinue IP during the 52 week double-blind treatment period will be followed until Week 
52 (or for a minimum of 12 weeks after last dose of IP for subjects for whom IP was 
discontinued within 12 weeks prior to Week 52). If discontinuation occurs during the second 
year extension period, subjects will be followed until Week 104 (or for a minimum of 
12 weeks after last dose of IP for subjects for whom IP was discontinued within 12 weeks 
prior to Week 104). The subject may continue to receive Sponsor-provided MMF until the end 
of the subject’s participation in the study. 
3.9.6 
Withdrawal of the informed consent 
Subjects are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment. 
A subject who withdraws consent will always be asked about the reason(s) (see Section 3.9.2) 
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.  
3.9.7 
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 e-mails, 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, e-mails, text messages, numbers called, individuals spoken to if not 
subject, and documentation that 2 certified/registered letters were sent. 
3.9.8 
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 112), regardless of the number of doses of IP 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
90 (231) 
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. 
A subject will be considered to have completed the double-blind treatment period if they were 
followed up until Week 60 or if they entered the second year extension period. 
A subject will be considered to have completed the second year extension period if the subject 
was followed up until the end of the study (Week 112). 
3.9.9 
Procedures for discontinuation of a subject from investigational product 
Discontinuation of IP does not necessarily mean discontinuation of follow-up or termination 
of study participation. Subjects who are discontinued from the IP should be followed up to 
continue to undergo all study-related visits/procedures for the full treatment period (Table 2) 
in order to support the final efficacy and safety analysis for anifrolumab (see Section 8). 
Subjects who discontinue IP earlier than 12 weeks before Week 52 will be followed until 
Week 52. Those discontinued within 12 weeks prior to Week 52 will need to have follow-up 
beyond Week 52 to complete a 12 week safety observation period after the last dose of IP 
administration. 
Subjects who discontinue IP in the second year extension period will be followed until Week 
104. Those discontinued within 12 weeks prior to Week 104 will need to have follow-up 
beyond Week 104 to complete a 12-week safety observation period after the last dose of IP 
administration. 
The reason for premature discontinuation of IP will be documented in the source documents 
and recorded in the eCRF. 
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 IP prior to their 
completion of the study and wishes to continue with only selected study assessments; 
prioritised assessments are listed in Section 4.2.2. 
For subjects who wish to withdraw from the study completely refer to Section 3.9.4. 
If a subject is withdrawn from study, see Section 3.10. 
3.10 
Criteria for withdrawal  
Screening failures are subjects who have provided informed consent but who were 
subsequently found to 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 ‘Screen 
failure’(the potential subject who does not meet one or more criteria required for participation 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
91 (231) 
in a trial, this reason for study withdrawal is only valid for not randomised subjects). For 
eligibility for re-screening of a subject refer to Section 4.1.1.  
3.11 
Discontinuation of the study 
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or not recruiting. AstraZeneca may 
also terminate the entire study prematurely if concerns for safety arise within this study or in 
any other study with anifrolumab.  
The study may be stopped if, in the judgement of the Sponsor, study subjects are placed at 
undue risk because of clinically significant findings that: 
• 
Meet individual stopping criteria (see Section 3.9 for reasons for 
discontinuation of IP) or are otherwise considered significant 
• 
Are assessed as causally related to IP  
• 
Are not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES  
The Study Plan detailing the procedures from screening through Week 52 is presented in 
Table 2. The Study Plan detailing the procedures during follow-up is presented in Table 3. 
The Study Plan detailing the procedures for the second year extension period (Week 56 to 
Week 104) is presented in Table 4. The Study Plan detailing the procedures during follow-up 
in the second year extension period is presented in Table 5. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
92 (231) 
Table 2 
Study plan detailing the procedures from screening through Week 52 treatment period (double-blind 
period) 
Study Period 
Sc 
Treatment Period 
 
Days 
-30 
to 
-1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
- 
Visit Number 
SV 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UNa 
Study Week 
- 
W0 
W4 
W8  
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52/DCb, 1 
- 
Visit Window 
- 
 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
Written informed 
consent/Assignment of Screening 
ID number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PtGA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS (Screening) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS (V1-V16) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PHQ-8 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Screening renal biopsyc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local clinical evaluation  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adjudicationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue biomarkere 
 
(optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Second renal biopsy (optional)f 
 
 
 
 
 
 
 
For eligible subject once after Week 24 
 Local clinical evaluation 
 
 
 
 
 
 
 
X 
 
Adjudication (optional) 
 
 
 
 
 
 
 
X 
 
Tissue biomarkere 
 
(optional) 
 
 
 
 
 
 
 
X 
eGFR using MDRD formula 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
93 (231) 
Study Period 
Sc 
Treatment Period 
 
Days 
-30 
to 
-1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
- 
Visit Number 
SV 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UNa 
Study Week 
- 
W0 
W4 
W8  
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52/DCb, 1 
- 
Visit Window 
- 
 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLE and LN medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR Classification Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examination 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Focused physical examination 
 
 
X 
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 
X 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Cushingoid features 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Chest X-rayg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pap smearh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood collection for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening labsi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 FSH in post-menopausal 
 females only 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Pregnancy test in females 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
94 (231) 
Study Period 
Sc 
Treatment Period 
 
Days 
-30 
to 
-1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
- 
Visit Number 
SV 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UNa 
Study Week 
- 
W0 
W4 
W8  
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52/DCb, 1 
- 
Visit Window 
- 
 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
 
QFT-G test (TB testing) j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 QFT-G test (TB testing, 
 only if indeterminate at 
 screening/previous visits) 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunology profilek  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
IFN test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B cell countl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid profilem  
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 Lupus serology tests (C3, 
 C4, anti-dsDNA) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pre-dose ADA  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 Pre-dose PK blood 
sample 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Xn 
 
 
Post-dose PK blood sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum MPAo 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Serum and Plasma 
 
biomarkers 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Type I IFN signature with 
 21-gene assay (PD 
marker) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
95 (231) 
Study Period 
Sc 
Treatment Period 
 
Days 
-30 
to 
-1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
- 
Visit Number 
SV 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UNa 
Study Week 
- 
W0 
W4 
W8  
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52/DCb, 1 
- 
Visit Window 
- 
 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
 RNA transcript profiling 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Pharmacogenomics 
 
(optional) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Cardiovascular risk assessment  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine collection for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hour UPCRp 
Xq 
Xr 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Spot UPCR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test in females 
of childbearing potential 
onlys 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Urinalysis (including 
 microscopic examination)t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Local urinalysis (including 
microscopic examination) 
for selected sitesu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinary biomarkers 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
SLEDAI-2K 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SLICC/ACR Damage Index (SDI) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
PGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEs/AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
96 (231) 
Study Period 
Sc 
Treatment Period 
 
Days 
-30 
to 
-1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
- 
Visit Number 
SV 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UNa 
Study Week 
- 
W0 
W4 
W8  
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52/DCb, 1 
- 
Visit Window 
- 
 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
Steroid tapering  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Extra-renal flare (SLEDAI-2K 
based Flare Assessment Instrument) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Verify eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic examination for 
chloroquine/hydroxychloroquine 
toxicity (if applicable)v 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X2 
 
Sponsor-provided MMFw 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ACR=American College of Rheumatology; ADA=anti-drug antibodies; AE=adverse event; AESI=adverse event of special interest; Anti-dsDNA=anti-double 
stranded deoxyribonucleic acid; C3=third component of complement; C4=fourth component of complement; C-SSRS=Columbia-Suicide Severity Rating 
Scale; DC=early discontinuation; dsDNA=double stranded deoxyribonucleic acid; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; 
FSH=follicle-stimulating hormone; IFN=interferon; IP=investigational product; PGA=Physician’s Global Assessment; QFT-G=QuantiFERON-TB Gold; 
MDRD=Modification of Diet in Renal Disease formula; MMF=mycophenolate mofetil; MPA=mycophenolic acid; LN=lupus nephritis; 
PD=pharmacodynamics; PtGA=patient global assessment; PHQ-8=Personal Health Questionnaire Depression. Scale; PK=pharmacokinetic; PRR=partial 
renal response; RNA=ribonucleic acid; Sc=screening; SAE=serious adverse event; SLE=systemic lupus erythematosus; SLEDAI-2K=Systemic Lupus 
Erythematosus Disease Activity Index 2000; SLICC/ACR=Systemic Lupus International Collaborating Clinics/American College of Rheumatology; SV= 
screening visit; TB=tuberculosis; UN=unscheduled; UPCR=urine protein/creatinine ratio 
a 
Not all assessments indicated for the Unscheduled Visit need to be performed. The assessments are to be performed at the discretion of the Investigator, 
as clinically indicated.  
b 
Subjects with early discontinuation of IP should continue to attend visits according to the Study Plan. However a 24-hour UPCR sample should be 
collected within 4 weeks of IP discontinuation decision (unless the next scheduled visit is within 4 weeks of this decision, and includes this test already) 
and before the start of a new treatment for LN. If at any point after IP discontinuation is performed, the subject decides to discontinue from the study 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
97 (231) 
without completing all scheduled visits up to Week 52/Visit 14, an early discontinuation visit needs to be performed as soon as possible after the study 
discontinuation decision is made. 
c 
Renal biopsy performed within 12 weeks prior to signing the ICF or during the screening period. 
d 
An external renal biopsy adjudication group will adjudicate renal biopsies post-randomisation. The biopsies for adjudication should be sent soon after 
randomisation. 
e 
Immunostaining, epigenetic and gene expression studies. 
f 
Renal biopsy may be performed at the discretion of the investigator based on clinical indication and local practice for subjects who meet withdrawal 
criteria for worsening lupus nephritis at Week 24 or later and for subjects not achieving Complete Renal Response at Week 52 (if subject signs the 
separate ICF). 
g 
Chest X-ray should be performed only in subjects who have not had a chest X-ray within 12 weeks prior to signing the ICF. Posterior-anterior or 
anterior-posterior and lateral images are required in order to visualize lungs unless limited by local practice. 
h 
At screening, female subjects with an intact cervix must have a Pap smear if they have not had a normal Pap smear within 2 years prior to signing the 
ICF. Additionally, female subjects with an intact cervix should have a Pap smear at or soon after Week 48 to ensure that there is no evidence of new 
cervical dysplasia and the results must be found to meet eligibility requirements as described in Appendix K and available by Week 60 or IP 
administration will be discontinued as described in Appendix K.  
i 
Screening laboratory includes HbA1c (diabetic subjects only), HbsAg, HBcAb (reflex DNA testing if isolated HBcAb positive), hepatitis C antibody, 
and HIV. A reflex test is a test that must be performed based on the results of a prior test (pre-set criteria). HBV DNA levels in subjects who are HBcAb 
positive at screening will be tested monthly for HBV DNA. To remain eligible for the study, the subject’s HBV DNA levels must remain below the 
LLOQ as per central laboratory. 
j 
If the test result is indeterminate, the test must be repeated at least one time by the central laboratory as soon as possible. 
k 
Immunology profile includes quantitative immunoglobulins (IgA, IgG, IgM), ANA, and anti-RNP, anti-Smith, anti-SSA (Ro), anti-SSB (La), and 
anti-cardiolipin antibodies. 
l 
B cell count (CD19+ cells) for those who received rituximab or other B cell-depleting therapy >26 weeks prior to signing ICF. See exclusion criterion 
No. 17. 
m 
Subjects will be required to fast for at least 8 hours prior to assessment of lipid profile. If the subject has not fasted, he/she should fast before the next 
visit, and the test can be done at that visit. 
n 
For subjects who do not continue in the second year extension period, there is no dosing at Visit 14, however a PK sample will be collected. 
o 
Mycophenolate mofetil dose should be withheld until samples for the mycophenolic acid blood draw has been collected on that visit day. 
p 
Starting from Week 0 visit, the 24-hour UPCR sample must always be collected before the administration of IP at the marked visits. The collection of 
the 24-hour UPCR sample should start preferably in the morning of the day before the scheduled visit and end in the morning of the day of the visit. The 
urine collection can be done within 1 day prior to the visit if the urine sample can be kept refrigerated until the day of the visit. If refrigeration is not 
possible, subjects should select the coolest possible place to store their urine sample eg, a cool room or use a portable cooler with ice/ice pack. Subjects 
who prematurely discontinue IP should have the 24-hour UPCR measurement within 4 weeks of the decision to discontinue IP and before the start of a 
new treatment for LN. 
q 
Two samples of 24-hour urine collection are required during screening period to assess eligibility. One sample is to be collected at the start of the 
screening process (screening sample). The other sample is to be collected within 14 days prior to the expected date of randomisation. Without the results 
of the second (stratification) sample, subjects cannot be randomised. Turn-around time for results from central laboratory is up to 7 days. On rare 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
98 (231) 
occasion an extension of the 30-day screening window may be allowed if the re-collection of the 24-hour UPCR or other required samples is necessary 
or if the results needed for randomisation are delayed. 
r 
The baseline sample must be provided on Day 1 prior to randomisation and administration of dose. 
s 
This will be done locally from Visit 1 onwards.  
t 
If the subject is menstruating, this must be specified in the eCRF. 
u 
This will be in addition to the central laboratory urinalysis. This will include urine sediment examination for red blood cells (RBC), white blood cells 
(WBC), and cellular casts (WBC, RBC and mixed) and hematuria on a dipstick test. 
v 
Randomised subjects who receive anti-malarial therapy within 12 months prior to signing the ICF must have an eye exam by a qualified professional 
either within 12 months prior to signing the ICF or subjects who start on anti-malarial therapy during the Screening Period within 12 weeks after signing 
ICF.  
w 
Check accountability and dispense Sponsor-provided MMF. 
1 
All Week 52 laboratory samples (blood and urine, including 24-hour UPCR sample) should be collected between Week 50 to Week 52, to allow 
assessment of PRR requirement for the second year participation. 
2 
IP infusion at Week 52 is only for subjects who are continuing in second year extension period.  
 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
99 (231) 
Table 3 
Study plan detailing the procedures during follow-up (for subjects not participating in the second year 
extension period) 
Study Period 
Follow-Up Period 
Days 
393±7 (8 weeks post final dose) 
421±7 (12 weeks post final dose) 
Visit Number 
15 (Week 56) 
16 (Week 60) 
PtGA 
 
X 
C-SSRS (V1-V16) 
X 
X 
PHQ-8 
 
X 
Vital signs 
X 
X 
Tuberculosis Questionnaire 
X 
X 
Physical examination 
X 
X 
Weight 
X 
X 
Blood collection for: 
 
 
 
Serum chemistry/haematology 
X 
X 
 
Lupus serology tests (C3, C4, anti-ds 
 
DNA) 
X 
X 
 
Type I IFN signature with 21-gene assay 
 
(PD marker) 
 
X 
 
RNA transcript profiling 
 
X 
 
ADA 
X 
X 
 
PK blood samplesa 
X 
X 
 
Serum and plasma biomarkers 
 
X 
 
QFT-G test (TB testing), if applicableb 
X 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
100 (231) 
Study Period 
Follow-Up Period 
Days 
393±7 (8 weeks post final dose) 
421±7 (12 weeks post final dose) 
Visit Number 
15 (Week 56) 
16 (Week 60) 
Urine collection for: 
 
 
 
Spot UPCR 
X 
X 
 
Urinalysis (including microscopic 
 
examination)c 
X 
X 
 
Local urinalysis (including 
 
microscopic examination)  for selected 
 
sitesd 
X 
X 
 
Urinary biomarkers 
X 
X 
 
Urine pregnancy tests (using dipstick) 
X 
X 
eGFR using MDRD formula  
X 
X 
SLEDAI-2K 
X 
X 
PGA 
X 
X 
AEs/SAEs/AESIs 
X 
X 
SLEDAI-2K based Flare Assessment Instrument 
X 
X 
Concomitant medications 
X 
X 
Sponsor-provided MMFe 
X 
 
Second renal biopsy (optional)f 
X 
 
Local clinical evaluation 
X 
 
Adjudication (optional) 
X 
 
Tissue biomarkerg (optional) 
X 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
101 (231) 
ADA=anti-drug antibody; AE=adverse event; AESI=adverse event of special interest; Anti-dsDNA=anti-double stranded deoxyribonucleic acid; C3=third 
component of complement; C4=fourth component of complement C-SSRS=Columbia-Suicide Severity Rating Scale; eGFR= Estimated Glomerular Filtration 
Rate; IFN=interferon; MDRD= Modification of Diet in Renal Disease; MMF=mycophenolate mofetil; PGA=Physician’s Global Assessment; PtGA=patients 
global assessment; PHQ-8=Personal Health Questionnaire Depression Scale; PK=pharmacokinetic; RNA=ribonucleic acid; SAE=serious adverse event; 
SLEDAI-2K=Systemic Lupus Erythematosus Disease Activity Index 2000; TB=tuberculosis; UPCR=urine protein/creatinine ratio.  
a 
Although there is no dosing at Weeks 56 and 60, PK sample will be collected. 
b 
For subjects with a negative QFT-G at baseline and no symptoms of active TB: If the Week 52 QFT-G was indeterminate or positive, please refer to 
Section 5.2.9.3, Tuberculosis monitoring during the study. 
c 
If the subject is menstruating, this must be specified in the eCRF. 
d 
This will be in addition to the central laboratory urinalysis. This will include urine sediment examination for red blood cells (RBC), white blood cells 
(WBC) and cellular casts (WBC, RBC and mixed) and hematuria on a dipstick test. 
e 
Dispense Sponsor-provided MMF and check accountability. At Week 60, only accountability is to be checked. 
f 
For subjects who meet withdrawal criteria for worsening lupus nephritis at Week 24 or later and for subjects not achieving Complete Renal Response at 
Week 52 (if subject signs the separate ICF). Renal biopsy may be performed at the discretion of the Investigator based on clinical indication and local 
practice. 
g 
Immunostaining, epigenetic and gene expression studies. 
 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
102 (231) 
Table 4 
Study plan detailing the procedures from Week 56 to Week 104 during the second year extension period 
Study Period  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
701 
729 
- 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
UNa 
Study Week 
W56 
W60  W64 
W68 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104/DCb 
- 
Visit Window 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
PtGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Renal biopsy (optional)c 
If clinically indicated for flare 
 
Local clinical evaluation 
X 
 
Adjudication (optional) 
X 
 
Tissue biomarker 
(optional) 
X 
eGFR using MDRD formula 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Focused physical examination 
X 
X 
X 
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 
 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tuberculosis Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pap smeard 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood collection for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QFT-G test (TB testing) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
103 (231) 
Study Period  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
701 
729 
- 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
UNa 
Study Week 
W56 
W60  W64 
W68 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104/DCb 
- 
Visit Window 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
QFT-G test (TB testing, only if 
indeterminate at previous 
visits) 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunology profilee  
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Lipid profilef  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Lupus serology tests (C3, 
C4, anti-dsDNA) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pre-dose ADA  
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Pre-dose PK blood sample 
 
 
 
X 
 
 
 
X 
 
 
 
 
Xg 
 
 
Serum and Plasma 
biomarkers 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Type I IFN signature with 
21-gene assay (PD marker) 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
RNA transcript profiling 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Urine collection for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hour UPCRh 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Spot UPCR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
104 (231) 
Study Period  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
701 
729 
- 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
UNa 
Study Week 
W56 
W60  W64 
W68 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104/DCb 
- 
Visit Window 
±7 D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
±7D 
 
 
Pregnancy test in females 
of childbearing potential 
onlyi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis (including 
microscopic examination)j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Local urinalysis (including 
microscopic examination) 
for selected sitesk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SLEDAI-2K 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SLICC/ACR Damage Index 
(SDI) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
PGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEs/AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Steroid tapering  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Extra-renal flare (SLEDAI-2K 
based Flare Assessment 
Instrument) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IP administrationl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Sponsor-provided MMFm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ACR=American College of Rheumatology; ADA=anti-drug antibodies; AE=adverse event; AESI=adverse event of special interest; Anti-dsDNA=anti-double 
stranded deoxyribonucleic acid; C3=third component of complement; C4=fourth component of complement; dsDNA=double stranded deoxyribonucleic acid; 
DC=early discontinuation; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone; IFN=interferon; 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
105 (231) 
IP=investigational product;  PGA=Physician’s Global Assessment; QFT-G=QuantiFERON-TB Gold; MDRD=Modification of Diet in Renal Disease formula; 
MMF=mycophenolate mofetil; MPA=mycophenolic acid; LN=lupus nephritis; PD=pharmacodynamics; PtGA=patient global assessment; 
PK=pharmacokinetic; RNA=ribonucleic acid; SAE=serious adverse event; SLE=systemic lupus erythematosus; SLEDAI-2K=Systemic Lupus Erythematosus 
Disease Activity Index 2000; SLICC/ACR=Systemic Lupus International Collaborating Clinics/American College of Rheumatology; TB=tuberculosis; 
UN=unscheduled; UPCR=urine protein/creatinine ratio 
Note: Study period: Transition from the main study to extension period.  
a 
Not all assessments indicated for the Unscheduled Visit need to be performed. The assessments are to be performed at the discretion of the Investigator, 
as clinically indicated.  
b 
Subjects with early discontinuation of IP should continue to attend visits according to the Study Plan. However a 24-hour UPCR sample should be 
collected within 4 weeks of IP discontinuation decision (unless the next scheduled visit is within 4 weeks of this decision, and includes this test already) 
and before the start of a new treatment for LN. If at any point after IP discontinuation is performed, the subject decides to discontinue from the study 
without completing all scheduled visits up to Week 104/Visit 29, a discontinuation visit needs to be performed as soon as possible after the study 
discontinuation decision is made. 
c 
Renal biopsy may be performed at the discretion of the investigator based on clinical indication and local practice for subjects who meet withdrawal 
criteria for worsening lupus nephritis at Week 60 or later and for subjects not achieving Complete Renal Response at Week 52 (if subject signs the 
separate ICF). 
d 
Female subjects with an intact cervix should have a Pap smear between Week 100 and Week 104 to ensure that there is no evidence of new cervical 
dysplasia.  
e 
Immunology profile includes quantitative immunoglobulins (IgA, IgG, IgM), ANA, and anti-RNP, anti-Smith, anti-SSA (Ro), anti-SSB (La), 
anti-cardiolipin antibodies. 
f 
Subjects will be required to fast for at least 8 hours prior to assessment of lipid profile. If the subject has not fasted, he/she should fast before the next 
visit, and the test can be done at that visit. 
g 
PK sample for Week 104: Although there is no dosing at Visit 29 (Week 104), pre-dose PK sample will be collected. 
h 
The collection of the 24-hour UPCR sample should start preferably in the morning of the day before the scheduled visit and end in the morning of the 
day of the visit. The urine collection can be done within 1 day prior to the visit if the urine sample can be kept refrigerated until the day of the visit. If 
refrigeration is not possible, subjects should select the coolest possible place to store their urine sample, eg, a cool room or use a portable cooler with 
ice/ice pack. Subjects who prematurely discontinue IP should have the 24-hour UPCR measurement within 4 weeks of the decision to discontinue IP and 
before the start of a new treatment for LN.  
i 
This will be done locally from Visit 17 onwards.  
j 
If the subject is menstruating, this must be specified in the eCRF. 
k 
This will be in addition to the central laboratory urinalysis. This will include urine sediment examination for red blood cells (RBC), white blood cells 
(WBC) and cellular casts (WBC, RBC and mixed) and hematuria on a dipstick test. 
l 
First dose in extension period must be between Weeks 52 (+14 days) and 60. 
m 
Check accountability and dispense Sponsor-provided MMF. 
 
 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
106 (231) 
Table 5 
Study plan detailing the procedures during follow-up (second year extension period) 
Study Period 
Follow-Up Period 
Days 
756±7 (8 weeks post final dose) 
784±7 (12 weeks post final dose) 
Visit Number 
30 (Week 108) 
31 (Week 112) 
PtGA 
 
X 
Vital signs 
X 
X 
Tuberculosis Questionnaire 
X 
X 
Physical examination 
X 
X 
Weight 
X 
X 
Blood collection for: 
 
 
 
Serum chemistry/haematology 
X 
X 
 
Lupus serology tests (C3, C4, anti-ds 
 
DNA) 
X 
X 
 
Type I IFN signature with 21-gene assay 
 
(PD marker) 
X 
X 
 
RNA transcript profiling 
X 
X 
 
ADA 
X 
X 
 
PK blood samplesa 
X 
X 
 
Serum and plasma biomarkers 
 
X 
 
QFT-G test (TB testing), if applicableb 
X 
Urine collection for: 
 
 
 
Spot UPCR 
X 
X 
 
Urinalysis (including microscopic 
 
examination)c 
X 
X 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
107 (231) 
Study Period 
Follow-Up Period 
Days 
756±7 (8 weeks post final dose) 
784±7 (12 weeks post final dose) 
Visit Number 
30 (Week 108) 
31 (Week 112) 
 
Local urinalysis (including 
 
microscopic examination)  for selected 
 
sitesd 
X 
X 
 
Urine pregnancy tests (using dipstick) 
X 
X 
eGFR using MDRD formula  
X 
X 
SLEDAI-2K 
X 
X 
PGA 
X 
X 
AEs/SAEs/AESIs 
X 
X 
SLEDAI-2K based Flare Assessment Instrument 
X 
X 
Concomitant medications 
X 
X 
Sponsor-provided MMFe 
X 
 
Renal biopsy (optional)f 
X 
 
Local clinical evaluation 
X 
 
Adjudication (optional) 
X 
 
Tissue biomarkerg (optional) 
X 
ADA=anti-drug antibody; AE=adverse event; AESI=adverse event of special interest; Anti-dsDNA=anti-double stranded deoxyribonucleic acid; C3=third 
component of complement; C4=fourth component of complement; eGFR= Estimated Glomerular Filtration Rate; IFN=interferon; MDRD= Modification of 
Diet in Renal Disease; MMF=mycophenolate mofetil; PGA=Physician’s Global Assessment; PtGA=patients global assessment; PK=pharmacokinetic; 
RNA=ribonucleic acid; SAE=serious adverse event; SLEDAI-2K=Systemic Lupus Erythematosus Disease Activity Index 2000; TB=tuberculosis; 
UPCR=urine protein/creatinine ratio.  
a 
Although there is no dosing at Weeks 108 and 112, PK sample will be collected. 
b 
For subjects with a negative QFT-G at baseline and no symptoms of active TB: If the Week 104 QFT-G was indeterminate or positive, please refer to 
Section 5.2.9.3, Tuberculosis monitoring during the study. 
c 
If the subject is menstruating, this must be specified in the eCRF. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
108 (231) 
d 
This will be in addition to the central laboratory urinalysis. This will include urine sediment examination for red blood cells (RBC), white blood cells 
(WBC), and cellular casts (WBC, RBC and mixed) and hematuria on a dipstick test. 
e 
Dispense Sponsor-provided MMF and check accountability. At Week 112, only accountability is to be checked. 
f 
For subjects who meet withdrawal criteria for worsening lupus nephritis at Week 60 or later and for subjects not achieving Complete Renal Response at 
Week 104 (if subject signs the separate ICF). Renal biopsy may be performed at the discretion of the Investigator based on clinical indication and local 
practice. 
g 
Immunostaining, epigenetic and gene expression studies. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
109 (231) 
4.1 
Screening/Enrolment period 
At screening, subjects are assessed to ensure that they meet eligibility criteria. Once the 
subject signs the ICF, they are considered enrolled in the study. Subjects who do not meet 
these criteria must not be randomised into the study. These subjects will be considered as 
screen failures (See Section 3.10). 
Screening procedures will be performed according to the Screening Study Plan (Table 2), 
from Day 30 to Day -1. Screening visit may be conducted as multiple visits, S1, S2, Sx, where 
laboratory evaluations can be completed initially. 
Chest X-rays, renal biopsy, and Pap smears may be completed any time 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 parameter may be repeated once within the screening period. 
On rare occasion an extension of the 30 day screening window may be allowed if the re-
collection of the 24-hour UPCR or other required samples is necessary or if the results needed 
for randomisation are delayed.  Before the Week 0 (Day 1) visit, a notification from the study 
Sponsor/Designee Medical Monitor should be obtained, confirming that subject meets LN 
diagnosis related eligibility criteria. The details of eligibility confirmation process will be 
documented separately for the site (Site Manual), and for the study team (Eligibility Process). 
4.1.1 
Re-screening subjects who screen fail 
If a subject fails screening for reason(s) which, in the opinion of the Investigator, may change 
to make the subject eligible, the subject may be re-screened one time. In this case, the subject 
will re-sign the informed consent document and all screening procedures will be performed 
except those assessments which may be still within the specified periods (eg, chest X-ray, 
renal biopsy, TB test). If a subject does not meet eligibility criteria on the basis of a laboratory 
value, then the laboratory parameter may be repeated once within the screening period; this 
will be re-testing so that re-screening is not required. If the subject fails screening twice, they 
may not undergo further screening for this study except on a case by case basis, after 
discussion and approval from the Sponsor/Designee Medical Monitor. 
4.1.2 
Medical history  
A complete medical history by body system will be completed during screening. This will also 
include history of allergies and anaphylaxis, concomitant diseases, viral reactivation events, 
and previous manifestations of SLE. Various risk factors for atherosclerosis will be assessed 
as part of the demographics at screening. On Day 1, the medical history will be reviewed and 
any changes since screening will be documented, if applicable. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
110 (231) 
4.1.3 
SLE and LN medication history 
All prescription medications the subject has ever taken for SLE and LN should be documented 
in the subject's file (except for only minor dose adjustments if these were done ˃3 months 
prior to the ICF signature date), including prior use of cyclophosphamide, MMF, oral and 
parenteral corticosteroids; if these were discontinued, then reasons for discontinuation must be 
included. Any medications ongoing at the time of informed consent or received following 
signing the ICF are considered concomitant medications. Any non-prescription medications, 
eg, naturopathic or ayurvedic remedies ever used for SLE or for any other purpose should be 
documented, as well as continuing use of any non-prescription remedies not excluded from 
use during the study period. 
4.2 
Treatment period 
Procedures during the treatment period will be performed according to the Treatment Period 
Study Plan (Table 2 and Table 4), from Week 0 (Day 1) to Week 104. The patient-reported 
outcome assessments should be completed by the subject prior to all other evaluations, and 
prior to the infusion, as disease assessments/clinical evaluations may confound the results.  
On Day 1, in addition to the eligibility confirmation by study Medical Monitor/Designee, the 
Principal Investigator must ensure that the subject still meets eligibility criteria, including Day 
1 assessments according to the Treatment Period Study Plan (Table 2).  
Subjects confirmed to be eligible will be randomised.  
Subjects will have scheduled visits at 4-week intervals to complete protocol-specified 
assessments and IP administration according to the Treatment Period Study Plan (Table 2). 
The primary endpoint will be assessed at Week 52. For subjects who prematurely discontinue 
IP and are not willing to continue to participate in the study refer to Section 3.9. 
The SLE Data Medical Review Team (Section 9.2.4) will perform an ongoing review of all 
SLE and LN data in conjunction with the relevant AE, concomitant medications and central 
laboratory data. 
For subjects who meet withdrawal criteria for worsening LN at Week 24 or later and for 
subjects not achieving CRR at Week 52, a second renal biopsy may be performed at the 
discretion of the Principal Investigator based on clinical indication and local practice. A 
separate consent is required for this second biopsy. 
4.2.1 
Week 52 visit 
Study objectives will be assessed at Visit 14 (Week 52). A 24-hour UPCR must be performed 
to assess the primary endpoint. Investigational sites should contact subjects prior to this visit 
in order to ensure the subject is compliant with the protocol to support the study objectives. 
Laboratory samples, including the 24-hour UPCR may be collected within 14 days prior to the 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
111 (231) 
scheduled Visit 14(Week 50 - Week 52- see Table 2 footnote b), so that results are available 
for determining if subjects are eligible for continued IP dosing in the second year of the study.  
4.2.1.1 
Assessment criteria for participation in the second year extension period 
(Week 52) 
The 24-hour UPCR sample collected between Week 50 to Week 52 for the Week 52 response 
assessment will be used to assess criteria for participation in the second year extension period. 
The eGFR measured between Week 50 and Week 52 will be used to assess eligibility for 
participation in the second year extension period.  
4.2.1.2 
Initiation of dosing in the second year extension period (Week 52 to Week 60) 
All efficacy and safety assessments for Week 52 must be completed prior to initiation of 
dosing in the second year extension period. The first dose in the second year extension period 
must be administered between Week 52 (+14 days) and Week 60. Prior to administering the 
first dose in the second year extension period, the Principal Investigator must confirm that all 
Week 52 safety assessments (including the ECG) are performed and that subject does not 
meet any withdrawal criteria. The Week 52 QFT-G test results must be available prior to 
Week 56 and results of the Pap smear must be found to meet eligibility requirements as 
described in Appendix K and available by Week 60 or IP administration will be discontinued.  
4.2.1.3 
Week 104 visit 
The last dose of IP will be administered at Week 100. At Week 104, a 24-hour UPCR sample 
must be collected. Investigational sites should contact subjects prior to this visit in order to 
ensure the subject is compliant with the study procedure to support the study objectives.  For 
subjects who discontinue IP between Week 52 and Week 100, and are not willing to continue 
to participate in the study refer to Section 3.11. 
4.2.2 
Follow-up visits after premature discontinuation of investigational product 
Subjects who agree to continue scheduled visits until Week 52 (if IP discontinued prior to 
Week 52) or Week 104 (if IP discontinued after Week 52): 
Subjects who prematurely discontinue IP (see Section 3.9) should have a 24-hour UPCR 
measurement within 4 weeks of the decision to discontinue IP and before the start of a new 
treatment for LN. 
Subjects who discontinue IP will be asked to return for all regular clinic visits. All study 
assessments will be performed if possible; however, at a minimum, the following assessments 
should be completed: 
• 
Lupus Serology tests (anti-dsDNA antibodies, C3, C4) 
• 
PGA (Physician’s Global Assessment) 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
112 (231) 
• 
24-hour urine for protein, creatinine and spot UPCR  
The following safety assessments should also be completed: 
• 
Serum chemistry, haematology, urinalysis 
• 
Vital signs 
• 
Physical examination, weight 
• 
Adverse events including AESIs 
• 
TB Questionnaire 
• 
Concomitant medications 
Subjects who are unwilling to continue to Week 52 or Week 104: 
If during the 52 week double-blind treatment period, the subject is unwilling to continue 
through Week 52, he/she should complete Week 52 visit and be followed for 12 weeks after 
the last administration of IP by completing the Follow-up Visits, unless consent is withdrawn. 
If during the second year extension period, the subject is unwilling to continue through Week 
104, he/she should complete Week 104 visit and be followed for 12 weeks after the last 
administration of IP by completing the Follow-up Visits, unless consent is withdrawn. 
If the subject does not agree to return for any clinic visits and perform the laboratory testing 
requirements of these visits, he/she will be asked if he/she can be followed on a monthly basis 
via telephone calls for 12 weeks after last dose of IP administration. At these calls, he/she will 
be asked about AEs/SAEs, lupus symptoms, and lupus medications. Steroid bursts will also be 
captured. 
Subjects who withdraw consent: 
If the subject indicates his/her intention to withdraw consent, attempts should be made to 
complete the Week 52/discontinuation or Week 104/discontinuation visit as applicable before 
the consent is withdrawn. However, no study procedures or data collection can occur after the 
subject withdraws consent.  
Adverse events will be followed up per Section 6.5.2. 
4.3 
Unscheduled visit 
There may be times a subject needs to have an unscheduled visit. Potential assessments for 
such a visit are listed on the Treatment Period Study Plan (Table 2 and Table 4). The 
Investigator should determine and note the reason for the unscheduled visit and the 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
113 (231) 
assessments to be completed based on the reason for the unscheduled visit. Concomitant 
medications and AEs should be completed whenever a subject has an unscheduled visit. 
4.4 
Follow-up period 
Procedures will be performed according to the Follow-up Period Study Plan (Table 3 and 
Table 5).  
Subjects who complete the double-blind treatment period (Week 52) but do not continue with 
IP treatment will have follow-up visits at Week 56 and Week 60. Subjects who complete the 
second year extension will have follow-up visits at Week 108 and Week 112. Subjects who 
discontinue the IP before Week 52 and are not continuing on the study schedule should 
complete the Week 52 procedures. Subjects who discontinue the IP between Week 52 and 
Week 104 and are not continuing on the study schedule should complete Week 104 
procedures. All other early discontinuation subjects should be followed until Week 52 or 
Week 104 (or for a minimum of 12 weeks after last dose of IP for subjects for whom IP was 
discontinued within 12 weeks prior to Week 52 or Week 104) (see Section 3.9). 
5. 
STUDY ASSESSMENTS 
The Investigator will ensure that all study assessment data are recorded in the eCRF and also 
ensure the accuracy, completeness, and timeliness of the data recorded and of the provision of 
answers to data queries according to the Clinical Study Agreement. The Investigator will sign 
the completed eCRFs. A copy of the completed eCRFs will be archived at the study site. 
The Site Manual will include a description of specific procedures. All the assessments and 
laboratory tests (unless otherwise specified) will be done prior to administration of IP. 
5.1 
Efficacy assessments 
Efficacy measurements will be made at the times indicated in the Study Plan (for assessments 
to be performed at Screening and treatment period, see Table 2 and Table 4, respectively, and 
for those at Follow-up, see Table 3 and Table 5). 
The efficacy assessments based on laboratory tests include: 
• 
Urine protein to creatinine ratio: This consists of: 
− 
24-hour UPCR: The 24-hour UPCR will be determined on a 24-hour 
UPCR sample. 
This will be performed twice during the screening period, Weeks 0, 12, 
24, 36, 52, 64, 76, 88, and 104 and at Early Discontinuation visit.  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
114 (231) 
During the screening period two samples will be required:  
• 
Screening sample at the start of the screening process, after the ICF is 
signed and  
• 
Stratification sample within 14 days prior to the expected day of 
randomisation. Without the results of the second (stratification) sample, 
subjects cannot be randomised. Turn-around time for results from central 
laboratory is up to 7 days.  
Starting from Week 0, the 24-hour UPCR sample must always be collected before the 
administration of IP. The sample collected at Week 0 (Day 1) will be the baseline sample 
which must be provided on Day 1 prior to randomisation and administration of first dose of 
IP.  
The collection of the 24-hour UPCR sample should start preferably in the morning of the day 
before the scheduled visit and end in the morning of the day of the visit. The urine collection 
can be done within 1 day prior to the visit if the urine sample can be kept refrigerated until the 
day of the visit. The sample should be kept refrigerated whenever possible. If refrigeration is 
not possible, subjects should select the coolest possible place to store their urine sample, eg, a 
cool room or use a portable cooler with ice/ice pack. 
In case subject has a medical reason which would impact the validity of the assessment of 
proteinuria (eg, urinary tract infection, heavy menstruation), or the sample was not collected 
appropriately, the collection of the sample may be done/repeated as follows: 
• 
Screening samples: As soon as possible before the next scheduled 
sampling is due 
• 
Week 0: Prior to IP administration (which may require the Visit 1 to be 
postponed) 
• 
Weeks 12, 24, 36, 52, 64, 76, 88, and 104: Within 2 weeks of the actual 
date of visit when the collection was due and if applicable, before any 
change in SOC or concomitant medications is made (Week 52 sample 
must be collected before second year extension period dosing) 
The 24-hour UPCR will be used only for the primary and secondary endpoints, the PRR, 
aCRR, graded CRR, and graded aCRR criteria at Week 52 and Week 104, the 24-hour UPCR 
and CRR at Week 104 and to determine withdrawal criteria at Weeks 12, 24 and 52. 
• 
Spot UPCR: Spot UPCR will be performed at all visits and will be used 
for the calculation of SLEDAI-2K and for the CRR and PRR 
classification, when evaluating time to achieve renal response modified to 
include OCS tapering requirement as well as for the CRR and PRR 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
115 (231) 
classification for flare assessments. All assessments except as noted 
above for the 24-hour UPCR will be based on the spot UPCR. The 
change in proteinuria will also be assessed based on spot UPCR at Weeks 
24, 52 and 104. The spot UPCR sample should be taken prior to 
administration of IP, on a clean catch urine sampling. The same urine 
sample can be used for spot UPCR and sediment analysis. 
• 
Urine sediment examination will be performed at all visits: Selected sites 
will perform local urinalysis including a microscopic examination. The 
microscopic examination must be assessed by trained personnel, and can 
be assessed by the site or a local laboratory. This data will be used for 
exploratory analyses. This will be in addition to the central laboratory 
urinalysis. 
• 
Estimated glomerular filtration rate based on the MDRD formula 
calculated by the central laboratory. Refer to the Laboratory Manual for 
specifics. 
The efficacy assessments based on clinical evaluation include SLEDAI-2K (Section 5.1.2, 
Appendix F), PGA (Section 5.1.4), OCS reduction (Section 5.1.5), and SDI (Section 5.1.3). 
The assessments for quality of life and patient-reported outcomes are summarised in 
Section 5.3.1. 
5.1.1 
Renal biopsy 
Renal biopsy is required within 12 weeks prior to screening or during the screening period for 
inclusion in the study and must meet inclusion criterion number 6 and not meet exclusion 
criterion number 10. (Note: If renal biopsy is performed during the screening period, adequate 
time should be allowed before the next scheduled urine sample collection). 
Renal biopsy adjudication 
Biopsies will be evaluated locally and the local classification will be used to confirm the 
eligibility criteria. Screening biopsy slides will then be submitted for adjudication by an 
external adjudication committee consisting of nephropathologists with special expertise in LN. 
The biopsies will be assessed for all elements of the ISN/RPS classification, the NIH activity, 
chronicity indices, and the presence of concomitant conditions. The submission of screening 
biopsies for adjudication is required to participate in the study. The process for adjudication 
will be defined in a separate document (Renal Biopsy Adjudication Charter). Data obtained 
during the adjudication will be used for exploratory and sensitivity analyses. 
A second renal biopsy is recommended for subjects who meet withdrawal criteria for 
worsening LN at Week 24 or later and for subjects not achieving CRR at Week 52. This 
biopsy will be performed at the discretion of the Investigator based on clinical indication and 
local practice. A separate consent is required for this second biopsy. Second biopsies will be 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
116 (231) 
read locally first and, if the subject agrees, will then be submitted for adjudication to the 
external adjudication committee. Not agreeing to the review of the second biopsy by the 
adjudication group will not have any impact on the subject’s continuation in the study. If a 
clinically indicated renal biopsy is performed during the second year extension period, the 
subject’s consent will be required prior to the biopsy slides being submitted for adjudication. 
5.1.2 
Systemic Lupus Erythematosus Disease Activity Index 2000  
The SLEDAI-2K index (see Appendix F) consists of a list of organ manifestations, each with 
a definition. A certified Investigator or designated physician will complete the SLEDAI 2K 
assessment and decide whether each manifestation is “present” or “absent” in the last 30 days. 
The assessment also includes the collection of whole blood for analysis of C3, and C4 
complement levels, and anti-dsDNA antibodies. 
The proteinuria descriptor should be scored using the spot UPCR.  
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 30 days will be used 
in this study. 
Any missing SLEDAI-2K laboratory assessments should be repeated. 
5.1.3 
Systemic Lupus International Collaborating Clinics/American College 
Rheumatology damage index  
The SDI (Appendix N) has been developed to assess irreversible damage in SLE subjects 
independently of its cause (ie, included damage due to SLE activity, SLE-related scarring, 
therapy, comorbidities) but occurring after disease onset. 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 myocardial 
infarction 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, theoretically to a 
maximum of 47 points (Schwartz et al, 2009). 
5.1.4 
Physician’s Global Assessment  
A trained and certified Investigator will complete the PGA. The PGA represents the 
physician’s overall assessment of average disease severity on a Visual Analogue Scale (VAS) 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
117 (231) 
scale with 0 (none) to 3 (severe) disease activity over the last 30 days. The PGA for a given 
subject should be completed by the same physician whenever possible. 
PGA may be completed after the visit, to allow for laboratory results to be received, as long as 
this is done prior to the next scheduled visit. Therefore, the date of the associated scheduled 
visit (Week 0 etc.) will be used to determine baseline (and subsequent visits), and not the 
actual date of the assessment. 
The PGA is a modification of the classic analogue scale in that it is anchored with numbers 
from 0 to 3 demarcating mild, moderate and severe disease. The number 3 indicates severe 
disease and is at the very end of the scale. This refers to the most severe possible disease, and 
does not reflect the most severe ever 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. The mark made by the physician must be a single line, 
nearly perpendicular to the axis of the VAS line and not an “X”. Any disease rated greater 
than 2.5 is very severe. The range of moderate disease covers about 1.5 to 2.4. Mild disease 
falls below 1.5. Clearly, this is a bit like a logarithmic scale with greater distances or 
demarcations possible among more mild-moderate symptoms. This needs to be kept in mind 
when scoring the instrument. 
When scoring the PGA, always look back at the score from the previous protocol visit and 
move the mark relative to that 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. 
These instructions are quite discrete from those given for other analogue (Likert) scales and 
are specific for the scoring of the PGA.  
5.1.5 
Oral corticosteroid reduction 
Please refer to Section 7.7.3.2 for all information regarding steroid tapering.  
5.2 
Safety assessments 
Key safety assessments are AEs, AESIs, vital signs, physical examination, safety laboratory 
tests, ECGs, C-SSRS, PHQ-8, and SLEDAI-2K based Flare Assessment Instrument 
(Appendix M). Safety assessments will be made at the times indicated in the Study Plan (see 
Table 2, Table 3, Table 4, and Table 5). 
5.2.1 
Adverse events 
Adverse events, SAEs, and AESIs are defined in Sections 6.1, 6.2, and 6.4, respectively. 
Recording of AEs is described in Section 6.5 and reporting of SAEs in Section 6.6. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
118 (231) 
5.2.2 
Vital signs 
Vital signs (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). Temperature 
should be measured by the same methodology (eg, oral, tympanic) for a subject throughout 
the study. 
5.2.3 
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. 
5.2.3.1 
Complete physical examination 
A complete physical examination will be performed at the visits specified in the Study Plan 
(Table 2, Table 3, Table 4, and Table 5), and will include an assessment of the following: 
head, eyes, ears, nose and throat, lungs heart, abdomen, joints, muscles and soft tissues, 
neurologic system, skin, and lymph nodes. 
5.2.3.2 
Focused physical examination 
The focused physical examination will include an assessment of the organ systems required to 
complete protocol-specified assessment tool (SLEDAI-2K). Additional assessments should be 
done as clinically indicated. Abnormal findings will be recorded as part of AE, SAE, AESI, or 
lupus activity, as appropriate. 
5.2.3.3 
Pap smear 
Most cases of cervical cancer appear to be related to infection with human papilloma virus. 
Because of the potential for viral reactivation due to blockade of the interferon pathway, 
cervical dysplasia will be assessed 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 
signing the ICF 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 K for guidance.  
Female subjects with an intact cervix must have a Pap smear repeated between Week 48 and 
Week 52 and Week 100 and Week 104 to ensure that there is no evidence of new cervical 
dysplasia. If a Pap smear was performed between Week 48 and Week 52 and is not normal but 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
119 (231) 
shows no evidence of malignancy (eg, CIN III, CIS, or AIS), it should be repeated as per the 
subject’s gynaecologist’s recommendations. If the subject’s gynaecologist has recommended a 
repeat Pap smear be performed at a specified interval, the Pap smear should be obtained as 
recommended and the report provided in the source document. 
5.2.3.4 
Assessment of Cushingoid features 
Subjects will be assessed for Cushingoid features at the visits specified in the Treatment 
Period Study Plan (Table 2 and Table 4). Features, such as moon face, buffalo hump, purple 
or violaceous striae, central obesity, hirsutism, acne, easy bruising, and fragile skin will be 
captured separately within the study eCRF to evaluate whether resolution of same can occur 
overtime with OCS reduction. 
5.2.4 
Electrocardiogram 
A 12-lead ECG tracing will be performed locally at the visits specified in the Study Plan 
(Table 2 and Table 4). The Investigator or qualified designee must review the ECG for 
clinically significant changes. 
5.2.5 
Assessment of cardiovascular risk 
To understand the contribution of the chronic inflammatory response in SLE to dyslipidaemia 
(as a potential risk for accelerated subclinical arteriosclerotic cardiovascular disease) and the 
potential effects of anifrolumab treatment, lipids (including high density lipoprotein 
cholesterol, low density lipoprotein cholesterol, triglycerides [see Section 5.2.10.1]) will be 
measured during the study. Current and previous concomitant medications received for 
cardiovascular indications and other risk factors for cardiovascular disease such as smoking, 
hypertension, and diabetes should be collected and recorded. Assessment of cardiovascular 
risk will be completed as indicated in the Study Plan (Table 2 and Table 4).  
5.2.6 
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.  
The C-SSRS will be administered 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. 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 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
120 (231) 
the C-SSRS is administered by a rater other than the Investigator, it is recommended that the 
Investigator confirms suicidal ideation before making a referral to mental health services; 
however this should not delay the referral.  
5.2.7 
Personal Health Questionnaire Depression Scale–8 
The PHQ-8 consists of eight of the nine criteria on which the DSM-IV diagnosis of depressive 
disorders is based (American Psychiatric Association, 1994). 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 2 and 
Table 3). 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. 
5.2.8 
SLEDAI-2K based Flare Assessment Instrument 
SLEDAI-2K based Flare Assessment Instrument is modelled after the modified SELENA 
SLEDAI Flare Assessment Instrument specifically for this study to collect extra-renal flare 
data.  
Extra-renal flares will be assessed over the previous 30 days for the following components:  
• 
Flare assessment based on total score changes of non-renal components 
of the SLEDAI-2K 
• 
New/worse SLE manifestations (including items that are not included in 
the SLEDAI-2K instrument) 
• 
Hospitalisation (including hospitalisations due to LN) 
• 
PGA 
Please refer to Appendix M for details. Flare will be scored in comparison to the previous 
protocol visit (ie, over the past 30 days) and will only include findings which, in the opinion 
of the investigator, are due SLE disease activity within that timeframe. 
This assessment should be completed by the investigator or delegated/qualified physician. 
Training and certification of Investigators and designated site personnel who will be 
completing this assessment will be conducted. The method of training and training 
documentation is as described in Section 9.1.1 for the efficacy assessments. 
5.2.9 
Tuberculosis screening and monitoring 
5.2.9.1 
Screening evaluation 
A blood test for TB will be done at screening using QFT-G. This is an interferon-gamma 
release assay (IGRAs) test. Evaluation of all subjects by QFT-G test (to be performed by the 
central clinical laboratory) and chest X-rays must be completed prior to randomisation. Refer 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
121 (231) 
Section 3.1, inclusion criteria 16 (d) (iii) and (e). If an adequate (posterior-anterior or 
anterior-posterior and lateral posterior-anterior, unless limited by local practice) chest X-ray 
has been 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-G result 
(Cellestis, 2005). The false negative rate in this setting appears to be over 12%. Further, the 
performance of the test in the setting of immunosuppressant drugs has not been evaluated. Nor 
has it been evaluated in individuals with medical conditions other than, or in addition to, latent 
TB or TB disease. The guide also states that “Medical treatments or conditions that impair 
immune functions can potentially reduce IFN-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 LN study, false negative tests are possible, so a 
chest X-ray, posterior-anterior or posterior-anterior and lateral views is a relevant technique 
and warranted technique (unless limited by local practice) for detecting active pulmonary 
disease and minimising potential risk to study subjects.  
5.2.9.2 
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 the chest radiograph 
shows no evidence of active TB, and the subject has no symptoms or 
medical history consistent with active TB, treatment for latent TB must 
be initiated prior to the first IP administration and the subject must 
commit to completing the full duration of prophylaxis, which may mean 
completing prophylaxis during the study. Subjects may be re-screened if 
necessary to allow for local guidelines on latent TB treatment initiation. 
*Note: Newly positive can be a positive result after a previous 
indeterminate or negative result. 
• 
If the QFT-G test is positive at screening but the subject is not newly 
positive, the subject may be randomised if: 
− 
Previous or current active TB infection was ruled out and 
− 
The subject was previously diagnosed with latent TB and has 
documentation confirming completion of appropriate latent TB 
infection treatment or 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
122 (231) 
− 
The subject was previously diagnosed with latent TB and is currently 
receiving prophylactic treatment for latent TB and commits to 
completing the full duration of prophylaxis 
• 
If the screening QFT-G test is indeterminate, the test must be repeated at 
least one time by the central laboratory as soon as possible. The subject 
may be randomised if: 
− 
If the QFT-G test result remains indeterminate or becomes negative 
and 
− 
The chest radiograph shows no evidence of active TB and 
− 
There are no signs or symptoms of active TB and 
− 
There is no known recent close contact with anyone with active TB 
and 
− 
There is no history of latent TB (unless diagnosed with documentation 
of completion of appropriate treatment) or active TB 
Additionally, an expert specialising in TB may be consulted prior to randomisation, if deemed 
necessary in the opinion of the Investigator, after discussion with the Sponsor/Designee 
Medical Monitor. If the subject is randomised, additional QFT-G testing will be performed 
according to the Study Plan (Table 2, Table 3, Table 4, and Table 5). 
5.2.9.3 
Tuberculosis monitoring during the study 
If, during the study, a subject who had an indeterminate TB result at screening is determined 
to have a: 
• 
Positive QFT-G test result, confirm positive QFT-G on another blood 
sample and then the subject should be referred to a TB specialist. If a TB 
specialist is not available, the local country guidelines should be followed 
for further diagnostic work up and anti-TB treatment regimens. If no 
local guidelines exist for immunocompromised individuals, then CDC 
guidelines may be followed. This should also be reported as an AESI. 
Once latent TB is confirmed, treatment must be instituted immediately 
and no IP may be administered until treatment of latent TB has begun 
• 
Negative QFT-G test result, then the subject does not need to continue 
TB testing outlined for subjects with indeterminate results at screening 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
123 (231) 
• 
Indeterminate QFT-G test result, then the subject will continue in the 
study and TB testing will be performed as outlined for subjects with 
indeterminate results at screening 
End of treatment testing for subjects with negative QFT-G at baseline and no symptoms of 
active TB. 
For subjects not continuing in second year extension period: 
• 
Week 52 QFT-G negative: no further testing.  
• 
Week 52 QFT-G indeterminate: repeat at Week 56. If negative no further 
testing, however if indeterminate repeat again at last visit Week 60.  
• 
QFT-G positive at Week 52 or later. Confirm positive QFT-G on another 
blood sample. If confirmed follow recommendations for positive QFT-G 
results during study. If repeat test is indeterminate or negative follow 
recommendation for indeterminate results above. Consider referral to TB 
specialist. 
For subjects continuing in second year extension period: 
• 
Week 104 QFT-G negative: no further testing.  
• 
Week 104 QFT-G indeterminate: repeat at Week 108. If negative no 
further testing, however if indeterminate repeat again at last visit 
Week 112.  
• 
QFT-G positive at Week 104 or later. Confirm positive QFT-G on 
another blood sample. If confirmed follow recommendations for positive 
QFT-G results during study. If repeat test is indeterminate or negative 
follow recommendation for indeterminate results above. Consider referral 
to TB specialist. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
124 (231) 
Tuberculosis questionnaire 
To aid in the early detection of new or reactivated TB, a TB questionnaire will be used to 
evaluate subjects for signs and symptoms of TB at every visit prior to receiving IP. If the 
evaluation raises suspicion that a subject may have new or reactivated TB, an immediate and 
thorough investigation should be undertaken including, where possible, consultation with 
experts specialising in TB.  
Investigators should be aware that TB in immunocompromised subjects may present as 
disseminated disease or with extra-pulmonary features and should be referred for appropriate 
treatment.  
5.2.10 
Safety laboratory tests 
The following are the laboratory-based safety assessments: 
• 
Screening laboratory tests 
• 
Haematology 
• 
Serum chemistry 
• 
Lipid profile 
• 
Urine analysis 
• 
Pregnancy tests 
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. 
All clinical laboratory tests will be performed in a central clinical laboratory at the times 
indicated in the Study Plan (Table 2, Table 3, Table 4, and Table 5).  
A serum pregnancy test (or serum FSH in post-menopausal females with menses absent for 
≥1 year) will be performed at screening at the central laboratory. If the result of the serum β 
hCG test is borderline or thought to be false positive the test can be repeated during the 
screening. The subject can continue if the repeat test is negative. At every visit after screening, 
urine pregnancy tests will be performed at the site using a dipstick. During the treatment 
period, urine pregnancy tests should be performed at each visit before administering the IP 
and Sponsor-provided MMF. Abnormal safety laboratory results should be repeated as 
clinically indicated, as soon as possible (preferably within 24 to 48 hours). 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
125 (231) 
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 or efficacy laboratory tests, even 
if the subject has received the IP.  
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 6.5. 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer to 
Appendix D ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
The laboratory variables that will be measured are summarised in Table 6. 
Table 6 
Clinical laboratory tests 
Screening only test 
Haemoglobin A1c (HbA1c; diabetic subjects only) 
Peripheral blood B lymphocyte count (CD19+ cells)-Only for subjects who received rituximab or other 
B cell-depleting therapy ˃26 weeks prior to signing ICF (see exclusion criterion No. 17) 
HbsAg 
HBcAb (reflex DNA testing if isolated HBcAb positive) 
Hepatitis C antibody 
HIV test 
TB screening 
QFT-G test (repeat test if result is indeterminate, as per Table 2 and Table 4) 
Coagulation panel 
Activated partial thromboplastin time, Prothrombin Time, INR 
Haematology 
WBC count with differential 
RBC count 
Haematocrit 
Haemoglobin 
Platelet count 
MCV 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
126 (231) 
MCHC 
Serum chemistry  
Calcium 
Chloride 
Potassium 
Sodium 
Bicarbonate 
AST* 
ALT* 
ALP* 
GGT 
BUN 
Creatinine 
eGFR (calculated) 
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. 
Immunology 
Immunology profile: ANA, anti-RNP antibody, anti-Smith antibody, anti-Sjogren’s Syndrome A 
[SSA] and anti-Sjogren’s Syndrome B [SSB] antibodies; anti-cardiolipin antibodies (IgA, IgM and 
IgG), and quantitative total immunoglobulin testing (IgA, IgG, IgM) 
Lupus serology tests (C3 and C4 complement, anti-ds DNA) 
Urinalysis 
Colour 
Clarity 
Specific gravity 
pH 
Protein  
Glucose 
Ketones 
Blood 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
127 (231) 
Bilirubin 
Microscopy including WBC/HPF, RBC/HPF, cellular casts 
Spot urine creatinine and protein, urine protein/creatinine ratio 
24-hour urine creatinine and protein, UPCR 
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 post-menopausal females with menses absent for ≥1 year 
ALP=alkaline phosphatase; ALT=alanine transaminase; ANA=antinuclear antibody; anti-RNP=anti-
ribonucleoprotein; AST=aspartate transaminase; β-hCG=β-human chorionic gonadotropin; BUN=blood urea 
nitrogen; C3=third component of complement; C4=fourth component of complement; CK=creatine kinase; 
DNA=deoxyribonucleic acid; eGFR=estimated glomerular filtration rate; GGT=gamma glutamyl transferase; 
HbA1c=glycosylated haemoglobin; HBcAb=hepatitis B core antibody; HbsAg=Hepatitis B surface antigen; 
HPF=high power field; HIV=human immunodeficiency virus; INR=International normalised ratio; MCHC=mean 
corpuscular haemoglobin concentration; MCV=mean corpuscular volume; QFT-G=QuantiFERON-TB Gold; 
RBC=red blood cell; WBC=white blood cell 
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. 
A reflex test is a test that is must be performed based on the results of a prior test (pre-set criteria). 
 
5.2.10.1 Laboratory assessments for cardiovascular risk assessments 
Subjects will have a fasting lipid profile (cholesterol, high density lipoprotein cholesterol, low 
density lipoprotein cholesterol, and triglycerides) completed at times indicated in the Study 
Plan (Table 2 and Table 4). Subjects will be required to fast for at least 8 hours prior to this 
assessment (see Section 3.8). 
5.2.11 
Immunological tests 
5.2.11.1 Immunology profile 
Subjects will have tests to determine immunology profile (ANA, anti-Smith, anti-RNP, 
anti-SSA, anti-SSB, and anti-cardiolipin antibodies), and quantitative immunoglobulins (IgA, 
IgG, IgM) completed at times indicated in the Study Plan (Table 2 and Table 4).  
5.2.11.2 Lupus serology 
Anti-dsDNA antibodies and complement C3 and C4 levels are commonly used as markers of 
SLE and of LN disease activity and comprise the serologic domain of the SLEDAI-2K. 
Subjects will have these tests performed at the times indicated in the Study Plan (Table 2, 
Table 3, Table 4, and Table 5). 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
128 (231) 
5.2.11.3 Anti-drug antibodies 
Instructions for immunogenicity (ADA and ADA neutralising antibodies [nAb]) sample 
collection, processing, storage, and shipment can be found in the separate Laboratory Manual 
provided to the centres. 
The pre-dose serum samples to measure the presence of ADA will be collected according to 
the Study Plan (Table 2, Table 3, Table 4, and Table 5). The presence or absence of ADA will 
be determined in the serum samples using validated bioanalytical methods.  
5.2.11.4 Neutralising antibodies 
Neutralising antibodies testing will only occur in samples that are ADA positive. Samples that 
are ADA negative will not be tested for nAb. The presence or absence of nAb will be 
determined using a validated bioanalytical method. 
5.2.12 
Mycophenolic acid levels 
The blood samples will be collected to explore trough MPA concentration in LN subjects. 
Relationship of MPA concentrations and AEs possibly related to MPA may also be explored. 
Serum samples for the determination of trough MPA levels will be collected at the times 
indicated in the Study Plan (Table 2). MPA concentrations will be analysed by a central 
laboratory on behalf of the Sponsor, using a validated bioanalytical method. The dose of 
MMF should be withheld until samples for the MPA blood draw test has been collected on 
that visit day.  
5.3 
Other assessments 
5.3.1 
Quality of life/pharmacoeconomic assessments 
5.3.1.1 
Patient Global Assessment  
Subjects will be asked to complete the PtGA at the times indicated in the Study Plan (Table 2, 
Table 3, Table 4, and Table 5). The PtGA is a single-item question that takes into account “all 
the ways that your illness affects how you are doing” over the last week. Responses range 
from 0 (very well) to 100 (very poor) on a 100 mm VAS. The subject must complete the PtGA 
(see Appendix T). 
5.4 
Pharmacokinetics 
5.4.1 
Collection of samples 
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 2, Table 3, Table 4, and Table 5). Post-
dose samples should be collected 15 minutes ± 5 minutes after completion of IP infusion. It 
must be noted that the duration of the IV infusion for administrating the IP will be no less than 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
129 (231) 
60 minutes for the first 3 doses (Visits 1, 2 and 3) and no less than 30 minutes, starting with 
Visit 4. 
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.  
5.4.2 
Determination of drug concentration 
Samples for determination of drug concentration in serum will be analysed by PPD on behalf 
of AstraZeneca, using an appropriate bioanalytical method.  Full details of the analytical 
method used will be described in a separate bioanalytical report. 
5.4.3 
Storage and destruction of pharmacokinetic samples 
Samples may be stored for up to 15 years or as per local regulation from the date of the last 
subject last visit (LSLV), after which they will be destroyed. 
5.5 
Pharmacodynamics 
Type I IFN-inducible signature in whole blood, as assessed by a 21-gene assay, will be used 
as a PD marker to follow the biologic effect of anifrolumab on its target throughout the study. 
5.5.1 
Collection of samples 
Whole blood will be collected for mRNA isolation at the visits indicated in the Study Plan 
(Table 2, Table 3, Table 4, and Table 5) 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. For 
detailed method descriptions refer the reader to the Laboratory Manual. 
5.5.2 
Storage, re-use and destruction of pharmacodynamic samples 
Samples collected for PD analysis may be stored for a maximum of 15 years from the date of 
the LSLV, or as per the local regulations, after which they will be destroyed.   
5.6 
Genetics 
There will be no mandatory genetic samples collection for this study.  
5.6.1 
Pharmacogenomics (optional) 
DNA from blood for genetic studies will be collected at baseline. DNA from blood for 
epigenetic studies will be collected at Week 0, Week 24 and Week 52. All genetic analyses 
will be limited to understanding LN or the efficacy and toxicity of anifrolumab and SOC. 
Analyses will include but may not be limited to single nucleotide polymorphism profiling, 
copy number variation analysis and epigenetic profiling by microarray.  
The collection of blood for pharmacogenomic analyses is optional. A separate ICF is required 
for these samples. The results from these investigations will not be reported in the CSR but in 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
130 (231) 
separate reports and in scientific publications as appropriate. Pharmacogenomics will not be 
included in the second year extension period. 
5.7 
Biomarker analysis  
The subject’s consent to the use of donated biological samples has to be taken. Biological 
samples (blood, urine, and tissue) will be collected and may be analysed for exploratory 
biomarkers to assess correlations with disease activity, effects of study drug, clinical outcomes 
and toxicity. 
The purpose of these tests is to gain a better understanding of LN, the role of IFNs in LN, the 
impact of anifrolumab on LN related abnormalities and to identify biomarker candidates with 
potential clinical applications in LN. The results from these investigations will not be reported 
in the CSR but in separate reports and in scientific publications as appropriate. 
5.7.1 
Serum and plasma biomarkers 
Serum and plasma samples will be collected for mechanistic studies during the visits specified 
in the Study Plan (Table 2, Table 3, Table 4, and Table 5). These studies may include soluble 
analytes, such as proteins, antibodies, peptides and immune complexes and will be conducted 
using a variety of technical approaches such as immunoassays, protein arrays, in vitro assays, 
and/or biochemical methods. The results from these investigations will not be reported in the 
CSR but in separate reports and in scientific publications as appropriate. 
5.7.2 
Urine biomarkers 
Urine samples will be collected for mechanistic studies during the visits specified in the Study 
Plan (Table 2 and Table 3). These studies may include soluble analytes such as proteins, 
peptides, antibodies and immune complexes and will be conducted using a variety of technical 
approaches such as immunoassays, protein arrays, in vitro assays, and/or biochemical 
methods. The results from these investigations will not be reported in the CSR but in separate 
reports and in scientific publications as appropriate. Urine biomarkers will not be assessed in 
the second year extension period. 
5.7.3 
RNA transcript profiling 
To better understand the impact of Type-1 interferon blockade on systemic immune processes 
whole blood samples will be collected as indicated in the Study Plan (Table 2, Table 3, 
Table 4, and Table 5) for retrospective analyses of genome wide transcriptome profiling. 
Transcriptome profiles will be assessed as potential markers predictive of response or as 
additional PD response biomarkers. The results from these investigations will not be reported 
in the CSR but in separate reports and in scientific publications as appropriate. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
131 (231) 
5.7.4 
Interferon test in whole blood 
Whole blood will be collected at screening in PAXgene tubes to measure the over expression 
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 primary intent of this test is to prospectively identify subjects with interferon “test-high” 
or interferon “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 to classify subjects into 2 groups: 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). 
5.7.5 
Tissue biomarkers: immunostaining, epigenetic and gene expression studies on 
renal biopsies (optional) 
These tests are in addition to the standard evaluation of renal biopsies and require a separate 
ICF. These studies will be done from existing clinical biopsy material (eg, fixed paraffin 
embedded tissue tissue). The studies will be limited to gain better understanding about the 
pathogenesis and the role of IFN in LN. A variety of techniques may be used, such as 
immunostaining for various inflammatory markers and gene expression and epigenetic 
analysis. The results from these investigations will not be reported in the CSR but in separate 
reports and in scientific publications as appropriate. 
5.7.6 
Storage, re-use and destruction of biological samples 
Samples may be stored for a maximum of 15 years from the date of the LSLV, or as per local 
regulation, after which they will be destroyed.  
5.7.7 
Labelling and shipment of biological samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (see 
Appendix B, ‘IATA 6.2 Guidance Document’). 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
5.7.8 
Chain of custody of biological samples  
A full chain of custody is maintained for all samples throughout their lifecycle. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
132 (231) 
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are stored at AstraZeneca R&D Mölndal Biobanken - 
Pepparedsleden 1 - 431 83 Mölndal - Sweden to be analysed at a facility to be selected by 
AstraZeneca at a later date, for up to 15 years or as per local regulation from the end of the 
study, which is expected to be in the third quarter of 2020. The samples will be destroyed after 
that. 
5.7.9 
Withdrawal of Informed Consent for donated biological samples  
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological samples is an integral part of the study, then the subject is 
withdrawn from further study participation.  
The Principal Investigator: 
• 
Ensures subjects’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca and Sponsor’s delegate 
• 
Ensures that biological samples from that subject, if stored at the study 
site, are immediately identified, disposed of /destroyed, and the action 
documented 
• 
Ensures that the subject and AstraZeneca are informed about the sample 
disposal. 
AstraZeneca ensures the organisations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
133 (231) 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. The Sponsor’s delegate Medical Services will provide 
an out of hours medical management service; contact details will be provided to Investigators 
and subjects (to be used only by healthcare professionals in case of emergency). 
6.1 
Definition of adverse events 
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
The term AE is used to include both serious and nonserious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
6.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-subject hospitalisation or prolongation of existing 
hospitalisation  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardise the subject or may 
require medical intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol. 
If a subject decides to have surgery to correct a pre-study condition that has not worsened 
since the ICF was signed or the surgery was planned before the ICF was signed, then the 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
134 (231) 
hospitalisation is not considered an SAE. If however, a new condition occurs or a pre-existing 
condition worsens and surgery is required, then the hospitalisation is considered an SAE. 
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 D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law. 
6.4 
Definition of Adverse Event of Special Interest 
An AESI is one of scientific and medical concern specific to understanding biologics and 
requires close monitoring and rapid communication by the Principal Investigator to the 
Sponsor/Sponsor’s delegate. An AESI may be serious or nonserious.  
Adverse Events of Special Interest will be assessed at each visit in the eCRF. 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, acute coronary syndrome, myocardial 
infarction, or cardiovascular death). 
An AESI that meets one 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 6.7. 
6.4.1 
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 AEs are reported as SAEs. It is 
expected that culture results and all diagnostic or therapeutic procedure results performed on a 
subject experiencing a serious non-opportunistic infection will be provided as an SAE update. 
Nonserious non-opportunistic infections will not be captured as AESIs. 
6.4.2 
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. Opportunistic infections 
are categorised as serious and reported as an SAE. 
Examples of opportunistic infections that may occur in SLE subjects include: Herpes zoster 
meningoencephalitis, Salmonella bacteremia, Pneumocystis jiroveci pneumonia or progressive 
multifocal leukoencephalopathy. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
135 (231) 
It is expected that culture results and all diagnostic or therapeutic procedure results performed 
on a subject experiencing a serious opportunistic infection will be provided as an SAE update. 
Since anifrolumab is an immunomodulatory agent and the Sponsor needs to understand the 
safety profile of this IP, including assessment of how anifrolumab may affect resistance to 
different types of infections, Investigators are asked to undertake appropriate microbiologic 
identification including culture and report culture results for all subjects who develop serious 
infections. 
6.4.3 
Anaphylaxis 
Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after 
contact with an allergy-causing substance, such as IP. For the purposes of this study, the 
definition detailed in Appendix L is provided as a simple and rapid means to make the 
diagnosis of anaphylaxis during infusion with IP. 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). 
6.4.4 
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 have pertinent biomarker and/or genetic testing results performed and to report 
these for any malignancies reported during the study. 
6.4.5 
Herpes zoster 
Herpes zoster is a viral infection characterised by a cutaneous vesicular eruption on an 
erythematous base presenting along dermatome(s) and usually associated with prodromal 
pain. Herpes zoster results from the reactivation of Varicella zoster virus; multiple 
dermatomes may be involved (>3 indicates disseminated disease) and organ or systemic 
infection may occur (invasive; therefore an opportunistic infection). Polymerase chain 
reaction (PCR) testing of samples from vesicles, biopsy or other specimens (eg, 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 AESI, 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. 
6.4.6 
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 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
136 (231) 
(IFN-γ release assay), radiographic imaging, body fluid and tissue sampling; presentation may 
include disseminated or latent disease. An infection may be new (at least conversion of a TB 
test to positive) or reactivation of dormant disease (new active disease in a previously TB test 
positive subject without prior evidence of active disease). 
• 
A bacteriologically confirmed TB case is one from whom 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 one who 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; and HIV status 
(World Health Organisation, 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-TB 
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. If no local guidelines exist for 
immunocompromised individuals, then CDC guidelines may be followed. Once latent TB is 
confirmed, treatment must be instituted immediately and no IP 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 the IP. 
6.4.7 
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 one of the following respiratory symptoms: cough, sore 
throat, or shortness of breath. 
Laboratory criteria for influenza include at least one of the following: isolation of influenza 
virus from a clinical specimen, detection of influenza virus nucleic acid in a clinical specimen, 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
137 (231) 
identification of influenza virus antigen by direct fluorescent antibody test in a clinical 
specimen, or influenza-specific antibody response. 
A confirmed case of influenza meets the clinical and laboratory criteria for the viral illness. 
Laboratory confirmation should be done using locally available, rapid, commercial tests 
approved by Regulatory Agencies and sampling respiratory specimens.  
Not all upper respiratory viral infections or gastrointestinal viral infections are influenza. In 
the case where a subject reports a viral infection severe enough to be considered, in the 
opinion of the investigator, influenza, a viral test should be performed (if possible) to confirm 
the diagnosis. Whether or not a test to confirm the diagnosis has been performed, if, in the 
opinion of the investigator, the subject has had influenza (the specific viral infection), this 
should be reported as an AESI. If the subject has had a viral infection that is less severe, then 
this should be reported as an AE only. 
6.4.8 
Vasculitis (non-systemic lupus erythematosus) 
Vasculitis (non-SLE) is defined as an inflammatory disorder of blood vessels involving 
arteries and/or veins and characterised by characteristic clinical signs/symptoms and 
diagnosed by biopsy, imaging such as angiography or blood tests such as findings of anti-
neutrophil cytoplasmic antibodies consistent with the diagnosis. Underlying causes should be 
identified, such as medications including investigational drug, infections or systemic 
inflammatory syndromes, wherever possible. See Appendix G for a list of vasculitic 
syndromes excluded from the study.  
6.4.9 
Major acute cardiovascular events 
As a measure of enhanced Pharmacovigilance, an independent Cardiovascular Event 
Adjudication Committee (CV-EAC) will review deaths (due to any cause) and all SAEs in 
both the Cardiac and Vascular MedDRA System Organ Classes and all SAEs in the Central 
Nervous System Vascular Disorders Standard Medical Query for evaluation. The CV-EAC 
chair may adjudicate some events that do not fall into the above categories. 
The CV-EAC will review cases of interest to determine if they meet accepted diagnostic 
criteria. Causality assessments will not be made by the CV-EAC, nor will the committee 
possess governance authority. The CV-EAC will be blinded regarding any information 
relating to the randomisation group. 
6.5 
Recording of adverse events 
6.5.1 
Time period for collection of adverse events 
Adverse events and SAEs will be collected from the time of signature of the ICF until the end 
of the subject’s participation in the study. Serious adverse events occurring within the 12 week 
post final dose period will be followed to resolution/stabilisation. Pregnancies occurring 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
138 (231) 
within the 12-week post final dose will be followed up until end of subject’s participation in 
the study or until the outcome of pregnancy is known (whichever is later). 
6.5.2 
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. 
6.5.3 
Variables 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped. For infusion-related AEs, in 
addition to date, time when the AE started and stopped must be collected  
• 
Maximum intensity 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP (yes or no) 
• 
Action taken with regard to IP 
• 
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 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
139 (231) 
(b) 
Life-threatening 
(c) 
In-patient hospitalisation or prolongation of existing hospitalisation 
− 
Date of hospitalisation 
− 
Date of discharge 
(d) 
Congenital abnormality or birth defect 
(e) 
Important medical event 
• 
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 in Section 6.2. An SAE is an 
AE that fulfils one 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 one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix A. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
140 (231) 
shown in Section 6.2. The Investigator should provide an assessment of the severity of each 
AE/SAE. 
6.5.4 
Causality collection 
The Investigator will assess causal relationship between IP 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 IP?’ 
For SAEs causal relationship will also be assessed for any other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A. 
6.5.5 
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 diagnosis is preferred (when possible) to 
recording of 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. 
6.5.6 
Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
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 IP. 
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/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE (or SAE, as appropriate). 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
141 (231) 
6.5.7 
Disease progression/worsening of systemic lupus erythematosus and lupus 
nephritis 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
SLE or LN. It may be an increase in the activity or severity of the existing manifestations of 
LN or SLE or the appearance of new manifestations. Disease progression should not be 
reported as an AE unless it fulfils criteria for SAE (please see Section 6.2 for definition of 
SAE). However, worsening of SLE or LN will be recorded in the disease assessment tools 
(SLEDAI-2K, PGA and PtGA). 
6.6 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the CRF. All safety forms and supportive 
documentation include laboratory tests, imaging reports, diagnostic test results, biopsy reports, 
and discharge summaries is to be sent to the Sponsor’s delegate Medical Services. 
If any SAE occurs in the course of the study, then the Investigator or other site personnel 
inform the appropriate AstraZeneca representatives within one day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site or designee 
within 1 business day of initial receipt for all SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel should inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
immediately but no later than 24 hours of when he or she becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the DataLabs 
system, an automated e-mail alert is sent to the designated AstraZeneca representative. 
If the DataLabs system is not available, then the Investigator or other study site personnel 
reports the SAE to the Sponsor’s delegate Medical Services on the study specific paper SAE 
form by telephone, FAX, or e-mail. The SAE report form must be completed in the electronic 
system as soon as the system is available again. 
SAE information should be sent to the Sponsor’s delegate Medical Services.  
The Sponsor’s delegate Medical Services, on behalf of AstraZeneca, is responsible for 
reporting certain SAEs as expedited safety reports to applicable regulatory authorities, Ethics 
Committees (ECs), and participating Investigators, in accordance with International 
Conference on Harmonisation (ICH) Guidelines and/or local regulatory requirements. 
Sponsor/Designee may be required to report certain SAEs to regulatory authorities within 7 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
142 (231) 
calendar days of being notified about the event; therefore, it is important that Investigators 
submit additional information requested by Sponsor/Sponsor’s delegate as soon as it becomes 
available. 
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure. 
6.7 
Reporting of adverse events of special interest 
Adverse Events of Special Interest will be assessed by the Investigator for severity, 
relationship to the IP, possible aetiologies, and whether the event also meets criteria of an 
SAE. All AESIs (serious or nonserious) will be recorded on the AE CRF (using a recognised 
medical term or diagnosis that accurately reflects the event). 
The reporting period for AESIs is the period immediately following the time that written 
informed consent is obtained through the end of subject participation in the study. All serious 
AESIs and nonserious AESIs are required to be reported within 24 hours and 72 hours of 
knowledge of the event, respectively, to the appropriate AstraZeneca representative. 
6.8 
Overdose 
• 
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the eCRF and on the 
Overdose CRF module. 
• 
An overdose without associated symptoms is only reported on the 
Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.6. 
For other overdoses, reporting must occur within 30 days. 
6.9 
Pregnancy 
All pregnancies occurring during the subjects' participation in the study and the outcomes of 
pregnancy should be reported to AstraZeneca or designee. In addition, if Investigators become 
aware of pregnancies occurring after the subject's participation in the study ended they should 
report them to AstraZeneca or designee in the following cases: 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
143 (231) 
• 
Female subject: Any conception occurring from the date of 
randomisation until 12 weeks after the last dose of IP and 6 weeks after 
the last dose of Sponsor-provided MMF administration (whichever is 
later). 
• 
Male subject: Any conception of female partner of the subject that occurs 
from the date randomisation until 12 weeks after the last dose of IP and 
90 days after the last dose of Sponsor-provided MMF administration 
(whichever is later). 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. 
The outcome of any conception should be followed up and documented on the pregnancy 
outcome form and reported within 1 day (no later than 24 hours) of when the Investigator 
becomes aware of it. 
6.9.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, IP and Sponsor-provided MMF 
should be discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 or designee within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Principal Investigator to ensure 
that all relevant information is provided to the AstraZeneca Patient Safety data entry site 
within 1 or 5 calendar days for SAEs (see Section 6.6) 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 up until 
the outcome of pregnancy is known so that the pregnancy outcome can be determined and 
reported to AstraZeneca or designee and the regulatory authorities. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
144 (231) 
6.9.2 
Paternal exposure  
Male subjects should refrain from fathering a child or donating sperm during the study and for 
12 weeks following the last dose of IP and for 90 days following the last dose of Sponsor-
provided MMF (whichever is later).  
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 until the 
outcome of pregnancy is known. 
6.10 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the subject or 
has the potential to cause harm to the subject.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject. 
Medication error includes situations where an error.  
• occurred 
• was identified and intercepted before the subject received the drug 
• did not occur, but circumstances were recognised that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
• Drug name confusion 
• Dispensing error eg, medication prepared incorrectly, even if it was not actually given 
to the subject 
• Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet  
• Drug not stored as instructed eg, kept in the fridge when it should be at room 
temperature  
• Wrong subject received the medication (excluding IVRS/IWRS errors) 
• Wrong drug administered to subject (excluding IVRS/IWRS errors) 
Examples of events that do not require reporting as medication errors in clinical studies: 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
145 (231) 
• Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error  
• Subject accidentally missed drug dose(s) eg, forgot to take medication 
• Accidental overdose (will be captured as an overdose) 
• Subject failed to return unused medication or empty packaging 
• Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.   
If an medication error occurs  in the course of the study, then the Principal 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 works with the Principal Investigator to ensure 
that all relevant information is completed within 1 or 5 calendar days if there is an SAE 
associated with the medication error (see Section 6.6) and within 30 days for all other 
medication errors. 
6.11 
Management of investigational product-related toxicities and 
MMF-related warnings and precautions 
6.11.1 
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 L. 
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. 
6.11.2 
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 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
146 (231) 
obtained when indicated and results should be reported with the SAE or AESI. Failure to 
obtain this information will impair the Sponsor’s ability to characterise the benefit-risk profile 
of anifrolumab. 
Subjects who develop a new infection while undergoing treatment with IP should receive 
appropriate medical therapy, as determined by local standards, and be monitored closely until 
the condition resolves. IP should not be administered to a subject with a clinically significant, 
active infection as determined by the Investigator (see Section 3.8). For any active infection 
(eg, Varicella zoster infection/chickenpox) or significant exposure to any infection (eg, 
Varicella zoster infection in a naive subject, bacterial pneumonia), the Investigator should 
consider whether to interrupt IP administration, and should notify the Sponsor/Designee 
Medical Monitor.  
Similarly, if a subject presents with signs or symptoms where opportunistic infections are 
considered (eg, Central nervous system symptoms consistent with progressive multifocal 
leukoencephalopathy or herpes encephalitis, or atypical pneumonia suggesting pneumocystis 
jiroveci pneumonia), IP should be interrupted until the Principal 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 IP 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. 
6.11.3 
MMF-related warnings and precautions 
During the screening period while discussing informed consent, potential study subjects 
should be informed on the risks of using MMF based on the local prescribing information. 
The risks of using MMF include, but are not limited to, the following: 
• 
Embryofoetal toxicity/teratogenic potential: Exposure to MMF during 
pregnancy is associated with increased first-trimester foetal loss and 
increased risk of congenital malformation. MMF should not be used in 
lactating females. Due to the risk of male to female transfer of MMF and 
metabolites in seminal fluid, all male subjects treated with MMF should 
use condoms. Please refer to Section 3.1 for additional information on 
contraception requirements for this study. 
• 
Serious infection: The use of immunosuppression, including MMF, is 
associated with increased risk of infection with bacterial, viral, protozoal, 
fungal, reactivated viral and/or opportunistic infections. Infections may 
result in sepsis and may be fatal. 
• 
Malignancy: The use of immunosuppression, including MMF, alone or in 
combination, poses an increased risk of developing lymphomas and other 
malignancies, especially of the skin. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
147 (231) 
• 
Haematologic abnormalities: Neutropenia may be associated with MMF. 
Cases of pure red cell aplasia have been reported with MMF in 
combination with other immunosuppression. 
• 
Gastrointestinal: MMF has been associated with infrequent cases of 
gastrointestinal ulceration, haemorrhage, pancreatitis, and perforation. 
Refer to the locally approved MMF prescribing guide/product characteristics for additional 
details on risks and AEs associated with MMF. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Anifrolumab 
150 mg/mL solution of 
anifrolumab (clear colourless to 
slightly yellow) intended for IV 
administration following 
dilution into 0.9% saline 
 
Placebo 
Solution (clear) intended for IV 
administration following 
dilution into 0.9% saline 
 
 
Each vial of IP or placebo contains 1.3 mL fill volume.  
IP and placebo will be supplied to the site as follows: 
• 
Visits 1-3: 6 vials per carton  
• 
Visits 4-28: 2 vials per carton 
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 IP and placebo must be performed by a trained unblinded team member (eg, 
pharmacist, study nurse) at the site. When diluted as directed in the IP 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. 
CCI
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
148 (231) 
7.2 
Dose and treatment regimens 
The IP, anifrolumab or placebo, will be administered via controlled IV infusion pump into a 
peripheral vein over no less than 60 minutes for the first 3 doses (Visits 1, 2 and 3). Starting 
with Visit 4, IP can be administered as an IV infusion via an infusion pump over no less than 
30 minutes. 
• 
Basic Regimen: Anifrolumab 300 mg IV Q4W for 13 doses plus SOC or 
• 
Intensified Regimen: Anifrolumab 900 mg IV Q4W for the first 3 doses 
followed by 300 mg IV Q4W for an additional 10 doses plus SOC or 
• 
Placebo: IV Q4W plus SOC 
Subjects who do not meet withdrawal criteria at Week 52 (as defined in Section 3.9) will 
continue to receive blinded IP (anifrolumab 300 mg or placebo IV Q4W) for an additional 13 
doses plus SOC for another 52 weeks (second year extension period). 
7.2.1 
Dose preparation steps 
Anifrolumab 300 mg, 900 mg or matching placebo: Visits 1-3 
From a 100 mL IV infusion bag of 0.9% normal saline, withdraw and discard a volume of 
saline equal to 6.0 mL. Then add 1.0 mL from each of the 6 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. 
Anifrolumab 300 mg or matching placebo: Visits 4-28 
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 
A separate manual will be provided to the sites that specify the procedures to be followed 
prior to administering the IP. Please refer to this Study Drug Supply Plan for details. 
7.2.3 
Investigational product administration procedures 
• 
IP 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. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
149 (231) 
• 
IP 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 IP. 
• 
Because compatibility of anifrolumab with IV medications and solutions 
other than 0.9% sodium chloride for injection, (US Pharmacopeia), is not 
known, the IP solution should not be infused through an IV line in which 
other solutions or medications are being administered. 
• 
IP will be administered as an IV infusion via an infusion pump over no 
less than 60 minutes for the first 3 doses (Visits 1, 2, and 3). Starting with 
Visit 4, IP can be administered as an IV infusion via an infusion pump 
over no less than 30 minutes.  
• 
Immediately following the completion of IP 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 IP dosing. 
• 
An emergency cart should be available in the infusion suite. See 
Appendix L. 
7.2.4 
Subject monitoring/procedures during and after the infusion 
Subjects will be monitored during the administration of the IP and for at least 2 hours after the 
first 3 infusions (Weeks 0, 4, and 8). If there are no safety concerns, for subsequent infusions 
subjects will be monitored during administration of the IP and for a minimum of one hour 
after completion of the IV infusion thereafter (Week 12 to Week 100).  
Monitoring will include vital signs (temperature, BP, pulse rate, respiratory rate) in a sitting 
position at the following times: 
• 
Shortly before the IV infusion (up to 20 minutes before the IP infusion 
starts) 
• 
Every 15±5 minutes during infusion 
• 
Immediately after completion of administration of IP, including post-dose 
saline flush (within 20 minutes after completion of post-dose saline flush) 
• 
Every 30±5 minutes after completion of IP infusion (not including saline 
flush) for at least 2 hours after IP infusion for the first 3 doses (Week 0 
[Day 1] to Week 8) and for at least 1 hour, thereafter (Week 12 to Week 
100) 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
150 (231) 
• 
Samples for PK laboratory assessments should be collected 15±5 minutes 
after completion of IP infusion (not including saline flush) after dosing 
on Week 0 (Day 1) and Week 48 
Vital signs may be taken more frequently, based on Investigator judgement.  
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 IP infusion and the duration of IP administration will be recorded. 
The duration of IP infusion and duration of IP 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 IP is first infused into the subject. Infusion stop time is 
defined as the time point where the infusion pump completes infusion of 
the IP, not including the saline flush. 
For example: an infusion with a start time of 12:00 PM would have an 
infusion duration recorded as 30 minutes (the 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. 
Intravenous bag compatibility studies demonstrate that anifrolumab is compatible with IV 
bags and ancillaries comprised of materials as described in Table 7 and Table 8. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
151 (231) 
Table 7 
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 
Latex-free, PVC-free, and DEHP-free polyolefin 
0.9% saline 
PVC and DEHP 
0.9% saline 
Polyethylene 
0.9% saline 
Polypropylene 
0.9% saline 
Ethylene polyvinyl acetate 
PVC=Polyvinyl chloride; DEHP= diethylhexyl phthalate 
 
Table 8 
Compatible materials of construction for ancillaries (eg, infusion 
tubing) 
Materials of Construction 
Polyethylene 
PVC with DEHP 
PVC (latex-free and DEHP-free) 
Polyethylene (latex-free and DEHP-free) 
Polybutadiene 
PVC=Polyvinyl chloride; DEHP=diethylhexyl phthalate 
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. Vials and cartons will be labelled with double-blind 
labels. 
The label will include the following information: 
• 
Name of Sponsor (AstraZeneca) 
• 
IP/Sponsor-provided MMF dosage form, route of administration, and 
quantity of dosage units 
• 
Storage conditions 
• 
Study code 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
152 (231) 
• 
Enrolment code or Randomisation code 
• 
Directions for use 
• 
The name of the Principal Investigator, where applicable (this is to be 
added on the label when the IP/Sponsor-provided MMF is dispensed) 
• 
The period of use eg, expiry date, where required. 
The following standard statement will be included: ‘for clinical study use only’ 
Before the kit is dispensed to the subject, the Investigator must fill in the required information 
on the empty lines on the front cover page, locate the page with local label text, and 
demonstrate to the subject. Booklet labels must be opened to find the full label text in local 
language. 
7.4 
Storage 
IP and Sponsor-provided MMF should be kept in a secure place under appropriate storage 
conditions. The IP should be stored at 2 to 8°C (36 to 46°F) and must not be frozen.  
7.5 
Compliance 
The administration of IP and Sponsor-provided MMF should be recorded in the appropriate 
sections of the CRF. The IP will be administered by study site personnel, who will monitor 
compliance. 
7.6 
Accountability 
The IP and Sponsor-provided MMF provided for this study will be used only as directed in the 
study protocol. 
The Investigator’s or site’s designated unblinded team member trained to prepare the IP is 
required to maintain accurate IP accountability records. Upon completion of the study, copies 
of IP accountability records will be returned to AstraZeneca or designee. All unused IP 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 IP will be provided to the sites. 
7.7 
Concomitant and other treatments  
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting the Investigator. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
153 (231) 
Concomitant (including immunosuppressant) medications should be administered consistently 
and if possible after all visit assessments, including IP administration and post infusion PK 
blood draws (if applicable), with the exception of subjects with a previous infusion-related 
reaction who are to receive acetaminophen/paracetamol (which should be given after all visit 
assessments other than the infusion have been completed, and prior to starting the infusion).  
Subjects who are taking concomitant medications must be informed that on the day of the 
study visit, these medications are to be taken only after the study assessments are completed 
(if clinically appropriate) or as advised by the Investigator. 
7.7.1 
Anti-hypertensive agents and statins 
Angiotensin-Converting-Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Blockers 
(ARB) may be adjusted to optimise their anti-hypertensive effects up to Week 4. Changes in 
other classes of anti-hypertensive agents (calcium channel blockers, β-blockers, α-receptor 
blockers) are allowed as clinically indicated to optimise blood pressure. 
Statins must be kept at stable doses after Day 1. Decreases in the dose are allowed only to 
reduce statin-related side effects. 
Cholestyramine must be discontinued prior to the day of randomisation. 
7.7.2 
Excluded medications 
7.7.2.1 
Medications that are excluded after signing the ICF 
Receipt of any of these medications leads to immediate discontinuation of IP: 
• 
Cyclophosphamide 
• 
IFN therapy (α 2a and 2b, beta 1a and 1b, and pegylated IFNs α 2a and 
2b) 
• 
Investigational agents 
• 
Biologic immunomodulators (including belimumab, abatacept, 
rituximab) 
• 
Tofacitinib 
• 
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) 
• 
BCG vaccine 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
154 (231) 
• 
Any immunoglobulin (Ig) therapy 
• 
Exceeding the number or dose of protocol-allowed methylprednisolone 
pulses (oral or IV) 
• 
Any medications or treatment modality listed in Appendix H 
7.7.2.2 
Restricted medications 
As anifrolumab is an investigative immunomodulatory agent, non-protocol permitted changes 
to immune modifiers or immunosuppressants during the study are not allowed. If a subject 
receives one of the following after randomisation, the Investigator must notify the 
Sponsor/Designee Medical Monitor immediately. The Designee Medical Monitor will 
determine with the Sponsor if the subject may continue to receive IP, however, the subject 
would be considered a non-responder for assessments such as CRR. 
• 
Azathioprine 
• 
Methotrexate 
• 
Leflunomide 
• 
Tacrolimus 
• 
Mizoribine 
• 
Cyclosporine 
• 
Cholestyramine 
• 
Increase in corticosteroids (except methylprednisolone pulses) above the 
protocol-allowed doses or duration. For any increase in 
methylprednisolone pulses, please see Section 7.7.2.1. 
• 
Corticosteroids with a long biologic half-life (eg, dexamethasone, 
betamethasone) 
7.7.3 
Standard of care immunosuppressive treatment during the study 
Standard of care treatment for LN will consist of the combination of MMF and 
corticosteroids.  
7.7.3.1 
Mycophenolate mofetil 
From the day of randomisation onwards until the end of subject’s participation in the study, 
MMF will be supplied by the Sponsor to the subjects.  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
155 (231) 
The target dose of MMF will be 2 gm/day during the 52 week double-blind treatment period, 
where the dose is titrated to the target dose between randomisation and Week 8. Adjustments 
of the dose due to suboptimal response, toxicity, or intolerability are allowed if needed 
according to guidelines described below. A maximum dose of 3.0 gm/day is allowed up to 
Week 24 for subjects with suboptimal response between Weeks 8 and 24, and needs to be 
reduced to ≤2.0 gm/day by Week 32. The dose of MMF has to be stable from Week 40 to 
Week 52. 
It is not mandatory for a subject to receive 2 gm/day of MMF if local treatment standards 
dictate a lower dose to be given (eg, for constitutionally small subjects). During the 52 week 
double-blind treatment period, the minimum dose of MMF is 1.0 gm/day between Week 8 and 
Week 52. Subjects who do not tolerate the minimum MMF dose will be considered non-
responders for responder analyses (such as CRR), but will be allowed to continue to receive 
investigational product. 
In the second year extension period, MMF dose should be ≤2 gm/day or ≤Week 52 dose, 
whichever is lower. If MMF dose >2 gm/day at Week 52, taper to ≤2 gm/day will be required 
by Week 60. Failure to do so will lead to withdrawal from IP. A decrease in MMF dose is 
allowed at the investigator’s discretion between Week 52 to Week 92. The dose of MMF must 
be stable from Week 92 to Week 104. 
During the second year extension period there is no minimum dose requirement for MMF. 
However, if MMF is discontinued and a different immunosuppressant is started at any time 
during the study, IP will be discontinued. A decrease below the minimum dose or withholding 
MMF for 14 days or less for MMF-related side effects, such as gastrointestinal side effects, 
cytopenias or infection is acceptable at any time throughout the study. (If during the 52 week 
double-blind treatment period MMF has to be withheld or decreased below the minimum dose 
for more than 14 days, the subject will be considered a non-responder for responder analyses 
(such as CRR), but may continue to receive IP. This will not be considered as non-compliance 
or protocol deviation, because the withdrawal of MMF is for safety reasons). 
Subject with premature discontinuation of IP will continue to receive Sponsor-provided MMF 
(unless subject is pregnant) at the investigator’s discretion until subject’s participation ends. 
Initial adjustment of MMF dose to achieve or maintain the target dose (Randomisation 
through Week 8) 
• 
Subjects who are receiving MMF at a dose of 2 gm/day at Week 0 
(Day 1) will continue this dose 
• 
Subjects who are not taking MMF at Week 0 (Day 1), or subjects who are 
taking less than 2 gm/day, the dose will be titrated up with the goal of 
achieving a dose of 2 gm/day (or the therapeutic target dose if local 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
156 (231) 
treatment standards dictate a lower dose) by Week 2 (but not later than 
Week 8, if dose escalation is limited by intolerability).  
Titration of MMF should follow accepted local practice guidelines, 
including appropriate laboratory monitoring for toxicity. 
• 
Subjects, who at Week 0 (Day 1) are taking MMF doses >2 gm/day will 
have their dose reduced to 2 gm/day by Week 8 unless they meet criteria 
for suboptimal response (see below for suboptimal response) 
MMF dose between Week 8 and 24 
The dose of MMF will be kept stable from Week 8 through Week 24 unless dose escalation to 
a maximum of 3 gm/day is necessary for suboptimal response (defined below) or a dose 
reduction is necessary to manage toxicity or intolerability. 
Criteria for suboptimal response: 
A suboptimal response is defined by UPCR values shown below at two independent 
measurements taken at least 2 weeks apart: 
• 
Spot UPCR >3 mg/mg and  
• 
Spot UPCR <15% decrease compared to baseline spot UPCR 
If a subject meets the criteria at or after Week 8, the dose may be escalated or kept above 2 
gm/day. After initial confirmation of suboptimal response, MMF can be increased up to 3 
gm/day until Week 16 without re-testing for the suboptimal response criteria. The dose of 
MMF must be kept stable from Week 16 unless suboptimal response criteria are met or dose 
reduction is necessary for intolerability or MMF-related AEs. A temporary decrease below the 
minimum dose, or withholding MMF for 14 days or less, for MMF-related side effects, such 
as gastrointestinal side effects, for cytopenias or infection is acceptable.  
Mycophenolate mofetil dose between Week 24 and Week 52: 
For subjects who are taking >2 gm/day of MMF at Week 24, the dose of MMF must be 
decreased to a maximum dose of 2 gm/day by Week 32. The dose can be decreased below 2 
gm/day after Week 24 until Week 40 at the discretion of the investigator. The dose of MMF 
must be stable from Week 40 through Week 52 (unless a dose reduction is necessary to 
manage toxicity or intolerability).  
MMF dose from Week 52 to Week 104: 
For subjects who continue in the second year extension the target dose of MMF will be 
≤2 gm/day or ≤Week 52 dose, whichever is lower. If the MMF dose is >2 gm/day at Week 52, 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
157 (231) 
it must be tapered to ≤2 gm/day by Week 60. Failure to achieve MMF dose ≤2 gm/day by 
Week 60 will lead to discontinuation from IP. A decrease in MMF dose or discontinuation of 
MMF is allowed at the investigator’s discretion between Week 52 to Week 92. If the MMF 
dose is decreased during the extension period, return to an MMF dose of ≤2 gm/day but not 
exceeding the Week 52 dose is allowed. 
MMF dose must not be changed from Week 92 to Week 104.  
7.7.3.2 
Corticosteroids 
Initial corticosteroid treatment to control LN and SLE: 
Subjects may enter the study taking daily OCS at a maximum dose of 0.5 mg/kg/day of 
prednisone-equivalent not to exceed 40 mg/day. In addition, subjects will receive IV (or oral, 
if applicable) methylprednisolone pulse 500 mg on the day of randomisation, prior to 
receiving the IP, unless they received a methylprednisolone pulse of ≥500 mg within 10 days 
prior to randomisation. Subjects may also receive one additional (optional) dose of IV (or oral, 
if applicable) methylprednisolone pulse (≤500 mg) for renal or extra-renal disease activity 
after the Week 0 (Day 1) visit up to and including the Week 8 visit. Methylprednisolone pulse 
can be divided and administered on two consecutive days but the cumulative dose must not 
exceed 500 mg. 
Steroid tapering during the 52 week double-blind treatment period: 
Oral corticosteroid dose tapering is required during the study with the goal of tapering OCS to 
prednisone-equivalent of ≤10 mg/day by Week 12 and prednisone-equivalent of ≤7.5 mg/day 
by Week 24. The rate of tapering is at the discretion of the Investigator; a recommended 
tapering schedule is provided in Appendix O. If subjects experience an increase in SLE 
disease activity upon tapering of OCS their dose may be returned to a dose equal or less as the 
dose prior to the taper. The return to the pre-taper dose will not be considered an OCS “burst 
and taper”. The pre-taper dose for various periods is defined as follows: 
• 
Week 0 to Week 12: dose at randomisation 
• 
After Week 12 to Week 24: the Week 12 dose 
• 
After Week 24 to Week 40: the Week 24 dose 
Subjects unable to taper OCS to ≤15 mg/day at Week 12 or <15 mg/day at Week 24 will be 
discontinued from IP treatment. However, subjects who exceed the maximum daily OCS dose 
at the Week 12 or Week 24 visits may continue to receive IP if the current dose is part of a 
protocol-allowed temporary OCS dose (eg, burst and taper) increase. Subjects who cannot be 
returned to their pre-increase dose within 14 days from the start of burst will have their IP 
discontinued at the next visit. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
158 (231) 
The subjects discontinued from IP treatment will be followed until Week 52 (or for a 
minimum of 12 weeks after last dose of IP for subjects for whom IP was discontinued within 
12 weeks prior to Week 52). 
Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
7.5 mg/day up to Week 40. Steroid tapering will not be permitted from Week 40 to Week 52.  
Steroid “burst and taper” 
A steroid burst is defined as one of the following: 
Oral corticosteroid increase up to a maximum daily dose of 0.5 mg/kg/day (maximum 
40 mg/day) prednisone-equivalent dose for up to a total of 14 days and that must be fully 
administered and tapered to less than or equal to the pre-burst starting dose by the end of the 
14th day. Any course of OCS burst must not extend beyond Week 40 during the first year 
(starting after Week 0) and Week 92 during the second year extension period (starting after 
Week 52), regardless of when the course was started. 
OR 
A maximum of 1 instance of intra-articular, tendon sheath or 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 burst (and vice versa). 
Steroid burst is allowed as follows: 
• 
From randomisation to Week 40: One burst and taper of corticosteroids 
for increased SLE disease activity or for non-SLE activity is allowed. 
Subjects who receive more than one steroid “burst and taper” or who 
violate the above criterion may continue to receive IP after approval by 
Sponsor/Designee Medical Monitor, but will be considered non-
responders for subsequent responder analyses (such as CRR), regardless 
of whether the OCS “burst” was administered for increased SLE activity 
or non-SLE causes.  
• 
Increase in corticosteroids from Week 40 to Week 52: No increase in 
OCS, or the use of IV or intra-articular, tendon sheath or bursal injections 
is allowed from Week 40 until Week 52 assessment. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
159 (231) 
Corticosteroid dose from Week 52 to Week 100 
• 
If the OCS dose is >7.5 mg/day at Week 52, tapering to ≤7.5 mg/day is 
required by Week 60. Failure to achieve ≤7.5 mg/day by Week 60 will 
lead to discontinuation from IP. 
• 
OCS dose must be tapered to ≤5 mg/day at Week 80. OCS tapering 
below 5 mg/day is allowed at any time until Week 92.  
• 
No change in OCS dose will be allowed from Week 92 to Week 104.  
• 
One burst and taper will be allowed between Week 52 and Week 92. 
Increase in corticosteroids for the prevention of adrenal insufficiency 
For a severe illness, surgery, or symptoms of adrenal insufficiency, if clinically warranted, the 
following can be used, in addition to the “burst and taper” described above: 
• 
Oral or IV hydrocortisone up to 100 mg every 8 hours on the first day 
followed by half that dose for 2 days before returning to their usual dose 
or 
• 
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 
oral prednisone or equivalent for a total of up to 14 days. 
Subjects who receive either of these corticosteroid regimens for the prevention of adrenal 
insufficiency between Week 40 and Week 52 will be considered as a non-responder for the 
Week 52 analyses. 
7.7.4 
Other concomitant medications 
Medications 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 electronic Case Record Form (eCRF). Subjects should not start 
naturopathic, herbal, ayurvedic remedies, nutritional/dietary supplements, vitamins, and/or 
minerals without discussing with the Investigator. 
7.7.4.1 
Topical therapy 
Concurrent use of topical therapy for cutaneous lupus erythematosus (eg, topical 
corticosteroids, topical immunosuppressants) is permitted. During the study, topical therapy 
may be reduced or discontinued based on clinical manifestations and Investigator discretion. 
Should cutaneous skin manifestations reoccur, the same topical therapy may be resumed at 
same dose as was being used at the time of randomisation. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
160 (231) 
It is encouraged that no new dermatologic preparations be initiated for the duration of the 
study. Subjects should use sunscreen (list as concomitant medication for SLE) and avoid sun 
exposure for the duration of the study. 
7.7.4.2 
Anti-proteinuric agents (ACEI or ARB) 
Use of these are allowed during the study if they had been started at least 10 days prior to the 
assessment of the second screening 24-hour UPCR sample (the first sample for 24-hour UPCR 
is collected at the start of the screening process and the second sample is collected within 14 
days prior to the expected date of randomisation). The dose may be adjusted to optimise 
anti-hypertensive effects or to reduce ACEI/ARB-related side effects up to Week 4. The dose 
must be kept stable from Week 4 through Week 104 (unless discontinued IP). Decreases in the 
dose are allowed only to reduce ACEI/ARB-related side effects such as hypotension, increase 
in creatinine, or cough. If cough develops, ACEI can be changed to ARB. 
7.7.4.3 
Anti-malarials 
The dose of anti-malarials will remain stable throughout the study except where a reduction of 
dose is necessary to manage anti-malarial related AEs. Any anti-malarial related abnormality 
should be managed according to local standards. Discontinuation of anti-malarials is allowed, 
if necessary, to manage anti-malarial related AEs. The subject can remain in the study even if 
anti-malarials are stopped.  
Randomised subjects who receive anti-malarial therapy within 12 months prior to signing the 
ICF must have an eye exam by a qualified professional either within 12 months prior to 
signing the ICF or subjects who start on anti-malarial therapy during the Screening Period 
within 12 weeks after signing the ICF. Anti-malaria-related abnormalities should be managed 
according to local standards. Anti-malarial-related abnormalities do not exclude subjects if 
they meet all other eligibility criteria. If eye exam is not performed within the protocol-
specified timeframe, it will be considered to be a protocol deviation. 
7.7.4.4 
Non-steroidal anti-inflammatory drugs 
No increase in the dose of or initiation of a new prescription non-steroidal anti-inflammatory 
drug (NSAID) should be made between signing the ICF and randomisation. For subjects 
receiving NSAIDs, concomitant proton pump inhibitors should be considered according to 
local practice and in concordance with considerations in the mycophenolate label. 
• 
The dose of prescription NSAIDs must remain stable from randomisation 
through Week 104 (unless discontinued IP) but can be reduced for 
reasons of toxicity but not for efficacy. Prescription NSAIDs should not 
be administered with other NSAIDs (including over-the-counter 
NSAIDs) except for low-dose aspirin (≤325 mg/day). 
• 
Non-prescription NSAIDs 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
161 (231) 
− 
NSAIDs for analgesic purposes that never exceed label-approved 
doses of NSAIDs may be used for pain as required, based on 
Investigator judgement for up to 1 week at a time 
− 
Low-dose aspirin (maximum of 325 mg/day) for cardioprotection is 
permitted. 
7.7.4.5 
Acetaminophen (Paracetamol): 
• 
Normal release (not extended release) acetaminophen/paracetamol may 
be used for pain as required 
• 
For 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 
7.7.4.6 
Narcotic analgesics 
These can be used during the study as clinically indicated. 
7.8 
Post Study Access to Study Treatment 
After Week 52, eligible participants will continue treatment for another 12 months in the 
second year extension period. 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
All personnel involved in the conduct of the study will remain blinded until the database soft 
lock and identification of protocol violations for the primary analysis at Week 52. Analyses 
will be performed by AstraZeneca or its delegates.  
The database will be soft-locked and the primary analysis will be performed once all subjects 
complete Week 52 or discontinue the study prior to Week 52. The Sponsor and Sponsor‘s 
delegates who are not directly involved in the management of sites will be unblinded to 
treatment assignments at the time of the primary analysis.  
Investigators and subjects who continue in the second year extension phase will continue to be 
blinded to their treatment. The database will be locked for the final analysis of the second year 
extension period once the last subject in the second year extension period completes Week 
112, or discontinues the second year extension period prior to Week 112. 
One interim analysis may be conducted after approximately 50% of subjects have completed 
the Week 52 visit. 
 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
162 (231) 
  Further details of the interim analysis will be specified in the interim 
analysis and communication plans prior to unblinding. 
A comprehensive SAP v1.0 was completed prior to 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. Details of all analyses, including sensitivity analyses are 
presented in the SAP. 
8.2 
Sample size estimate 
A total of 150 subjects will be randomised 1:1:1 to receive one of the two IV anifrolumab 
dosing regimens (Basic Regimen or Intensified Regimen) or placebo. 
The sample size is based on the following assumptions: 
• 
Reductions from baseline to Week 52 in 24-hour UPCR of 65% and 46% 
for the anifrolumab and placebo arms, respectively (ie, ratios of 24-hours 
UPCR from Week 52 to baseline of 0.35 and 0.54, respectively), based 
on data presented in Furie et al, 2014. 
• 
The log-transformed 24-hour UPCR values follow a normal distribution 
with a standard deviation (SD) of 0.8, based on data from the anifrolumab 
Phase 2b study (CD1013) 
Based on these assumptions, a sample size of 50 subjects per arm would result in an observed 
relative difference in the change from baseline to Week 52 in 24-hour UPCR of 0.65 (here 
expressed as the ratio, comparing anifrolumab to placebo), and a corresponding 95% 
confidence interval (CI) of (0.50, 0.85) comparing the pooled anifrolumab group (Basic and 
Intensified) with the placebo group. If the interim analysis is performed, a 0.001 two-sided 
alpha will be spent, and the final analysis will be based on 2-sided alpha of 0.049 (East 
Version 6.4). This sample size provides approximately 86% power with a 2-sided alpha of 
0.049 to reject the hypothesis of no effect (relative difference =1) for comparing the pooled 
anifrolumab treatment group with placebo. The minimal detectable relative difference in the 
change from baseline to Week 52 in 24-hour UPCR between the pooled anifrolumab treatment 
group versus placebo is approximately 0.76, corresponding to a reduction from baseline to 
Week 52 in 24-hour UPCR of 59% in the pooled anifrolumab group (ratio of 24-hour UPCR 
from Week 52 to baseline of 0.41). 
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. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
163 (231) 
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 IP 
and will be analysed according to randomised treatment (mITT principle). 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 one quantifiable serum PK 
observation post first dose will be included in the PK analysis dataset. All PK summaries will 
be based on this analysis set. 
8.4 
Outcome measures for analyses 
The baseline is defined as the last measurement prior to Day 1 dose administration. If the 
Day 1 value is missing or is invalid, the latest assessment prior to dose administration on 
Day 1 will serve as baseline. 
8.4.1 
Primary outcome variable 
The primary endpoint used to evaluate the effect of anifrolumab compared with placebo on 
LN disease activity is the relative difference in change from baseline to Week 52 in the 
24-hour UPCR. 
8.4.2 
Secondary outcome variables 
8.4.2.1 
Complete renal response 
To evaluate the effect of anifrolumab compared with placebo on renal response in LN 
subjects, the proportion of subjects achieving CRR at Week 52 will be used. A subject 
achieves CRR if all of the following criteria are met: 
• 
Estimated glomerular filtration rate (eGFR): 
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline 
of ≥20% 
• 
24-hour UPCR ≤0.7 mg/mg 
No discontinuation of IP or use of restricted medication beyond the protocol-allowed 
threshold before assessment. Allowed restricted medication is defined in Section 7.7 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
164 (231) 
8.4.3 
Exploratory outcome variables 
8.4.3.1 
 
 
8.4.3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.3.3 
 
 
8.4.3.4 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
165 (231) 
 
 
 
 
 
 
 
 
 
 
8.4.3.5 
Alternative Complete renal response 
To evaluate the effect of anifrolumab compared with placebo on renal response in LN subjects 
when urine sediment is considered in the definition, the proportion of subjects achieving 
aCRR at Week 52 and Week 104 will be used. A subject achieves aCRR if all of the following 
criteria are met: 
• 
eGFR: 
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline 
of ≥20% 
• 
24-hour UPCR ≤0.7 mg/mg 
• 
Inactive urine sediment (defined as <10 RBC/hpf) 
• 
No discontinuation of IP or use of restricted medication beyond the 
protocol-allowed threshold before assessment. Allowed restricted 
medication is defined in Section 7.7 
Please see Section 8.4.2.1 for definition of CRR.  
8.4.3.6 
Graded alternative complete renal response 
The effect of anifrolumab compared with placebo on renal response in LN subjects is further 
assessed using the difference in proportions of subjects achieving graded aCRR at Week 52 
and of subjects achieving aCRR at Week 104. A subject achieves graded aCRR if all 
following criteria are met: 
• 
A decrease in 24-hour UPCR: 
− 
For subjects with baseline UPCR >3 mg/mg: UPCR ≤1 mg/mg 
− 
For subjects with baseline UPCR ≤3 mg/mg: UPCR ≤0.7 mg/mg 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
166 (231) 
• 
eGFR: 
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline 
of ≥20% 
• 
Inactive urine sediment (defined as <10 RBC/hpf) 
• 
No discontinuation of IP or use of restricted medication beyond the 
protocol-allowed threshold before assessment. Allowed restricted 
medication is defined in Section 7.7 
8.4.3.7 
Sustained reduction of oral corticosteroid dose 
The effect of anifrolumab compared with placebo on the ability to reduce the OCS dose will 
be assessed in subjects with baseline OCS ≥10 mg/day prednisone-equivalent. Sustained 
reduction on OCS dose is assessed using the difference in proportions of subjects meeting all 
the following criteria:  
• 
Achieve an OCS dose of ≤7.5 mg/day prednisone-equivalent by Week 24 
• 
Maintain an OCS dose ≤7.5 mg/day prednisone-equivalent from Week 24 
to Week 52 
• 
No discontinuation of IP or use of restricted medication beyond the 
protocol-allowed threshold before assessment (see Section 7.7) 
The proportion of subjects achieving OCS tapering requirement will also be assessed at Week 
104: 
• 
Achieve an OCS dose of ≤5.0 mg/day prednisone-equivalent by Week 80 
• 
Maintain an OCS dose ≤5.0 mg/day prednisone-equivalent from Week 80 
to Week 104 
• 
No discontinuation of IP or use of restricted medication beyond the 
protocol-allowed threshold before assessment (see Section 7.7) 
8.4.3.8 
 
 
 
 
 
  
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
167 (231) 
 
 
 
 
 
 
  
 
 
 
8.4.3.9 
 
 
 
8.4.3.10 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
168 (231) 
8.4.3.11 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.3.12 
 
 
 
 
 
CCI
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
169 (231) 
8.4.3.13 Other exploratory endpoints 
 
 
 
  
SLEDAI-2K 
The effect of anifrolumab compared with placebo on SLEDAI-2K score will be evaluated 
using the difference in mean change from baseline to Week 52 and to Week 104.  
Non-renal SLEDAI-2K 
Extra-renal disease activity will be assessed by using the SLEDAI-2K score without the renal 
components (“non-renal SLEDAI-2K”). The effect of anifrolumab compared with placebo on 
non-renal SLEDAI-2K will be evaluated using the difference in mean change from baseline to 
Week 52 and to Week 104. 
Physician’s Global Assessment 
The effect of anifrolumab compared with placebo on PGA will be evaluated using the 
difference in mean change in PGA from baseline to Week 52 and to Week 104.  
SLICC/ACR Damage Index 
The endpoint used to evaluate the effect of anifrolumab compared with placebo on irreversible 
damage in SLE subjects is the mean change in SDI global score from baseline to Week 52 and 
to Week 104. 
8.4.4 
Patient-reported outcome variables 
Patient Global Assessment  
The difference between anifrolumab and placebo in the mean change from baseline in PtGA 
(measured on a VAS ranging from 0 to 100 mm) to Week 52 and to Week 104 will be 
assessed. 
8.4.5 
Safety variables 
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, reported AEs (including AESIs, see Section 6.4), 
PHQ-8 (up to Week 52), C-SSRS (up to Week 52), tuberculosis questionnaire, assessment of 
Cushingoid features, assessment of cardiovascular risk (fast lipid profile), and extra-renal 
flares using SLEDAI-2K based Flare Assessment Instrument. Marked abnormal ECG values 
or changes from baseline will be identified based on pre-determined criteria. Occurrence of 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
170 (231) 
suicidal behaviour and ideation, based on the C-SSRS, from baseline up to Week 52 will be 
explored. 
Change from baseline to each post-treatment time point where scheduled assessments were 
made will be calculated for relevant measurements. Adverse events will be summarised by 
means of descriptive statistics and qualitative summaries.  
8.4.5.1 
Other significant adverse events 
During the evaluation of the AE data, a medically qualified expert from Sponsor/Sponsor’s 
delegate team will review: 
• 
AESI: AESI are listed in Section 6.4. These will be reported in the CSR.  
• 
A list of AEs that were not reported as SAEs, or AEs leading to 
discontinuations: Based on the expert's judgement, 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 only in samples that were previously found to contain ADA, 
using a ligand binding assay. 
Immunogenicity variables will also be assessed for the second year extension period.  
8.4.7 
Pharmacokinetic variables 
Due to the limited sampling schedule, the PK assessments for both anifrolumab and 
mycophenolic acid will be primarily based on the observed steady-state serum trough 
(pre-dose) concentrations, Ctrough. For anifrolumab, maximum concentrations after the first 
and last dose will also be evaluated. 
Only Ctrough will be assessed for the second year extension period. 
8.4.8 
Lupus serology variables 
The outcome variable for anti-dsDNA antibodies, C3 and C4 complement levels will be the 
mean change from baseline over time in subjects with abnormal complement level at baseline, 
defined as complement level below lower limit of normal or elevated anti-dsDNA antibodies 
at baseline. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
171 (231) 
Lupus serology variables will also be assessed for the second year extension period. 
8.4.9 
Pharmacodynamic outcome variables 
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. 
IFN-21 gene PD signature will also be assessed for the second year extension period. 
8.5 
Methods for statistical analyses 
Missing data 
The study was designed to reduce the risk for missing data as much as possible through the 
following measures (see Section 7.7.3 for details): 
• 
From randomisation to Week 40, the study design allows for one burst 
and taper of corticosteroid for increased SLE disease activity or non-SLE 
causes. 
• 
The dose of MMF may be increased up to 3 gm/day in case of suboptimal 
response. 
• 
Subjects will receive IV methylprednisolone 500 mg on Week 0 (Day 1), 
prior to receiving the IP. 
• 
Subjects may also receive up to one additional (optional) dose of IV 
methylprednisolone (≤500 mg) for renal or extra-renal disease activity 
between Week 0 (Day 1) visit and Week 8 visit. 
• 
Subjects who require additional bursts of OCS will still be allowed to 
remain in the study, but will be considered non-responders for subsequent 
responder analyses (such as CRR). 
Subjects who discontinue IP will be followed up to come to each visit for the scheduled 
assessments through the Week 52 visit (or for a minimum of 12 weeks after last dose of IP for 
subjects for whom IP was discontinued within 12 weeks prior to Week 52).  
The following measures will be applied to the second year extension period to also reduce the 
risk for missing data: 
• 
From Week 52 to Week 92, the study design allows for one burst and 
taper of corticosteroid. 
• 
Subjects who require additional bursts of OCS during the second year 
extension period will still be allowed to remain in the study, but will be 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
172 (231) 
considered non-responders for subsequent responder analyses (such as 
CRR at Week 104). 
Subjects who discontinue IP in the second year extension period will continue to be followed 
until Week 104 (or for a minimum of 12 weeks after last dose of IP for subjects for whom IP 
was discontinued within 12 weeks prior to Week 104).  
Sensitivity analyses where missing data is handled in different ways will 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. 
Summary tables will be presented by treatment group including a pooled group comprising of 
both anifrolumab regimens. Details are presented in the SAP. 
95% CIs will be presented for estimated differences between treatments. If a model is used to 
estimate the treatment difference, the corresponding 95% CI according to the model will be 
presented. Otherwise, the unadjusted 95% CI will be used. Nominal p-values may be 
presented for endpoints not included in the strategy for preserving the type 1 error rate, but 
these cannot be interpreted in terms of statistical significance.  
Demography and baseline characteristics will be summarised by treatment group for the full 
analysis set. 
8.5.1 
Analysis of the primary variable 
The primary estimand is evaluating the efficacy on disease activity of the pooled anifrolumab 
groups relative to placebo in subjects with active proliferative LN. This is measured by the 
relative difference in change from baseline to Week 52 in the 24-hour UPCR. The full 
analysis set, defined as subjects who are randomised and received at least 1 dose of IP 
(modified Intention-To-Treat), will be used, in order to reflect the effect of the initially 
assigned and dosed IP. Further details regarding multiplicity adjustments can be found in 
Section 8.6. 
The analysis will be performed using a mixed model repeated measures (MMRM) fitted to 
log-transformed data comparing the pooled anifrolumab group with the placebo group, with 
fixed effects for treatment group, visit, stratification factors and log-transformed 24 hour 
UPCR at baseline.  An interaction term for visit and treatment will also be included in the 
model to allow the relationship to differ across treatment groups.  Note that visit will be fitted 
as a repeated variable in the model. Model assumptions will be checked and, if not met, 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
173 (231) 
appropriate data transformations may be applied or non-parametric approaches will be 
considered. Details will be presented in the SAP. 
The estimated treatment effect, corresponding 95% CI, and 2-sided p-value for the difference 
at Week 52 will be presented. The individual anifrolumab regimens will also be assessed 
using the same methodology. 24-hour UPCR will also be assessed at Week 104 and presented 
similary with nominal 2-sided p-values. 
Further, longitudinal presentations of results over time based on the same analysis, with the 
corresponding 95% CI, will be created. 
8.5.2 
Analysis of the secondary variable 
In addition to the 24-hour UPCR, a composite endpoint will be used to further evaluate the 
effect of anifrolumab on renal response using the composite endpoint defined in Section 8.4.2, 
combining response to treatment and lack of restricted therapy. For this analysis, the estimand 
of interest is the difference in change from baseline in renal response between anifrolumab 
and placebo, to reflect the effect of the initially assigned and dosed IP (full analysis set). 
Non-responder imputation is used, ie, subjects treated with restricted treatments beyond 
protocol-allowed threshold, and those discontinued for other reasons, will be regarded as 
non-responders. This estimand answers a clinically relevant question comparing the number 
of subjects able to both tolerate therapy sufficiently to remain on treatment to a given point in 
time and to achieve adequate response without further medication being required. 
The proportion of subjects achieving CRR in the anifrolumab pooled group will be compared 
to that in the placebo group using a Cochran-Mantel-Haenszel approach (Cochran, 1954) 
stratified by:  
• 
Results of IFN test at screening using a 4-gene type I IFN diagnostic test 
(IFN test-high versus. IFN test-low) 
• 
24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg (within 14 days prior to 
the expected date of randomisation). Without the results of the second 
(stratification) sample, subjects cannot be randomised. Turn-around time 
for results from central laboratory is up to 7 days. On rare occasion an 
extension of 30-day screening window may be allowed if re-collection of 
the 24-hour UPCR or other required samples is necessary or if the results 
needed for randomisation are delayed. 
Strata with low counts will be collapsed prior to the analysis. Details for collapsing of strata 
will be pre-specified in the SAP. Further details regarding multiplicity adjustments can be 
found in Section 8.6. 
The estimated treatment effect (ie, the difference in response rate for the pooled anifrolumab 
group versus the placebo group) and corresponding 95% CI for the difference at Week 52 and 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
174 (231) 
Week 104 will be presented. In addition, the response rate and the corresponding 95% CI 
within each pooled and treatment group will be presented. The treatment effect at other time 
points may also be evaluated in a similar way. The individual anifrolumab regimens will also 
be assessed and presented similarly. 
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 endpoints will be summarised by treatment group. 
CRR will also be assessed at Week 104 using the same methodology. Please see Section 8.4.2 
for more details. 
8.5.3 
Analysis of exploratory variables 
All exploratory analyses will be performed using the pooled and individual anifrolumab 
groups, as well as placebo. No formal statistical hypotheses will be tested, but nominal p-
values may be presented. 
Exploratory binary responder endpoints (at least PRR, aCRR, graded CRR, graded aCRR, 
sustained reduction of OCS, modified CRR and modified PRR) will be assessed similarly to 
CRR endpoint as described in Section 8.4.2.1. Response rate and the corresponding 95% CI 
comparing each anifrolumab group (including pooled anifrolumab group) with the placebo 
group will be presented. The treatment effects at Week 52 and Week 104 will be evaluated. 
Analyses of ordinal outcomes (such as CRR, PRR, no response) will also be performed. 
Further details are presented in the SAP. 
The time to achieve renal response and time to first renal flare will be reported descriptively. 
The number of renal flares and the flare rates will also be summarised.  Details are presented 
in the SAP.  
Continuous endpoints (including eGFR, spot UPCR, SLEDAI-2K, PGA, SDI, and PtGA) will 
be analysed using MMRMs with fixed effects for the appropriate baseline value, treatment 
group, visit, stratification factors and visit-by-treatment interaction term. 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 are presented in the SAP.  
Exploratory renal variables which are assessed at Week 52 will also be assessed at Week 104 
using the same methodology. 24-hour UPCR will also be assessed at Week 104 as an 
exploratory variable. Please see Section 8.4.3 for more details.  


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
175 (231) 
8.5.4 
Analysis of safety variables 
Adverse events (including AESIs) will be summarised by means of counts summaries by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred 
Term 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 summarised 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 
total number of attempts, total number of interrupted attempts, and total number of aborted 
attempts will be summarised for each treatment group. 
SLEDAI-2K based Flare Assessment Instrument to capture extra-renal flares: The SLEDAI 
2K based Flare Assessment Instrument has 2 sets of definitions: one for severe and one for 
mild/moderate flares. For the purpose of assessing extra-renal flares the renal components will 
not be considered for the SLEDAI 2K score. SLEDAI-2K based Flare will be summarised as 
appropriate. 
Other safety variables will be summarised as appropriate. Further details are provided in the 
SAP. 
8.5.5 
Renal biopsy: ISN/RPS classification, NIH activity and chronicity indices 
ISN/RPS classification, NIH activity and chronicity indices will be summarised as 
appropriate. For second biopsies, change from baseline in ISN/RPS classification and NIH 
activity and chronicity indices will also be summarised in a similar way. Details are presented 
in the SAP. 
8.5.6 
Analysis of immunogenicity variables 
Antibodies to anifrolumab will be summarised using descriptive statistics at each visit by 
treatment group. ADA titres-time profiles of anifrolumab by treatment group will be 
generated. The impact of ADA on PK and PD endpoints will be assessed. The potential 
association of ADA with safety and efficacy will be explored. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
176 (231) 
All immunogenicity variables will also be assessed as described for the second year extension 
period.  
8.5.7 
Analysis of 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, and PK profiles will be provided in the 
CSR or as an addendum to the CSR.  
Mycophenolic acid serum concentrations will be summarised using descriptive statistics at 
each visit by treatment group. Serum concentration-time profiles of MPA by treatment group 
will be generated. If applicable, additional PK parameters will be explored. 
All PK variables will also be assessed as described for the second year extension period.  
8.5.8 
Analysis of pharmacodynamic variables 
Pharmacodynamic variables will be summarised as appropriate. Further details are provided in 
the SAP. 
8.5.9 
Analysis of lupus serology variables 
Lupus serology variables will be reported as appropriate. Further details are provided in the 
SAP. 
8.5.10 
Subgroup analysis  
To explore the uniformity of the detected overall treatment effect on the primary, and when 
applicable, secondary and exploratory efficacy endpoints, subgroup analyses may be 
performed for the following factors:  
• 
IFN test (IFN test-high versus IFN test-low)  
• 
24-hour UPCR ≤3 mg/mg versus >3 mg/mg 
• 
Age (≥18 to 64 and ≥65 years)  
• 
Placebo response region (low placebo response rate versus high placebo 
response rate) 
Countries with low placebo response rate versus high placebo response rate are defined as: 
− 
Low: Australia, Belgium, France, Germany, Italy, South Africa, Spain, 
United Kingdom, United States 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
177 (231) 
− 
High: Argentina, Hungary, Republic of Korea, Mexico, Peru, Poland, 
Russian Federation, Serbia, Taiwan 
• 
Race (white; black or African American; Asian, native Hawaiian or other 
Pacific Islander; American Indian or Alaska native; other) 
• 
Screening biopsy classification (Class III, Class IV) 
• 
Number of methylprednisolone pulses (1, >1) 
• 
ADA result (positive at any time, negative) 
• 
OCS at baseline (≤20 mg/day, >20 mg/day) 
• 
eGFR at baseline (<60 mL/min/1.73m2, ≥60 mL/min/1.73m2) 
Full details of the subgroup analyses for both the first year period and the second year 
extension period will be pre-specified in the SAP.  
8.5.11 
Interim analysis 
Primary efficacy and safety analyses will be performed once all data from the main study (up 
to and including Week 52) is available, cleaned and frozen. The study will also be unblinded 
at this stage for the team performing the analysis.  
One interim analysis may be conducted after approximately 50% of subjects have completed 
the Week 52 visit. 
 
Even though there is no provision to stop the study early due to an 
efficacy claim, if the interim analysis is performed, a portion of the 2-sided alpha will be 
spent. A Peto-Haybittle spending function would therefore be used with a fixed 2-sided 
p-value threshold of 0.1% at the interim. The p-value threshold at the final analysis will be 
adjusted to account for the interim analysis, based on the actual observed information fraction 
for the primary endpoint. If as planned there are 75 patients included at the interim and 150 
patients at the final analysis, the critical threshold at the final analysis will be 4.9% (East 
Version 6.4). 
Additional and repeat analyses as previously defined will be performed at the end of the 
second year extension period. Additional details are provided in the SAP. 
8.6 
Testing strategy to account for multiplicity considerations 
While the primary and secondary objectives are defined based on the comparison between the 
pooled anifrolumab and placebo groups, the respective endpoints will also be tested for the 
individual anifrolumab regimens. The following hierarchical testing strategy (presented in 
Figure 3) will be used to provide strong control of the familywise error rate (FWER). As 
CCI


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
178 (231) 
described in Section 8.5.11, if the interim analysis is performed, some alpha will be spent, and 
the alpha at final analysis will be calculated based on a Peto-Haybittle spending function and 
the number of subjects at each analysis. The description below assumes that a 2-sided alpha of 
0.049 is being used at the final analysis.  
Figure 3 
Multiplicity correction at final analysis 
 
• 
Step 1: The pooled anifrolumab regimens will be tested versus placebo at 
a 2-sided 4.9% significance level with regards to 24-hour UPCR (primary 
endpoint). 
• 
Step 2: If the null hypothesis is rejected at Step 1, then the pooled 
anifrolumab regimens will be tested versus placebo at a 2-sided 4.9% 
significance level with regards to CRR (secondary endpoint). 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
179 (231) 
• 
Step 3: If the null hypothesis is rejected at Step 2, then both anifrolumab 
regimens are individually tested against placebo, each at 2.45% 
significance level, for both endpoints (24-hour UPCR and CRR). If both 
regimens can be rejected for either endpoint, then alpha can be recycled 
and both regimens can be tested at 4.9% significance level for the 
remaining endpoint. 
At Steps 1 and 2, strong control is due to the sequence testing. At Step 3, alpha is controlled 
given that the pooled hypothesis is tested first and if false, the two hypotheses corresponding 
to the two regimens for that endpoint cannot both be true. 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site staff 
Before the first subject is entered into the study, an AstraZeneca Designee will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and systems utilised. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.1.1 
Training and certification for systemic lupus erythematosus assessments 
In order to maintain consistent evaluation of SLE assessments 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 
• 
PGA 
• 
SLEDAI-2K based Flare Assessment Instrument  
• 
SDI 
These evaluations must be performed 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. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
180 (231) 
After attending study presentations (ie, Investigator Meeting) or after completion of training 
modules, all Investigators and designated site physicians must pass an examination in order to 
obtain certification for all disease evaluation assessments. Investigators and designated site 
personnel must be trained and certified prior to subjects entering screening at their respective 
sites. 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 SLE assessments. 
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. 
9.2 
Monitoring of the study 
During the study, an AstraZeneca Designee 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 Clinical Study 
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. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
181 (231) 
forwarded to the staff involved. The Principal Investigator will maintain a record of all 
individuals involved in the study (medical, nursing and other staff). 
9.2.1 
Source data 
Refer to the Clinical Study Agreement (CSA) for location of source data. 
9.2.2 
Study agreements 
The Principal Investigator 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 (CSP) and the CSA, the terms of CSP shall prevail with 
respect to the conduct of the study and the treatment of subjects and in all other respects, not 
relating to study conduct or treatment of subjects, the terms of the CSA shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.2.4 
SLE Data Medical Review Team  
Data for SLE disease activity and damage indices (SLEDAI-2K, PGA, and SDI) as well as 
SLEDAI-2K based Flare Assessment Instrument will be reviewed by an independent 
Sponsor’s delegate Medical Team. The SLE Data Medical Review Team (MR team) members 
are medically qualified individuals. The MR team will review all LN and SLE data in 
conjunction with any other relevant data (including medical history, AE, laboratory data, and 
concomitant medications as appropriate) that is necessary to characterise the subject’s SLE. 
The MR team members will have access to an internal expert on SLE disease activity and 
damage indices for unanticipated issues with regard to interpretation of these indices. 
A separate procedure will outline the review and escalation details. The MR Team will be 
utilised throughout the study to confirm SLEDAI-2K, PGA, SLEDAI-2K based Flare 
Assessment Instrument, and SDI scoring. The purpose of the independent review is to ensure 
medical plausibility, coherence, consistency, and clarity of data. The MR team will query any 
inconsistent scoring and follow for resolution of any discrepancy. The MR team will monitor 
trends in issues encountered during their review and liaise with the study team for additional 
training to be provided for the site staff or study monitoring team as appropriate. The MR 
team will remain blinded for the duration of the study. The MR team is separate from the 
Medical Monitoring team and works closely with the Medical Monitoring team. 
9.3 
Study timetable and end of study 
The end of the study is defined as ‘the date of the last protocol-specified visit/assessment for 
the last subject in the study’. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
182 (231) 
The study is expected to start in Quarter 3, 2015 and to end by Quarter 3, 2020. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with anifrolumab. 
9.4 
Data management 
Data management will be performed by Sponsor Designee, according to the Global Data 
Operations Plan.  
The Sponsor/Designee DataLabs system will be used for data collection and query handling. 
The Investigator will ensure that data are recorded on the CRFs as specified in the study 
protocol and in accordance with the instructions provided. 
The Principal Investigator ensures the accuracy, completeness, and timeliness of the data 
recorded and the provision of answers to data queries according to the CSA. The Principal 
Investigator will sign the completed CRFs. After the study is completed, CRFs are archived 
on a CD and sent to each site. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of MedDRA. Medications will be classified according to the WHO Drug 
Dictionary. All coding will be performed by the Sponsor/Designee 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 per Sponsor/Sponsor’s delegate’s processes. 
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Serious adverse event reconciliation 
Serious adverse event reconciliation reports are produced and reconciled with the patient 
safety database and/or the investigational site. SAE reconciliation between safety data and 
clinical data will be performed by the Sponsor/Sponsor’s delegate. The frequency depends on 
the expected volume of SAE reports and will be defined in the SAE Reconciliation Plan.  
Management of external data 
The data collected through third party sources will be obtained and reconciled against study 
data. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
183 (231) 
Steering committee 
The primary objective of the Lupus Nephritis Steering Committee is to ensure the validity and 
integrity of all of the data (efficacy and safety) as well as the conduct of the trial according to 
GCP guidelines and to provide guidance for program progression.  The safety of this trial will 
be reviewed by a distinct, separate committee known as the Data Safety Monitoring Board 
(DSMB) for whom a charter clearly documents their independent safety monitoring 
responsibilities. 
Interim analysis 
One interim analysis may be conducted after approximately 50% of subjects have completed 
the Week 52 visit.  
Primary analysis 
Primary efficacy and safety analyses will be performed once all data from the main study (up 
to and including Week 52) is available, cleaned and soft-locked. The study will also be 
unblinded at this stage for the team performing the analysis. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 
10.2 
Subject data protection 
The 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 (ie, before 
consenting of any subject into the study).  
The EC should approve all advertising used to recruit subjects for the study. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
184 (231) 
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. 
AstraZeneca or designee will provide Regulatory Authorities, ECs and Principal Investigators 
with safety updates/reports according to local requirements. 
Each Principal Investigator is responsible for providing the EC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the IP. AstraZeneca 
or designee will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements. 
10.4 
Informed consent 
The Principal Investigator (s) at each centre will: 
• 
Ensure 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. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
185 (231) 
10.5 
Changes to the Clinical Study Protocol and Informed Consent 
Form 
Study procedures will not be changed without the mutual agreement of the International 
Coordinating Investigator (ICI) 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 Principal Investigator. 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. 
10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the Clinical Study 
Protocol, Good Clinical Practice (GCP), guidelines of the International Conference on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre. 
11. 
LIST OF REFERENCES 
American Psychiatric Association, 1994 
American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental 
Disorders, 4th Edition. American Psychiatric Association, Washington, DC. 
Anders et al, 2014 
Anders HJ, Fogo AB. Immunopathology of lupus nephritis. Semin Immunopathol. 2014; 
36(4):443-459. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
186 (231) 
Arbuckle et al, 2003 
Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. 
Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N 
Engl J Med. 2003;349(16):1526-1533. 
Baccala et al, 2012 
Baccala R, Gonzalez-Quintial R, Schreiber RD, Lawson BR, Kono DH, Theofilopoulos AN. 
Anti-IFN-α/β receptor antibody treatment ameliorates disease in lupus-predisposed mice. J 
Immunol. 2012;189(12):5976-5984. 
Baechler et al, 2003 
Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. 
Interferon-inducible gene expression signature in peripheral blood cells of patients with severe 
lupus. Proc Natl Acad Sci USA. 2003;100(5):2610-2615. 
Baechler et al, 2004 
Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic 
lupus erythematosus. Curr Opin Immunol. 2004;16(6):801-807. 
Banchereau et al, 2004 
Banchereau J, Pascual V, Palucka AC. Autoimmunity through cytokine-induced dendritic cell 
activation. Immunity. 2004;20:539–550. 
Bauer et al, 2009 
Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, et al. Interferon-regulated 
chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation 
study. Arthritis Rheum. 2009;60(10):3098-3107. 
Bengtsson et al, 2000 
Bengtsson AA, Sturfelt G, Truedsson L, Blomberg J, Alm G, Vallin H, et al. Activation of 
type I interferon system in systemic lupus erythematosus correlates with disease activity but 
not with antiretroviral antibodies. Lupus. 2000;9:664-671. 
Bertsias et al, 2012 
Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JHM, et al. Joint 
European League Against Rheumatism and European Renal Association European Dialysis 
and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of 
adult and paediatric lupus nephritis. Ann Rheum Dis. 2012;71:1771-1782. 
Borchers et al, 2010 
Borchers AT, Naguwa SM, Shoenfeld Y, Gershwin ME. The geoepidemiology of systemic 
lupus erythematosus. Autoimmunity Rev. 2010;9:A277-A287. 
Cellestis, 2005 
Clinicians Guide to QuantiFERON®-TB Gold. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
187 (231) 
Chan, 2012 
Chan TM. Recent progress in the treatment of proliferative lupus nephritis. Amer J Med. 
2012;125:642-648. 
CHMP, February 2015 
CHMP Guideline on clinical investigation of medicinal products for the treatment of systemic 
lupus erythematosus and lupus nephritis (26 February 2015; EMA/CHMP/51230/2013). 
Crow, 2010 
Crow MK. Interferon-alpha: a therapeutic target in systemic lupus erythematosus. Rheum Dis 
Clin North Am. 2010;36(1):173-186. 
Crow and Wohlgemuth, 2003 
Crow MK, Wohlgemuth J. Microarray analysis of gene expression in lupus. Arthritis Res 
Ther. 2003;5:279-287. 
Dall’Era et al, 2005 
Dall'Era MC, Cardarelli PM, Preston BT, Witte A, Davis Jr, JC. Type I Interferon correlates 
with clinical and serologic manifestations of systemic lupus erythematosus. Ann Rheum Dis. 
2005; 64:1692-1697. 
Dall’Era et al, 2011 
Dall’Era M, Stone D, Levesque V, Cisternas M, Wofsy D. Identification of biomarkers that 
predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse 
cyclophosphamide. Arthritis Care Res. 2011;63(3):351-357. 
Dall’Era et al, 2015 
Dall’Era M, Cisternas M, Smilek D, Straub L, Houssiau F, Cervera R, et al. Predictors of 
long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus 
Nephritis cohort. Arthritis Rheumatol. 2015 [Epub ahead of print]. 
Fairhurst et al 2008 
Fairhurst AM, Mathian A, Connolly JE, Wang A, Gray HF, George TA, et al. Systemic IFN 
alpha drives kidney nephritis in B6.Sle123 mice. Eur J Immunol. 2008;38(7):1948-1960. 
Feng 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):2951-2962. 
Furie et al, 2014 
Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL, et al. Efficacy and 
safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. 
Arthritis Rheumatol. 2014;66(2):379-389. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
188 (231) 
Furst et al, 2013 
Furst DE, Clarke A, Fernandes AW, Bancroft T, Gajria K, Greth W et al. Medical costs and 
healthcare resource use in patients with lupus nephritis and neuropsychiatric lupus in an 
insured population. J Med Econ. 2013;16(4):500-509. 
Hahn et al, 2012 
Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, et al. 
American College of Rheumatology guidelines for screening, treatment and management of 
lupus nephritis. Arthritis Care Res. 2012; 64(6):797-808.  
Isenberg et al, 2010 
Isenberg, D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, et al. Influence of 
race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology. 
2010;49(1):128-140. 
Jørgensen et al, 2007 
Jørgensen TN, McKee A, Wang M, Kushnir E, White J, Refaeli Y, et al. Type I interferon 
signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and 
(B6.Nba2 × NZW)F(1) mice. Genes Immun. 2007;8(8):653-662. 
Kirou et al, 2005 
Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK. Activation of the 
interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with 
distinct serologic features and active disease. Arthritis Rheum. 2005;52(5):1491-1503. 
Korbet et al, 2013 
Korbet SM, Lewis EJ. Severe lupus nephritis: the predictive value of ≥50% reduction in 
proteinuria at 6 months. Nephrol Dial Transplant. 2013;28:2313-2318. 
Landolt-Marticorena et al, 2009 
Landolt-Marticorena C, Bonventi G, Lubovich A, Ferguson C, Unnithan T, Su J, et al. Lack of 
association between the interferon-alpha signature and longitudinal changes in disease activity 
in systemic lupus erythematosus. Ann Rheum Dis 2009;68(9):1440-1446. 
Li et al, 2009 
Li T, Carls GS, Panopalis P, Wang S, Gibson TB, Goetzel RZ. Long-term medical costs and 
resource utilization in systemic lupus erythematosus and lupus nephritis: a five-year analysis 
of a large Medicaid population. Arthritis and Rheum. 2009;61(6):755-763. 
Li et al, 2012 
Li X, Ren H, Zhang Q, Zhang W, Wu X, Xu Y et al. Mycophenolate mofetil or tacrolimus 
compared with intravenous cyclophosphamide in the induction treatment for active lupus 
nephritis. Nephrol Dial Transplant. 2012;27:1467-1472. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
189 (231) 
Liu et al, 2011 
Liu Z, Bethunaickan R, Huang W, Lodhi U, Solano I, Madaio MP, et al. Interferon-α 
accelerates murine systemic lupus erythematosus in a T cell-dependent manner. Arthritis 
Rheum. 2011;63(1):219-229. 
Manoharan et al, 2010 
Manoharan A, Madaio MP. Biomarkers in lupus nephritis. Rheum Dis Clin North Am. 
2010;36(1):131-143. 
Mathian et al, 2005 
Mathian A, Weinberg A, Gallegos M, Banchereau J, Koutouzov S. IFN-α induces early lethal 
lupus in preautoimmune (New Zealand Black X New Zealand White) F1 but not in BALB/c 
Mice. J Immunol. 2005;174:2499-2506. 
Mok et al, 2013 
Mok CC, Kwok RCL, Yip PSF. Effect of renal disease on the standardized mortality ratio and 
life expectancy of patients with systemic lupus erythematosus. Arthritis and Rheum. 
2013;65(8):2154-2160. 
Mulic-Bacic et al, 2008 
Mulic-Bacic S, Antic D, Krizic M, Hajdarovic A, Mulic E. Mycophenolate mofetil or 
intravenous cyclophosphamide in treatment of lupus nephritis. An Rheum Dis. 2008;67(Suppl 
II):349. 
Nacionales et al, 2007 
Nacionales DC, Kelly-Scumpia KM, Lee PY, Weinstein JS, Lyons R, Sobel E, et al. 
Deficiency of the type I interferon receptor protects mice from experimental lupus. Arthritis 
Rheum. 2007;56(11):3770-3783. 
Ong et al, 2005 
Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R, et al. Randomized controlled 
trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction 
therapy of proliferative lupus nephritis. Nephrology. 2005;10:504-510. 
Pelletier et al, 2009 
Pelletier EM, Ogale S, Yu E, Brunetta P, Garg J. Economic outcomes in patients diagnosed 
with systemic lupus erythematosus with versus without lupus nephritis: results from an 
analysis of data from a US Claims database. Clin Therapeutics. 2009;31(11):2653-2664. 
Peterson et al, 2004 
Peterson KS, Huang JF, Zhu J, D’Agati V, Liu X, Miller N, et al. Characterization of 
heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of 
laser-captured glomeruli. J Clin Invest. 2004;113(12):1722-1733. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
190 (231) 
Posner et al, 2007 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s Pediatric 
Suicidal Risk Analysis of Antidepressants Am J Psychiatry 2007; 164(7):1035-1043. 
Radhakrishnan et al, 2012 
Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading 
between the (guide)lines - application to the individual patient. Kidney Intl. 2012;82:840-856. 
Rahman and Isenberg, 2008  
Rahman A, Isenberg DA. Mechanisms of disease: systemic lupus erythematosus. N Engl J 
Med. 2008; 358(9):929-939. 
Rönnblom and Alm, 2003 
Rönnblom L, Alm GV. Systemic lupus erythematosus and the type I interferon system. 
Arthritis Res Ther. 2003;5:68-75. 
Sampson et al, 2006 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-second 
National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol. 2006;117(2):391-397. 
Santiago-Raber et al, 2003 
Santiago-Raber M-L, Baccala R, Haraldsson KM, Choubey D, Stewart TA, Kono DH, et al. 
Type I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med. 
2003;197:777-788. 
Schwartz et al, 2009 
Schwartz N, Rubinstein T, Burkly LC, Collins CE, Blanco I, Su L, et al. Urinary TWEAK as a 
biomarker of lupus nephritis: a multicenter cohort study. Arthritis Res Ther. 2009;11(5):R143. 
Touma et al, 2010 
Touma Z, Urowitz MB, Gladmann DD. SLEDAI-2K for a 30-day window. Lupus. 
2010;19:49-50. 
Triantafyllopoulou et al, 2010 
Triantafyllopoulou A, Franzke CW, Seshan SV, Perino G, Kalliolias GD, Ramanujam M, et 
al. Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by 
type I interferons and macrophages. Proc Natl Acad Sci USA. 2010;107(7):3012-3017. 
Tucci et al, 2008 
Tucci M, Quatraro C, Lombardi L, Pellegrino C, Dammacco F, Silvestris F. Glomerular 
accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. 
Arthritis Rheum. 2008;58(1):251-262. 


Clinical Study Protocol 
Drug Substance Anifrolumab  
Study Code D3461C00007 
Version 4.0 
Date 13 December 2017 
 
191 (231) 
US FDA, June 2010 
Guidance for Industry. Systemic Lupus Erythematosus-Developing Medical Products for 
Treatment. June 2010. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/ucm072063.pdf, accessed on 05 March 2015. 
World Health Organisation, 2014 
World Health Organisation. Definitions and reporting framework for tuberculosis – 2013 
revision (updated December 2014). Available at: 
http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf, accessed on 05 
March 2015. 
 


Document Name: 
                                                                    
 
Document Title: 
                                                                                                    
                                                                                                                                      
                                                                                                                                 
                                                                                                                                             
                                                                                                                  
 
Document ID: 
                                                                                   
 
Version Label: 
 
                  
 
 
 
 
 
 
 
     
            
                                          
              
 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
Signed By 
Meaning of Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.  
d3461c00007-csp-4
D3461C00007 Clinical Study Protocol Version 4
1.0
Approved
CURRENT
LATEST
14-Dec-2017 20:08 GMT+0000
Clinical Operations
Approval
15-Dec-2017 12:58 GMT+0000
Medical Monitor
Approval
15-Dec-2017 13:09 GMT+0000
Biostatistics Approval
15-Dec-2017 14:05 GMT+0000
Clinical Approval
CCI
PPD
PPD
PPD
PPD

SAP_001.pdf: 
• Protocol number: D3461C00007 
• Document title: A Multicentre, Randomised, Double-blind, Placebo controlled, 
Phase 2 Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects with 
Active Proliferative Lupus Nephritis 
• NCT number: NCT02547922 
• Version number:  5.0 
• Date of the document:  24 March 2020 


Statistical Analysis Plan
Study Code
D3461C00007
Edition Number
5.0
Date
24 March 2020
A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 2 
Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects 
with Active Proliferative Lupus Nephritis


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
2
TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
TABLE OF CONTENTS.....................................................................................2
LIST OF ABBREVIATIONS ..............................................................................7
AMENDMENT HISTORY................................................................................ 10
1
STUDY DETAILS............................................................................................. 17
Study objectives................................................................................................. 17
Primary objective............................................................................................... 17
Secondary objectives.......................................................................................... 17
Safety objective.................................................................................................. 17
Exploratory objectives ....................................................................................... 18
Study design ...................................................................................................... 22
Standard of care immunosuppressive treatment for lupus nephritis..................... 24
Oral corticosteroid burst and taper...................................................................... 25
Protocol-specified oral corticosteroid tapering for the double-blind 
treatment period ................................................................................................. 25
Management of oral corticosteroids during the second year extension 
period................................................................................................................. 26
Discontinuation of IP ......................................................................................... 26
Number of subjects ............................................................................................ 29
2
ANALYSIS SETS ............................................................................................. 30
Definition of analysis sets .................................................................................. 30
All subjects analysis set...................................................................................... 30
Full analysis set.................................................................................................. 30
Pharmacokinetic analysis set.............................................................................. 30
Violations and deviations ................................................................................... 30
3
PRIMARY AND SECONDARY VARIABLES................................................. 31
Primary outcome variable .................................................................................. 31
Secondary outcome variables ............................................................................. 32
Complete renal response .................................................................................... 32
Exploratory outcome variables........................................................................... 33
............................................ 33
............................................................................. 33
................................... 33
......................................................................... 33
Alternative complete renal response................................................................... 34
Graded alternative complete renal response........................................................ 34
Sustained reduction of oral corticosteroid dose................................................... 34
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
3
 
........................................................................................................ 36
.................................................................... 36
 
.......................................................................................... 36
......................................................................................................... 38
 
............................................................................................................... 39
Spot urine protein to creatinine ratio................................................................... 40
SLEDAI-2K....................................................................................................... 40
Non-renal SLEDAI-2K ...................................................................................... 41
Physician Global Assessment............................................................................. 41
SLICC/ACR Damage Index............................................................................... 41
Subject reported outcome variables.................................................................... 41
Patient Global Assessment ................................................................................. 41
Assessment of study population ......................................................................... 42
Demographic and baseline characteristic variables ............................................. 42
Stratification factors at randomisation ................................................................ 42
Surgical and medical history .............................................................................. 42
Prior and concomitant medications..................................................................... 42
Exposure of IP ................................................................................................... 43
Safety variables.................................................................................................. 43
Adverse events................................................................................................... 43
3.6.1.1
Other significant adverse events......................................................................... 46
3.6.1.2
Adverse events of special interest....................................................................... 46
Laboratory variables .......................................................................................... 46
Electrocardiograms ............................................................................................ 47
SLEDAI-2K-based flare assessment instrument ................................................. 47
Physical examination ......................................................................................... 48
Vital signs.......................................................................................................... 48
Cushingoid features............................................................................................ 49
Tuberculosis monitoring and questionnaire ........................................................ 49
C-SSRS.............................................................................................................. 50
Personal Health Questionnaire Depression Scale-8............................................. 51
Pharmacokinetics, pharmacodynamics, and immunogenicity.............................. 51
Immunogenicity variables .................................................................................. 51
Pharmacokinetic variables.................................................................................. 52
Pharmacodynamic outcome variables................................................................. 53
Lupus Serology variables ................................................................................... 53
4
ANALYSIS METHODS.................................................................................... 53
General principles .............................................................................................. 53
Visit windows.................................................................................................... 53
Statistical testing................................................................................................ 55
CCI
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
4
Presentation of results ........................................................................................ 57
Missing data....................................................................................................... 57
4.1.4.1
Observed case .................................................................................................... 58
4.1.4.2
Last observation carried forward ........................................................................ 59
4.1.4.3
Non-responder imputation.................................................................................. 59
Sensitivity analysis............................................................................................. 60
Examination of model assumptions .................................................................... 60
.............................................................................. 60
Analysis methods............................................................................................... 60
Analysis of the primary variable......................................................................... 60
Analysis of the secondary variable ..................................................................... 62
Analysis methods for exploratory outcome variables.......................................... 65
4.2.3.1
............................................ 65
4.2.3.2
............................................................................ 66
4.2.3.3
Oral corticosteroid management......................................................................... 66
4.2.3.4
Renal response modified to include oral corticosteroid tapering 
requirement........................................................................................................ 67
4.2.3.5
.................................................................... 67
4.2.3.6
 
.......................................................................................... 68
4.2.3.7
......................................................................................................... 68
4.2.3.8
 
............................................................................................................... 68
4.2.3.9
................................................................... 69
4.2.3.10
SLEDAI-2K....................................................................................................... 69
4.2.3.11
Non-renal SLEDAI-2K ...................................................................................... 69
4.2.3.12
Physician global assessment............................................................................... 69
4.2.3.13
SLICC/ACR Damage Index............................................................................... 69
Subject reported outcome variables.................................................................... 69
4.2.4.1
Patient Global Assessment ................................................................................. 69
Presentation of study population......................................................................... 70
4.2.5.1
Subject disposition............................................................................................. 70
4.2.5.2
Demographic and baseline characteristics .......................................................... 71
4.2.5.3
Exposure............................................................................................................ 71
Analysis methods for safety variables................................................................. 72
4.2.6.1
Adverse Events .................................................................................................. 72
4.2.6.2
Laboratory variables .......................................................................................... 74
4.2.6.3
ECGs ................................................................................................................. 75
4.2.6.4
SLEDAI-2K-based flare assessment instrument ................................................. 75
4.2.6.5
Vital signs.......................................................................................................... 75
4.2.6.6
Cushingoid features............................................................................................ 75
4.2.6.7
C-SSRS.............................................................................................................. 76
4.2.6.8
Personal Health Questionnaire Depression Scale-8............................................. 76
Analysis methods for pharmacokinetics, pharmacodynamics, and 
immunogenicity ................................................................................................. 76
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
5
4.2.7.1
Analysis methods for immunogenicity variables ................................................ 76
4.2.7.2
Analysis methods for pharmacokinetic variables ................................................ 77
4.2.7.3
Analysis methods for pharmacodynamic and lupus serology variables ............... 77
Subgroup analysis .............................................................................................. 78
5
INTERIM ANALYSES ..................................................................................... 80
Potential Interim analysis for futility .................................................................. 80
Potential Interim analysis for efficacy ................................................................ 81
6
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 82
7
REFERENCES .................................................................................................. 83
8
APPENDICES................................................................................................... 84
 
 
 
 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
6
LIST OF TABLES
Table 1
National Institutes of Health version of activity and chronicity 
indices...................................................................................................40
Table 2
Visit windows .......................................................................................53
Table 3
Overview of subgroup analyses at Week 24 ..........................................79
Table 4
Overview of subgroup analyses at Week 52 ..........................................79
Table 5
Overview of subgroup analyses at Week 104 ........................................79


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
aCRR
Alternative Complete Renal Response
ACEI
Angiotensin-converting-enzyme inhibitor
ADA
Anti-drug antibodies
AE
Adverse event
AESI
Adverse event of special interest
AIFA
Italian Medicine Agency
ALP
Alkaline phosphatase 
ALT
Alanine transaminase
ANA
Antinuclear antibody
ARB
Angiotensin II receptor blockers
AST
Aspartate transaminase
AUC
Area under the curve
BDR
Blind data review/Blind delivery review
BMI
Body mass index
C-SSRS
Columbia–Suicide Severity Rating Scale
C3
Third component of complement
C4
Fourth component of complement
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CPP
Comité de Protection des Personnes
CRR
Complete Renal Response
CSR
Clinical Study Report
CVA
Cerebrovascular accident 
dsDNA
Double-stranded deoxyribonucleic acid
DMPK
Drug metabolism and pharmacokinetics
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture 
eGFR
Estimated Glomerular Filtration Rate
GGT
Gamma glutamyl transferase


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
8
Abbreviation or 
special term
Explanation
hpf
high power field
ICF
Informed consent form
IFN
Interferon
Ig
Immunoglobulin
IM
Intra-muscular
ISN
International Society of Nephrology
IV
Intravenous
kg
kilograms
LTB
Latent tuberculosis
LTE
Long-term extension
m
metre
MACE
Major adverse cardiovascular events
MAD
Median absolute deviation
MDRD
Modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
min
minute
mITT
Modified intent-to-treat
mL
millilitres
MMF
Mycophenolate mofetil
mmHg
millimetres of mercury
MMRM
Mixed model for repeated measures
MPA
Mycophenolic acid
ms
milliseconds
nAb
Neutralising antibodies
NSAID
Non-steroidal anti-inflammatory drug
LN
Lupus Nephritis
OAE
Other significant AE
OCS
Oral corticosteroids
PD
Pharmacodynamic
PGA
Physician’s Global Assessment


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
9
Abbreviation or 
special term
Explanation
PHQ-8
Personal Health Questionnaire Depression Scale-8
PK
Pharmacokinetic(s)
PRR
Partial Renal Response
PtGA
Patient Global Assessment
Q
Question
Q-Q
Quartile-quartile
Q4W
Every 4 weeks
QTcB
QTc with Bazett’s formula
RBC
Red blood cell
RPS
Renal Pathology Society
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis system
SD
Standard deviation
SDI
Systemic Lupus International Collaborating Clinics (SLICC)/American 
College of Rheumatology (ACR) Damage Index
SI
Internal system of units
SLE
Systemic lupus erythematosus
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000
SOC
Standard of care
TB
Tuberculosis
TELVC
Treatment emergent laboratory/vital signs changes
ULN
Upper limit of normal
UPCR
Urine protein to creatinine ratio
VAS
Visual analogue scale
WHO
World Health Organisation


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
10
AMENDMENT HISTORY
Date
Brief description of change
18 Mar 2020
Version 5.0
Updated Statistical Analysis Plan (SAP) as follows:

Clarified that the “while on treatment” estimand includes data up to and 
including date of IP discontinuation, and if IP has not been reported as 
prematurely discontinued, available data up to and included Week 104 
will be used for continuous endpoint analyses. Otherwise, the date of IP 
discontinuation will be determined as the date of last IP administration. 
However, all subjects who have an infusion of IP within the Week 48 
analysis visit window will be determined to have completed treatment in 
the double-blind treatment period, and their Week 52 data will be
included in the analyses.

Clarification surrounding the Week 52 exemption of non-responder 
imputation due to discontinuation of IP was added.

Added table for programmatically identifying prohibited medications to 
Appendix A. 

Added numbering and clarifications, including some rewording, for 
restricted medication rules in Appendix B.

Specified the calculation to be used for Cochran-Mantel-Haenszel 
(CMH) p-values.

Added explanatory text for the time to achieve 24-hour UPCR ≤ 0.7 
mg/mg and time to achieve CRR variables in Section 3.1 and 3.2.1 
respectively. 

Clarification added that the tipping point analyses for CRR and sustained 
OCS response will only be statistically interpreted for a treatment 
comparison and visit if the nominal p-value for the treatment comparison 
from the main analysis of the endpoint at the specified visit is <0.05 (in 
favour of anifrolumab).

Added clarification that the “percent suppression of fold change” will be 
presented as the “percent of baseline IFN21 PD signature” in all 
summaries, figures and listings.

Updated all time to event variable censoring definitions to remove date 
of restricted medication, and to specify what date is used for censoring in 
the case of discontinuation of IP, depending on when the last dose if IP 
was received, and for subjects completing treatment. Flare exposure time 
was updated similarly.

Shift tables of changes in renal biopsy ISN/RPS classification from first 
to second years have been removed due to no renal biopsies being 
peformed in the second year.

The table summarising disallowed medications has been split into “on 
IP” and “off IP”. 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
11
Date
Brief description of change

 
 

During the blind delivery review (BDR; initiated 05 Feb 2020), it has 
been identified that the use of body weight-based (mg/kg) maximal daily 
oral corticosteroid (OCS) dose for classifying patients as non-responders
when receiving any OCS dose >0.5 mg/kg/day is considered to be too 
stringent and clinically inappropriate for the following reasons:
o
These marginally higher doses per body weight are very unlikely 
to be clinically meaningful and are not thought to confound the 
renal efficacy assessments, especially since additional
intravenous (IV) corticosteroid pulses up to 0.5 g are allowed 
early in study and these IV doses are not body weight-based and 
by far exceed 0.5 mg/kg/day threshold used for OCS.
o
Body weight often varies over time especially in patients with 
active renal disease and on corticosteroid treatment. Even minor 
changes in body weight can result in OCS dose exceeding the 
threshold at fluctuating time points.
o
For practical reasons the OCS dose must be rounded and 
adjusted to available strengths of OCS pills with risk of 
exceeding the threshold even if only slightly rounded upwards.
o
Using body weight to guide OCS dosing is commonly used as a 
rule of thumb in clinical practice, but exact calculations are 
rarely performed and as mentioned doses are commonly rounded 
to match available strengths of eg prednisolone pills.
Consequently, this specific threshold (>0.5 mg/kg/day) was removed 
from the following rule: Prednisone-equivalent >0.5 mg/kg/day or >40 
mg/day for 2 or more consecutive days after Day 1.
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
12
Date
Brief description of change
20 Mar 2019
Version 4.0
SAP to include updates to the restricted medications, non-responder rules and the 
interim analysis.
Interim analysis
Text was added to explain that the possible interim analysis will be either 
efficacy or futility, dependent on the results of a pivotal Phase 3 SLE study in 
anifrolumab. Non-binding stopping rules for the possible futility analysis have 
been included. 
Changes to statistical analysis
The method used to manage strata with low counts for the CMH analyses has 
been clarified and updated.
MedImmune will no longer be calculating the type I IFN 21-gene signature
parameters. Instructions on how to calculate these have been added to the SAP
Other changes
Medication beyond the protocol-allowed threshold and responder/non-responder 
criteria have been clarified in separate appendices (Appendix A and Appendix B, 
respectively). 
P-values will be presented to 4 decimal places.
The estimand for all continuous endpoints (including the primary endpoint) is 
changing to the “while on treatment strategy” from the “treatment policy 
strategy”.  The “while on treatment strategy” uses data up to Investigational 
Product (IP) discontinuation. The “treatment policy strategy” uses all collected 
data, irrespective of whether a subject discontinued IP or not. This change aims 
to deal with the risk of bias due to rescue medications after IP discontinuation. 
The sensitivity analysis will be changed to follow the “treatment policy 
strategy”.
The definition of oral corticosteroids at baseline has been updated.
OCS subgroup thresholds have been changed from (≤20 mg/day, >20 mg/day) to 
(<20 mg/day, ≥20 mg/day)


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
13
Date
Brief description of change
12 Feb 2018
Version 3.0
Updated SAP in line with Global Protocol Amendment 4, as follows:
The renal function and proteinuria components of renal response criteria 
was modified by changing the estimated glomerular filtration rate (eGFR) 
and 24-hour urine protein to creatinine ratio (UPCR) cut-off values.
For complete renal response (CRR), the alternative complete renal response 
(aCRR), the partial renal response (PRR), graded CRR, and graded aCRR, the 
cut-off values for the renal function (eGFR) was changed to: 

eGFR to ≥60 mL/min/1.73m2 or no confirmed decrease of eGFR from 
baseline of ≥20% 
For CRR and aCRR, the cut-off value for proteinuria (24-hour UPCR) was 
changed to:

24-hour UPCR to ≤0.7 mg/mg 
For graded CRR and graded aCRR, the cut-off values for proteinuria was 
changed to:

For subjects with baseline 24-hour UPCR of >3 mg/mg 24-hour UPCR 
cut-off was changed to ≤1 mg/mg

For subjects with baseline 24-hour UPCR of ≤3 mg/mg 24-hour UPCR 
cut-off was changed to ≤0.7 mg/mg
The flare definition for proteinuria (UPCR) was changed to >1.5 mg/mg.
Changes to objectives
aCRR and 24-hour UPCR were added as exploratory objectives at Week 104. 
Clarification was added that International Society of Nephrology (ISN)/Renal 
Pathology Society (RPS) classification and National Institute of Health (NIH) 
indices were also summarised based on CRR and PRR at Week 104.
Interim analysis
Text was added that an interim analysis may be performed after approximately 
50% of subjects have completed the Week 52 visit. 
 
 The statistical analysis plan (SAP) v1.0 
was completed and the last SAP amendment will be completed prior to 
unblinding of data.
 
 
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
14
Date
Brief description of change
Changes to statistical analysis
Text was added that strong control of the familywise error rate will be performed 
for the primary and secondary endpoints for the pooled anifrolumab group 
compared with placebo as well as the respective tests for the individual 
anifrolumab regimens and the testing strategy to account for multiplicity 
considerations has been described. The power and minimal detectable difference 
was updated based on the primary endpoint for the pooled anifrolumab group 
compared with placebo. The sample size will provide approximately 86% power 
with a 2-sided alpha of 0.049.

Text was added that the primary and secondary endpoints are based on 
the pooled anifrolumab group compared with the placebo group.

One additional subgroup; eGFR at baseline (<60 mL/min/1.73m2, ≥60 
mL/min/1.73m2) has been added. The geographic region subgroup has 
been renamed placebo response region.

The age subgroups were changed to ≥18 to 64 and ≥65 years.

It has been clarified that all personnel involved in the conduct of the 
study will remain blinded until database soft lock.
It has been clarified that nominal p-values can be presented for endpoints not 
included in the strategy for preserving type 1 error rate.
Other changes
It has been clarified that no increase in OCS, or the use of IV, intra-articular, 
tendon sheath or bursal injections is allowed from Week 40 until Week 52 
assessment.
Criteria for discontinuing IP at Week 52, Week 56 or Week 60 has been
included.
Assessment for 24-hour UPCR should be completed for subjects who 
discontinue IP.
Randomised subjects who receive anti-malarial therapy within 12 months prior 
to signing ICF must have an eye exam by a qualified professional within 12 
months prior to signing the ICF and that subjects starting anti-malarial therapy 
during the Screening Period must have an eye exam within 12 weeks after 
signing the ICF.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
15
Date
Brief description of change
12 Apr 2017
Version 2.0
Updated Statistical Analysis Plan (SAP) in line with Global Protocol 
Amendments 1 and 2, as follows:

Text was added to clarify that stratification sample for 24-hour urine 
protein to creatinine ratio (UPCR) can be obtained within 14 days prior 
to the expected date of randomisation. Without the results of this second 
(stratification) sample, subjects cannot be randomised. Turn-around time 
for results from central laboratory is up to 7 days. On rare occasion an 
extension of the 30-day screening window is allowed if the re-collection 
of the sample is necessary or the results needed for randomisation are 
delayed.

An error noted in relation to the duration of administration (first “12 
weeks” instead of first “3 doses of the investigational product”) has been 
corrected throughout the SAP.

The abbreviation “SFI” has been deleted throughout the SAP. The term 
SFI has been replaced by the term “SLEDAI-2K based Flare Assessment 
Instrument”

The outcome measure to evaluate the safety and tolerability of 
anifrolumab has been updated as “extra-renal flares using Systemic 
Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) based 
Flare Assessment Instrument”.

For the exploratory objectives, the criteria to determine improvement in 
24-hour UPCR for subjects with a baseline UPCR >3 mg/mg has been 
updated as >50% improvement from baseline and ≤3.0 mg/mg 
(previously <3.0).

A note has been added to clarify that MMF will be supplied by the 
Sponsor to the subjects from the day of randomisation onwards until the 
end of subject’s participation in the study. 

The criteria for discontinuing investigational product at any time have 
been updated to include: receipt >1 methylprednisolone pulse after the 
day of randomisation, receipt of any methylprednisolone pulse after 
Week 8, discontinuation of MMF and initiation of another 
immunosuppressant. In addition, text was added to clarify that decrease 
in eGFR is to be based on two independent samples.

The criteria for discontinuing investigational product at Week 12 and 
Week 24 have been revised to clarify the wording on oral corticosteroid 
and that decrease is eGFR is to be based on two independent samples. 
Cut-off values for nephrotic range UPCR have been aligned with that of 
UPCR values for stratification.

The minimum dose of MMF has been updated from ≤1.5 gm/day to ≤1.0 
gm/day.

Danazol, dapsone, sulfasalazine, and prednisolone have been removed 
from the list of restricted medications.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
16
Date
Brief description of change

Text was added to clarify the study design of the second year extension 
period. Eligible subjects enrolled in the original Phase 2 study will 
continue in their randomised treatment groups. The treatment groups will 
continue to receive investigational product infusions (anifrolumab 300 
mg or placebo) every 4 weeks (Q4W) starting at Week 52 for an 
additional 48 weeks in addition to standard of care (SOC) until Week 
100. Final efficacy assessment will be made at Week 104. Safety follow-
up will continue Q4W until Week 112.

Criteria for discontinuation of investigational product at Week 52 were 
added.

Criteria for discontinuation of investigational product during the second 
year extension period were added.

 
.

 

 

 

Two new subgroups were added: ADA (positive at any time, negative), 
and OCS dose at baseline (≤20 mg/day, >20 mg/day)
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
17
1
STUDY DETAILS
Study objectives
Primary objective
Primary Objective:
Outcome Measure:
To evaluate the efficacy of anifrolumab plus 
standard of care (SOCa) compared with
placebo plus SOC in subjects with active 
proliferative lupus nephritis (LN) measured 
by the relative difference in change from 
baseline to Week 52 in 24-hour urine protein 
to creatinine ratio (UPCR) 
24-hour UPCR
a Required SOC is described in Section 1.2.1
Secondary objectives
Secondary Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab plus 
SOC compared with placebo plus SOCa on the 
proportion of subjects achieving Complete 
Renal Response (CRR) at Week 52
CRR is defined as meeting all of the following:

Estimated glomerular filtration rate (eGFR) is

≥60 mL/min/1.73m2 or no confirmed 
decrease of eGFR from baseline of ≥20%

24-hour UPCR≤0.7 mg/mg

No discontinuation of investigational product (IP)
or use of restricted medicationb beyond the 
protocol-allowed threshold before assessment
eGFR is based on Modification of Diet in Renal 
Disease (MDRD) formula
a Required SOC is described in Section 1.2.1
b Allowed medication are described in Appendix A and Appendix B
Safety objective
Safety Objective:
Outcome Measures:
To characterise the safety and tolerability of 
anifrolumab
Adverse events (AEs) (including AEs of special 
interest [AESIs]), vital signs, physical examination, 
baseline and End of Treatment 12-lead 
electrocardiograms (ECG), and clinical laboratory 
tests (haematology, clinical chemistry, urinalysis), 
Columbia-Suicide Severity Rating Scale (C-SSRS), 
Personal Health Questionnaire Depression Scale-8
(PHQ-8), extra-renal flares using Systemic Lupus 
Erythematosus Disease Activity Index 2000 
(SLEDAI-2K)-based Flare Assessment Instrument .


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
18
Exploratory objectives
Exploratory Objectives:
Outcome Measures:
To evaluate the effect of anifrolumab plus SOCa
compared with placebo plus SOCa on:
 
 
 
 
 
 
 
 
 
 
 
Proportion of subjects achieving alternative 
CRR (aCRR) at Week 52 (and Week 104)
The difference between the CRR and the 
aCRR is the addition of a criterion regarding 
“inactive urine sediment”
aCRR is defined as meeting all of the following:

eGFR is
-
≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20%

24-hour UPCR ≤0.7 mg/mg

Inactive urine sediment (defined as <10 red 
blood cells [RBC]/hpf)

No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment
eGFR is based on MDRD formula
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
19
 
 
 
 
 
Proportion of subjects meeting Graded aCRR 
at Week 52 (and Week 104)
Graded aCRR is defined as meeting both the 24-hour 
UPCR and eGFR criteria:

A decrease in 24-hour UPCR:

For subjects with baseline UPCR 
>3 mg/mg: UPCR ≤1 mg/mg

For subjects with baseline UPCR 
≤3 mg/mg: UPCR ≤0.7 mg/mg

eGFR:

≥60 mL/min/1.73 m2 or no confirmed 
decrease of eGFR from baseline of ≥20%

Inactive urine sediment (defined as <10 
RBC/hpf)

No discontinuation of IP or use of restricted 
medicationb beyond the protocol allowed 
threshold before assessment
Proportion of subjects able to achieve 
sustained reduction in oral corticosteroids 
(OCS) dose at Week 52 or Week 104 
Sustained reduction of OCS dose:

Week 52: Prednisone-equivalent dose 
≤7.5 mg/day by Week 24 and not exceeding this 
dose through Week 52

Week 104: Prednisone-equivalent dose ≤5.0
mg/day by Week 80 and not exceeding this dose 
through Week 104
and

No discontinuation of IP or use of restricted 
medicationb beyond the protocol-allowed 
threshold before assessment 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
20
Proportion of subjects achieving CRR at 
Week 52 or Week 104 and achieving sustained 
reduction of OCS dose 
CRR (see definition of CRR above)
Sustained reduction of OCS dose (see definition 
above) 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
21
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean change in scores for overall disease 
activity from baseline to Week 52 (and to 
Week 104)
SLEDAI-2K
Mean change in score measures of non-renal 
disease activity from baseline to Week 52 (and 
to Week 104)
Non-renal components of SLEDAI-2K
Mean change in scores for overall disease 
activity from baseline to Week 52 (and to 
Week 104)
Physician Global Assessment (PGA)
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
22
Mean change in the Systemic Lupus 
International Collaborating Clinics/American 
College of Rheumatology (SLICC/ACR) 
Damage Index (SDI) score from baseline to 
Week 52 (and to Week 104)
SDI
Mean change in scores for patient-reported 
health status from baseline to Week 52 (and to 
Week 104)
Patient Global Assessment (PtGA) 
To evaluate the immunogenicity of 
anifrolumab, pharmacokinetics (PK), 
pharmacodynamics (the PK and 
immunogenicity results will be reported in the 
clinical study report)
Anti-drug antibodies (ADA), anifrolumab 
concentration and PK parameters, 21-gene type I 
interferon (IFN) gene signature
To evaluate the pharmacokinetics of 
mycophenolic acid (MPA)
MPA concentration and PK parameters (if applicable)
Mean change in lupus serology from baseline 
to Week 52 (and to Week 104)
Anti-dsDNA antibodies, C3 and C4 complement 
levels
 
 
 
a Required SOC is described in Section 1.2.1
b Allowed medication are described in Appendix A and Appendix B.
cNote: Spot UPCR will be used instead of 24-hour UPCR for the PRR and CRR classification, when 
evaluating time to achieve renal response modified to include OCS tapering requirement as well as for 
the PRR and CRR classification for flare assessment.
Study design
This is a Phase 2, multi-centre, multinational, randomised, double-blind (prior to the primary 
analysis), placebo-controlled study to evaluate the efficacy and safety of two IV treatment 
regimens of anifrolumab versus placebo, while taking protocol-specified SOC treatment with 
mycophenolate mofetil (MMF) and corticosteroids, in subjects with active biopsy-proven 
proliferative LN. The study will be performed in adult subjects, 18 to 70 years of age. The 
study duration is approximately 116 weeks (including screening, treatment and follow-up 
periods) for those subjects who meet the criteria for the second year extension period and 
approximately 64 weeks for those subjects who do not meet the criteria for the second year 
extension period.
In this study, approximately 150 subjects will be randomised in a 1:1:1 ratio to receive one of 
two IV anifrolumab dosing regimens or placebo, which will continue until Week 52, as 
follows:

Basic Regimen: Anifrolumab 300 mg IV Q4W for 13 doses plus SOC or
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
23

Intensified Regimen: Anifrolumab 900 mg IV Q4W for the first 3 doses followed 
by 300 mg IV Q4W for 10 doses plus SOC or 

Placebo: IV Q4W plus SOC
The primary objective will be evaluated at Week 52. After Week 52, eligible subjects will 
continue with their randomised treatment plus SOC until Week 104. Those subjects not 
eligible to continue with treatment based on the Week 52 assessments will complete the 8
weeks of additional safety follow-up to complete involvement in the study.
After all randomised subjects have completed the 52-week double-blind period the database 
will be soft-locked, and the primary analysis will be performed, including the assessment of 
the primary, secondary, exploratory and safety objectives. This analysis will also encompass 
all available data collected after the 52-week time point. At this stage the Sponsor and 
Sponsor’s delegate who are not directly involved in the management of sites will be unblinded 
to randomised treatment, but the subjects and investigators will remain blinded (single-blind). 
The end of study analysis will be performed after all subjects have completed the second year 
extension period, and the database will be locked. One interim analysis may be conducted 
after approximately 80% of subjects have completed the Week 52 visit or would have 
completed if they had not discontinued the study. 
 
 
 
IP will be administered as an IV infusion via an infusion pump over no less than 60 minutes 
for the first 3 doses (Visit 1, 2 and 3). Starting with Visit 4, IP can be administered as an IV 
infusion via an infusion pump over no less than 30 minutes. 
Randomisation will be stratified using two factors:

Results of IFN test at screening using a 4-gene type I IFN test (IFN test-high 
versus IFN test-low)

24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg (based on 24-hour UPCR 
performed on a sample obtained within 14 days prior to the expected date of
randomisation). Without the results of the second (stratification) sample, subjects 
cannot be randomised. Turn-around time for results from central laboratory is up to 
7 days. 
On rare occasion an extension of the 30-day screening window may be allowed if 
re-collection of the 24-hour UPCR or other required samples is necessary or if the results 
needed for randomisation are delayed.
Renal biopsy performed within 12 weeks prior to signing the informed consent form (ICF) or 
during the screening period will be considered as the screening biopsy. Biopsies will be 
evaluated locally and the local classification will be used to confirm the eligibility criteria. 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
24
The biopsy must reveal Class III (±class V) or class IV (±class V) LN according to the World 
Health Organisation (WHO) or 2003 International Society of Nephrology/Renal Pathology 
Society (ISN/RPS) classification. An external renal biopsy adjudication group will adjudicate 
renal biopsies post-randomisation.
The overall study duration is approximately 116 weeks:
A Screening Period: Up to 30 days 
Treatment Period:
The total treatment period is up to 100 weeks (26 doses administered Q4W).
-
52 week double-blind treatment period: IP will be administered Q4W 
from Week 0 to Week 48 for a total of 13 doses. The primary endpoint will
be evaluated at Week 52.
-
Second year extension period: At Week 52, eligible subjects will continue 
treatment with randomised IP (anifrolumab 300 mg or placebo) 
administration Q4W from Week 52 to Week 100 for a total of 13 doses. The 
last efficacy assessments will be performed at Week 104.
Follow-up: After the completion of the last IP treatment (Week 48 for subjects who are not 
participating in the second year extension period and Week 100 for subjects who participate in 
the second year extension period) subjects will continue in the study for another 12 weeks of 
safety follow-up after the last administration of IP.
Standard of care immunosuppressive treatment for lupus nephritis
Standard of care treatment for LN will consist of the combination of MMF and 
corticosteroids.  From the day of randomisation onwards until the end of subject’s 
participation in the study including the second year extension period, MMF will be supplied 
by the Sponsor and Sponsor’s delegate to subjects. The target dose of MMF will be 2 gm/day 
during the first year of the study, where the dose is titrated to the target dose between 
randomisation and not later than Week 8. It is not mandatory for a subject to receive 2 gm/day 
of MMF if local treatment standards dictate a lower dose to be given (e.g., for constitutionally 
small subjects). During the 52-week double-blind treatment period, the minimum dose of 
MMF is 1.0 gm/day between Week 8 and Week 52. Adjustments of the dose due to 
suboptimal response, toxicity, or intolerability are allowed if needed. A maximum dose of 3.0 
gm/day is allowed up to Week 24 for subjects with suboptimal response between Weeks 8 and 
24, which needs to be reduced to ≤2.0 gm/day by Week 32. The dose of MMF has to be stable 
from Week 40 to Week 52.
In the second year, extension period, MMF dose should be ≤2.0 gm/day or ≤Week 52 dose, 
whichever is lower. If MMF dose is > 2.0 gm/day at Week 52, taper to ≤2 gm/day will be 
required by Week 60. Failure to do so will lead to withdrawal from IP. A decrease in MMF 
dose is allowed at the investigator’s discretion between Week 52 to Week 92. The dose of 
MMF must be stable from Week 92 to Week 104. 
Subjects may enter the study taking daily OCS at a maximum dose of 0.5 mg/kg/day of 
prednisone-equivalent not to exceed 40 mg/day. In addition, subjects will receive IV (or oral, 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
25
if applicable) methylprednisolone pulse 500 mg on the day of randomisation, prior to 
receiving the IP, unless they have received a methylprednisolone pulse of ≥500 mg within 10 
days prior to randomisation. Subjects may receive one additional (optional) dose of IV (or 
oral, if applicable) methylprednisolone pulse (≤500 mg) for renal or extra-renal disease 
activity after the Week 0 (Day 1) visit up to and including the Week 8 visit.
Methylprednisolone pulse can be administered on two consecutive days but the cumulative 
dose must not exceed 500 mg.
Details on other medications permitted during the study are given in Appendix A to Appendix 
C.
Oral corticosteroid burst and taper
From randomisation to Week 40, subjects may receive 1 burst of OCS for increased extra 
renal SLE disease activity or for non-SLE activity. Subjects who receive more than 1 burst 
during this time may continue in the study but will be considered non-responders (based on 
the conditions in Appendix B) for subsequent responder analyses (such as CRR), regardless of 
whether the burst was administered for increased SLE or non-SLE activity.  No increase in 
OCS is allowed from Week 40 until Week 52 assessment. One burst and taper is allowed 
between Week 52 and Week 92. Further details are given in Appendix B.
Protocol-specified oral corticosteroid tapering for the double-blind treatment 
period
OCS tapering is required during the study with the goal of tapering OCS to 
prednisone-equivalent of ≤10 mg/day by Week 12 and prednisone-equivalent of ≤7.5 mg/day 
by Week 24.  If subjects experience an increase in SLE disease activity upon tapering of OCS 
their dose may be returned to a dose less than or equal to the dose prior to the taper. The return 
to the pre-taper dose will not be considered an OCS “burst and taper” (see Section 1.2.2). 
Subjects who are unable to taper OCS to ≤15 mg/day at Week 12 or <15 mg/day at Week 24 
will be discontinued from IP treatment. However, subjects who exceed the maximum daily 
OCS dose at the Week 12 or Week 24 visits may continue to receive IP if the current dose is 
part of a protocol allowed temporary OCS dose (e.g., burst and taper) increase. Subjects who 
cannot be returned to their pre-increase dose within 14 days from the start of burst will have 
their investigational product discontinued at the next visit.
The subjects discontinued from IP treatment before Week 48 will be followed until Week 52 
(or for a minimum of 12 weeks after last dose of investigational product for subjects for whom 
IP was discontinued within 12 weeks prior to Week 52).
Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
7.5 mg/day up to Week 40. Steroid tapering will not be permitted between Week 40 and Week 
52. After the Week 52 primary endpoint assessments are completed additional OCS tapering 
can be done.  


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
26
Management of oral corticosteroids during the second year extension period
The following rules apply to OCS during the second year extension period. Further details are 
provided in Appendix B.

If OCS >7.5mg/day at Week 52, tapering to ≤7.5mg/day is required by Week 60. 
Failure to achieve ≤7.5 mg/day by Week 60 will lead to discontinuation from IP.

OCS tapering goal ≤5 mg/day at Week 80. Tapering below 5 mg/day is allowed 
any time until Week 92.

No change in OCS dose will be allowed from Week 92 to Week 104. 

One burst and taper is allowed between Week 52 and Week 92.
Discontinuation of IP
Criteria for discontinuing IP for worsening of LN or SLE (at any time):
Blinded IP will be discontinued in subjects who meet pre-defined criteria for worsening LN or 
SLE. Subjects may receive rescue treatment as clinically indicated. Subjects who had their IP
discontinued will be followed according to the study schedule and should have a 24-hour 
UPCR measurement within 4 weeks of the decision to discontinue IP and before the start of a 
new treatment for LN. These subjects will be followed until Week 52 (or for a minimum of 
12 weeks after last dose of IP for subjects for whom IP was discontinued within 12 weeks 
prior to Week 52). If discontinuation occurs during the second year extension period, subjects 
will be followed until Week 104 (or for a minimum of 12 weeks after last dose of IP for 
subjects for whom IP was discontinued within 12 weeks prior to Week 104).

>30% decrease in eGFR compared to baseline due to LN and eGFR <60 
mL/min/1.73 m2 (on two independent samples) or

Increase in renal or extra renal lupus activity requiring prohibited systemic 
immunosuppressive treatment (e.g. cyclophosphamide, rituximab, 
belimumab)

Receipt of >1 methylprednisolone pulse after the day of randomisation

Receipt of any methylprednisolone pulse after Week 8

The IP will be discontinued if MMF is discontinued and another 
immunosuppressant is initiated
Criteria for discontinuation of IP for worsening of LN or SLE at Week 12 and Week 24:

eGFR <75% of baseline and <60 mL/min/1.73 m2 (on two independent 
samples) or

Nephrotic range UPCR (confirmed by a second measurement at least two 
weeks after the first measurement):


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
27

Subjects with 24-hour UPCR ≤3 mg/mg at baseline will be withdrawn 
if 24-hour UPCR increases by >50% from baseline to >3.5 mg/mg

Subjects with 24-hour UPCR >3 mg/mg at baseline will be withdrawn 
if 24-hour UPCR at Week 24 >3.5 mg/mg and there is <60% 
improvement from baseline or

Inability to adhere to corticosteroids requirements: 

Inability to reduce OCS to ≤15 mg/day prednisone-equivalent at Week 
12

Inability to reduce OCS to <15 mg/day by Week 24
Subjects who exceed the maximum daily OCS dose at the Week 12 or Week 24 visits may 
continue to receive IP if the current dose is part of a temporary increase in OCS dose (e.g., 
protocol-allowed burst and taper). Subjects who cannot be returned to their pre-increase dose 
within 14 days from the start of increase will have their IP discontinued at the next visit.
Criteria for discontinuing IP at Week 52:
Subjects not meeting the criteria to continue for the second year extension period will not 
receive any IP at Week 52 and will complete the study after completing the required follow-up 
visits.
Subjects meeting the following criteria may continue to receive blinded IP between Weeks 52 
and 100.
(i)
Meeting all of the following criteria based on the renal portion of the PRR 
definition:

eGFR is:
-
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from 
baseline of ≥20%

Improvement in 24-hour UPCR:
-
For subjects with a baseline UPCR ≤3 mg/mg: <1.0 mg/mg
-
For subjects with a baseline UPCR >3 mg/mg: >50% 
improvement from baseline and ≤3.0 mg/mg
Renal discontinuation criteria must be confirmed in two separate samples. 
The second measurement should be at least 1 week after the first 
measurement.
(ii)
No discontinuation of IP.
(iii)
Negative HIV test after signed the Main ICF
Criteria for discontinuing IP at Week 52, Week 56 or Week 60:

Failure to obtain Pap smear after Week 48 with result available at Week 60 at latest


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
28

Pap smear result not meeting the eligibility criteria (see Appendix K of the 
Protocol) at Week 52, 56, or 60 of a Pap smear obtained after Week 48

Failure to obtain Week 52 QuantiFERON test result by Week 56
Criteria for discontinuing IP at Week 60 and later:

OCS >7.5 mg/day (except one OCS burst and taper)

MMF >2 gm/day or >Week 52 dose, if Week 52 dose <2 gm/day
Subjects who discontinue the IP during the second year extension period will be followed 
until Week 104 (or for a minimum of 12 weeks after last dose of IP for subjects for whom IP
was discontinued within 12 weeks of Week 104).
Criteria for discontinuation of IP for reasons other than lack of efficacy at any time 
during the study:
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 one of 
the following:
(a)
Subject is unable to comply with protocol-specified visits and/or 
procedures due to conflicts not related to clinical study
(b)
An AE or laboratory abnormality is of concern to the subject, but not 
clinically significant to physician
(c)
The subject is concerned about possibility of receiving placebo or 
ineffective treatment
(d)
Subject wishes to participate in another clinical study
(e)
Subject is interested in taking a treatment that is not allowed in this 
study
(f)
Subject perceives logistics at the clinical site to be unacceptable
(g)
Other reason
2. Lost to follow-up
3. Adverse event that, in the opinion of the Investigator of the Sponsor and Sponsor’s 
delegate/Designee Medical Monitor, contraindicates further dosing with IP
4. Severe non-compliance with the study protocol
5. The Investigator or Sponsor and Sponsor’s delegate/Designee Medical Monitor 
deems withdrawal as being in the subject’s best interest


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
29
6. Pregnancy, positive pregnancy test, or subject expresses an interest in becoming 
pregnant
7. Isolated HBcAb positivity with HBV DNA above the LLOQ confirmed by the 
central laboratory
8. Positive HIV test
9. Receipt of any excluded medications
10. The use of restricted medications if the Sponsor and Sponsor’s delegate/Designee 
Medical Monitor, in consultation with the Sponsor and Sponsor’s delegate, 
determines the subject must be discontinued
11. A diagnosis of active TB, premature discontinuation of treatment for latent TB, or 
noncompliance with latent TB therapy. Note: Duration of treatment for latent TB 
should follow the local practice. If local practice is not defined, then Centers for 
Disease Control and Prevention (CDC) guidance for immunocompromised patients 
should be used.
12. Subject is unblinded by the Investigator 
Additional restrictions related to concomitant medications are discussed in Appendix A and 
Appendix B.
Further details can be found in Section 3.9.4 of the clinical study protocol.
Number of subjects
A total of approximately 150 subjects will be randomised 1:1:1 to receive one of the two IV 
anifrolumab dosing regimens (Basic Regimen or Intensified Regimen) or placebo.
The sample size is based on the following assumptions:

Reductions from baseline to Week 52 in 24-hour UPCR of 65% and 46% for the 
anifrolumab and placebo arms, respectively (i.e., ratios of 24-hours UPCR from 
Week 52 to baseline of 0.35 and 0.54, respectively), based on data presented in 
(Furie R, 2014).

The change from baseline in the log-transformed 24-hour UPCR values follow a 
normal distribution with a standard deviation (SD) of 0.8, based on data from the 
anifrolumab Phase 2b study (CD1013)
Based on these assumptions, a sample size of 50 subjects per arm would result in an observed 
relative difference in the change from baseline to Week 52 in 24-hour UPCR of 0.65 (here 
expressed as the ratio, comparing anifrolumab to placebo), and a corresponding 95% 
confidence interval (CI) of (0.50, 0.85) comparing the pooled anifrolumab group (Basic and 
Intensified) with placebo group. Under the assumption that the interim analysis is performed


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
30
with 120 subjects, a 0.001 2-sided alpha will be spent, and the final analysis will be based on a 
2-sided alpha of 0.0499 (East Version 6.4). If the study is not stopped for futility, this sample 
size provides approximately 87% power for the primary analysis with a 2-sided alpha of 
0.0499 to reject the hypothesis of no effect (relative difference =1) for comparing the pooled 
anifrolumab treatment group with placebo. The minimal detectable relative difference in the 
change from baseline to Week 52 in 24-hour UPCR between the pooled anifrolumab treatment 
group versus placebo is approximately 0.76, corresponding to a reduction from baseline to 
Week 52 in 24-hour UPCR of 59% in the pooled anifrolumab group (ratio of 24-hour UPCR 
from Week 52 to baseline of 0.41).
Based on the above assumptions, if a futility analysis is performed with a boundary for the 
predictive power of 20% and supposing that 120 subjects will be included in the interim 
analysis and 150 subjects at the final analysis, the corresponding treatment effect boundary for 
relative difference in the change from baseline to Week 52 in 24-hour UPCR between the 
pooled anifrolumab treatment group versus placebo will be 0.81. This would result in an 
overall power of 86% (to continue the study after the futility analysis and reject the hypothesis 
of no effect with a 2-sided alpha of 0.0499).
2
ANALYSIS SETS
Definition of analysis sets
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.
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 one dose of IP
and will be analysed according to randomised treatment (modified intent-to-treat [mITT]
principle). Any major deviations from randomised treatment will be listed and considered 
when interpreting the safety data.
Pharmacokinetic analysis set
All subjects who received anifrolumab and who had at least one quantifiable serum PK 
observation post first dose will be included in the PK analysis dataset. All PK summaries will 
be based on this analysis set.
Violations and 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 
summarised.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
31
The final list of protocol deviations will be finalised and documented prior to unblinding the 
study data and will be based on deviations as defined in the study Protocol Deviation 
Specification.
During the blind data review (BDR) meetings, protocol deviations will be classified as 
important or other depending on the impact of the deviation to the analysis and/or the impact 
to subjects. Only important protocol deviations will be listed and tabulated in the Clinical 
Study Report (CSR). All protocol deviations are regularly reviewed per the protocol deviation 
specification document.
3
PRIMARY AND SECONDARY VARIABLES
The baseline is defined as the last measurement prior to Day 1 dose administration. If the 
Day 1 value is missing or is invalid, the latest assessment prior to dose administration on 
Day 1 will serve as baseline.  If only dates (not times) are recorded then if an assessment 
occurs on the same day as Day 1 dose administration, it will be considered to have occurred 
prior to dose administration. 
Baseline OCS dose will be defined as the maximum daily OCS dose taken between Day 1 and
Day 7, inclusive. If no OCS are taken by the subject on Day 1 or on or before Day 7, the 
baseline OCS dose will be 0 mg/day.
If not stated otherwise, change from baseline will be calculated as value at the respective time 
point minus value at baseline. 
MMF at randomisation is defined to be the Day 1 MMF dose. If the Day 1 MMF dose is 
missing, or no MMF is taken by the subject on Day 1, the MMF dose at randomisation will be 
defined as the Day 2 MMF dose.
Renal biopsies will be adjudicated, however any changes in WHO or ISN/RPS classification 
values due to adjudication will only be used for sensitivity analyses to evaluate the 
relationship between biopsy findings and baseline disease activity or response to therapy. For 
all other analyses and summaries, the local classification of WHO or ISN/RPS will be used.
Primary outcome variable
The primary endpoint used to evaluate the effect of anifrolumab compared with placebo on 
LN disease activity is the relative difference in change from baseline to Week 52 in the 
24-hour UPCR.
The time to 24-hour UPCR ≤ 0.7 mg/mg will be analysed as a supportive analysis and will be 
derived for subjects with baseline 24-hour UPCR > 0.7 mg/mg as the date of first 24-hour 
UPCR ≤ 0.7 mg/mg minus the date of first dose of IP.  If the subject did not achieve 24-hour 
UPCR ≤ 0.7 mg/mg, the time to 24-hour UPCR ≤ 0.7 mg/mg will be censored at the earliest of
the following:

Date of withdrawal from the study;


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
32

Discontinuation of IP in case of premature discontinuation of IP where the last IP dose 
is not in the Week 48 analysis visit window;

Date of the Week 52 observation used in analysis (or the date of the last observation 
before Week 52 if the Week 52 observation is missing) in case of premature 
discontinuation of IP where the last IP dose is in the Week 48 analysis visit window;

Date of the Week 104 observation used in analysis (or the date of the last observation 
before Week 104 if the Week 104 observation is missing);

Database extract date.
Secondary outcome variables
Complete renal response
To evaluate the effect of anifrolumab compared with placebo on renal response in LN 
subjects, the proportion of subjects achieving CRR at Week 52 will be used. A subject 
achieves CRR if all of the following criteria are met:

Estimated glomerular filtration rate (eGFR):
-
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from 
baseline of ≥20%

24-hour UPCR ≤0.7 mg/mg

No discontinuation of IP or use of restricted medication beyond the protocol-
allowed threshold before assessment. Allowed restricted medications are
defined in Appendix A and Appendix B.
The time to achieve CRR will be analysed as supportive analysis and will be derived as the 
date of first CRR minus the date of first dose of IP.  If the subject did not achieve CRR, the 
time to achieve CRR will be censored at the earliest of the following:

Date of withdrawal from the study; 

Discontinuation of IP in case of premature discontinuation of IP where the last IP dose 
is not in the Week 48 analysis visit window;

Date of the latest of the Week 52 24-hour UPCR and eGFR observations used in 
analysis (or the date of the latest 24-hour UPCR or eGFR observation before Week 52 
if the Week 52 observations are missing) in case of premature discontinuation of IP 
where the last IP dose is in the Week 48 analysis visit window;

Date of the Week 104 24-hour UPCR and eGFR observations used in analysis (or the 
date of the latest 24-hour UPCR or eGFR observation before Week 104 if the Week 
104 observations are missing);

Database extract date.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
33
Exploratory outcome variables
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
34

 
Alternative complete renal response
To evaluate the effect of anifrolumab compared with placebo on renal response in LN subjects 
when urine sediment is considered in the definition, the proportion of subjects achieving 
aCRR at Week 52 and Week 104 will be used. A subject achieves aCRR if all of the following 
criteria are met:

eGFR:
-
≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline of 
≥20%

24-hour UPCR ≤0.7 mg/mg

Inactive urine sediment (defined as <10 RBC/hpf)

No discontinuation of IP or use of restricted medication beyond the protocol-
allowed threshold before assessment. Allowed restricted medications are defined in
Appendix A and Appendix B.
Graded alternative complete renal response
The effect of anifrolumab compared with placebo on renal response in LN subjects will also 
be further assessed using the difference in proportions of subjects achieving graded aCRR at 
Week 52 and of subjects achieving graded aCRR at Week 104. A subject achieves graded 
aCRR only if all following criteria are met:

A decrease in 24-hour UPCR:

For subjects with baseline UPCR >3 mg/mg: UPCR ≤1 mg/mg

For subjects with baseline UPCR ≤3 mg/mg: UPCR ≤0.7 mg/mg

eGFR:

≥60 mL/min/1.73 m2 or no confirmed decrease of eGFR from baseline of 
≥20%

Inactive urine sediment (defined as <10 RBC/hpf)

No discontinuation of IP or use of restricted medication beyond the protocol 
allowed threshold before assessment. Restricted medications are defined in
Appendix A and Appendix B.
Sustained reduction of oral corticosteroid dose
The effect of anifrolumab compared with placebo on the ability to reduce the OCS dose will 
be assessed in subjects with baseline OCS ≥20mg/day prednisone-equivalent. Sustained 
reduction of OCS dose is assessed using the difference in proportions of subjects meeting all 
the following criteria: 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
35

Achieve an OCS dose of ≤7.5 mg/day prednisone-equivalent by Week 24

Maintain an OCS dose ≤7.5 mg/day prednisone-equivalent from Week 24 to 
Week 52

No discontinuation of IP or use of restricted medication beyond the 
protocol-allowed threshold before assessment.  Allowed restricted medications are 
defined in Appendix A and Appendix B.
The proportion of subjects achieving OCS tapering requirement will also be assessed at Week 
104:

Achieve an OCS dose ≤5.0 mg/day prednisone-equivalent by Week 80

Maintain an OCS dose ≤5.0 mg/day prednisone-equivalent from Week 80 to Week 
104

No discontinuation of IP or use of restricted medication beyond the protocol 
allowed threshold before assessment. Allowed restricted medications are defined in
Appendix A and Appendix B.
The standardised area under the curve (AUC) of OCS dose up to Week 52, up to Week 104, 
and from Week 52 to Week 104 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 for calculating the AUC 
up to Week 52 and up to Week 104. If the start date is before the date of Week 52 (date of 
Visit 14), the date of Visit 14 will be used instead for calculating the AUC from Week 52 to 
Week 104. If the end date is after the date of Week 52 (date of Visit 14) or after the date of 
Week 104 (date of visit 29), the date of Visit 14 and Visit 29 respectively will be used instead 
for calculating the AUC up to Week 52 and Week 104. The AUC for each single dose will be 
derived by the daily dose (mg/day) multiplied with the duration (days). The AUC is the sum 
of the AUCs of the single doses. The AUC of OCS dose will only be calculated if all 
necessary data are available up to Visit 14 (i.e., daily prednisone equivalent OCS dose can be 
calculated) or Visit 29 respectively. For subjects who discontinued IP before Visit 14 or Visit 
29 respectively, the AUC will be calculated up to the date of discontinuation of IP. If a subject 
does not receive any OCS dose (i.e., no corresponding medication documented) the AUC for 
this subject will be set to 0. The standardised AUC will be derived as:

For standardised AUC up to Week 52: AUC divided by the available days (date of 
Visit 14 / date of discontinuation of IP – date of Day 1 + 1) multiplied by 364 (52 
weeks).

For standardised AUC from Week 52 to Week 104: AUC divided by the available 
days (date of Visit 29 / date of discontinuation of IP – date of Visit 14 + 1) 
multiplied by 364 (52 weeks).

For standardised AUC up to Week 104: AUC divided by the available days (date 
of Visit 29 / date of discontinuation of IP – date of Day 1 + 1) multiplied by 728 
(104 weeks).


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
36
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
37
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
38
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
39
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
40
 
 
SLEDAI-2K
The effect of anifrolumab compared with placebo on SLEDAI-2K score will be evaluated 
using the difference in mean change from baseline to Week 52 and to Week 104.
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
41
The SLEDAI-2K assessment (see Appendix F in the clinical study protocol) consists of 24 
lupus-related items. It is a weighted instrument, in which descriptors are multiplied by a 
particular organ’s “weight” and then these are totalled into the final score. The SLEDAI-2K 
score range is 0 to 105 points with 0 indicating inactive disease. The SLEDAI-2K will be 
calculated using a timeframe of 30 days in this study.  
Non-renal SLEDAI-2K
Extra-renal disease activity will be assessed by using the SLEDAI-2K score (as defined in 
Appendix E in the clinical study protocol) without the renal components (“non-renal 
SLEDAI-2K”). The renal components that will not be included for this assessment are 
proteinuria, hematuria, pyuria and urinary casts.  The score range for the non-renal SLEDAI-
2K is therefore 0 to 89 with 0 indicating inactive disease.  The effect of anifrolumab compared 
with placebo on non-renal SLEDAI-2K will be evaluated using the difference in mean change 
from baseline to Week 52 and Week 104.  
Physician Global Assessment
The effect of anifrolumab compared with placebo on PGA will be evaluated using the 
difference in mean change in PGA from baseline to Week 52 and to Week 104. 
PGA is a visual analogue scale (VAS) measuring the physician’s overall assessment of 
average disease severity over the last 4 weeks and ranges from 0 (none) to 3 (severe).
PGA may be completed after the visit, to allow for laboratory results, as long as this is done 
prior to the next scheduled visit. Therefore, the date of the associated scheduled visit (Week 0 
etc.) will be used to determine baseline (and subsequent visits), and not the actual date of the 
assessment.
SLICC/ACR Damage Index
The endpoint used to evaluate the effect of anifrolumab compared with placebo on irreversible 
damage in SLE subjects is the mean change in SDI global score (as defined in Appendix M in 
the clinical study protocol) from baseline to Week 52 and to Week 104. SDI will be listed by 
organ system. 
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.  Damage over time can be stable or increase (but not decrease 
from the baseline value), theoretically to a maximum of 47 points.
Subject reported outcome variables
Patient Global Assessment
The difference between anifrolumab and placebo in the mean change from baseline in PtGA 
to Week 52 and to Week 104 will be assessed.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
42
PtGA is a VAS completed by subjects asking a single-item question “Considering all the ways 
in which illness and health conditions may affect you at this time, please make a mark below 
to show how you are doing”.  The VAS measures from 0 mm (Very Well) to 100 mm (Very 
Poorly).
Assessment of study population
Demographic and baseline characteristic variables
Demographic characteristics (including geographic region [Asia Pacific: Australia, Republic
of Korea, Taiwan; Europe: Belgium, France, Germany, Hungary, Italy, Poland, Russian 
Federation, Serbia, Spain, South Africa, United Kingdom; Latin America: Argentina, Mexico,
Peru; North America: United States], age, sex, ethnicity and race) and baseline characteristics 
(including height, weight, body mass index [BMI] and disease characteristics [including 
SLEDAI-2K, PGA, SLICC/ACR, OCS use, OCS dose, time from LN diagnosis to 
randomisation, 4-gene type I IFN status, antinuclear antibody [ANA], anti-dsDNA, C3, C4, 
24-hour UPCR, spot UPCR, eGFR, inactive urine sediment and MMF dose at randomisation]) 
will be assessed.
Stratification factors at randomisation
Stratification factors are:

Results of IFN test at screening using a 4-gene type I IFN test (high versus low)

24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg (based on 24-hour UPCR performed 
on a sample obtained within 14 days prior to the expected date of randomisation).
Without the results of the second (stratification) sample, subjects cannot be 
randomised. Turn-around time for results from central laboratory is up to 7 days. 
On rare occasion an extension of 30-day screening window may be allowed if the 
re-collection of the 24-hour UPCR or other required samples is necessary or if the results 
needed for randomisation are delayed. The number of subjects in each strata will be 
summarised.
Surgical and medical history
Surgical and medical histories will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Medical history will be evaluated separately for past 
and current conditions as given in the electronic case report form (eCRF).
Prior and concomitant medications
All medications will be coded using the latest version of the WHO Drug Dictionary.
Any medications taken by the subject prior to the first dose date of IP 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 IP up to Week 104, inclusive, will be considered 
concomitant medication. Any medication that started prior to the first dose of IP and ended 
after the first dose up to Week 104 or is ongoing will be considered as both prior and 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
43
concomitant medication.  Medications that start during the follow-up period will only be 
displayed in listings. 
In the case that the end date of a concomitant medication (including sponsor provided MMF) 
is the same as the start date of another record of the same ATC code and same administration 
route, the end date of the record with the earlier start date will be considered to be one day 
earlier than the recorded end date, to avoid double counting of medication use in one day.
If a medication cannot be classified as prior or concomitant due to missing or partial dates, the 
imputation rules as given in Appendix D will be applied. 
Exposure of IP
The duration of exposure to the IP per subject is defined as the number of days between the 
start and the end dates of IP plus the dosing frequency time:
Duration of exposure (days) = (Last dosing date + 28 days) – first dosing date + 1.
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 (i.e. 4 weeks, 8 weeks, 
12 weeks, …, 104 weeks).
The time to discontinuation of IP is the same as the duration of exposure. 
Safety variables
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, C-SSRS (up to Week 52), PHQ-8 (up to Week 
52), SLEDAI-2K based Flare Assessment Instrument, tuberculosis questionnaire, assessment 
of Cushingoid features, assessment of cardiovascular risk (fasting lipid profile) and reported 
AEs (including AESIs).
Any overdose report information collected will be listed only.
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 IP and on or before the subject’s Week 104 visit (Week 52 for C-
SSRS and PHQ-8), or last visit if they withdraw early from the study.  
Adverse events
Adverse events experienced by the subjects will be collected throughout the entire study, 
including the second year extension period, and will be coded using the latest version of 
MedDRA.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
44
Adverse event data will be categorised 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 the 
screening visit and date and time of onset < date and time of the first dose of IP.
AEs occurring during screening will only be listed.

AEs occurring during treatment:
An AE during treatment is defined as an AE with a date and time of onset ≥ date and 
time of first dose of IP and ≤ date of last dose of IP + 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 
IP + 28 days and ≤ date of last dose of IP + 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 
IP + 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 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 acute AE is defined as an AE with a date of onset on any day of administration of IP and a 
time of onset on or after the start of administration of IP or a date of onset occurring on the 
subsequent day. If an AE has a missing onset date, then unless the stop date of the AE 
indicates otherwise, this will be considered as an acute AE. Similarly, if an AE has a partial 
onset date, then unless the partial onset date or the stop date indicates otherwise, this will be 
considered acute AE.
Adverse events during treatment will also be presented by time intervals of the first onset of 
the event. For this analysis, repeated events with the same preferred term will not be 
considered (i.e. if a subject has more than one event with the same preferred term, only the 
event with the earliest date of onset will be used). For partial or missing dates, the rules as 
described above will be used. The following time intervals (defined as exact weeks, 
independent of the study visits and with no visit windowing) are defined:

Day 1 to < Week 12:
AEs with date of onset ≥ date of first administration of IP and < date of first 
administration of IP plus 84 days


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
45

Week 12 to < Week 24:
AEs with date of onset ≥ date of first administration of IP plus 84 days and < 
date of first administration of IP plus 168 days

Week 24 to < Week 36:
AEs with date of onset ≥ date of first administration of IP plus 168 days and < 
date of first administration of IP plus 252 days

Week 36 to < Week 48:
AEs with date of onset ≥ date of first administration of IP plus 252 days and < 
date of first administration of IP plus 336 days

Week 48 to < Week 60:
AEs with date of onset ≥ date of first administration of IP plus 336 days and < 
date of first administration of IP plus 420 days

Week 60 to < Week 72:
AEs with date of onset ≥ date of first administration of IP plus 420 days and < 
date of first administration of IP plus 504 days

Week 72 to < Week 84:
AEs with date of onset ≥ date of first administration of IP plus 504 days and < 
date of first administration of IP plus 588 days

Week 84 to < Week 96:
AEs with date of onset ≥ date of first administration of IP plus 588 days and < 
date of first administration of IP plus 672 days

Week 96 to < Week 100:
AEs with date of onset ≥ date of first administration of IP plus 672 days and < 
date of first administration of IP plus 756 days

≥ Week 100:
AEs with date of onset ≥ date of first administration of IP plus 756 days
The event rate per 100 subject years is defined as the number of subjects with an event divided 
by the sum of exposure time in days (e.g. date of last dose of IP + 28 days - day of first dose 
of IP + 1 day for summary of AEs during treatment) for all subjects in the analysis set 
multiplied by 365.25 days/year multiplied by 100.
The time to first onset of herpes zoster during treatment will be derived as date of first onset 
of herpes zoster – date of first administration of IP + 1. AEs with an onset date before the date 
of first administration of IP and AEs with an onset after 28 days after the date of last 
administration of IP will not be considered for the time to first onset of herpes zoster during 
treatment. If a subject has no herpes zoster during treatment, the time to first onset will be 
censored at the date of last administration of IP + 28 days.
For herpes zoster, an alternative event rate per 100 subject years will be derived as the number 
of subjects with herpes zoster divided by the sum of time at risk in days for all subjects in the 
analysis set multiplied by 365.25 days/year multiplied by 100. The time at risk is defined as 
time (including start and end date) from start of period (e.g. date of first administration of IP
for events during treatment) to the date of first event, discontinuation or completion of the 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
46
study, or the database extract date, whatever comes first. This alternative event rate may also 
be calculated for other AESIs if suggested by data. This will be discussed during the BDR 
meeting and the decision will be made before unblinding the data.
3.6.1.1
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 (OAEs) 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.
3.6.1.2
Adverse events of special interest
Adverse events of special interest will be recorded as such in the eCRF. MACE events will be 
classified according to the assessments of the Cardiovascular Event Adjudication Committee. 
AESIs are defined as follows:

Non-opportunistic serious infections

Opportunistic infections

Anaphylaxis

Malignancy

Herpes zoster

Tuberculosis (TB), including latent TB (LTB)

Influenza

Vasculitis (non-SLE)

MACE (as adjudicated)
AESIs are further defined in the clinical study protocol.  An AESI that meets one of the 
seriousness outcomes listed in Section 6.2 of the clinical study protocol will also be 
categorised as an SAE. 
Laboratory variables
Parameters of haematology, clinical chemistry, urinalysis (outlined in Table 4, Section 5.4 of 
the clinical study protocol) and of fasting lipid profile (high density lipoprotein cholesterol, 
low density lipoprotein cholesterol, and triglycerides) will be examined.
Laboratory data will be reported in SI units. Changes from baseline in haematology, clinical 
chemistry and lipid profile variables will be calculated.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
47
Absolute values will be compared to the reference range as 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.
Treatment emergent laboratory/vital signs changes (TELVC) will be defined for on-treatment 
values according to the reference ranges given in Appendix F. 
Urinalysis data that is continuous will be reported and summarised as for haematology and 
clinical chemistry data.  Categorical urinalysis data will be categorised as negative (0), trace
(trace), or positive (+, ++, +++, or >+++) at each time-point. Treatment-emergent changes will 
also be assessed. Treatment-emergent changes of urinalysis data are defined as 

Negative/+ at baseline to ++, +++, ++++ at any on-treatment value OR 

Increase of from baseline of at least ++ at any on-treatment value.
For the liver function tests: aspartate transaminase (AST), alanine transaminase (ALT), 
alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and total bilirubin, the 
multiple of the upper limit of the normal (ULN) range (see Appendix F) will be calculated for 
each data point as follows:
Multiple=Value/ULN (i.e. if the ALT value was 72 IU/L (ULN = 36) then the multiple would 
be 2)
Subjects meeting any of the following biochemical criteria for Hy’s law (potential Hy’s Law) 
at any point during the study will be flagged:

AST ≥3x ULN

ALT ≥3x ULN

Total bilirubin ≥2x ULN
Electrocardiograms
A 12-lead ECG tracing will be performed locally at screening, Week 52 and Week 104. The 
Investigator or qualified designee will review the ECG for clinically significant acute changes.  
The following categories used for analysis:

Normal,

Abnormal, not clinically significant

Abnormal, clinically significant.
The number of subjects in each category will be presented.
SLEDAI-2K-based flare assessment instrument
The SLEDAI-2K based Flare Assessment Instrument will be used to assess the extra-renal 
flares. Flares will be categorised as mild/moderate or severe and defined as any one criterion 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
48
in either the mild/moderate and/or severe flare categories. New or worsened manifestation 
should only be reported for manifestations of SLE. The distinction between mild and 
moderate flare will be based on investigators’ judgement. The SLEDAI-2K based Flare 
Assessment Instrument consists of the following parts: 

Mild/moderate flare
-
Change in non-renal components of the SLEDAI-2K
-
New/worse manifestations of SLE
-
PGA

Severe flare
-
Change in non-renal components of the SLEDAI-2K
-
New/worse manifestations of SLE
-
Hospitalisation
-
PGA
See Appendix M in the clinical study protocol for further details.  Flares will be scored in 
comparison to the previous study visit (i.e. over the past 30 days) and will only include 
findings which, in the opinion of the investigator, are due to SLE disease activity within that 
timeframe.
Physical examination
Complete physical examinations will be performed and will include an assessment of the 
following components: general appearance, head and neck, skin, lymph nodes, thyroid, 
musculoskeletal/extremities, cardiovascular, respiratory, abdomen, neurological, genital/rectal 
and breast.
A focused physical examination will also be performed at specific on-treatment visits and this 
will include an assessment of the organ systems required to complete protocol-specified 
SLEDAI-2K assessment tool. Additional assessments will be done as clinically indicated. 
Abnormal findings will be recorded as part of medical history, AE, SAE, AESI, or lupus 
activity, as appropriate.
Vital signs
Vital signs will be obtained at each visit and measured several times around each infusion of 
IP as follows:

Subjects will be monitored during the administration of the IP and for at least two 
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 IP and 
for a minimum of one hour after completion of the IV infusion thereafter (Week 16 to 
Week 100). 

Vital signs in a sitting position will be taken:


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
49
-
Shortly before the infusion (up to 20 minutes before the beginning of the 
infusion)
-
Every 15±5 minutes during infusion
-
Immediately after completion of administration of IP, including post-dose 
saline flush (within 20 minutes after completion of the post-dose saline flush)
-
Every 30±5 minutes after completion of IP administration (not including saline 
flush) for at least 2 hours after the first 3 doses (Week 0 to Week 8) of IP are 
administered, and for at least 1 hour, thereafter (Week 12 to 100)
Vital signs may also be taken more frequently if the investigator judges this to be appropriate.
The following vital signs will be examined:

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 
G and classified as low (below range), normal (within range or on limits) or high (above 
range). All values (absolute and change) falling outside the reference ranges will be flagged.
On-treatment values will be classified as TELVC according to reference ranges given in
Appendix G.
Weight (kg) and BMI (kg/m2) will be measured at all study visits and examined using the 
difference in mean change from baseline longitudinally over time.  BMI will be calculated at 
all visits using the associated visit weight measurement and the height measured at screening.
Cushingoid features
Subjects will be assessed for Cushingoid features such as moon face, buffalo hump, purple or 
violaceous striae, central obesity, hirsutism, acne, easy bruising, and fragile skin which will be 
captured separately within the study eCRF to evaluate whether resolution of same can occur 
overtime with OCS reduction. These features will be presented by visit. 
Tuberculosis monitoring and questionnaire
Regular testing for TB/LTB will be assessed during the study.  In addition, to aid in the early 
detection of new or reactivated TB, a TB questionnaire will be used to evaluate subjects for 
signs and symptoms of TB at every visit prior to receiving IP.  Any confirmed incidence of 
TB/LTB will be recorded as an AESI (see Section 3.6.1.2).  All TB test results will be 
included as part of the laboratory outputs.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
50
C-SSRS
The C-SSRS is an assessment tool that evaluates suicidal ideation and behaviour.  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 Q in the clinical study protocol for further details).
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale in an increasing order of severity from 
1 to 10 to facilitate the definitions of the comparative variables.

Category 1 – Wish to be Dead

Category 2 – Non-specific Active Suicidal Thoughts

Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act

Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan

Category 5 – Active Suicidal Ideation with Specific Plan and Intent

Category 6 – Preparatory Acts or Behaviour

Category 7 – Aborted Attempt

Category 8 – Interrupted Attempt

Category 9 – Actual Attempt (non-fatal)

Category 10 – Completed Suicide
The Suicidal Ideation or Behaviour Score will be derived from the C-SSRS categories as the 
maximum suicidal ideation or behaviour category (1-10 on the C-SSRS) present at the 
assessment. The score will be derived at each assessment for each subject. Non-suicidal 
self-injurious behaviour will be assigned if no ideation or behaviour is present.
Composite variables based on the above re-ordered categories are defined for assessments 
during screening, during treatment, and during follow-up, respectively (with the same 
definitions for the study periods as given for AEs in Section 3.6.1), as follows:
Suicidal ideation: A “yes” answer at any time in the respective study period to any one of the 
5 (re-ordered) suicidal ideation questions (Categories 1-5) on the C-SSRS.
Suicidal behaviour: A “yes” answer at any time in the respective study period, to any one of 
the 5 (re-ordered) suicidal behaviour questions (Categories 6-10) on the C-SSRS.
No suicidal ideation or behaviour: No “yes” answer at any time in the respective study period 
to any one of the 10 (re-ordered) suicidal ideation and behaviour questions (Categories 1-10) 
on the C-SSRS.
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.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
51
Occurrence of suicidal behaviour and ideation, based on the C-SSRS, from baseline up to 
Week 52 will be presented.
Personal Health Questionnaire Depression Scale-8
The PHQ-8 assesses symptoms of depression over the last 2 weeks by asking eight questions 
related to depression (see Appendix R in the clinical study protocol for more details).  
The mean change from baseline in PHQ-8 total score will be assessed by visit up to Week 52
as well as at Week 60. The PHQ-8 total score will be derived as the sum of the 8 single item 
scores, each ranging from 0 (not at all) to 3 (nearly every day).  If more than one item is 
missing, then the value of the scale is set to missing. 
Pharmacokinetics, pharmacodynamics, and immunogenicity
Immunogenicity variables 
Anti-drug antibodies (ADA) assessments will be conducted utilising a tiered approach (screen, 
confirm, titre). 
The proportion of subjects with ADA responses during the treatment and follow-up periods
will be summarised.  Anti-drug antibody response categories summarised will include (but are 
not limited to):

ADA prevalence: a positive ADA result at any visit including study baseline and all 
post-baseline measurements

ADA negative: does not meet criteria for ADA positive

Subjects who are ADA positive at baseline only

Subjects who are ADA positive post-baseline only

Subjects who are ADA positive at both baseline and post-baseline

Subjects who are ADA positive by visit

Subjects who are ADA positive at a post-baseline measurement for the first time (for 
subjects who are ADA negative at baseline) by visit

ADA persistently (4 months) positive: positive at ≥2 post-baseline assessments, with 
≥16 weeks between first and last positive or positive at last post-baseline assessment
(for subjects who are ADA negative at baseline)

ADA prolonged (6 months) persistently positive: positive at ≥ 2 post-baseline 
assessments, with ≥24 weeks between first and last positive or positive at last post-
baseline assessment (for subjects who are ADA negative at baseline)

ADA prolonged (12 months) persistently positive: positive at ≥ 2 post-baseline 
assessments, with ≥48 weeks between first and last positive or positive at last post-
baseline assessment (for subjects who are ADA negative at baseline)

ADA transiently (<4 months) positive: at least 1 post-baseline ADA positive 
assessment and not fulfilling the conditions of ADA persistently positive (for subjects
who are ADA negative at baseline)


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
52

ADA positive with titre ≤median of maximum titre. To calculate the median of 
maximum titre, take the maximum value for each subject, then calculate the median of 
these values across all subjects (for subjects who are ADA negative at baseline and ≥ 1 
post-baseline ADA result available).

ADA positive with titre > median of maximum titre (for subjects who are ADA 
negative at baseline and ≥ 1 post-baseline ADA result available).

Neutralising antibody (nAb) incidence: post-baseline nAb positive result only (not 
positive at baseline)

Prolonged (6 months) nAb positive: nAb positive at ≥2 post-baseline assessments, 
with ≥24 weeks between the first and last positive or positive at last post-baseline 
assessment (for subjects who are nAb negative at baseline).

Prolonged (12 months) nAb positive: nAb positive at ≥2 post-baseline assessments, 
with ≥48 weeks between the first and last positive or positive at last post-baseline 
assessment (for subjects who are nAb negative at baseline).
For the presentation of ADA results at a single time point (e.g. 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 (e.g. 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 (minimum 
required dilution) will be imputed as 30.
The presence of nAb will be tested in all ADA-positive samples using a ligand binding assay. 
The following variables will be evaluated:

Proportion of subjects with at least one non-missing ADA result (at any time) who are 
nAb positive at any time

Proportion of subjects with at least one non-missing ADA result (at any time) who are 
nAb positive for the first time by visit

Proportion of subjects with a non-missing ADA result (at a specific visit) who are nAb 
positive by visit
Pharmacokinetic variables 
PK samples will be collected both pre and post-dose for specific infusions of investigational 
treatment.  Due to the limited sampling schedule, the PK assessment for both anifrolumab and 
mycophenolate will be primarily based on the observed steady-state serum trough (pre-dose) 
concentrations, Ctrough. For anifrolumab, maximum concentrations after the first and last dose 
of the first year will also be evaluated.  
Individual concentrations will be reviewed for exclusion from descriptive statistics by 
identifying outliers and reviewing dosing information and sample collection times. Analysis to 
determine if the identified concentrations should be excluded includes visual inspection of 
PK-time profiles and comparison of descriptive stats with identified concentrations excluded 
and included. 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
53
In the second year extension period, only Ctrough will be assessed.
Pharmacodynamic outcome variables 
The IFN21 gene PD signature is calculated as the mean expression level of 21 IFN-inducible 
genes in lupus nephritis subjects compared to the expression level in control samples from 
healthy individuals. The IFN21 gene PD signature following treatment is compared to the 
IFN21 signature at baseline for each subject at multiple timepoints after treatment. The 
“percent suppression of fold change” will be presented as the “percent of baseline IFN21 PD 
signature” in all summaries, figures and listings.
This variable will be derived as defined in Appendix H.
Lupus Serology variables
The outcome variable for anti-dsDNA, C3 and C4 complement levels will be the mean change 
from baseline longitudinally up to Week 104 in subjects with abnormal complement level at 
baseline, defined as complement level below lower limit of normal, or elevated anti-dsDNA at 
baseline.
Elevated anti-dsDNA is defined as an anti-dsDNA value above the lower limit for a positive 
value.
4
ANALYSIS METHODS
General principles
Visit windows
For visit based analyses, the variables will be summarised based on the scheduled days with 
adjusted analysis-defined visit windows. The adjusted analysis-defined windows are 
summarised below:
Table 2
Visit windows
Adjusted Defined Windows Visit
Scheduled Study Day
Maximum Windows
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 Day ≤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 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
54
Adjusted Defined Windows Visit
Scheduled Study Day
Maximum Windows
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 
421
407≤ Study Day ≤434 
Week 64
449
435≤ Study Day ≤462
Week 68
477
463≤ Study Day ≤490
Week 72
505
491≤ Study Day ≤518
Week 76
533
519≤ Study Day ≤546
Week 80
561
547≤ Study Day ≤574
Week 84
589
575≤ Study Day ≤602
Week 88
617
603≤ Study Day ≤630
Week 92
645
631≤ Study Day ≤658
Week 96
673
659≤ Study Day ≤686
Week 100
701
687≤ Study Day ≤714
Week 104
729
715≤ Study Day ≤742
Week 108
756
743≤ Study Day ≤770
Week 112
784
771≤ Study Day ≤798
For assignment of data to time points using the visit windows, study day will be defined as 
(Date of assessment – date of first administration of IP) +1. Using this definition, the day of 
first dose of IP will be 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. 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
55
If a visit window does not contain any observations, then the data will remain missing. 
For overall analyses not based on any particular study visit, all data will be listed and/or 
analysed, including any repeat or unscheduled visits, unless otherwise specified.
Statistical testing
While the primary and secondary objectives are defined based on the comparison between the 
pooled anifrolumab and placebo groups, the respective endpoints will also be tested for the 
individual anifrolumab regimens. The following hierarchical testing strategy (presented in 
Figure 1) will be used to provide strong control of the familywise error rate (FWER). As 
described in Section 5, if the interim analysis is performed, some alpha will be spent, and the 
alpha at final analysis will be calculated based on a Peto-Haybittle spending function and the 
number of subjects at each analysis. The description below assumes that a two-sided alpha of 
0.0499 is being used at the final analysis. If the interim analysis is not performed, the 
hierarchical testing strategy at the final analysis will use a two-sided alpha of 0.05.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
56
Figure 1
Multiplicity correction at final analysis

Step 1: The pooled anifrolumab regimens will be tested versus placebo at a 
2-sided 4.99% significance level with regards to 24-hour UPCR (primary 
endpoint).

Step 2: If the null hypothesis is rejected at Step 1, then the pooled 
anifrolumab regimens will be tested versus placebo at a 2-sided 4.99% 
significance level with regards to CRR (secondary endpoint).

Step 3: If the null hypothesis is rejected at Step 2, then both anifrolumab 
regimens are individually tested against placebo, each at 2.50% significance 
level, for both endpoints (24-hour UPCR and CRR). If both regimens can be 
rejected for either endpoint, then alpha can be recycled and both regimens 
can be tested at 4.99% significance level for the remaining endpoint.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
57
At Steps 1 and 2, strong control is due to the sequence testing. At Step 3, alpha is controlled 
given that the pooled hypothesis is tested first and if false, the two hypotheses corresponding 
to the two regimens for that endpoint cannot both be true.
Presentation of results
All analyses will use SAS® version 9.3 or higher. Summary tables will be presented by 
treatment group, and will include a pooled group comprising of both anifrolumab regimens.  
Treatment groups will be presented in the following order: anifrolumab basic regimen, 
anifrolumab intensified regimen, all anifrolumab and placebo. For continuous endpoints, data 
only up to IP discontinuation will be analysed. If IP has not been reported as prematurely 
discontinued, available data up to and including Week 104 will be used for continuous 
endpoints analyses. Otherwise, the date of IP discontinuation will be determined as the date of 
last IP administration. However, all subjects who have an infusion of IP within the Week 48 
analysis visit window will be determined to have completed treatment in the double-blind 
treatment period, and their Week 52 data will be included in the analyses. Additionally, 
subjects who are determined to have completed treatment and have a Week 52 visit will not be 
imputed as non-responders at Week 52 for discontinuation of IP. The treatment policy 
sensitivity analysis of 24-hour UPCR will be analysed using all available data. Data (including 
derived variables) will be presented in listings sorted by treatment group and subject number. 
Unless otherwise noted, categorical data will be presented using counts and percentages with 
the denominator for percentages being the number of subjects in the analysis set by treatment 
group. Percentages will be rounded to one decimal place; except 100% which will be 
displayed without any decimal places. Percentages will not be displayed for zero counts.
Unless otherwise noted, continuous variables will be summarised using the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. The 
minimum and maximum values will be displayed to the same level of precision as the raw 
data, the mean and median to a further decimal place and the SD to two additional decimal 
places.  Any CI’s, CVs, geometric means and any quartile values will also be presented to one 
more decimal place than the raw data.
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 endpoints 
not included in the strategy for preserving the type I error rate, but these cannot be interpreted 
in terms of statistical significance.  The presentation of p-values will be to four decimal places 
unless a p-value is less than 0.0001, in which case “<0.0001” will be displayed.   
Missing data
The study was designed to reduce the risk for missing data as much as possible through the 
following measures:

From randomisation to Week 40, the study design allows for one burst and taper of 
corticosteroid for increased SLE disease activity or non-SLE causes.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
58

The dose of MMF may be increased up to 3 gm/day in case of suboptimal response.

Subjects will receive IV methylprednisolone 500 mg on Week 0 (Day 1), prior to 
receiving the IP.

Subjects may also receive up to one additional (optional) dose of IV 
methylprednisolone (≤500 mg) for renal or extra-renal disease activity between Week 
0 (Day 1) visit and Week 8 visit. This optional dose can be given over two consecutive
days.

Subjects who require additional bursts of OCS will still be allowed to remain in the 
study, but will be considered non-responders for subsequent responder analyses (such 
as CRR).
Subjects who discontinue IP will be followed up and asked to come to each visit for the 
scheduled assessments through the Week 52 visit (or for a minimum of 12 weeks after last 
dose of IP for subjects for whom IP was discontinued within 12 weeks prior to Week 52). 
The following measures will be applied to the second year extension period to also reduce the 
risk for missing data:

From Week 52 to Week 92, the study design allows for one burst and taper of 
corticosteroid.

Subjects who require additional bursts of OCS during the second year extension period 
will still be allowed to remain in the study, but may be considered non-responders for 
subsequent responder analyses (such as CRR at Week 104).
Subjects who discontinue IP in the second year extension period will be followed up until 
Week 104 (or for a minimum of 12 weeks after last dose of IP for subjects for whom IP was 
discontinued within 12 weeks prior to Week 104). 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of <x (i.e. below the lower limit of quantification) or >x (i.e. above the upper limit of 
quantification) will be imputed as x in the calculation of summary statistics but displayed as 
<x or >x in the listings.
Details about imputation of partial or missing dates are given in Appendix D. The imputation 
of single missing items for the derivation of a total score is described in Appendix E.
4.1.4.1
Observed case
A mixed model for repeated measures (MMRM) will be used for all continuous endpoints 
based on the observed data. MMRM allows the inclusion of repeated effects and the 
specification of an appropriate variance-covariance structure, which will model any missing 
data. 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
59
4.1.4.2
Last observation carried forward 
For secondary and exploratory responder efficacy endpoints, any component with missing 
value will be imputed using last observation carried forward (LOCF) if only single 
(non-consecutive) visits are missing data for that component. In the event of two or more 
consecutive visits with missing data for the same component, the last observed post-baseline 
value prior to the first missing value will be carried forward only for the first missing value of 
each sequence, and subjects will be imputed as non-responders for the specific responder 
endpoint for the second visit on, where data is missing. The responder endpoint is derived 
based on the imputed values.
If one or more components of SLEDAI 2K and SDI are missing, then the LOCF approach will 
be used to impute the missing component score. However, if less than 50% of the respective 
components are available, the data will not be imputed. Additionally, in the event of two or 
more consecutive visits with missing data for the same component, the last observed 
post-baseline value prior to the first missing value will be carried forward only for the first 
missing value of each sequence, and the component score will remain missing for the second 
visit onwards. 
4.1.4.3
Non-responder imputation
For the analysis of the secondary and exploratory efficacy responder endpoints (excluding 
time to modified renal response), subjects will be imputed as non-responders from time at 
which the criteria are met, in the following cases:
a) Medication criteria
Subjects who meet any of the following medication criteria:
-
Subjects who receive any restricted medication (see Appendix A and 
Appendix B) after randomisation or beyond any protocol allowed 
thresholds will be considered a non-responder from the time the respective 
medication was administered up to and including Week 104.
-
Subjects who meet any of the corticosteroid criteria (see Appendix B) will 
be considered a non-responder from the time the condition is met, up to and 
including Week 24, Week 52, Week 80 or Week 104, depending on the 
condition and when it is met.
-
Subjects who meet any of the MMF criteria (see Appendix B) will be 
considered a non-responder from the time the condition is met, up to and 
including to Week 24, Week 52, Week 80 or Week 104, depending on the 
condition and when it is met.
b) Discontinued IP
Subjects who prematurely discontinue from IP, including subjects who withdraw from 
the study. All subjects who have an infusion of IP within the Week 48 analysis visit 
window will be determined to have completed treatment in the double-blind treatment 
period.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
60
Non-responder imputation will be applied at all scheduled visits, including missing visits.  If a 
subject does not have a response at a visit, they will be imputed as a non-responder (note that 
unless IP was discontinued or any of the medication criteria above are met, LOCF will be 
applied to missing values at the first missed visit in case of consecutive missed visits and the 
non-responder imputation will be applied to the response values determined after LOCF 
imputation.  See Section 4.1.4.2 for more details on LOCF).
Sensitivity analysis
Sensitivity analyses where missing data is handled in different ways will be carried out for the 
primary endpoint. To examine the impact of missing data, including the impact of 
non-responder imputation due to permanent discontinuation of IP, tipping point analyses will 
be performed for endpoints specified in Section 4.2. These analyses will vary the assumptions 
about outcomes among the subsets on the treatment arms that discontinue IP early. Details of 
the sensitivity analyses are provided in Section 4.2 with each associated endpoint.
Examination of model assumptions
Underlying model assumptions for all statistical models will be checked with graphical 
displays (e.g. plots of residuals versus predicted values, histograms with normal density 
overlaid, quartile-quartile [Q-Q] plots showing the residual quantiles versus quantiles of a 
normal distribution) as appropriate. If any model assumptions are not met, appropriate (or 
alternative) data transformations or the use of non-parametric approaches will be discussed as 
soon as is appropriate. The decision about an appropriate approach will be made before 
unblinding the data.
 
 
 
 
 
 
 
 
 
 
.
Analysis methods
Analysis of the primary variable
The primary estimand is evaluating the efficacy on disease activity of the pooled anifrolumab
groups relative to placebo in subjects with active proliferative LN. This is measured by the 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
61
relative difference in change from baseline to Week 52 in the 24-hour UPCR. The full 
analysis set (as defined in Section 2.1.2) will be used, and any data collected after IP 
discontinuation will be excluded from the analysis, in order to reflect the effect of the initially 
assigned and dosed IP (anifrolumab or placebo), prior to the occurrence of the intercurrent 
event of IP discontinuation, applying a “while on treatment” estimand strategy. The individual 
anifrolumab regimens will also be assessed but not as part of the primary analysis. 
The estimand for all continuous endpoints (including the primary endpoint) follows the “while 
on treatment” strategy, which includes data only up to IP discontinuation. If IP has not been 
reported as prematurely discontinued, available data up to and including Week 104 will be 
used for continuous endpoints analyses. Otherwise, the date of IP discontinuation will be 
determined as the date of last IP administration. However, all subjects who have an infusion of 
IP within the Week 48 analysis visit window will be determined to have completed treatment 
in the double-blind treatment period, and their Week 52 data will be included in the analyses.  
The primary analysis will be performed using an MMRM fitted to log-transformed data 
comparing the pooled anifrolumab group with the placebo group, with fixed effects for 
treatment group, visit, stratification factors and log-transformed 24-hour UPCR at 
baseline. An interaction term for visit and treatment will also be included in the model to 
allow the relationship to differ across treatment groups. Note that visit will be fitted as a 
repeated variable in the model. Denominator degrees of freedom will be estimated using the 
Kenward-Roger approximation. An unstructured correlation pattern will be used to estimate 
the variance-covariance of the within-subject repeated measures. In the case that the model 
does not converge using an unstructured covariance matrix, the heterogeneous Toeplitz 
covariance structure will be evaluated, followed by the heterogeneous autoregressive of first 
order, heterogeneous compound symmetry, and homogeneous compound symmetry 
covariance structures in the case of further non-convergence. The restricted maximum 
likelihood method will be used.
Separate MMRMs will be fitted to all data from baseline to Week 52 for the analyses of Week 
12 to Week 52, and to all data from baseline to Week 104 for the analyses of Week 64 to 
Week 104. 
Stratification factors are:

Results of IFN test at screening using a 4-gene type I IFN test (high versus low)

24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg (based on 24-hour UPCR performed 
on a sample obtained within 14 days prior to the expected date of randomisation).
Without the results of the second (stratification) sample, subjects cannot be 
randomised. Turn-around time for results from central laboratory is up to 7 days. On 
rare occasion an extension of 30-day screening window is allowed if re-collection of 
the sample is necessary or the results needed for randomisation are delayed.
The 24-hour UPCR values will be log-transformed before analysis and the results will be 
back-transformed for presentation. Model assumptions will be checked as defined in Section 
4.1.6.  The estimated treatment effect, corresponding 95% CI, and two-sided unadjusted


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
62
p-value for the difference at Week 52 and nominal p-values for the difference at all other 
post-baseline visits will be presented. 
The following sensitivity analyses will also be performed to assess the robustness of the 
primary analysis:

Treatment policy analysis: Includes all data collected, irrespective of whether a subject 
discontinued IP.

Biopsy analysis: Excludes any subjects whose adjudicated kidney biopsy results show 
them to be ineligible for study entry (i.e. subjects whose adjudicated kidney biopsy 
results are not class III or class IV)
Subgroup analyses will be performed as described in Section 4.3.
Summary statistics for 24-hour UPCR and change from baseline will be presented by week. 
Longitudinal presentations of results over time (i.e. for each post-baseline visit up to Week 
104 where 24-hour UPCR is recorded) based on the same main analysis, with the 
corresponding 95% CI, will be created.  Mean changes from baseline for 24-hour UPCR will 
be displayed in a longitudinal plot by treatment group only for the first year, where the 
estimated adjusted means with corresponding 95% CI at each visit will be displayed. A 
Kaplan-Meier plot will also be produced for time to 24-hour UPCR ≤0.7 mg/mg by treatment 
group for the whole study.
Analysis of the secondary variable
As a secondary endpoint, a composite endpoint is used to evaluate the effect of anifrolumab 
on renal response.  For this analysis the estimand of interest is the difference in change from 
baseline at Week 52 in renal response between anifrolumab and placebo, to reflect the effect 
of the initially assigned IP (full analysis set). This estimand answers a clinically relevant 
question comparing the number of subjects able to both tolerate therapy sufficiently to remain 
on treatment to a given point in time and to achieve adequate response without further 
medication being required.  Any missing data will be imputed as defined in Section 4.1.4.
The proportion of subjects achieving CRR in the anifrolumab pooled group will be compared 
with the placebo group using a CMH approach (Stokes ME, 2012) stratified by: 

Results of IFN test at screening using a 4-gene type I IFN test (IFN test-high versus 
test-low)

24-hour UPCR ≤3.0 mg/mg versus >3.0 mg/mg at screening (within 14 days prior to 
the expected date of randomisation). Without the results of the second (stratification) 
sample, subjects cannot be randomised. Turn-around time for results from central 
laboratory is up to 7 days. On rare occasion an extension of 30-day screening window 
is allowed if re-collection of the sample is necessary or the results needed for 
randomisation are delayed.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
63
The individual anifrolumab regimens will also be assessed but not as part of the secondary 
analysis. The analysis can be described as follows:

There are nij subjects in each stratum, where i is the stratum, and j is the treatment 
group. The number of responders is xij. The proportion of responders is denoted as 
pij = xij / nij. 
Strata with low counts will be pooled with adjacent strata. If a sub-stratum within the 
IFN-low stratum has less than 16 subjects (in the pooled treatment group, i.e. placebo 
pooled with the respective anifrolumab group that is tested), then the two IFN-low 
sub-strata will be pooled together. If a sub-stratum within the IFN-high stratum has 
less than 16 subjects (in the pooled treatment group), then the two IFN-high sub-strata 
will be pooled together. If the two IFN-low sub-strata are pooled together and the two 
IFN-high sub-strata are pooled together, and any of these strata has less than 16 
subjects (in the pooled treatment group) then all strata will be pooled together.

For each stratum, the difference in proportion of subjects achieving CRR is calculated 
as di = piA – piP, where A and P denote the different treatment groups (anifrolumab and 
placebo, respectively). 

Weights for each stratum, wi, are calculated as niP × niA / (niA + niF). The weighted 
difference is calculated as 
 =
∑	
	
∑	

The SE of the weighted difference under the null hypothesis is given by 
 = ∑[	
(
	)]
(∑	)
(
	) = 	.(1 −	.)	
	(	 −1)
	. = 	.
	.
= 	 + 	
	 + 	

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 below. The 95% confidence interval can be 
generated using the weighted difference ± Z0.975 × SE.
(
	) = 	
∗(1 −	
∗)
	
+ 	
∗(1 −	
∗)
	
	 
∗= 	 + 2
	 + 4


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
64

The 95% confidence interval for the weighted proportion (∑	
	
	 /) in a treatment 
group j can be generated using a normal approximation and independence between 
strata, where pij* are used as above 
$	 
 = %	 & = 	 
∗(1 −	 
∗)/	 
$ 
 = ' 	

	
$	 
 /
 = ' 	
	

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 2 ,1 −-./ 01
()
*+ 123, where 
Prob(.) is the distribution function of the standard normal distribution.
The estimated treatment effect (the difference in response rate for each anifrolumab regimen 
versus placebo) and corresponding 95% CI for the difference at Week 52 and Week 104 will 
be presented. In addition, the response rate and the corresponding 95% CI within each 
treatment group will be presented. 
The following sensitivity analyses will also be performed to assess the robustness of this 
secondary outcome variable at Week 52 and Week 104:

A tipping point analysis to examine the impact of missing data, including the impact of 
non-responder imputation due to permanent discontinuation of IP. The analysis for 
each treatment group, and the pooled anifrolumab group, will only be statistically
interpreted if the nominal p-value from the analysis of CRR detailed above, for the 
respective comparison with placebo at the specified visit, is <0.05 (in favour of 
anifrolumab). This analysis will vary the assumptions about outcomes among the 
subsets of subjects on the treatment arms who permanently discontinued IP early, and 
can be described as:
-
The proportions of responders will be analysed using a Pearson’s chi-squared 
test, i.e., disregarding the stratification factors that are used in the main analysis 
(CMH).
-
Subjects who permanently discontinued IP early having not received restricted 
medications prior to discontinuation are by definition imputed as 
non-responders. For this sensitivity analysis, these subjects will be considered 
as having had the potential of being responders if they continued into the study 
until Week 52. 
-
At each step of the analysis one of these subjects switches from non-responder 
to responder, and the Pearson’s chi-squared test is re-run. The results 
(statistical significance) will be presented for each anifrolumab treatment arm 
as well as the pooled anifrolumab group in a grid where the x-axis and the 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
65
y-axis represent the number of subjects that have had their values imputed as 
non-response values and are assumed as responders for the placebo arm and the 
active arm respectively. The region where the conclusion changes, will be 
considered as the tipping point.
-
The grid will be divided into three regions, limited in the top by the expected 
number of subjects that have had their values imputed as non-response values
in the active arm which would have been responders if not permanently 
discontinued IP early (based on the active response rate in the observed cases): 

Likely – its right limit is the expected number of subjects that have had 
their values imputed as non-response values in the placebo arm which 
would have been responders if not permanently discontinued IP early 
(based on the placebo response rate in the observed cases);

Uncertain – its right limit is the expected number of subjects that have 
had their values imputed as non-response values in the placebo arm
which would have been responders if not permanently discontinued IP
early (based on the active response rate in the observed cases);

Unlikely – it is the region to the right of the uncertain region.

Biopsy sensitivity analysis: Based on the main analysis it excludes any subjects whose 
adjudicated kidney biopsy results show them to be ineligible for study entry. 
Subgroup analyses will be performed as described in Section 4.3.
Longitudinal presentations of results over time (i.e. for each post-baseline visit up to Week 
104 where CRR based on 24-hour UPCR can be derived) based on the same analysis, with the 
corresponding 95% CI, will be created. Bar plots showing the proportion of subjects who are 
responders/non-responders for CRR at Week 24 and Week 52 by treatment group (including 
CIs and number of subjects included in the analysis) will be provided by 24-hour UPCR at 
screening (≤ 3 mg/mg and > 3 mg/mg). Additionally, the individual components of CRR will 
be summarised over time by treatment group.
The proportion of subjects achieving CRR based on 24-hour UPCR at Week 52 and at Week 
104 will also be presented in a summary table alongside the proportion of subjects achieving 
CRR based on spot UPCR at Week 52 and at Week 104 together with a summary of the 
individual components.
In addition, the time to achieve CRR by treatment group will be presented in a Kaplan-Meier 
plot including the number of subjects at risk at each visit.
Analysis methods for exploratory outcome variables
All analyses of the exploratory outcome variables will be conducted with the full analysis set.
4.2.3.1
 
 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
66
 
 
  
4.2.3.2
 
 
    
 
 
 
 
 
 
  
 
 
4.2.3.3
Oral corticosteroid management
The exploratory endpoint used to evaluate the effect of the anifrolumab regimens versus 
placebo on the ability to achieve a sustained reduction of OCS dose is the difference in 
proportions of subjects able to taper OCS to ≤7.5 mg/day prednisone-equivalent by Week 24 
and maintain this dose through Week 52. The effect of the anifrolumab regimens versus 
placebo will also be evaluated on the ability to achieve a sustained reduction of OCS dose 
using the difference in proportions of subjects able to taper OCS to ≤5.0 mg/day 
prednisone-equivalent by Week 80 and maintain this dose through Week 104.
The same CMH approach as described in Section 4.2.2 will be used to estimate the treatment 
differences between the anifrolumab regimens and placebo at Week 52 and at Week 104.  Any 
missing data will be imputed as defined in Section 4.1.4.  
Subgroup analyses will be performed as described in Section 4.3.
Reduction of OCS dose will also be assessed at Week 24 by examining the proportions of 
subjects able to taper OCS to ≤7.5 mg/day prednisone-equivalent by Week 24, using the same 
analysis approach. Reduction of OCS dose will also be assessed at Week 80 by examining the 
proportions of subjects able to taper OCS to ≤5.0 mg/day prednisone-equivalent by Week 80, 
using the same analysis approach.
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
67
In order to examine the impact of missing data, a tipping point analysis as described in Section 
4.2.2 will also be performed for the sustained reduction of OCS dose at Week 52 and Week 
104. The analysis for each treatment group, and the pooled anifrolumab group, will only be 
statistically interpreted if the nominal p-value from the main analysis of sustained reduction of 
OCS dose detailed above, for the respective comparison with placebo at the specified visit, is 
<0.05 (in favour of anifrolumab).
Daily OCS doses and changes from baseline will be presented by descriptive statistics by visit 
for all subjects.
Additionally, the daily OCS dose will be displayed graphically by a longitudinal plot 
presenting the means and corresponding SDs. The number of subjects will also be included in 
the graph.
Shift plots (scatter plot) for the daily OCS dose presenting baseline values versus Week 24 
values, baseline values versus Week 52 values and Week 52 values versus Week 104 values
will also be provided. A diagonal line indicating no change will be included in this shift plot.
Furthermore, the standardised AUC up to Week 52, up to Week 104 and from Week 52 to 
Week 104 will be summarised by treatment group for all subjects.
4.2.3.4
Renal response modified to include oral corticosteroid tapering requirement
The renal response endpoints CRR and PRR will be modified to include an OCS tapering 
requirement and used to evaluate the effect of anifrolumab on renal response.
The same CMH approach as described in Section 4.2.2 will be used to estimate the treatment 
differences between the anifrolumab regimens and placebo at Week 52 and at Week 104.  Any 
missing data will be imputed as defined in Section 4.1.4.  Modified CRR and PRR will also be 
assessed at Week 24 by examining the proportions of subjects who achieve CRR/PRR and are 
also able to taper OCS to ≤7.5 mg/day prednisone-equivalent by Week 24, using the same 
analysis approach.
A bar plot showing the proportion of subjects who achieve modified CRR or PRR by 
treatment group (including CIs and number of subjects included in the analysis) will be 
provided for both Weeks 24 and 52.
4.2.3.5
 
 
 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
68
4.2.3.6
 
 
 
 
  
 
 
 
4.2.3.7
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2.3.8
 
 
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
69
 
 
 
4.2.3.9
 
 
 
4.2.3.10
SLEDAI-2K
Change from baseline in SLEDAI-2K will be evaluated using the same summaries and 
analysis approach except SLEDAI-2K data will not be log transformed, as specified in Section 
4.2.3.5, with the appropriate substitution for the baseline value.
4.2.3.11
Non-renal SLEDAI-2K
Change from baseline in non-renal SLEDAI-2K will be evaluated using the same summaries 
and analysis approach except non-renal SLEDAI-2K data will not be log transformed, as 
specified in Section 4.2.3.5, with the appropriate substitution for the baseline value.  
4.2.3.12
Physician global assessment
Change from baseline in PGA will be evaluated using the same summaries and analysis 
approach except PGA data will not be log transformed, as specified in Section 4.2.3.5, with 
the appropriate substitution for the baseline value.
4.2.3.13
SLICC/ACR Damage Index
Change from baseline in SDI will be evaluated using the same analysis approach and
summaries (except that SDI data will not be log-transformed) as specified in Section 4.2.3.5, 
with the appropriate substitution for the baseline value.  SDI will also be analysed by baseline 
SDI (≥ 1 vs 0).
Subject reported outcome variables
4.2.4.1
Patient Global Assessment
Change from baseline in PtGA will be evaluated using the same summaries and analysis 
approach except PtGA data will not be log transformed, as specified in Section 4.2.3.5, with 
the appropriate substitution for the baseline value.
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
70
Presentation of study population
4.2.5.1
Subject disposition
The number and percentage of subjects randomised, randomised but not treated with IP, and 
not randomised will be summarised by treatment group for the all subjects analysis set.
The number and percentage of subjects completing the double-blind treatment period of the 
study up to and including Week 52 and the number and percentage of subjects withdrawing 
from the study during the double-blind treatment period including reason for withdrawal, will 
be summarised by treatment group for the full analysis set .  
The number and percentage of subjects completing treatment with IP during the double-blind 
treatment period up to and including Week 48 (i.e. with last administration of IP at Visit 13),
the number and percentage of subjects permanently discontinuing the treatment with IP during 
the double-blind treatment period including reason for withdrawal, and the number and 
percentage of subjects who discontinued the treatment with IP after completing treatment with 
IP in the double-blind treatment period and did not enter the second year extension period
including reason for withdrawal, will be summarised by treatment group for the full analysis 
set.
The number and percentage of subjects continuing into the second year extension period of 
the study from Week 52 up to and including Week 112 will be summarised by treatment 
group for the full analysis set.  
The number and percentage of subjects completing the second year extension period of the 
study from Week 52 up to and including Week 112 and the number and percentage of subjects 
withdrawing from the study during the second year extension period including reason for 
withdrawal, will be summarised by treatment group for subjects who continued in the second 
year extension period.
The number and percentage of subjects completing treatment with IP during the second year 
extension period from Week 48 up to and including Week 100 (i.e. with last administration of 
IP at Visit 26) and the number of subjects permanently discontinuing the treatment with IP
during the second year extension period including reason for withdrawal, will be summarised 
by treatment group for the subjects who continued into the second year extension period.
The number and percentage of subjects not continuing into the second year extension period 
of the study including reason for not continuing, will be summarised by treatment group for 
the full analysis set.  
The number and percentage of subjects completing the study up to and including Week 112
and the number and percentage of subjects withdrawing from the study including reason for 
withdrawal, will be summarised by treatment group for the full analysis set.  
The number and percentage of subjects completing treatment with IP up to and including 
Week 100 (i.e. with last administration of IP at Visit 28) and the number of subjects 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
71
permanently discontinuing the treatment with IP including reason for withdrawal, will be 
summarised by treatment group for the full analysis set.
A summary of number and percentage of subjects in each country and each site by treatment 
group and overall will be provided for the full analysis set.
Summaries of important protocol deviations and analysis sets will be provided.
4.2.5.2
Demographic and baseline characteristics
Demography and baseline characteristics will be presented by descriptive statistics by 
treatment group as well as overall for the full analysis set. 
Stratification factors at randomisation will be presented by descriptive statistics by treatment 
group as well as overall for the full analysis set.
Past and current medical history will be summarised separately by MedDRA system organ 
class and preferred term. Surgical history will be listed.
Prior and concomitant medications will be summarised separately by WHO Drug Dictionary 
ATC classification (ATC level 1), and preferred term. A summary of disallowed concomitant 
medication taken on or after the date of first dose of study treatment which would lead to the 
classification of a subject as a non-responder will be provided, splitting into medications 
received while on IP or while off IP, based on medication start date. For subjects having 
prematurely discontinued IP, medications received after IP initiation and before or on the date 
of last IP administration will be considered “on IP”. However, for subjects who have a last
infusion of IP within the Week 48 analysis visit window, medications received after IP 
initiation and before or on the date of Week 52 (or the date of Week 48 + 28 days in case that 
Week 52 was missed) will be considered “on IP”. Medications received after the date of last 
IP administration, in case of premature IP discontinuation will be considered to be “off IP”.
A summary of ACE inhibitors and ARBs taken during the study will be presented separately.  
A list of preferred terms for inclusion in this summary will be finalised and agreed prior to 
study database lock and unblinding.
4.2.5.3
Exposure
Exposure will be summarised by treatment group for the full analysis set. 
Summary statistics will be provided for the cumulative duration of exposure. The number and 
percentage of subjects treated ≥4 weeks, ≥8 weeks, and up to 104 weeks in 4-weekly intervals 
will be provided. 
The number and percentage of subjects with infusions will be presented by total number of 
infusion (i.e. 1, 2, …, 13) and in 4-weekly intervals (i.e. 4 weeks, 8 weeks, 12 weeks, …, 
100 weeks). 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
72
Furthermore, the time to discontinuation of IP will be presented as Kaplan-Meier plot 
including the number of subjects at risk (i.e. still on IP).  
Subjects with complications (e.g. an interruption) in any infusion will be presented in a listing.
Analysis methods for safety variables
Safety variables will be summarised by treatment group for the full analysis set.
4.2.6.1
Adverse Events
If not stated otherwise, all summaries described below will be presented separately for 

AEs during treatment

AEs during follow-up
For summaries during follow-up, only subjects with any study documentation after the date of 
last dose of IP + 28 days will be considered.
An overall summary of subjects with at least one AE in the following categories will be 
presented, and will include the event rate per 100 subject years, and total exposure in years for 
each treatment group:

Any AE

Any acute AEs
This category will not be included in the summary during follow-up.

Any AE with outcome = death

Any SAE (including events with outcome = death)

Any AE leading to discontinuation of IP
o
This category will not be included in the summary during follow-up.

Any AE related to IP by investigator’s judgement

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 (non-SLE)
-
Any AESI of major acute cardiovascular events (MACE as adjudicated)

Any other significant AE


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
73
The number and percentage of subjects with at least one AE (i.e. multiple occurrences of an 
AE in 1 subject will only be counted once) will be summarised by MedDRA system organ 
class and preferred term (unless specified otherwise) for the following AE categories. These 
summaries will also include the event rate per 100 subject years and total exposure in years
for each treatment group (unless specified otherwise).

Any AE

Any AE above reporting threshold of 2% of subjects in any treatment group in the full 
analysis set. 
This summary will be presented by preferred term for AEs during treatment only.

Any non-serious AE above reporting threshold of 5% of subjects in any treatment group in 
the full analysis set
This summary will not include the event rate per 100 subject years and total exposure in 
years.

Any SAE with outcome = death
This summary will be presented for SAEs with an outcome of death during the treatment 
and follow-up periods combined.

Any SAE (including events with outcome = death)

Any AE leading to discontinuation of IP
This summary will be presented for AEs during treatment only.

Any AE by relationship to IP (yes, no)
(multiple occurrences of an AE in 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 be presented for AEs during treatment only.

Any AE by maximum intensity (mild, moderate, severe)
(i.e. multiple occurrences of an AE in 1 subject will only be counted once with the 
maximum intensity in this AE)
This summary will be presented for AEs during treatment only.

Any AESI
This summary will not be presented by system organ class but by AESI category 
(non-opportunistic serious infections, opportunistic infections, anaphylaxis, malignancy, 
herpes zoster, tuberculosis, influenza and vasculitis [non- SLE]).

Any other significant AE
This summary will be presented for AEs during treatment only.

Any AE by time interval (as detailed in Section 3.6.1) for the first onset of event
This summary will be presented for AEs during treatment only.
Cardiovascular outcome events 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.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
74
The time to first onset of herpes zoster during treatment will be presented as a 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 summarised for events during screening, during treatment, and during 
follow-up. The total time at risk will also be presented.
An overall summary of subjects with AE’s in pre-specified categories will also be presented 
by ADA category.
Key subject information for subjects with an AE with outcome of death, subjects with serious 
AEs, subjects with an AE leading to discontinuation of IP, subjects with cardiovascular events
and subjects with AESIs, respectively, will be provided.
All AEs and AEs in ADA positive (at any time) subjects will be listed.
4.2.6.2
Laboratory variables
Observed values and changes from baseline of laboratory data for haematology, clinical 
chemistry 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) for each of the parameters presenting baseline values versus 
minimum post-baseline values and maximum post-baseline values, 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 summarised by visit. Additionally, the number and percentage of 
subjects with at least one TELVC value will be presented. 
The number and percentage of subjects with laboratory values below, within or above the 
corresponding normal range will be presented by visit. Urinalysis will be summarised as shift 
tables from baseline to the last on-treatment value for each parameter. Furthermore, the 
number and percentage of subjects with treatment-emergent changes will be summarised by 
parameter.  In addition, observed values and change from baseline and pre-specified 
categories will be summarised by visit for any continuous variables.
In order to identify potential Hy’s Law cases, the number and percentage of subjects in 
categories based on multiples of ULN for maximum on-treatment ALT and AST by maximum 
total bilirubin will be presented in a table. The table will include the following categories: < 
and ≥2xULN for total bilirubin and < 3xULN, ≥ 3 - < 5xULN, ≥ 5 - < 10xULN and ≥
10xULN for ALT/AST.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
75
Individual subject data will be presented f or all subjects who meet the criteria for potential 
Hy’s law. The relevant laboratory parameters (ALT, AST, total bilirubin and ALP) will be 
tabulated showing all visits for these subjects. Subjects with elevated ALT or AST (ALT or 
AST ≥ 3xULN) and elevated total bilirubin (≥ 2xULN) at any time during the study (not 
necessarily at the same time) will be included.
4.2.6.3
ECGs
The number and percentage of subjects with normal, abnormal, not clinically significant and 
abnormal, clinically significant ECG results will be presented as a shift table from baseline to 
last observation on treatment.
Individual ECG parameters will not be summarised or analysed as the data is not collected.
4.2.6.4
SLEDAI-2K-based flare assessment instrument
The flare rate per of subject years for extra-renal flares will be presented overall, and by 
timing (“on-treatment” and “off-treatment”), for mild/moderate flares, severe flares and any 
flares, respectively. An “on-treatment” flare is defined as a flare with a date of onset after the 
date of first dose of IP and on or prior to the date of last dose of IP + 28 days. An “off-
treatment” flare is defined as a flare with a date of onset after the date of last dose of IP + 28 
days. Where a flare has been marked as both mild/moderate and severe, it will be considered 
to be severe for the purposes of this summary.
4.2.6.5
Vital signs
Observed values and changes from baseline of pulse, systolic blood pressure, diastolic blood 
pressure, respiration rate and body temperature, respectively, will be summarised by pre, 
during and post infusion, time, visit and treatment group.  As multiple values are recorded 
during infusion and post-infusion, the average value during infusion and the average value 
post-infusion will also be calculated for each subject at each visit (along with the change from 
baseline for these average values) and these will be included in the summary tables along with 
the individual values.
For each parameter with available criteria, the number and percentage of subjects with 
TELVC values will be summarised by visit. Additionally, the number and percentage of 
subjects with at least one TELVC value will be presented. 
For each parameter, the number and percentage of subjects with values below, within or above 
the corresponding normal range will be presented by visit. In addition, this information will be 
presented as shift tables from baseline to each post-baseline visit. 
Observed values and changes from baseline of body weight and BMI will be summarised.
4.2.6.6
Cushingoid features
The number and percentage of subjects will be summarised for each feature by visit and 
treatment group.  For subjects with baseline OCS ≥10 mg/day prednisone or equivalent, the 
summary will be repeated by OCS status at Week 52 (target OCS dose of ≤7.5 mg/day 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
76
reached versus target OCS dose of ≤7.5 mg/day not reached) and at Week 104 (target OCS 
dose of ≤5.0 mg/day reached versus target OCS dose of ≤5.0 mg/day not reached).
4.2.6.7
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 presented by treatment group 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 summarised by treatment group for 
attempts during screening, during treatment and during follow-up, respectively.
Subjects with a suicidal ideation or behaviour at any time up until Week 52 will be presented 
in a listing.
4.2.6.8
Personal Health Questionnaire Depression Scale-8
Observed values and changes from baseline in PHQ-8 total score will be presented with 
descriptive statistics by visit and treatment group.
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. If not stated otherwise, all analyses of 
pharmacokinetics will be performed for the PK analysis set by treatment group.
4.2.7.1
Analysis methods for immunogenicity variables
The proportion of subjects with ADA results as described in Section 3.7.1 will be presented 
together with descriptive statistics of the available titres. Descriptive statistics will include n 
(number of reportable titres), minimum, quartiles (1st quartile, median and 3rd quartile) and 
maximum.
ADA response and the corresponding titre will be summarised at baseline and at all scheduled 
post-baseline visits in the study period by treatment group for the full analysis set.  In 
addition, the proportion of ADA positive subjects will be presented cumulatively.  
A summary of key subject information will be provided for ADA positive subjects.
The analyses of impact of ADA on PK and PD endpoints are described in Sections 4.2.7.2 and 
4.2.7.3. 
Pre-specified AE categories and hypersensitivity events during the on-treatment period will be 
summarised by ADA status (positive, negative).


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
77
Additional summaries of immunogenicity data may be generated based on the results of the 
above analyses.
4.2.7.2
Analysis methods for pharmacokinetic variables
Anifrolumab serum concentrations will be summarised using descriptive statistics by visit 
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 by treatment group will be generated as 
plots of mean values (including SD) by time point in a semi-log scale and a linear scale. This 
will be presented for all values and additionally for values measured before administration 
(Ctrough).
The potential influence of demographic covariates such as body weight, race, sex and age will 
be explored. Furthermore, potential correlation between anifrolumab concentrations and 21-
gene type IFN PD signature will be explored. These analyses will be performed by 
MedImmune’s Clinical Pharmacology and Drug Metabolism and Pharmacokinetics (DMPK) 
group.
Impact of ADA on PK will be explored by spaghetti plots of individual concentration data 
over time using different styles by ADA result (positive at any time/negative). This will be 
presented for all values and additionally for values measured before administration (Ctrough). 
Summaries of anifrolumab serum concentrations by visit and ADA status (positive, negative)
will be presented. 
Mycophenolic acid serum concentrations will be summarised using descriptive statistics as 
specified above at each visit by treatment group. Serum concentration-time profiles of MPA 
by treatment group will also be generated. Analyses of mycophenolic acid serum 
concentrations will be performed on the full analysis set.
4.2.7.3
Analysis methods for pharmacodynamic and lupus serology variables
IFN21 gene PD signature as percent of baseline IFN21 PD signature will be summarised by 
time point for subjects who are IFN test-high at randomisation. The median absolute deviation 
(MAD) will also be included in this summary.  Furthermore, the median percent of baseline 
IFN21 PD signature (including MAD) over time will be presented as a line plot for the same 
population.
The impact of ADA on IFN21 gene PD signature will be explored. For IFN test-high subjects, 
IFN21 gene PD signatures as percent of baseline IFN21 PD signature will be summarised 
descriptively by ADA status (ADA negative/positive at any time) and ADA positive 
subgroups (ADA persistently/prolonged persistently positive, ADA titre > median, ADA nAb 
positive) by timepoint and treatment group.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
78
For subjects who are positive for anti-dsDNA at baseline and abnormal complement level at 
baseline, respectively, observed values and changes from baseline of anti-dsDNA, C3 and C4 
complement levels will be summarised by visit, providing the frequency of positive data 
allows.
Subgroup analysis
To explore the uniformity of the detected overall treatment effect, subgroup analyses will be 
performed for the following factors: 

Type I IFN 4-gene test at screening (IFN test-high, IFN test-low) 

24-hour UPCR at screening ≤3 mg/mg, >3 mg/mg

Age (≥18 to 64, ≥65 years) 

Placebo response region (low placebo response rate versus high placebo response rate)
Countries with a low placebo response rate versus high placebo response rate are 
defined as [Low: Australia, Belgium, France, Germany, Italy, South Africa, Spain, 
United Kingdom, United States], [High: Argentina, Hungary, Republic of Korea, 
Mexico, Peru, Poland, Russian Federation, Serbia, Taiwan] 

Race (white; black or African American; Asian, native Hawaiian or other Pacific 
Islander; American Indian or Alaska native; other)

Screening biopsy classification (class III, class IV, mixed [class III or IV + class V])

Number of methylprednisolone pulses (1, >1). Pulses are counted during the whole 
study.

ADA result (Positive at any time, Negative)

OCS at baseline (<20 mg/day, ≥20 mg/day)

eGFR at baseline (<60 mL/min/1.73m2, ≥60 mL/min/1.73m2)
Table 3, Table 4 and Table 5 give an overview of subgroup analyses to be performed at Week
24, 52 and Week 104, respectively. Where necessary (e.g. for subgroup analysis based on 
stratification factors), the model factors will be reduced. If not stated otherwise, the subgroup
analysis will not be performed for a sub-population if any treatment group consists of less than 
10 subjects within that sub-population.  Where a sub-population contains less than 10 subjects
in any treatment group, only ns and treatment estimates will be presented (no treatment 
comparisons will be presented).
Forest plots will be used to summarise the estimates of the treatment effect for the applicable 
subgroups. 


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
79
Table 3
Overview of subgroup analyses at Week 24
Analysis
IFN test
24-hour UPCR
OCS at baseline
24-hour UPCR
X
X
X
CRR
X
X
X
Table 4
Overview of subgroup analyses at Week 52
Analysis
IFN test
24-hour UPCR
Age
Placebo response
Race
Number of 
methylprednisolone 
pulses
Screening biopsy
ADA result
OCS at baseline
eGFR at baseline
24-hour UPCR
X
X
X
X
X
X
X
X
X
X
CRR
X
X
X
X
X
X
X
X
X
aCRR
X
X
X
PRR
X
X
X
X
Graded CRR
X
X
X
X
OCS tapering
X
X
X
X
X
Table 5
Overview of subgroup analyses at Week 104
Analysis
IFN test
24-hour UPCR
OCS at baseline
eGFR at baseline
24-hour UPCR
X
X
X
X
CRR
X
X
X
X


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
80
Analysis
IFN test
24-hour UPCR
OCS at baseline
eGFR at baseline
PRR
X
X
Graded CRR
X
X
OCS tapering
X
X
5
INTERIM ANALYSES
One interim analysis either for efficacy or futility may be conducted after approximately 80% 
of subjects have completed the Week 52 visit or would have completed Week 52 if they had 
not discontinued the study. Primary efficacy and safety analyses will be performed once all 
data from the main study (up to and including Week 52) is available, cleaned and soft-locked. 
The study will also be unblinded at this stage for the team performing the analysis. 
Potential Interim analysis for futility
The objective of a potential interim analysis for futility is to give consideration for stopping 
the study early, should the chance of detecting a statistically significant difference with 
placebo for the primary endpoint at the final analysis be sufficiently small given the interim 
data. Non-binding futility rule for stopping the study will be used if a futility analysis is 
performed. Even though non-binding futility boundary will be used for stopping the study, if 
interim analysis for futility is performed, a portion of the 2-sided alpha will still be spent. A 
Peto-Haybittle spending function would be used with a fixed 2-sided p-value threshold of 
0.1% at the interim. The p-value threshold at the final analysis will be adjusted to account for 
the interim analysis, based on the actual observed information fraction for the primary 
endpoint. Under the assumption that there are 120 subjects included at the interim and 150 
subjects at the final analysis, the critical threshold at the final analysis will be 4.99% (East 
Version 6.4).
Considerations for stopping the study may be given if based on the observed effect at the 
interim analysis, the probability of detecting a statistically significant difference with placebo 
for the primary endpoint at the final analysis as measured by the predictive power (Herson, 
1979), is no higher than 20%. The predictive power will be derived from the following 
expression:
-4
567584 -.4 = Ф :(1 −;)<=
 ,>?.?@ ∙√; −CDEFGHIJK73L,
where


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
81
-
Ф denotes the cumulative distribution function of a standard normal distribution;
-
>?.?@ is the Z-score at the lower tail corresponding to a 2-sided alpha level 0.0499 
assuming 120 patients in the interim analysis (lower tail is used instead of upper due to 
using a logarithmic scale);
-
CNEFG is the observed at the interim analysis log-transformed relative difference in the 
change from baseline to Week 52 in 24-hour UPCR between the pooled anifrolumab 
treatment group versus placebo;
-
IEFG is the information at the futility analysis IEFG = O%CNEFG&P
<=, which can be 
estimated as 1/QQRQ
2
, where QQRQ
2
is the standard error of the relative difference in 
change from baseline in 24-hour UPCR on a logarithmic scale from the MMRM model 
for the primary endpoint at the interim analysis;
-
; is the fraction of information ; =
STUV
STWX =
YFZ[\] ^E _`G	\YGa 	Y Gb\ 	YG\]	Z `Y`cda	a
\e_\fG\g YFZ[\] ^E _`G	\YGa 	Y Gb\ E	Y`c `Y`cda	a, if IE	Y = O%CNE	Y&P
<= is the 
information at the final analysis. 
The above derivation is based on the weighted average of the conditional power over values of 
the difference with placebo θ, drawn from the posterior distribution below, which is obtained 
using an uninformative prior (Jennison & Turnbull, 2000):
C|jEFG ~ l :CNJK7, 1
IEFG
L,
The conditional power is the conditional probability that the final test statistic will exceed a 
critical value given the data observed thus far and an assumption about the pattern of the data 
to be observed in the remainder of the study, expressed as:
m.
575.n -.4 = 1 −Ф o(1 −;)<=
 ,CDEFGHIJK7 ∙√; −>?.?p@3 + CIJK7
;
q1 −;r.
Based on the above, the corresponding treatment effect boundary providing 20% predictive 
power can be calculated as:
sEFG = 4 t:>0.025 + >1−20%H1
; −1L 
;
IEFG
x
An observed effect CDEFG worse than sEFG corresponds to a predictive power less than 20%.
Potential Interim analysis for efficacy
 
 Even though there is no provision to stop the study early due to an 
efficacy claim, if an interim analysis for efficacy is performed, a portion of the 2-sided alpha 
CCI


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
82
will be spent. A Peto-Haybittle spending function would therefore be used with a fixed 
2-sided p-value threshold of 0.1% at the interim. The p-value threshold at the final analysis 
will be adjusted to account for the interim analysis, based on the actual observed information 
fraction for the primary endpoint. Under the assumption that there are 120 subjects included at 
the interim and 150 subjects at the final analysis, the critical threshold at the final analysis will 
be 4.99% (East Version 6.4).
6
CHANGES OF ANALYSIS FROM PROTOCOL
A possible interim analysis for futility may be performed, following results from a pivotal 
Phase 3 SLE study for anifrolumab in subjects with SLE. In the case that there is sufficient 
evidence to suggest that anifrolumab in addition to SOC is not beneficial over placebo in 
addition to SOC for subjects with SLE, consideration can be giving for stopping this study 
early for ethical reasons. The presence of such evidence can be evaluated only after obtaining 
results from the second anifrolumab pivotal study in SLE.
The threshold for the analysis of sustained reduction in OCS has been updated from 10 to 20.
The OCS at baseline subgroup categories are changed from (≤20 mg/day, >20 mg/day) in the 
protocol to (<20 mg/day, ≥20 mg/day) in the SAP for consistency with the sustained reduction 
in OCS endpoint definition.


Statistical Analysis Plan 
Study Code D3461C00007
Edition Number 5.0
Date 24 March 2020
7
REFERENCES
Austin H, M. L. (1983). Prognostic factors in Lupus Nephritis. American Journal of Medicine, 
75, 382-391.
Furie R, N. K.-V. (2014). Efficacy and safety of abatacept in lupus nephritis: a twelve-month, 
randomized, double-blind study. Arthritis Rhematology, 66(2), 379-389.
Herson, J. (1979). Predictive probability early termination plans for phase II clinical trials. 
Biometrics, 35, 775-783.
Jennison, C., & Turnbull, B. (2000). Group sequential methods with applications in clinical 
trials. Chapman & Hall.
Levey AS, C. J. (2006). Using Standardized Serum Creatinine Values in the Modification of 
Diet in Renal DIsease Study Equation for Estimating Glomerular Filtration Rate. 
Annals of Internal Medicine, 145(4), 247-254.
Stokes ME, D. C. (2012). Categorical Data Analysis using SAS (Third ed.). USA: SAS 
Institute.
Weening J, D. V. (2004). The classification of glomerulonephritis in systemic lupus 
erythematosus revisited. Kidney International, 65, 521-530.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d3461c00007-sap-ed-5
Document Title:
D3461C00007 Statistical Analysis Plan Edition 5
Document ID:
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
25-Mar-2020 13:35 UTC
Content Approval
25-Mar-2020 13:37 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
CCI