Clinical trial NCT04181762
Conditions: Lupus Nephritis
Keywords: Systemic Lupus Erythematosus (SLE) Lupus Nephritis (LN) secukinumab renal biopsy estimated Glomerular Filtration Rate (eGFR) Urine Protein-to-Creatinine Ratio (UPCR) Standard of Care (SoC) background therapy
Sponsor: Novartis Pharmaceuticals
Start date: 2020-07-07; Completion date: 2023-09-13
Enrollment: 275 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a pivotal, randomized, double-blind, placebo-controlled trial evaluating at Week 52 the efficacy and safety of secukinumab versus placebo in patients with active lupus nephritis (ISN/RPS Class III or IV, with or without co-existing class V features) also receiving background standard of care therapy (SoC).

Detailed description:
The study consisted of the following parts:

* Screening (up to 42 days/6 weeks)
* Run-in period (optional): For subjects who received Mycophenolic acid (MPA) as SoC induction therapy as per investigator's decision and who were not already on MPA at Screening, MPA dosing was initiated during a run-in period before Randomization (for up to 4 weeks prior to the first dose of secukinumab)
* Treatment Period: Duration of 104 weeks of treatment with secukinumab/placebo in addition to SoC treatment (with last dose given at Week 100)
* Secukinumab dosing was started with initial dosing of 300 mg s.c. injections at Baseline, Weeks 1, 2, 3, and 4, followed by dosing every 4 weeks
* Follow-up period: Duration of 8 weeks (last visit performed 12 weeks after last dose of study medication) for all except for subjects entering extension study CAIN457Q12301E1 (NCT05232864).

A total of 275 subjects were enrolled and were randomized to secukinumab 300 mg (n = 137) or placebo (n = 138) until study termination. Recruitment in this study was stopped on 26-May-2023. The CAIN457Q12301 study was terminated early by Novartis due to futile results from interim analysis 1 (IA1). There was no safety related reasons for early termination or concerns for the subjects in the study. The decision was made to terminate both the core and the related extension study in view of treatment futility of the core study.

Arms: arm 1: A blinded, weekly, subcutaneous (s.c.) secukinumab 300 mg loading regimen was administered for the first 4 weeks followed by a monthly maintenance dose in all randomized subjects thereafter. arm 2: A blinded, weekly, subcutaneous (s.c.) matching placebo loading regimen was administered for the first 4 weeks followed by a monthly maintenance dose in all randomized subjects thereafter.
Interventions: intervention 1: secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: STUDY DRUG intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
Official Title:    A Two-year, Phase III Randomized, Double-blind, Parallel-group, Placebo-
controlled Trial to Evaluate the Safety, Efficacy, and Tolerability of 300 
mg s.c. Secukinumab Versus Placebo, in Combination With SoC 
Therapy, in Patients With Active Lupus Nephritis
NCT Number: 
 NCT04181762 
Document Date: 
 Protocol Amendment 1: 17-February-2023
                                 Original Protocol: 11-October-2019


Novartis Research and Development 
Secukinumab (AIN457) 
 Clinical Trial Protocol CAIN457Q12301
A two-year, phase III randomized, double-blind, parallel-
group, placebo-controlled trial to evaluate the safety, 
efficacy, and tolerability of 300 mg s.c. secukinumab 
versus placebo, in combination with SoC therapy, in 
patients with active lupus nephritis 
Document type: 
Amended Protocol Version 
Regulatory agency 
Identifier Number(s): 
2019-003211-57 
Version number: 
01 (Clean) 
Study Phase: 
III 
Acronym: 
SELUNE 
Approval date: 
17-Feb-2023
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 


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Amended Protocol Version 01 (Clean) 
Protocol No. CAIN457Q12301 
Table of Contents 
Table of Contents ................................................................................................................ 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 11 
Amendment 1 (17-Feb-2023) ............................................................................................ 13 
Protocol summary .............................................................................................................. 16 
1 
Introduction ....................................................................................................................... 21 
1.1 
Background ............................................................................................................ 21 
1.1.1 
Lupus nephritis ...................................................................................... 21 
1.1.2 
Scientific rationale for targeting IL-17 in lupus nephritis ..................... 22 
1.1.3 
Secukinumab ......................................................................................... 23 
1.2 
Purpose .................................................................................................................. 24 
2 
Objectives and endpoints ................................................................................................... 24 
2.1 
Primary estimand ................................................................................................... 27 
2.2 
Secondary estimands ............................................................................................. 28 
3 
Study design ...................................................................................................................... 29 
4 
Rationale ............................................................................................................................ 32 
4.1 
Rationale for study design ..................................................................................... 32 
4.1.1 
Rationale for choice of background therapy ......................................... 32 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 33 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 33 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 34 
4.4.1 
First interim analysis ............................................................................. 34 
4.4.2 
Second interim analysis ......................................................................... 34 
4.5 
Risks and benefits .................................................................................................. 35 
4.6 
Rationale for public health emergency mitigation procedures .............................. 36 
5 
Population .......................................................................................................................... 36 
5.1 
Inclusion criteria .................................................................................................... 36 
5.2 
Exclusion criteria ................................................................................................... 37 
6 
Treatment ........................................................................................................................... 39 
6.1 
Study treatment ...................................................................................................... 39 
6.1.1 
Investigational and control drugs .......................................................... 39 
6.1.2 
Additional study treatments .................................................................. 40 
6.1.3 
SoC background therapy ....................................................................... 40 


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6.1.4 
Treatment arms/group ........................................................................... 42 
6.1.5 
Treatment duration ................................................................................ 42 
6.2 
Other treatment(s) .................................................................................................. 42 
6.2.1 
Concomitant therapy ............................................................................. 42 
6.2.2 
Prohibited medication ........................................................................... 44 
6.2.3 
Rescue medication ................................................................................ 44 
6.3 
Participant numbering, treatment assignment, randomization .............................. 44 
6.3.1 
Participant numbering ........................................................................... 44 
6.3.2 
Treatment assignment, randomization .................................................. 45 
6.4 
Treatment blinding ................................................................................................ 45 
6.5 
Dose escalation and dose modification.................................................................. 46 
6.5.1 
Dose modifications ................................................................................ 46 
6.5.2 
Follow-up for toxicities ......................................................................... 46 
6.6 
Additional treatment guidance ............................................................................... 47 
6.6.1 
Treatment compliance ........................................................................... 47 
6.6.2 
Recommended treatment of adverse events .......................................... 47 
6.6.3 
Emergency breaking of assigned treatment code .................................. 47 
6.7 
Preparation and dispensation ................................................................................. 48 
6.7.1 
Handling of study treatment and additional treatment .......................... 49 
7 
Informed consent procedures ............................................................................................ 50 
8 
Visit schedule and assessments ......................................................................................... 51 
8.1 
Screening ............................................................................................................... 57 
8.1.1 
Information to be collected on Screening failures ................................ 57 
8.1.2 
Re-screening .......................................................................................... 58 
8.2 
Participant demographics/other Baseline characteristics ....................................... 58 
8.2.1 
Demography .......................................................................................... 58 
8.2.2 
SLE/LN medical history/diagnosis ....................................................... 58 
8.2.3 
Prior SLE/LN medications and therapy ................................................ 58 
8.2.4 
Renal biopsy .......................................................................................... 58 
8.2.5 
Standard of care induction therapy ....................................................... 59 
8.2.6 
Smoking history .................................................................................... 59 
8.2.7 
Cardiovascular medical history ............................................................. 59 
8.2.8 
Relevant medical history/ current medical conditions .......................... 59 
8.2.9 
Prior and concomitant medications ....................................................... 60 
8.2.10 
Determination of the tuberculosis status ............................................... 60 
8.2.11 
Hepatitis and human immunodeficiency virus (HIV) screen ................ 60 
8.2.12 
Electrocardiogram (ECG) ..................................................................... 61 


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8.3 
Efficacy .................................................................................................................. 61 
8.3.1 
Complete Renal Response (CRR) ......................................................... 61 
8.3.2 
Partial Renal Response (PRR) .............................................................. 62 
8.3.3 
Average daily dose of corticosteroids ................................................... 62 
8.3.4 
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue©) ................................................................................. 62 
8.3.5 
Short Form Health Survey (SF-36) ....................................................... 62 
8.3.6 
Lupus Quality of Life (LupusQoL) ....................................................... 63 
8.3.7 
Urinary sediment ................................................................................... 63 
8.3.8 
Appropriateness of efficacy assessments .............................................. 63 
8.4 
Safety ..................................................................................................................... 64 
8.4.1 
Physical examination ............................................................................ 64 
8.4.2 
Vital signs.............................................................................................. 64 
8.4.3 
Height and weight ................................................................................. 65 
8.4.4 
Laboratory evaluations .......................................................................... 65 
8.4.5 
Pregnancy and assessments of fertility ................................................. 67 
8.4.6 
Other safety evaluations ........................................................................ 68 
8.4.7 
Appropriateness of safety measurements .............................................. 68 
8.5 
Additional assessments .......................................................................................... 68 
8.5.1 
Patient reported outcomes (PRO).......................................................... 68 
 
 69 
8.5.3 
Trial Feedback Questionnaire (TFQ) .................................................... 71 
 
 71 
 
 72 
8.5.6 
Biomarkers ............................................................................................ 73 
9 
Study discontinuation and completion .............................................................................. 75 
9.1 
Discontinuation ...................................................................................................... 75 
9.1.1 
Discontinuation of study treatment ....................................................... 75 
9.1.2 
Withdrawal of informed consent ........................................................... 76 
9.1.3 
Lost to follow-up ................................................................................... 77 
9.1.4 
Early study termination by the sponsor ................................................. 77 
9.2 
Study completion and post-study treatment .......................................................... 77 
10 Safety monitoring and reporting ........................................................................................ 78 
10.1 
Definition of adverse events and reporting requirements ...................................... 78 
10.1.1 
Adverse events ...................................................................................... 78 
10.1.2 
Serious adverse events .......................................................................... 79 
10.1.3 
SAE reporting........................................................................................ 80 


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10.1.4 
Pregnancy reporting .............................................................................. 81 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 81 
10.2 
Additional Safety Monitoring ................................................................................ 82 
10.2.1 
Liver safety monitoring ......................................................................... 82 
10.2.2 
Data Monitoring Committee ................................................................. 83 
10.2.3 
Steering Committee ............................................................................... 83 
11 Data Collection and Database management ...................................................................... 83 
11.1 
Data collection ....................................................................................................... 83 
11.2 
Database management and quality control ............................................................ 84 
11.3 
Site monitoring ...................................................................................................... 84 
11.4 
Data protection ...................................................................................................... 85 
12 Data analysis and statistical methods ................................................................................ 85 
12.1 
Analysis sets .......................................................................................................... 86 
12.2 
Subject demographics and other Baseline characteristics ..................................... 86 
12.3 
Treatments ............................................................................................................. 86 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 87 
12.4.1 
Definition of primary endpoint(s) ......................................................... 87 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 87 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 87 
12.4.4 
Handling of missing values not related to intercurrent events .............. 87 
12.4.5 
Sensitivity analyses ............................................................................... 88 
12.4.6 
Supplementary analyses ........................................................................ 88 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 88 
12.5.1 
Secondary efficacy endpoints ............................................................... 88 
12.5.2 
Safety endpoints .................................................................................... 92 
12.6 
Analysis of exploratory endpoints ......................................................................... 93 
12.6.1 
Patient reported outcomes ..................................................................... 95 
 
 95 
12.6.3 
DNA and RNA ...................................................................................... 96 
12.6.4 
Biomarkers ............................................................................................ 96 
 
 96 
12.7 
Interim analyses ..................................................................................................... 96 
12.7.1 
First interim analysis ............................................................................. 96 
12.7.2 
Second interim analysis ......................................................................... 97 
12.8 
Sample size calculation.......................................................................................... 97 
12.8.1 
Primary endpoint(s) ............................................................................... 97 
12.8.2 
Secondary endpoint(s) ........................................................................... 98 


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13 Ethical considerations and administrative procedures ...................................................... 99 
13.1 
Regulatory and ethical compliance ........................................................................ 99 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 99 
13.3 
Publication of study protocol and results............................................................... 99 
13.4 
Quality Control and Quality Assurance ............................................................... 100 
14 Protocol adherence .......................................................................................................... 100 
14.1 
Protocol amendments........................................................................................... 100 
15 References ....................................................................................................................... 101 
16 Appendices ...................................................................................................................... 107 
16.1 
ACR Criteria for Diagnosis of SLE ..................................................................... 107 
16.2 
International Society of Nephrology/Renal Pathology Society (ISN/RPS) 
2003 classification of LN..................................................................................... 109 
16.3 
Estimation of eGFR by the CKD-EPI ................................................................. 110 
16.4 
Recommended Diagram for administration of Standard of Care ........................ 111 
16.5 
Guidelines for administering PROs ..................................................................... 112 
 
. 114 
 
 116 
 
 116 
16.9 
Liver event and Laboratory trigger Definitions and Follow-up Requirements ... 117 
16.10 Clinically notable laboratory values .................................................................... 120 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 24 
Table 6-1 
Investigational and control drug ............................................................ 39 
Table 6-2 
Background therapy .............................................................................. 40 
Table 6-3 
Guidance for corticosteroid (prednisone equivalent) taper ................... 41 
Table 8-1 
Assessment Schedule ............................................................................ 52 
 
 71 
 
 73 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 82 
Table 12-1 
Power for primary endpoint .................................................................. 98 
Table 12-2 
Summary of power for binary secondary endpoints ............................. 98 
Table 12-3 
Summary of power or continuous endpoints ........................................ 98 
Table 12-4 
Summary of power for time to event endpoints .................................... 99 
Table 16-1 
Liver event and laboratory trigger definitions .................................... 117 
Table 16-2 
Follow up requirements for liver events and laboratory triggers ........ 117 


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Table 16-3 
Safety Analyses: Expanded Limits and Notable Criteria .................... 120 
List of figures 
Figure 3-1 
Study design .......................................................................................... 30 
Figure 12-1 
Testing strategy ..................................................................................... 90 


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Protocol No. CAIN457Q12301 
List of abbreviations 
 
 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibodies 
ANCOVA 
analysis of covariance 
anti-dsDNA 
Anti-double stranded DNA 
 
 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
 
 
BMI 
Body Mass Index 
BAFF 
B-cell activating factor
CFR 
Code of Federal Regulation 
CHMP 
Committee for Medicinal Products for Human Use 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
 
 
CNIs 
calcineurin inhibitors 
COAs 
Clinical Outcome Assessments 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Clinician reported outcomes 
CRR 
Complete Renal Response 
CT 
computed tomography scan 
CYC 
cyclophosphamide 
 
 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
ERA 
Enthesitis-Related Arthritis 
ERA-EDTA 
European Renal Association – European Dialysis and Transplant Association 
ESRD 
end-stage renal disease 
EULAR 
European League Against Rheumatism 
FACIT-Fatigue© Functional Assessment of Chronic Illness Therapy - Fatigue 


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Protocol No. CAIN457Q12301 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
h 
hour 
HbA1c 
Hemoglobin A1c 
HDL 
High Density Lipoprotein 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
hsCRP 
High sensitivity C-reactive protein 
i.v.
intravenous 
ICH 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
 
 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Individual Research Results 
IRT 
Interactive Response Technology 
ISN 
International Society of Nephrology 
JIA 
Juvenile idiopathic arthritis 
JPsA 
Juvenile psoriatic arthritis 
 
 
LDL 
Low Density Lipoprotein 
LFT 
Liver function test 
 
 
LLN 
lower limit of normal 
LLQ 
lower limit of quantification 
LN 
lupus nephritis 
mAb 
Monoclonal antibody 
 
 
mCRR 
modified Complete Renal Response 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
ml 
milliliter(s) 
MMF 
Mycophenolate mofetil 
MMRM 
Mixed-Effect Model Repeated Measure 
MPA 
mycophenolic acid 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
nr-axSpA 
non-radiographic axial spondyloarthritis 


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o.d.
once a day 
p.o.
per oral 
PA 
Posterior / Anterior view 
PCS 
physical component summary 
PD 
pharmacodynamic(s) 
PFS 
Prefilled syringe 
 
 
PK 
pharmacokinetic(s) 
PRR 
partial renal response 
PRO 
Patient reported outcomes 
PsA 
Psoriatic arthritis 
PsO 
Plaque psoriasis 
PT 
Prothrombin time 
PY 
Patient Year 
QoL 
Quality of Life 
RBC 
red blood cell(s) 
RNA 
ribonucleic acid 
RPS 
Renal Pathology Society 
s.c.
subcutaneous 
SAE 
serious adverse event 
SARS-CoV2 
Severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SF-36 
Medical Outcome Short Form (36) Health Survey 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SLE 
systemic lupus erythematosus 
 
 
SoC 
standard of care 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
total bilirubin 
TEAE 
Treatment-emergent adverse event 
TFQ 
Trial Feedback Questionnaire 
 
 
 
 
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
UPCR 
Urine Protein-to-Creatinine Ratio 
WBC 
white blood cell(s) 
WHO 
World Health Organization 


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Amended Protocol Version 01 (Clean) 
Protocol No. CAIN457Q12301 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
 A group of individuals who share a common exposure, experience or characteristic, or 
a group of individuals followed-up or traced over time 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects 
of the investigational drug. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g., 100 mg once a 
day, 75 mg twice a day)  
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained (i.e., prior to starting any of the procedures described in the protocol) 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same participants 
under different treatment conditions being compared. Attributes of an estimand include 
the population, variable (or endpoint) and treatment of interest, as well as the 
specification of how the remaining intercurrent events are addressed and a population-
level summary for the variable. 
Intercurrent 
events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as well as their 
associated treatment controls. This includes any placebos, any active controls, as well 
as approved drugs used outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by the protocol 
when used within approved indication/dosage. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that dispense 
study drug using an IRT system. 
Part 
A single component of a study, which contains different objectives or populations within 
that single study. Common parts within a study are: a single dose part and a multiple 
dose part, or a part in patients with established disease and in those with newly-
diagnosed disease. 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" terminology is 
used in the protocol whereas term "Subject" is used in data collection and for data 
analysis 
Participant 
number 
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc. 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as Screening, Baseline, titration, washout, etc. 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when study drug 
was discontinued whichever is later. 
Study treatment 
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational medicinal 
product(s) 


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Amended Protocol Version 01 (Clean) 
 
Protocol No. CAIN457Q12301 
 
Study treatment 
discontinuation 
Point/time when subject permanently stops taking study treatment for any reason; may 
or may not also be the point/time of premature subject withdrawal. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g., as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event. 
Withdrawal of 
consent (WoC) 
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop the use of their data and biological samples (opposition to use data and biological 
samples) AND no longer wishes to receive study treatment AND does not agree to 
further protocol required assessments. This request should be made in writing 
(depending on local regulations) and recorded in the source documentation. 
 


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Amended Protocol Version 01 (Clean) 
 
Protocol No. CAIN457Q12301 
 
Amendment 1 (17-Feb-2023) 
Amendment rationale  
The key purposes of Amendment 1 are to: 
Decrease the overall study sample size from 460 to 400 participants based on recent literature 
reporting results of Phase 3 studies in adult lupus nephritis populations (Furie et al 2020,  
Rovin et al 2021). In those two Phase 3 clinical trials (comparing voclosporin or belimumab 
versus placebo in combination with standard of care therapy with tapered doses of 
corticosteroids) with a study design similar to this current protocol, the complete renal response 
(CRR) rates at Week 52 for the placebo groups are lower than those reported in previous clinical 
trials in the same population (CRR rates at Week 52 in placebo arms were 23-25% versus a 
previously reported rate of 30% (Mysler et al 2013, Rovin et al 2012)). The placebo response 
rate in this study is therefore expected to be lower than originally assumed, which allows for a 
smaller sample size while retaining adequate statistical power. 
1. Replace the O’Brien-Fleming method with the Pocock method for alpha spending so that 
the superiority analysis (at the second interim analysis) can utilize more alpha and achieve 
higher power. This adjustment is made to compensate for the delay of the study triggered 
by the COVID-19 pandemic.  
2. Incorporate the estimand framework based on the ICH E9(R1) guideline “addendum on 
estimands and sensitivity analysis in clinical trials: to the guideline on statistical principles 
for clinical trials”, adopted in November 2019, after the release of the original study 
protocol (version 00, dated 11-Oct-2019).  
3. Address a Health Authority recommendation which was received for this study in 2020, 
pointing at the potential of corticosteroid overuse to confound the primary endpoint. The 
intercurrent event of “overuse of corticosteroid” was clearly defined and the strategy to 
handle it is specified as the non-responder composite endpoint strategy. 
4. Clarify the normal estimated glomerular filtration rate as (eGFR) ≥ 60mL/min/1.73m2, 
which is a component of the primary endpoint. 
In addition, further clarifications and corrections are made as specified below: 
5. Add clarifying details to the secondary efficacy analyses.  
6. Update the intercurrent event strategies for certain secondary estimands. 
7. Re-calculate the power for the secondary analyses based on the new sample size.  
8. Categorize the interim analyses as the first and second interim analyses. The first interim 
analysis includes the first futility analysis 
. The second interim analysis 
contains the superiority interim analysis and a second futility analysis.  
 
  
10. Removal of barrier method of contraception, which does not fulfill the criteria for highly 
effective contraception, and clarify that highly effective contraception is required during 
the study for any woman of childbearing potential due to Standard of Care background 
medications. 


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Amended Protocol Version 01 (Clean) 
 
Protocol No. CAIN457Q12301 
 
Lastly, Amendment 1 addresses commitments and comments received from EC/HAs to 
the original protocol, and introduces additional minor clarifications and administrative 
changes. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The following sections have been changed in the amended protocol: 
• Protocol Summary: Changes made to study participant number, and definition of active 
urinary sediment.  
• Section 1: Information on recently approved treatments for LN and newly approved 
secukinumab indications were added. 
• Section 2: The estimand framework has been added. Intercurrent events and the strategies 
to handle them were added in the endpoint definition.  
• Section 2: Estimated glomerular filtration rate (eGFR) was clarified. 
• Section 2: Exploratory objective endpoints was clarified. 
• Section 3: Guidance added for retest of inclusion / exclusion assessments. 
• Section 3: Information on the extension study was added. 
• Section 4.4: Interim analyses were categorized as first and second interim analyses. 
Another futility analysis would be performed at the second interim analysis.  
• Section 4.5: Reference for exposure- adjusted incidence rate of SAEs was added. 
• Section 4.6: was added to address public health emergency mitigation procedures. 
• Section 5: Total study sample size was updated from 460 to 400. 
• Section 5: Definition of “active urinary sediment” as presence of cellular casts (white 
blood cell or red blood cell casts) or hematuria (> 5 red blood cells per high power field or 
above the laboratory reference range) was clarified 
• Section 5.2: Exclusion criteria for barrier method of contraception removed, and guidance 
for country specific contraception requirements clarified. 
• Section 5.2: Timeframe for chest X-ray, CT or MRI clarified. 
• Section 6.1.4: Number of participants was updated from 230 to 200 per treatment arm 
• Section 6.1.5: Information on extension study was added. 
• Section 6.2.2: Updated information on administration of vaccines was added 
 
 
 
 
• Section 6.4: Details regarding return of Individual Results to Patients were added. 
• Section 8.1: Clarification on screening period was added. 
• Section 8.2.4: Clarification on Central Pathologist Charter for renal biopsy was added. 
• Section 8.4: Verbiage on safety assessment in Public Health emergency was added. 


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• Section 8.5: Verbiage on Clinical outcome assessment in Public Health emergency was 
added. 
• Section 8.5: Verbiage on additional spot urine was added for optional biomarker informed 
consent. 
 
 
• Section 11.4: Data Protection section was added to describe how data will be handled.  
• Section 12.4: Components of the primary endpoint were clarified and intercurrent event 
strategies, sensitivity analysis, modified complete renal response and treatment policy 
estimand sections were updated. 
• Section 12.5: Estimand definitions for the secondary variables removed. 
• Section 12.6: Secondary efficacy endpoints were clearly stated.  
• Section 12.7: Interim analyses were categorized as first and second interim analyses. 
Another futility analysis would be performed at the second interim analysis.  
• Section 12.7: O’Brien-Fleming method was replaced with Pocock method for alpha 
spending so that the superiority analysis (at the second interim analysis) could utilize more 
alpha and achieve higher power. Note that the overall Type I error rate is still controlled. 
• Section 12.7: The information proportion of the first and second interim analyses were 
altered due to the change of the overall sample size. 
• Section 12.8: The overall sample size was changed from 460 to 400 based on an updated 
lower placebo response rate. 
• Section 12.8: The powers for primary and secondary efficacy analyses were updated with 
the new sample size. 
• Section 15: New references were added. 
This protocol amendment also includes editorial revisions, corrections, and clarifications 
throughout the protocol to improve consistency. In addition, the term 'subject' is replaced 
throughout the protocol with the term 'participant' and 'patient'. 
IRBs/IECs 
A copy of this amended protocol will be sent to Institutional Review Boards (IRBs)/ 
Independent Ethic Committees (IECs) and Health Authorities. 
The changes described in this amended protocol are substantial and require IRB/IEC and Health 
Authority approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent (Global Model) that takes into account the changes 
described in this protocol amendment. 


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Protocol summary 
Protocol number 
CAIN457Q12301 
Full Title 
A two-year, phase III randomized, double-blind, parallel-group, placebo-controlled trial 
to evaluate the safety, efficacy, and tolerability of 300 mg s.c. secukinumab versus 
placebo, in combination with SoC therapy, in patients with active lupus nephritis 
Brief title 
Study of safety, efficacy and tolerability of secukinumab versus placebo, in combination 
with SoC therapy, in patients with active lupus nephritis 
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation 
type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this trial is to evaluate the efficacy and safety of subcutaneous 
secukinumab 300 mg compared to placebo, in combination with standard of care 
therapy (SoC), in patients with active lupus nephritis (ISN/RPS Class III or IV, with or 
without co-existing class V features). Background SoC will consist of induction therapy 
with mycophenolic acid (MPA) (which refers to Mycophenolate mofetil (MMF) 
(Cellcept® or generic equivalent), or enteric-coated MPA sodium (Myfortic® or generic 
equivalent) at equivalent doses (oral), or Cyclophosphamide (CYC) (i.v.), followed by 
maintenance therapy with MPA (MMF, enteric-coated MPA sodium, or their generics). 
In addition, all participants will receive i.v. and/or oral corticosteroids. 
The aim of the study is to demonstrate the efficacy and safety of secukinumab in LN 
that will enable registration for the indication of lupus nephritis. 
Primary 
Objective(s)  
The primary objective is to demonstrate that secukinumab 300 mg is superior to 
placebo in Complete Renal Response (CRR) rate at Week 52 in active lupus nephritis 
(ISN/RPS Class III or IV, with or without co-existing Class V features) patients on a 
background of SoC therapy 
Secondary 
Objectives 
Objective 1: To demonstrate superiority of secukinumab compared to placebo in 
change from Baseline in 24-hour UPCR at Week 52 
Objective 2: To demonstrate superiority of secukinumab compared to placebo in 
proportion of patients achieving partial renal response (PRR) at Week 52 
Objective 3: To demonstrate superiority of secukinumab compared to placebo in 
average daily dose of oral corticosteroids administered between Week 16 and Week 52 
Objective 4: To demonstrate superiority of secukinumab compared to placebo in 
proportion of patients achieving PRR at Week 24 
Objective 5: To demonstrate superiority of secukinumab compared to placebo in time to 
achieve CRR 
Objective 6: To demonstrate superiority of secukinumab compared to placebo in time to 
achieve PRR 
Objective 7: To demonstrate superiority of secukinumab compared to placebo in time to 
achieve first morning void Urine Protein-to-Creatinine Ratio (UPCR) ≤ 0.5 mg/mg 
Objective 8: To demonstrate superiority of secukinumab compared to placebo in 
change in Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-
Fatigue©) score at Week 52 
Objective 9: To demonstrate superiority of secukinumab compared to placebo in 
patient’s health related quality of life via Medical Outcome Short Form Health Survey 
(SF-36 Physical Component Summary (PCS)) score at Week 52 
Objective 10: To demonstrate superiority of secukinumab compared to placebo in 
change of LupusQoL (Physical Health) score at Week 52 
Objective 11: To evaluate the safety and tolerability of secukinumab s.c. as an add-on 
therapy to Standard of Care in lupus nephritis patients 
Objective 12: To estimate the proportion of patients with maintained renal response at 
Week 104 


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Objective 13: To estimate the proportion of patients with improved or maintained renal 
response at Week 104 
Study design 
This is a pivotal, randomized, double-blind, placebo-controlled trial evaluating at Week 
52 the efficacy and safety of secukinumab versus placebo in patients with active lupus 
nephritis also receiving background SoC regimen. In addition, long-term efficacy, safety 
and tolerability will be collected up to 2 years. 
Population 
The study population will be comprised of adult male and female participants in the age 
range of 18-75 years with a renal biopsy (results current or within the 6 months prior to 
Screening) showing active glomerulonephritis WHO or ISN/RPS Class III or IV LN 
[excluding III (C), IV-S (C) and IV-G (C)], with or without co-existing class V features, 
who are inadequately controlled with previous SoC defined as having UPCR ≥1 mg/mg 
and active urinary sediment defined as hematuria (presence of >5 red blood cells 
(RBC)/ high power field (hpf) or above the laboratory reference range) OR presence of 
cellular casts (RBC or WBC casts). 
Approximately 400 participants, randomized into two treatment arms (1:1 active: 
placebo), are planned. At randomization, participants will be stratified on the basis of 
the SoC induction therapy they will receive during the study, MPA or CYC-based, to 
ensure a balanced representation in each of the treatment arms (secukinumab or 
placebo). The target will be to have a maximum of 25% of randomized participants 
receiving CYC-based induction therapy. 
Key Inclusion 
criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Adult male and female participants aged 18 - 75 years old at the time of Baseline 
2. Confirmed diagnosis of: 
- 
SLE with documented history of at least 4 of the 11 criteria for SLE as defined 
by the American College of Rheumatology (ACR). [NOTE: The 4 criteria do 
not have to be present at the time of Screening], 
OR 
- 
Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-
dsDNA antibodies. 
3. Active lupus nephritis, as defined by meeting the 4 following criteria: 
- 
Biopsy within 6 months prior to Screening visit indicating active 
glomerulonephritis WHO or ISN/RPS Class III or IV LN [excluding III (C), IV-S 
(C) and IV-G (C)]; participants are permitted to have co-existing Class V. If no 
biopsy was performed within 6 months of Screening, a biopsy will need to be 
performed during the Screening period, after all other inclusion/exclusion 
criteria would have been verified. 
- 
UPCR ≥ 1 mg/mg at Screening 
- 
eGFR > 30 mL/min/1.73m2 by Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) 
- 
Active urinary sediment as defined by at least 1 of the following: 
- 
Hematuria >5 RBC/hpf or above the laboratory reference range. 
- 
Presence of cellular casts (RBC or WBC). 
4. Participants must be currently on MPA, or willing to initiate SoC induction therapy 
for LN according to the institutional practices using MPA (MMF or enteric-coated 
MPA sodium) or low-dose CYC in addition to corticosteroids. 
5. If the participant is on cholesterol-lowering agents, the dose must be stable for at 
least 7 days prior to Randomization. 
6. Participants must be treated with anti-malarials (e.g., hydroxychloroquine), unless 
contra-indicated, and the dose must be stable for at least 10 days prior to 
Randomization. 
7. Able to provide signed informed consent. 
Key Exclusion 
criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this 
study. 


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1. Severe renal impairment as defined by i.) Stage 4 CKD, or ii.) presence of oliguria 
(defined as a documented urine volume < 400 mL/24 h), or iii.) ESRD requiring 
dialysis or transplantation 
2. Known intolerance/hypersensitivity to MPA (MMF or enteric-coated MPA sodium), 
or oral corticosteroids, or any component of the study treatment 
3. Participants having received any other biologic immunomodulatory therapy within 6 
months prior to Screening, excluding belimumab where 3 months are acceptable 
4. Previous exposure to secukinumab (AIN457) or any other biologic drug targeting 
IL-17 or the IL-17 receptor 
5. Participants having received any investigational drug within 1 month or five times 
the half-life, whichever is longer 
6. Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) 
within the 12 weeks prior to Baseline 
7. Treatment with a systemic calcineurin inhibitor (e.g., cyclosporine, tacrolimus) 
within 12 weeks prior to Baseline 
8. CYC use (i.v. or oral) within the month prior to Baseline 
9. Participants requiring dialysis within the previous 12 months before Screening 
10. History of renal transplant 
11. Any severe progressive or uncontrolled concurrent medical condition, including 
recent severe thromboembolic events, that, in the opinion of the principal 
investigator, renders the participant unsuitable for the trial 
12. Active ongoing inflammatory diseases that might confound the evaluation of the 
benefit of secukinumab therapy, including inflammatory bowel disease 
13. Presence of investigator-identified significant medical problems which at the 
investigator’s discretion will prevent the patient from participating in the study, 
including but not limited to the following: myocarditis, pericarditis, poorly controlled 
seizure disorder, acute confusional state, depression, severe manifestations of 
neuropsychiatric SLE (NPSLE) 
14. Chest X-ray, computerized tomography (CT) scan, or MRI with evidence of ongoing 
infectious or malignant process, obtained within three months prior to Screening 
and evaluated by a qualified physician 
15. History of chronic, recurrent systemic infections, active tuberculosis infection, or 
active systemic infections during the last two weeks (exception: common cold) prior 
to Randomization 
16. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis 
C at Screening or Randomization 
17. History of lymphoproliferative disease or any known malignancy or history of 
malignancy of any organ system treated or untreated within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases (except 
for skin Bowen’s disease or basal cell carcinoma or actinic keratoses that have 
been treated with no evidence of recurrence in the past 12 weeks, carcinoma in 
situ of the cervix or non-invasive malignant colon polyps that have been removed) 
18. Any of the following abnormal laboratory values on Screening evaluations as 
reported by Central Laboratory: 
· Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase > 
2.5xULN 
· Hemoglobin < 8g/dL 
· Neutrophils < 1.0 x 109/L 
· Platelet count < 50 x 109/L 
19. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of venous access) 
20. History or evidence of ongoing alcohol or drug abuse, within the last six months 
before Randomization 
21. Pregnant or lactating women 


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22. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of 
contraception during the entire study or longer if required by locally approved 
prescribing information (e.g., in European Union (EU) 20 weeks). Of note: the 
highly effective methods of contraception are mandated due to SoC medications 
used as per protocol (MPA and CYC). 
Study treatment 
At Baseline, all eligible participants will be randomized to one of the two treatment arms 
in a 1:1 ratio via Interactive Response Technology (IRT): 
• Arm 1: approximately 200 participants with LN will receive secukinumab 300 mg 
s.c. (2 x 1.0 mL PFS of 150 mg dose) at Randomization, Weeks 1, 2 and 3, and 
every 4 weeks from Week 4 until Week 100 
• Arm 2: approximately 200 participants with LN will receive placebo s.c. (2 x 1.0 mL 
PFS of 0 mg dose) at Randomization, Weeks 1, 2 and 3, and every 4 weeks from 
Week 4 until Week 100 
At Randomization, participants will be stratified on the basis of the SoC induction therapy 
they will receive during the study, MPA or CYC-based, to ensure a balanced 
representation in each of the treatment arms (secukinumab or placebo). 
Efficacy 
assessments 
• Assessment of CRR 
• Time to achieve UPCR ≤ 0.5 mg/mg 
• Assessment of PRR  
• Average daily dose of oral corticosteroids 
• Time to achieve CRR 
• Time to achieve PRR 
• FACIT-Fatigue© score 
• SF-36 PCS score 
• LupusQoL Physical Health score 
Key safety 
assessments 
• Physical examinations 
• Vital signs 
• Height and weight 
• Laboratory evaluations (hematology, clinical chemistry, coagulation panel, local 
urinalysis, 24-hour urine collection, lipid panel, 
 
 and pregnancy test) 
• Chest X-ray 
• Evaluation of AEs and SAEs 
Other 
assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Biomarkers (urine and serum) 
• Pharmacogenetics; DNA and RNA analysis 
Data analysis 
The primary efficacy endpoint is the CRR at Week 52 with the consideration of 
intercurrent events. See Section 2.1 for detail. 


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The statistical hypothesis tested for the primary objective is that there is no difference 
in the proportion of patients fulfilling the response criteria at Week 52 between the 
secukinumab regimen and placebo regimens. 
Let pj denote the proportion of responders at Week 52 for treatment regimens j, 
 j = 0, 1 where 
· 0 corresponds to placebo regimen, 
· 1 corresponds to secukinumab, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e., 
H1: secukinumab is not different to placebo regimen with respect to CRR at Week 52 
Logistic regression model adjusting for SoC, race and Baseline UPCR will be used for 
the primary analysis. Difference in marginal response proportions with p-value and 
respective 95% confidence interval will be estimated from the logistic regression model. 
Safety analyses will include summaries of AEs, laboratory measurements, and vital 
signs. 
Full details of all data analyses will be specified in the statistical analysis plan. 
Key words 
Systemic Lupus Erythematosus (SLE), Lupus Nephritis (LN), secukinumab, renal 
biopsy, estimated glomerular filtration rate (eGFR), Urine Protein-to-Creatinine Ratio 
(UPCR), Standard of care (SoC) background therapy 


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1 
Introduction 
1.1 
Background 
1.1.1 
Lupus nephritis 
Lupus nephritis is estimated to affect more than one-half of SLE patients and is a severe 
manifestation in SLE (Cervera et al 2003). 
Immune complex formation in LN related to a plethora of autoantibodies, especially anti-
dsDNA and anti-nucleosome antibodies, is the result of systemic autoimmunity and is a 
hallmark of the disease (Waldman and Madaio 2005, Nowling and Gilkeson 2011) that is 
generally treated by systemic immunosuppression. Once formed, immune complexes activate 
complement, which can injure renal cells leading to either mesangial LN (class I, II), 
proliferative LN (class III, IV), membranous LN (class V) and advanced sclerotic LN (class 
VI). However, pathogenesis of LN is complex and involves both the innate and adaptive 
immune systems; various cytokines, immune tissues and cell types are involved in its 
pathogenesis. Intra-renal inflammation is maintained via local cytokine and chemokine 
production, and by cells of the innate immune system such as neutrophils, that are attracted into 
the glomerulus and interstitium. Targeting local release of proinflammatory cytokines by 
blocking single cytokine pathways may enhance treatment efficacy in autoimmunity without 
increasing systemic immunosuppression (Allam and Anders 2008). 
Lupus nephritis is characterized by glomerular endothelium, podocyte, tubulointerstitial and 
vascular injury. Specific leukocyte subsets, including IL-17-producing T helper type 17 (TH17) 
cells, drive inflammation and contribute to renal immunopathology (Yu et al 2017). 
Lupus nephritis is categorized histologically into 6 classes by the International Society of 
Nephrology/Renal Pathology Society (ISN/RPS) classification system (Weening et al 2004, 
Markowitz and D'Agati 2007). Treatments include management with corticosteroids together 
with anti-malarials for lower stage disease, followed by more aggressive immunosuppressive 
therapies for more severe disease, and ultimately renal transplant. 
Class III and IV LN are detected in approximately 39 to 71.9% of LN patients, and from the 
deposition of immune complexes in the subendothelial space of the glomerular capillaries 
(Wang et al 2018). Both these classes of LN are considered to have similar lesions that differ 
by severity and distribution. Class IV diffuse LN is distinguished from class III on the basis of 
involvement of more than 50% of glomeruli with endocapillary lesions. Patients with class III 
and IV LN require aggressive therapy with glucocorticoids and immunosuppressive agents 
including cyclophosphamide (CYC), mycophenolate mofetil (MMF), rituximab as well as 
calcineurin inhibitors (CNIs) (Hahn et al 2012). 
Lupus nephritis is associated with significant morbidity and mortality, even with current 
treatments. With current induction and maintenance therapies, the risk of developing LN-related 
end-stage renal disease (ESRD) at 5, 10, and 15 years remained at 11%, 17%, and 22%, 
respectively, for the last decade (Tektonidou et al 2016, Faurschou et al 2010). Two new 
therapeutic options for LN patients on top of SoC include the calcineurin inhibitor (CNI) 
voclosporin (Rovin et al 2021) and the soluble B-cell activating factor (BAFF) blocking 
monoclonal antibody (mAb) belimumab (Furie et al 2020). However, there remains a high 


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unmet medical need and the effects of these agents on long-term outcomes are unknown. 
Therefore, despite those recent drug approvals, LN continues to be associated with significant 
morbidity and mortality (Lichtnekert et al 2022).The European League Against Rheumatism 
(EULAR)/European Renal Association – European Dialysis and Transplant Association (ERA-
EDTA) and ACR guidelines are uniform in their recommendations for therapy for class III and 
IV LN and include a sequence of induction and maintenance phases. For patients with class III 
or IV proliferative glomerulonephritis, the guidelines recommend induction therapy with MPA 
(MMF or enteric-coated MPA sodium) or intravenous (i.v.) CYC, with or without initial pulses 
of i.v. methylprednisolone. With current induction regimens, less than 60% of class III to V 
patients achieve a complete or partial response (Appel et al 2009). Among those who attain a 
complete renal response (CRR) with current standard-of-care (SoC), nearly half of the patients 
had a relapse. The incidence rate of relapse in these patients was 5 to 15 per 100 patient year 
(PY) (Grootscholten and Berden 2006). 
Despite the aggressive nature of SoC treatment, and the addition of voclosporin and belimumab 
as further treatment options available for LN, only up to 40% of patients achieve a CRR after 1 
year (Rovin and Parikh 2014, Furie et al 2020, Rovin et al 2021). In addition, current LN 
treatment regimens have substantial side effects from glucocorticoids and prolonged 
immunosuppression (Schwartz et al 2014). Immunosuppressed LN patients are at significant 
risk of developing serious infections. In a multiethnic Medicaid cohort, the incidence rate of 
serious infections was more than 2-fold higher in LN than in SLE patients (Feldman et al 2015). 
Thus, given the severity of the condition, there is a high unmet medical need for more effective 
therapies with a favorable benefit:risk profile for the treatment of LN patients. 
1.1.2 
Scientific rationale for targeting IL-17 in lupus nephritis 
Animal model studies have demonstrated that the IL-17 and upstream IL-23 pathways 
contribute to renal injury in experimental models of LN or glomerulonephritis. IL-23 receptor 
deficiency decreased the number of IL-17A-producing double-negative (DN) T cells, produced 
less anti-DNA antibodies and prevented glomerulonephritis in lupus-prone C57BL/6-lpr/lpr 
mice (Kyttaris et al 2010); treatment with an anti-IL-23 antibody in the same mouse model 
ameliorated nephritis and was accompanied by a reduction of IL-17A produced by in 
vitro stimulated splenocytes post-treatment (Kyttaris et al 2013). Both IL-23p19 and IL-17A 
knock-out mice developed less severe nephritis in a T cell-mediated murine model of 
nephrotoxic nephritis (Paust et al 2009). Elevated expression of IL-17A was observed in lupus-
prone Fcgr2b knock-out mice, which develop fatal lupus glomerulonephritis, while mice 
lacking IL-17 displayed increased survival and protection from glomerulonephritis 
(Pisitkun et al 2014). Additional support for a role of IL-17A in LN has been provided in the 
pristane-induced LN mouse model, in which absence of IL-17A led to decreased renal 
inflammation and renal injury, along with reduced levels of anti-DNA antibodies 
(Summers et al 2014). In this model, macrophages as well as neutrophils were the main 
producers of IL-17A. Thus, based on these animal data, blocking IL-17A in LN may prove 
beneficial in limiting glomerular inflammation and renal damage. 
A growing number of studies in patients with LN indicate that IL-17A and Th17 cells play 
important roles in the pathogenesis of LN, contributing to glomerular injury and the persistence 
of inflammation and renal damage (Zhang et al 2009, Crispín et al 2008) and high levels of IL-


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17 predict poor histopathological outcomes after immunosuppressive therapy in patients with 
LN (Zickert et al 2015). A set of T cells infiltrates the kidneys of patients with LN and represent 
the major source for IL-17 (Crispín and Tsokos 2008). IL-17 has the potential to induce the 
production of additional inflammatory cytokines and chemokines and to promote recruitment 
of inflammatory cells such as monocytes and neutrophils to inflamed organs. Higher levels of 
glomerular IL-17 and IL-23 expression are observed in renal biopsies from class IV LN patients 
as compared with those from minimal change nephropathy patients and normal controls. Both 
glomerular IL-17 and IL-23 expression levels positively correlate with renal histological 
activity index scores for LN patients (Chen et al 2012). The urinary expression of Th17-related 
genes, including those for IL-17 and IL-23, is increased and associated with the activity of LN 
(Kwan et al 2009). 
Additional evidence shows that neutrophil recruitment to the kidney starts several hours after 
the induction of nephrotoxic nephritis and is partly mediated by IL-17A-producing γδ T cells 
(Kurts et al 2013). 
Th17 
cells 
promote 
intra-renal 
IL-17A 
expression 
in 
LN 
(Crispín and Tsokos 2008). IL-17 can also drive T cells away from maturing into a regulatory 
T cell phenotype that can suppress autoantibody production and attenuate the systemic immune 
response (Bettelli et al 2006). 
An imbalance between inflammatory Th17 and regulatory T cells and the secretion of 
inflammatory cytokines including IL-17A amplify the immune response in LN by inducing the 
local production of chemokines and cytokines, as well as the recruitment of neutrophils and 
monocytes. This ultimately contributes to persistent inflammation and kidney damage in LN 
(Koga et al 2017). IL-17A can also act directly on kidney cells such as mesangial cells 
(Paust et al 2009 ), tubular epithelial cells (Hirai et al 2012) and podocytes (Yan et al 2018), 
thereby increasing inflammation, T cell and neutrophil infiltration, and disruption of renal 
function leading to proteinuria. Therefore, a pathogenic model for glomerulonephritis is 
emerging in which Th17 cells infiltrate the kidney and IL-17A (as well as potentially other 
cytokines) produced by Th17 cells acts directly on resident kidney cells to induce cytokines and 
chemokines that lead to further recruitment of Th17 cells and neutrophils into the tissue, 
resulting in renal tissue damage (Krebs et al 2017).  
A case report of a patient with refractory LN and concomitant psoriasis vulgaris suggests that 
treatment with the IL-17A inhibitor secukinumab may have contributed to an improvement in 
renal function and a decrease in urine protein levels in this patient (Satoh et al 2018). An 
additional case was reported of a childbearing woman with SLE who developed refractory LN 
despite use of all standard therapeutic options. After starting secukinumab, clinical and 
biological features improved, and complete renal response was achieved (Costa et al 2021). 
1.1.3 
Secukinumab 
Secukinumab is a recombinant high-affinity fully human monoclonal anti-human IL-17A 
antibody of the IgG1/kappa isotype. 
Secukinumab is currently approved in more than 100 countries worldwide. The product is 
indicated for the treatment of adults and children aged 6 years and above with moderate to 
severe plaque psoriasis (PsO), as well as adults with psoriatic arthritis (PsA), ankylosing 
spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA). It is also approved 


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for two juvenile idiopathic arthritis (JIA) subtypes (juvenile PsA (JPsA) and enthesitis-related 
arthritis (ERA)).  
The outcome of the extensive Novartis clinical program comprising more than 25 Phase III 
studies and at least 17,000 participants studied over a period of up to 5 years in these indications 
has shown that secukinumab offers robust and clinically meaningful efficacy to these patients 
and is complemented by a consistently favorable benefit:risk profile. The safety profile of 
secukinumab was indeed consistent and comparable across all indications supporting its long-
term use in these chronic inflammatory conditions. 
Based on the available data suggesting that IL-17 is an appropriate therapeutic target for patients 
with LN, secukinumab has the potential to be an effective therapy for patients with active LN 
(ISN/RPS Class III or IV, with or without co-existing Class V features), when used in 
combination with SoC therapy. 
1.2 
Purpose 
The purpose of this trial is to evaluate the efficacy and safety of subcutaneous secukinumab 300 
mg compared to placebo, in combination with standard of care therapy (SoC), in patients with 
active lupus nephritis (ISN/RPS Class III or IV, with or without co-existing class V features). 
Background SoC will consist of induction therapy with mycophenolic acid (MPA) (which refers 
to Mycophenolate mofetil (MMF) (Cellcept® or generic equivalent), or enteric-coated MPA 
sodium (Myfortic® or generic equivalent) at equivalent doses (oral)), or Cyclophosphamide 
(CYC) (i.v.), followed by maintenance therapy with MPA. In addition, all participants will 
receive i.v. and/or oral corticosteroids. 
The aim of the study is to demonstrate the efficacy and safety of secukinumab in LN that will 
enable registration for the indication of lupus nephritis. 
Within this document, at each time MPA will be mentioned without further information, 
it will refer to Cellcept®, Myfortic® or generic equivalent at equivalent doses. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To demonstrate that secukinumab 300 mg is superior 
to placebo in Complete Renal Response (CRR) rate 
at Week 52 in active lupus nephritis (ISN/RPS Class 
III or IV, with or without co-existing Class V features) 
patients on a background of SoC therapy. 
• 
Proportion of participants achieving CRR at 
Week 52 
CRR at Week 52 is an endpoint defined as 
meeting all of the following: 
• Estimated glomerular filtration rate 
(eGFR) ≥ 60 mL/min/1.73 m2 or no less 
than 85% of Baseline 
• 24-hour urine protein-to-creatinine ratio 
(UPCR) ≤ 0.5 mg/mg 
• No treatment discontinuation before Week 
52 


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Objective(s) 
Endpoint(s) 
• The participant did not receive more than 
10 mg/day prednisone equivalent for ≥ 3 
consecutive days or for ≥ 7 days in total 
during Week 44 through Week 52 
 
Secondary objective(s) 
Endpoint(s) for secondary objective(s)* 
• 
To demonstrate superiority of secukinumab 
compared to placebo in change from baseline in 
24-hour UPCR at Week 52 
• 
Change from Baseline in 24-hour UPCR at 
Week 52  
• 
To demonstrate superiority of secukinumab 
compared to placebo in proportion of patients 
achieving partial renal response (PRR) at Week 52 
• 
Proportion of participants achieving PRR at 
Week 52 defined as: 
• ≥ 50% reduction in 24-hour UPCR to sub-
nephrotic levels (≤ 3 mg/mg) 
and 
• eGFR ≥ 60 mL/min/1.73 m2 or no less than 
85% of Baseline 
• 
To demonstrate superiority of secukinumab 
compared to placebo in average daily dose of oral 
corticosteroids administered between Week 16 and 
Week 52 
• 
Average daily dose of oral corticosteroids 
administered between Week 16 and Week 52 
compared to placebo 
• 
To demonstrate superiority of secukinumab 
compared to placebo in proportion of patients 
achieving PRR at Week 24 
• 
Proportion of participants achieving PRR at 
Week 24 defined as: 
• 
≥ 50% reduction in 24-hour UPCR to sub-
nephrotic levels (≤ 3 mg/mg) 
and 
• 
eGFR ≥ 60 mL/min/1.73 m2 or no less than 
85% of Baseline 
• 
To demonstrate superiority of secukinumab 
compared to placebo in time to achieve CRR 
• 
Time to achieve CRR up to Week 52 
 
• 
To demonstrate superiority of secukinumab 
compared to placebo in time to achieve PRR 
• 
Time to achieve PRR up to Week 52 
 
• 
To demonstrate superiority of secukinumab 
compared to placebo in time to achieve first 
morning void UPCR ≤ 0.5 mg/mg 
• 
Time to achieve first morning void UPCR ≤ 0.5 
mg/mg up to Week 52 
 
• 
To demonstrate superiority of secukinumab 
compared to placebo in change in Functional 
Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue©) score at Week 52  
• 
Improvement in FACIT-Fatigue© mean change 
of score from Baseline at Week 52 compared 
to placebo 
 
• 
To demonstrate superiority of secukinumab 
compared to placebo in patient’s health related 
quality of life via Medical Outcome Short Form 
Health Survey (SF-36 Physical Component 
Summary (PCS)) score at Week 52 
• 
Improvement in SF-36 PCS mean change from 
Baseline at Week 52 compared to placebo  
Secondary objective(s) 
Endpoint(s) for secondary objective(s)* 
• 
To demonstrate superiority of secukinumab 
compared to placebo in change of LupusQoL 
(Physical Health) score at Week 52 
• 
To evaluate the safety and tolerability of 
secukinumab s.c. as an add-on therapy to 
Standard of Care in lupus nephritis patients  
• 
Improvement in LupusQoL Physical Health 
mean change of score from Baseline at Week 
52 compared to placebo 
• 
Incidence of Treatment-emergent AEs 
(TEAEs) / SAEs from Baseline to Week 52; 
vital signs and body measurements, standard 
chemistry and hematology up to Week 52 


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• 
To estimate the proportion of patients with 
maintained renal response at Week 104 
• 
Estimate the proportion of participants with 
CRR at Week 104 within participants who had 
achieved CRR at Week 52 in the secukinumab 
group 
• 
To estimate the proportion of patients with 
improved or maintained renal response at Week 
104 
• 
Estimate the proportion of participants with 
improved or maintained response (PRR or 
CRR) in participants who had achieved at least 
PRR at Week 52 in the secukinumab group 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 


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• 
To perform exploratory 
pharmacogenomic analysis based on 
blood samples for DNA and RNA 
analysis (optional assessments) 
• 
Evaluate the relationship of genetic polymorphisms and 
transcriptomic data with treatment response 
*Intercurrent events of the secondary efficacy endpoints and the strategies to handle these are specified in 
Section 2.2. 
2.1 
Primary estimand 
The primary clinical question of interest to be answered in the trial is:  
What is the effect of subcutaneous secukinumab 300 mg compared with placebo on achieving 
CRR at Week 52, in patients with active LN (ISN/RPS Class III or IV, with or without co-
existing class V features), on a background of SoC therapy? 
CRR is defined as 
1. eGFR ≥ 60 mL/min/1.73m2 or no less than 85% of Baseline 
AND 
2. 24-hour UPCR ≤ 0.5 mg/mg 
This question gives rise to the primary estimand, which has the following attributes with respect 
to the primary question: 


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• Population: Participants with active LN (ISN/RPS Class III or IV, with or without co-
existing class V features), as defined by the inclusion and exclusion criteria of the study 
Section 5. 
• Treatment: The randomized treatment (the investigational therapy subcutaneous 
secukinumab 300 mg or the placebo), in combination with SoC. More details about the 
treatment are provided in Section 6. 
• Endpoint: An endpoint meeting all of the following: 
• CRR at Week 52; 
• If the participant discontinues the treatment before Week 52, then the participant will 
be considered as a non-responder (composite endpoint strategy); 
• If the participant has overuse of corticosteroid (> 10 mg/day prednisone equivalent for 
≥ 3 consecutive days or ≥ 7 days in total) between Week 44 and Week 52, then the 
participant will be considered as a non-responder (composite endpoint strategy). 
• Summary measure: Difference in marginal response proportions of achieving CRR at 
Week 52, between secukinumab and placebo. 
2.2 
Secondary estimands 
The secondary clinical questions of interest to be answered in the trial are:  
What are the effects of subcutaneous secukinumab 300 mg compared with placebo in patients 
with active LN (ISN/RPS Class III or IV, with or without co-existing class V features), on a 
background of SoC therapy, in the following variables? 
1. Change from Baseline in 24-hour UPCR at Week 52 
2. Proportion of patients achieving PRR at Week 52 
3. Average daily dose of oral corticosteroids administered between Week 16 and Week 52 
compared to placebo 
4. Proportion of patients achieving PRR at Week 24 
5. Time to achieve CRR up to Week 52 
6. Time to achieve PRR up to Week 52 
7. Time to achieve first morning void UPCR ≤ 0.5 mg/mg up to Week 52 
8. Improvement in FACIT-Fatigue© mean change from Baseline at Week 52 
9. Improvement in SF-36 PCS mean change from Baseline at Week 52 
10. Improvement in LupusQoL Physical Health mean change from Baseline at Week 52 
The estimands for secondary objectives are described by the following attributes: 
• Population: Participants with active LN (ISN/RPS Class III or IV, with or without co-
existing class V features), as defined by the inclusion and exclusion criteria of the study in 
Section 5. 
• Treatment: The randomized treatment (the investigational therapy subcutaneous 
secukinumab 300 mg or placebo), in combination with SoC. More details about the 
treatment are provided in Section 6. 
For binary variables (PRR at Week 52, and PRR at Week 24): 
PRR is an endpoint defined as: 


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1. eGFR ≥ 60 mL/min/1.73m2 or no less than 85% of Baseline 
AND 
2. ≥ 50% reduction in 24-hour UPCR to sub-nephrotic level (≤ 3 mg/mg) compared to 
Baseline. 
• Endpoint: An endpoint meeting all of the following: 
• PRR at the time point of interest; 
• (For both PRR at Week 52 and Week 24) if the participant discontinues the treatment 
before the timepoint of interest, the participant will be considered as a non-responder 
(composite endpoint strategy); 
• (For PRR at Week 52 only) if the participant experiences overuse of corticosteroid 
(> 10 mg/day prednisone equivalent for ≥ 3 consecutive days or ≥ 7 days in total) 
between Week 44 and Week 52, then the participant will be considered as a non-
responder (composite endpoint strategy). 
• Summary measure: Difference in marginal response proportions of achieving PRR at the 
time point of interest, between secukinumab and placebo. 
For continuous variables (24-hour UPCR, average daily dose of oral corticosteroids, SF-36 
PCS, FACIT-Fatigue©, and LupusQoL physical health): 
• Endpoint: An endpoint meeting all of the following: 
• Variable (e.g., change from Baseline in UPCR) of interest at timepoint of interest; 
• If the participant discontinues the treatment before the timepoint of interest, the 
observed value of the variable will be used (treatment policy strategy); 
• (For 24-hour UPCR, SF-36 PCS, FACIT-Fatigue©, and LupusQoL physical health 
only) if the participant experiences overuse of corticosteroid, the observed value will 
still be used (treatment policy strategy). 
• Summary measure: Difference in variable means between the secukinumab and placebo 
arms. 
For time-to-event variables (time to achieve CRR, time to achieve PRR, and time to achieve 
first morning void UPCR ≤ 0.5 mg/mg): 
• Endpoint: An endpoint meeting all of the following: 
• Time to response of interest (e.g., CRR); 
• If the participant discontinues the treatment before achieving the event, then the time 
to response will be censored at Week 52 (composite endpoint strategy); 
• Summary measure: Hazard ratio of secukinumab vs placebo. 
3 
Study design 
This is a pivotal, randomized, double-blind, placebo-controlled trial evaluating at Week 52 the 
efficacy and safety of secukinumab versus placebo in patients with active LN also receiving 
background SoC regimen. Long-term efficacy, safety and tolerability will be collected up to 2 
years.  


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The SoC regimen will consist of induction therapy with MPA or CYC, followed by maintenance 
therapy with MPA. The choice of background SoC induction therapy will be at investigator's 
discretion. At Randomization, participants will be stratified on the basis of the SoC induction 
therapy they will receive during the study, MPA or CYC-based, to ensure a balanced 
representation in each of the treatment arms (secukinumab or placebo). The target will be to 
have a maximum of 25% of randomized participants receiving CYC-based induction therapy. 
In addition, steroids will be administered through i.v. pulses followed by oral daily doses as 
described in Section 6.1.3 SoC background therapy. 
The primary endpoint analysis will be performed after all participants have completed the visit 
associated with the primary endpoint (Week 52). Although the unblinding of selected members 
of the Novartis Global Clinical Team will occur after the Week 52 database lock, original 
randomization to active treatment versus placebo will continue to remain blinded to all 
investigators, site personnel, participants, and monitors until the final database lock. The study 
consists of the following parts: 
a. Screening (up to 42 days/6 weeks) 
b. Run-in period (optional): For participants who will receive MPA as SoC induction therapy 
as per investigator's decision and who are not already on MPA at Screening, MPA dosing 
will be initiated during a run-in period before Randomization (for up to 4 weeks prior to 
the first dose of secukinumab) 
c. Treatment Period: Duration of 104 weeks of treatment with secukinumab/placebo in 
addition to SoC treatment (with last dose given at Week 100) 
d. Follow-up period: Duration of 8 weeks (last visit performed 12 weeks after last dose of 
study medication) 
Figure 3-1 
Study design 
 
Screening to Randomization (Screening and Run-in period): 
A Screening period of up to 6 weeks will be used to assess participant´s eligibility and to adjust 
for concomitant medication(s) (Day -42 to -1). While this duration should provide enough time 
to evaluate eligibility of the participant, including renal biopsy evaluation, it could be extended 


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on a case-by-case basis, to be discussed with the Sponsor, to allow for a retest of 
inclusion/exclusion assessments. If participants do not have a renal biopsy obtained within 6 
months of the Screening visit, a renal biopsy should be performed. This renal biopsy should be 
performed after confirming that the participant meets all other inclusion/exclusion criteria. 
Participants who will receive MPA-based SoC induction therapy for the treatment of active LN 
as per investigator's decision, and not already on MPA when entering Screening, will be 
initiated on MPA during the run-in period (-28 to -1) as described in Section 6.1.3 SoC 
background therapy. 
Treatment period: Treatment period covers time between Randomization (Baseline) through 
EOT. 
At Baseline, eligible participants will be randomized in a 1:1 ratio to secukinumab 300 mg s.c. 
or placebo. Approximately 200 participants will be randomized to each of the two treatment 
arms. A blinded, weekly, s.c. secukinumab or placebo loading regimen will be administered for 
the first 4 weeks followed by a monthly maintenance dose in all randomized participants 
thereafter. At the end of the treatment period at Week 104, the planned End of Treatment (EOT) 
visit will be performed.  
Participants who discontinue study treatment prematurely for any reason other than withdrawal 
of informed consent before Week 104 will not be considered as discontinued from the 
study. Those participants should perform the EOT study visit 4 weeks after their last study 
treatment administration. Thereafter, participants should continue attending all subsequent 
scheduled site visits for study assessments. Participants who are unwilling to continue attending 
further study visits after prematurely discontinuing the study treatment, should attend the End 
of Study (EOS) visit 12 weeks after the last administration of study treatment. Please refer to 
Section 9.1.1 Discontinuation of study treatment for further details. 
In addition, starting at Week 52, participants who are not deemed, by the investigator, to achieve 
the desired benefit from the study treatment, should be considered for rescue medication. In 
case a prohibited medication (as defined in Section 6.2.2 Prohibited medication) is used as 
rescue medication, the participant should be discontinued from study treatment. 
Follow-up period: An EOS visit is to be done for all participants. The EOS visit will be 
performed 12 weeks after last study treatment administration for all participants who complete 
the 104 weeks treatment period, or who discontinue prematurely from study treatment and study. 
For participants who discontinue study treatment prematurely but continue attending study 
visits, please refer to Section 9.1.1 Discontinuation of study treatment for detailed guidelines. 
Participants enrolling into the extension study CAIN457Q12301E1 will not be required to 
complete the follow-up period, as their ongoing safety information will be recorded in the 
extension trial. 
Safety assessments will include physical examinations, vital signs, standard clinical laboratory 
evaluations, hematology (including blood coagulation assays), blood chemistry, urinalysis, 
adverse and serious adverse event monitoring. 


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4 
Rationale 
4.1 
Rationale for study design 
The double-blind, randomized, placebo-controlled, parallel-group design will enable the 
evaluation of the benefit-risk of the proposed secukinumab dose regimen in an adequate and 
well-controlled setting, minimizing potential bias in reporting of safety and efficacy data. 
A recommended steroid tapering regimen will be initiated in all randomized participants during 
the treatment period. The tapering schedule (timing and dose decrease) will depend on the 
Baseline corticosteroid dose. The tapering regimen, as described in Section 6.1.3 SoC 
Background therapy, is in alignment with common medical practice in LN and is designed to 
minimize steroid-related toxicity and avoid confounding the primary efficacy assessment. 
CRR is a preferred primary outcome for induction and maintenance therapy in LN. It is 
demonstrated as clinically significant improvement of renal function during the induction phase, 
shown by improvement of eGFR and signs and symptoms of renal injury like protein excretion. 
The primary endpoint assessment is planned at Week 52 as recommended by various guidelines. 
The two-year duration (104 weeks) will provide additional safety and efficacy data as well as 
the durability of response. 
An assessment of PRR will be conducted as a secondary endpoint in the trial and will evaluate 
the proportion of participants who improved while not achieving a CRR. Considering the long 
duration of the study (104 weeks), maintenance of CRR and prevention of renal flares are also 
secondary outcomes that may be evaluated.
 
 
 
4.1.1 
Rationale for choice of background therapy 
The SoC background therapy that all participants will receive was selected as it corresponds to 
the treatment recommendations of the ACR and EULAR/ERA-EDTA guidelines for induction 
and maintenance therapy for patients with ISN/RPS Class III or IV LN, with or without co-
existing class V features, ( Bertsias et al 2012), (Hahn et al 2012), (Palmer et al 2017). 
The choice of background SoC regimen for induction will be left at investigator's discretion, 
with a maximum of 25% of randomized participants receiving CYC-based induction therapy 
(stratification at Randomization will ensure balanced representation in both groups, 
secukinumab or placebo). SoC background regimen will consist of induction therapy with MPA 
or low-dose CYC regimen, followed by maintenance therapy with MPA, along with 
glucocorticoids: 
• MPA and CYC are considered equivalent for the induction of remission in patients with 
ISN/RPS Class III or IV LN, with or without co-existing class V features 
• The low dose intravenous CYC regimen for induction was selected, as it presents a better 
efficacy/toxicity ratio than high-dose intravenous CYC 
• Corticosteroid administration as per the above-mentioned guidelines are considered a 
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4.2 
Rationale for dose/regimen and duration of treatment 
Secukinumab dosing will start with initial dosing of 300 mg s.c. injections at Baseline, Weeks 
1, 2, 3, and 4, followed by dosing every 4 weeks. This dosing regimen is approved for treatment 
of other autoimmune diseases (PsO, PsA). Available data in PsO and PsA strongly suggest that 
secukinumab operates at the plateau of the dose-exposure-response curve in these autoimmune 
diseases, which is one of the reasons to select this dose level in LN as well. As clearly 
demonstrated in the development program for PsO, it is expected that the initial weekly dosing 
during the first month will enable rapid achievement of effective drug concentrations and lead 
to a more rapid onset of clinical response. 
It has to be noted that due to kidney damage, proteinuria is commonly observed in patients with 
LN. The effect of renal impairment on the PK of biologics is dependent on the ability of the 
compound to undergo glomerular filtration, which is largely driven by molecular weight (MW). 
Secukinumab has a MW of ca. 148 kDa, and renal clearance usually plays a minimal role in the 
elimination of biologics with MW greater than 69 kDa (Meibohm and Zhou H 2012). An 
association between increased Baseline proteinuria and increased clearance was observed in the 
population PK analysis of belimumab (a human mAb that inhibits B-cell activating factor, 
BAFF) in SLE (Struemper et al 2013). Also, there is evidence that in some forms of renal 
disease, such as diabetic nephropathy, there may be an increase in the renal elimination of IgGs 
(Bakoush et al 2002). However, slight changes in distribution volume or increased clearance of 
secukinumab in LN patients will probably not dramatically change the PK characteristics of 
secukinumab.  
In addition, the secukinumab dosing regimen used in the study is associated with a reassuring 
safety profile, as confirmed in multiple clinical trials (up to 5 years) and in the post-marketing 
setting. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
A placebo arm is included for the whole duration of the study treatment. Due to the nature of 
the disease and the primary outcome measure used (CRR), a placebo arm is necessary to obtain 
reliable efficacy measurements for comparison between the active treatment and the placebo. 
In addition, all participants, including those assigned to the placebo arm, will receive 
background SoC therapy as recommended within the EULAR/ERA-EDTA and ACR guidelines 
for the induction and maintenance treatment of patients with active ISN/RPS class III or IV LN 
[excluding III (C), IV-S (C) and IV-G (C)], with or without co-existing class V features.  
As recommended by the same guidelines, all participants will also receive hydroxychloroquine 
(HCQ) as adjunctive medication unless contraindicated. Treatment with lipid-lowering statin 
and of renin-angiotensin-aldosterone system inhibitors (ACE inhibitors /ARBs) is allowed. 
The FDA (FDA 2018) and the Committee for Medicinal Products for Human Use (CHMP) 
recommend double blind, parallel-group, randomized trial designs. Per the CHMP guideline 
(Committee for Medicinal Products for Human use (CHMP) 2015), a superiority trial design 
against an active comparator or placebo is preferred in LN. Placebo-controlled trials are 
acceptable provided that placebo is given as add-on to SoC therapy. 


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4.4 
Purpose and timing of interim analyses/design adaptations 
The study team, site staff, investigators and participants will remain blinded to the interim data 
and results of the analysis for both the first and second interim analyses described below. These 
analyses will be conducted by independent statisticians and programmers from a contract 
research organization (CRO) and will be evaluated by an independent data monitoring 
committee (DMC). 
In addition to those interim analyses, the primary endpoint analysis will be performed after all 
participants have completed the visit associated with the primary endpoint (Week 52). At time 
of the primary endpoint analysis, although the unblinding of selected members of the Novartis 
Global Clinical Team will occur, investigators/site personnel, participants and monitors will 
remain blinded until the final study analyses are completed. Additional safety analyses may be 
performed between the second interim analysis and the Week 52 final analysis if needed to 
support health authority interactions following a statistically significant result at the second 
interim analysis. 
4.4.1 
First interim analysis 
The first interim analysis will be performed when approximately 138 participants 
(approximately 35% of the total 400 participants) are expected to complete 52 weeks of 
treatment (including those who discontinue the treatment early). 
Futility analysis 
A futility analysis will be performed at the first interim analysis. A Go/No-Go decision will be 
taken at this futility analysis based on predictive probability of achieving statistical significance 
for the primary estimand. Futility stopping rules will be defined in the DMC charter. 
 
 
 
 
 
 
 
4.4.2 
Second interim analysis 
The second interim analysis will be performed when approximately 308 participants 
(approximately 77% of all 400 participants) complete 52 weeks of treatment. The results from 
this interim analysis will support the decision-making concerning the current clinical study, i.e., 
to continue or to stop the trial based on efficacy (superiority or futility) and/or safety findings.  


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Superiority analysis 
An alpha spending function will be used to calculate the nominal p-value threshold for the 
superiority analysis. This method will maintain the overall type-I error rate for the primary and 
secondary endpoints. Further details are provided in Section 12.8.2.  
Futility analysis 
A second futility analysis will also be conducted at the time of the second interim analysis. 
Futility stopping rules will be specified in the DMC charter.  
4.5 
Risks and benefits 
Current standard of care therapies comprise of conventional immunosuppressants which are not 
fully efficacious in all patients and associated with significant toxicities. Based on the scientific 
rationale for targeting IL-17 pathway in lupus, and the data available on secukinumab, IL-17 
inhibition by secukinumab has a potential therapeutic benefit for lupus nephritis patients who 
are clinically active despite standard of care treatment. 
Secukinumab has demonstrated positive benefit risk in the treatment of multiple chronic 
inflammatory diseases, including e.g., PsA, AS, PsO, nr-axSpA and JIA (ERA and JPsA 
subtypes). 
Secukinumab therapy has a well-established and well-described safety profile based on 
extensive post-marketing experience and continued clinical trial patient exposure since its 
approval for the first indication of moderate to severe plaque psoriasis. Details of the risk and 
benefits are outlined in the current version of the Investigator's Brochure (IB). 
The safety and tolerability of secukinumab as an add-on to SoC will be evaluated. Based on the 
favorable safety profile of secukinumab and the known safety profile of the SoC treatments for 
LN, it is unlikely that the addition of secukinumab to the LN SoC regimens will result in 
unacceptably high risks, particularly for serious infections. In a pooled analysis of psoriasis 
clinical trial data from 3993 patients, the crude incidence of severe AEs of infections was 2.6% 
for any 300 mg and 2.2% for any 150 mg [IB 26 Jun 2021 – 25 Jun 2022, data on file]. A 
published meta-analysis found that, in patients treated for lupus nephritis, the crude incidence 
rates of serious infections have been reported at 26.7% with high-dose glucocorticoids, 15.1% 
with cyclophosphamide, and 11.6% with MMF (Singh et al 2016). Additionally, in the pooled 
secukinumab psoriasis trial data, the exposure-adjusted incidence rate of SAEs of infections 
was 1.4/100 PY for any 300 mg (N=1410) and 1.1/100 PY (N=1395) [IB 26 Jun 2021 – 25 Jun 
2022, data on file], while the risk of serious infections with a combined regimen of MMF and 
corticosteroids was reported at 19/100 PY (Rovin et al 2012, Mysler et al 2013). 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, and periodic review of safety data 
by an independent DMC. Additional information can be found in the IB for secukinumab. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and must agree that in 
order to participate in the study, they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 


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From the standpoint of the overall risk-benefit assessment, the current trial with secukinumab 
is justified. 
4.6 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local or regional authorities (i.e., 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures and permitted/approved by local or regional health 
authorities and ethics committees as appropriate. 
5 
Population 
The study population will be comprised of adult male and female participants in the age range 
of 18-75 years with a renal biopsy (current or within the 6 months prior to Screening) showing 
active glomerulonephritis WHO or ISN/RPS Class III or IV LN [excluding III (C), IV-S (C) 
and IV-G (C)], with or without co-existing class V features, who are inadequately controlled 
with previous SoC defined as having UPCR ≥ 1 mg/mg and active urinary sediment (presence 
of hematuria (> 5 RBC/ hpf or above the laboratory reference range)) OR presence of cellular 
casts (RBC or WBC casts).Approximately 400 participants, randomized into two treatment 
arms (1:1 active: placebo), are planned. At Randomization, participants will be stratified on the 
basis of the SoC induction therapy they will receive during the study, MPA or CYC-based, to 
ensure a balanced representation in each of the treatment arms (secukinumab or placebo). The 
target will be to have a maximum of 25% of randomized participants receiving CYC-based 
induction therapy. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Adult male and female participants aged 18 - 75 years old at the time of Baseline. 
2. Confirmed diagnosis of: 
• SLE with documented history of at least 4 of the 11 criteria for SLE as defined by the 
American 
College 
of 
Rheumatology 
(ACR) 
(Tan et al 1982) 
revised 
by 
(Hochberg 1997). [NOTE: The 4 criteria do not have to be present at the time of 
Screening], 
OR 
• LN as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. 
3. Active lupus nephritis, as defined by meeting the 4 following criteria: 
• Biopsy within 6 months prior to Screening visit indicating active glomerulonephritis 
WHO or ISN/RPS Class III or IV LN [excluding III (C), IV-S (C) and IV-G (C)]; 
patients are permitted to have co-existing Class V. If no biopsy was performed within 
6 months of Screening, a biopsy will need to be performed during the Screening period, 
after all other inclusion/exclusion criteria would have been verified. 
• UPCR ≥ 1 mg/mg at Screening. 


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• eGFR > 30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI). 
• Active urinary sediment (presence of cellular casts (RBC or WBC casts)) or 
hematuria (> 5 red blood cells per high power field or above the laboratory reference 
range). 
4. Participants must be currently on MPA, or willing to initiate SoC induction therapy for LN 
according to the institutional practices using MPA or low-dose CYC in addition to 
corticosteroids. For guidance, see published guidelines such as by (Bertsias et al 2012, 
Hahn et al 2012). 
5. If the participant is on cholesterol-lowering agents, the dose must be stable for at least 7 
days prior to Randomization. 
6. Participants must be treated with anti-malarials (e.g., hydroxychloroquine), unless contra-
indicated, and the dose must be stable for at least 10 days prior to Randomization. 
7. Able to provide signed informed consent. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Severe renal impairment as defined by i.) Stage 4 CKD, or ii.) presence of oliguria (defined 
as a documented urine volume < 400 mL/24 h), or iii.) ESRD requiring dialysis or 
transplantation. 
2. Known intolerance/hypersensitivity to MPA, or oral corticosteroids, or any component of 
the study drug(s). 
3. Participants having received any other biologic immunomodulatory therapy within 6 
months prior to Screening, excluding belimumab where 3 months are acceptable. 
4. Previous exposure to secukinumab (AIN457) or any other biologic drug targeting IL-17 or 
the IL-17 receptor. 
5. Participants having received any investigational drug within 1 month or five times the half-
life of enrollment, whichever is longer. 
6. Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) within the 
12 weeks prior to Baseline. 
7. Treatment with a systemic calcineurin inhibitor (e.g., cyclosporine, tacrolimus) within 12 
weeks prior to Baseline 
8. CYC use (i.v. or oral) within the month prior to Baseline. 
9. Participants requiring dialysis within the previous 12 months before Screening. 
10. History of renal transplant. 
11. Any severe progressive or uncontrolled concurrent medical condition, including recent 
severe thromboembolic events, that, in the opinion of the principal investigator, renders the 
participant unsuitable for the trial. 
12. Active ongoing inflammatory diseases that might confound the evaluation of the benefit of 
secukinumab therapy, including inflammatory bowel disease. 
13. Presence of investigator-identified significant medical problems which at the investigator’s 
discretion will prevent the patient from participating in the study, including but not limited 


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to the following: myocarditis, pericarditis, poorly controlled seizure disorder, acute 
confusional state, depression, severe manifestations of neuropsychiatric SLE (NPSLE). 
14. Chest X-ray, computerized tomography (CT) scan, or MRI with evidence of ongoing 
infectious or malignant process, obtained within 3 months preceding the Screening visit and 
evaluated by a qualified physician. 
15. History of chronic, recurrent systemic infections, active tuberculosis infection, or active 
systemic infections during the last two weeks (exception: common cold) prior to 
Randomization. 
16. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at 
Screening or Randomization. 
17. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system treated or untreated within the past 5 years, regardless of whether there 
is evidence of local recurrence or metastases (except for skin Bowen’s disease or basal cell 
carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the 
past 12 weeks, carcinoma in situ of the cervix or non-invasive malignant colon polyps that 
have been removed). 
18. Any of the following abnormal laboratory values on Screening evaluations as reported by 
Central Laboratory: 
• 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase > 2.5xULN 
• 
Hemoglobin < 8g/dL 
• 
Neutrophils < 1.0 x 109/L 
• 
Platelet count < 50 x 109/L 
19. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of venous access). 
20. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
Randomization. 
21. Pregnant or lactating women. 
22. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
the entire study or longer if required by locally approved prescribing information (e.g., in 
European Union (EU) 20 weeks). Of note: the highly effective methods of contraception 
are mandated due to SoC medications used as per protocol (MPA and CYC). 
Highly effective contraception methods include: 
• Total abstinence, when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy [with or without 
hysterectomy], total hysterectomy or tubal ligation at least six weeks before taking 
study treatment). In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment. 
• Male sterilization (at least 6 months prior to Screening). The vasectomized male partner 
should be the sole partner for that participant. 


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• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS). 
In case of use of oral contraception, women should have been stable on the same 
treatment for a minimum of 3 months prior to Randomization. 
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the informed consent form (ICF). 
If stricter female or male contraception requirements are specified in the country-specific 
label for induction and maintenance standard of care medications, they must be followed. 
Note: Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks prior to enrollment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment is she considered not of childbearing potential. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Novartis Global Clinical Supply (GCS) will supply the following study treatments:  
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
AIN457 150mg / 
1mL 
Solution for 
Injection 
Subcutaneous use 
Double blinded 
prefilled syringes 
(PFS) 
Novartis Pharma 
AG 
AIN457 0 mg / 1mL 
(Placebo) 
Solution for 
Injection 
Subcutaneous use 
Double blinded 
prefilled syringes 
(PFS) 
Novartis Pharma 
AG 
The PFSs are packed in a double blinded fashion and do not need to be prepared. 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. The investigational treatment packaging has a 2-part label. A unique 
Randomization number is printed on each part of this label, which corresponds to placebo or 
active treatment.  
The study treatments will be labeled as follows: Double blind secukinumab and placebo PFS 
will be labeled AIN457 150 mg/1 mL/Placebo. 


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6.1.2 
Additional study treatments 
No other study treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
SoC background therapy 
All participants will receive SoC background regimen for induction and maintenance therapy.  
Table 6-2 
Background therapy 
Name of the medication 
Dosage Form 
Route of administration 
Availability 
MMF/MPA 
Tablet 
Oral 
Open-label participant 
packs 
CYC 
Powder for solution for 
infusion 
Intravenous 
Open-label participant 
packs 
Corticosteroids 
Tablets and/or Solution 
for injection 
Oral and/or Intravenous 
use 
Open-label participant 
packs 
Background SoC medications will NOT be provided by Novartis GCS and must be handled at 
the country level. 
6.1.3.1 
Induction therapy 
The induction therapy will consist of either MPA or low-dose CYC, in combination with 
corticosteroids. The choice of the induction SoC therapy, MPA or low-dose CYC will be left at 
the investigator's discretion. To ensure a balanced representation in both treatment arms 
(secukinumab or placebo), participants will be stratified at time of Randomization according to 
their SoC induction therapy. A maximum of 25% of participants receiving CYC-based SoC 
induction therapy will be allowed to be randomized in the study (maximum of 100 participants 
in the study). 
MPA: 
Target dose during the first six-month treatment period (MPA induction period) is 2 g/day of 
MMF or equivalent dosage of enteric-coated MPA of 1440 mg/day. If required, a dose up to 3 
g/day of MMF or equivalent dosage of enteric-coated MPA of 2160 mg/day is allowed, based 
on Investigator’s judgement. A reduction of MPA dose is only allowed in case of toxicity, as 
per Investigator's decision. 
Optional Run-in period 
Participants not already on MPA at study entry will be initiated, after verification of eligibility, 
on an MMF dose of 1 g/day (divided q12h or an equivalent dosage of enteric-coated MPA of 
720 mg/day. The dose must be increased to 2 g/day of MMF or equivalent dosage of enteric-
coated MPA in the second week, and up to 3 g/day of MMF or equivalent dosage of enteric-
coated MPA in the third week when required. If participants experience adverse effects that 
prevent up-titration as described, an additional 1 week of titration is permitted. If MMF/MPA 
dose escalation is clinically inappropriate as judged by the investigator, or inconsistent with 
local treatment guidelines, participants can take a dose of 1-2 g/day MMF or equivalent dosage 
of enteric-coated MPA in the absence of observed toxicity. 


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Low-dose CYC: 
The low-dose CYC induction treatment consists of 6 administrations of 500 mg i.v. CYC every 
2 weeks. All i.v. CYC administration will be performed according to the site and/or local 
guidelines, including the administration of any medication for prophylaxis of potential toxicities. 
The first i.v. CYC administration will be performed at Baseline visit, after all 
inclusion/exclusion criteria would have been verified. 
Corticosteroids: 
Pulse i.v. corticosteroid should be initiated at Baseline visit (500–1000 mg methylprednisolone 
daily) for a maximum of 3 doses. This will be followed by daily administration of oral 
glucocorticoids at initial dose of 0.3 to 0.5 mg/kg/day to be tapered within 16 weeks to the 
minimal dose necessary to control disease (see recommended guidance on Table 6-3). 
Participants who cannot take the pulse i.v. corticosteroid therapy should directly start on 0.3-
0.5 mg/kg/day oral dose of glucocorticoid followed by the above-described tapering. 
Participants having already received pulse i.v. corticosteroids up to a cumulative dose of 3000 
mg within 12 weeks prior to Baseline do not need to repeat the i.v. pulse. For these participants 
already on corticosteroids at Baseline, a predefined steroid taper regimen (see Table 6-3) should 
be implemented. 
In all cases, from Week 16 onward, the target dose of oral corticosteroids is 5 mg daily 
(prednisone equivalent). 
Table 6-3 
Guidance for corticosteroid (prednisone equivalent) taper 
Initial Dose 
40 mg 
30 mg 
20 mg 
Week 2 
30 
25 
15 
Week 4 
25 
20 
15 
Week 6 
20 
15 
10 
Week 8 
15 
10 
10 
Week 12 
10 
10 
10 
Week 16 and thereafter 
maintain at 5 mg where 
possible 
* acceptable dose range 
5 
*7.5 – 2.5 
5 
*7.5 – 2.5 
5 
*7.5 – 2.5 
6.1.3.2 
Maintenance therapy 
After the induction period (6 months for MPA-based induction; 12 weeks for CYC-based 
induction), all participants must receive MPA-based maintenance therapy. 
The target dose during the maintenance period is 1-2 g/day of MMF or of equivalent dosage of 
enteric-coated MPA. Further reduction of MMF to 0.5 g/day or of equivalent dosage of enteric-
coated MPA is allowed as per Investigator's decision. 
In addition, all participants will receive a maintenance dose of oral corticosteroids as per  
Table 6-3 above, with a target dose of 5 mg/day prednisone equivalent (2.5-7.5 mg/day 
acceptable dose range) from Week 16. 


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A recommended diagram for administration of SoC background therapy from the Run-In period 
until Week 24 is provided in Appendix 16.4. 
6.1.4 
Treatment arms/group 
At Baseline, all eligible participants will be randomized to one of the two treatment arms in a 
1:1 ratio via Interactive Response Technology (IRT): 
• Arm 1: approximately 200 participants with LN will receive secukinumab 300 mg s.c. (2 x 
1.0 mL PFS of 150 mg dose) at Randomization (i.e., Baseline). 
• Arm 2: approximately 200 participants with LN will receive placebo s.c. (2 x 1.0 mL PFS 
of 0 mg dose) at Randomization (i.e., Baseline). 
At Randomization, participants will be stratified on the basis of the SoC induction therapy they 
will receive during the study, MPA or CYC-based, to ensure a balanced representation in each 
of the treatment arms (secukinumab or placebo).  
6.1.5 
Treatment duration 
Participants will receive investigational treatment at Baseline, Weeks 1, 2 and 3, followed by 
administration every 4 weeks starting at Week 4, until Week 100. Participants will self-
administer all secukinumab or placebo doses at the investigational site. Participants, who have 
completed the entire treatment period of this study up to and including Week 104 will be offered 
participation in the extension study CAIN457Q12301E1, if the investigator deems secukinumab 
therapy beneficial for these patients. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Form (CRF). 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the patient should continue participation in 
the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Guidelines for the use of specific medications are provided below. 
Participants may continue on the concomitant medication listed below provided they are on a 
stable dosage as described below and until the end of study. However, investigators may change 
the dose of concomitant medications during the study for safety reasons based on their clinical 
judgement. Each concomitant medication should be captured/recorded in the eCRF at every 
visit, including the dose changes when appropriate. 


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Anti-malarials 
Participants will remain on one stable background anti-malarial medication (e.g., 
hydroxychloroquine) in addition to the SoC medication. Participants who have not taken 
previously anti-malarial medication should be initiated on an anti-malarial at least 10 days prior 
to Randomization (unless contraindicated) and remain on a stable dose throughout the trial. 
Refer to Section 5.1 Inclusion Criteria. 
Anti-hypertensive medication 
Participants already taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin 
receptor blockers (ARBs) at Screening should remain on the same dose throughout the study 
unless precluded by toxicity or if dose adjustment is required for hypertensive control. 
Combination therapy with an ACE inhibitor and an ARB will not be allowed. For participants 
not already receiving one of these agents, it is recommended that treatment with an ACE 
inhibitor or ARB should be initiated during Screening (unless contraindicated) and be given at 
a stable dose for at least 7 days prior to Randomization. These therapies should not be initiated 
after study Baseline. 
Cholesterol-lowering drugs 
Concomitant treatment with cholesterol-lowering drugs (e.g., statins) will continue if prescribed 
prior to the study and will be recorded in the eCRF. Statin treatment can be initiated during the 
course of the study if considered required by the Investigator. If the participant is on a 
cholesterol-lowering agent already at the time of Screening, the dose must be stable for at least 
7 days prior to Randomization. 
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 
NSAIDs may have impact upon renal function and therefore should only be used during the 
trial if deemed necessary by the Investigator, e.g., in cases such as the following: 
• treatment of pleuritis and pericarditis. 
• treatment of arthritis pain that is unresponsive to other treatment modalities (e.g., 
analgesics) 
Osteoporosis Prevention /Treatment 
Participants not already taking vitamin D (400 IU/day) and calcium supplements (1200 mg/day 
of calcium citrate or 1500 mg/day calcium carbonate) are allowed to start these medications, at 
the investigator’s discretion (see ACR 2001). The above dosages can be modified as per local 
medical practice, to adhere to the dosage commonly used in each country. 
Other Permitted Therapy 
• Low dose aspirin for cardio-protection may be used at Investigator’s discretion. 
• Participants who use oral contraceptives or hormone-replacement therapy should continue 
their use. 
• Any prophylaxis for CYC-induced toxicities, as per site and or local guidelines, if 
participant is to receive low-dose CYC-based induction treatment. 
All other concomitant medications deemed necessary will be reviewed by the Investigator and 
decisions made on a case-by-case basis. 


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Note: Concomitant medications will not be provided by Novartis and must be supplied by the 
study center. 
6.2.2 
Prohibited medication 
The following treatments are prohibited after Screening and during the course of the trial due 
to their mechanisms of action that can confound the study results. If administered, the 
participant is to be withdrawn from the study treatment:  
• Initiation of CYC treatment (oral or i.v.) outside of the protocol planned low-dose CYC 
induction therapy for participants elected to receive CYC-based induction 
• Initiation of rituximab or belimumab therapy 
• Use of any other systemic biologic/non-biologic immunomodulatory treatment, including 
use of i.v. corticosteroids as rescue medication  
• Administration of live vaccines 
Of note, the administration of other vaccines is acceptable, including the use of an 
inactivated, viral-vector- or mRNA-based SARS-CoV2 vaccine that is approved or the use 
of which has been authorized by the Health Authority in the respective country. The 
decision for vaccinating patients participating in this study against SARS-CoV2 is at the 
discretion of the Investigator, taking into consideration the individual patient’s 
characteristics such as the presence of co-morbidities, prior and concomitant medications, 
as well as further risk factors applying to the patient.  
6.2.3 
Rescue medication 
Rescue medication is defined as any new medication used because the participant's disease is 
not adequately controlled by the investigational study treatment in addition to the SoC 
background therapy. 
Although no participant will be restricted from receiving necessary rescue medications for lack 
of benefit or worsening of the disease (e.g., experiencing a renal flare), participants will be 
discontinued from the study treatment if they are treated with prohibited medications (as 
described in Section 6.2.2). The choice of the rescue medication will be based on the treating 
Investigator's assessment and applicable regulatory guidelines. 
Participants who discontinue investigational treatment can continue to attend all subsequent 
scheduled visit assessments unless informed consent is withdrawn as described in Section 9.1.1 
Discontinuation of study treatment. If study investigational treatment is discontinued, 
participants may take study-prohibited medication under the investigator's guidance and as per 
locally approved prescribing information. 
Use of rescue medication must be recorded on the appropriate eCRF page. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Subject Number (Subject No.) that is assigned 
when the participant is first enrolled for Screening and is retained as the primary identifier for 
the participant throughout his/her entire participation in the trial. The Subject No. consists of 


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the Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential participant number suffixed to it, so that each participant is numbered uniquely across 
the entire database. Upon signing the informed consent form, the participant is assigned to the 
next sequential Subject No. available. 
6.3.2 
Treatment assignment, randomization 
At Baseline visit, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
subject randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
Randomization will be stratified by the SoC induction therapy participants will receive (MPA 
or CYC-based). A maximum of 25% of the randomized participants will receive low-dose CYC 
induction therapy (up to 50 participants per treatment arm). This will ensure that participants 
can be treated with SoC therapy as per site and/or local guidelines, and a balanced repartition 
within the two treatment arms. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
This is a double-blind, randomized treatment trial. 
Participants, investigator staff, persons performing the assessments will remain blinded to the 
identity of the treatment from the time of Randomization until final database lock, using the 
following methods: 
(1) Randomization data are kept strictly confidential until the time of unblinding and will not 
be accessible by anyone else involved in the study with the following exceptions: 
• Specific vendors whose role in the clinical trial requires their unblinding (e.g., IRT) 
• Global Clinical Supply 
• The designated Novartis study team members involved in the primary endpoint analysis 
 
 
(2) The identity of the treatments will be concealed by the use of study treatments in the form 
of PFS, filled with secukinumab or placebo, that are all identical in packaging, labeling, 
appearance and schedule of administration. 


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As the primary endpoint analysis will be performed at Week 52, there will be a database lock 
when all participants have completed Week 52 assessments. Summary results may be shared 
internally and externally; additionally, after the study is completed and study results are made 
publicly available, upon request by participants, the Study Doctor will ensure individual 
research results (IRR) are returned to participants.  
If the DMC provides a positive recommendation after the second interim analysis, designated 
members from the Novartis Global Team may have access to unblinded results. However, 
subjects and site staff directly involved in the conduct of the trial, i.e., investigator staff and 
persons performing the assessments, will remain blinded to individual treatment allocation until 
the conclusion of the study to ensure study integrity is maintained. For details regarding the 
planned Interim Analyses, refer to Section 4.4 Purpose and timing of interim analyses/design 
adaptation, and Section 12.7 Interim analyses. 
A final database lock will occur when all participants have completed the study. After the Week 
104 analysis has been conducted, the Novartis clinical team will notify the investigative staff 
and the IRT system and site personnel and the participant will be unblinded to the originally 
assigned treatment arms. 
The high sensitivity C-reactive protein (hsCRP) results from samples collected during the 
treatment period will be revealed only after database lock and analyses are completed. 
6.5 
Dose escalation and dose modification 
Investigational study treatment dose adjustments are not permitted. 
6.5.1 
Dose modifications 
Study treatment interruption is only permitted if, in the opinion of the investigator, a participant 
is deemed to be placed at a significant safety risk unless dosing is temporarily interrupted. In 
such cases, study treatment should be interrupted only during the time that this risk is present 
and ongoing. Study treatment can be restarted at the next scheduled visit after resolution of the 
safety risk. 
Any study treatment interruption must be recorded on the appropriate eCRF. 
6.5.2 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant abnormal laboratory value, must be followed up in accordance with 
what is clinically indicated per the investigator until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrist, etc., should be consulted as deemed necessary. 


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6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
6.6.1.1 
Study treatment compliance 
Administration of study treatment will occur at the study site through Week 100. The first study 
treatment administration will occur at the Baseline/Randomization visit only after eligibility 
criteria have been confirmed, all study Baseline assessments have been performed, and the 
scheduled blood samples have been drawn. 
Compliance is expected to be 100% unless temporary interruption is needed for safety reasons 
as described in Section 6.5.1. Compliance will also be assessed by a Novartis monitor using 
information provided by authorized site personnel. 
All doses of study treatment administration will be recorded on the appropriate eCRF page. 
6.6.1.2 
Standard of care treatment compliance 
All intravenous administration of SoC, like CYC or pulses of glucocorticoids as specified in 
Section 6.1.3 SoC background therapy, must be administered at the study site under the 
supervision of appropriate personnel. Doses administered and dates should be recorded on the 
appropriate eCRF pages. 
Oral doses of MPA or corticosteroids, as specified in Section 6.1.3, will be taken by the 
participant at home. 
The investigator must promote compliance by instructing the participant to take the SoC 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the SoC treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit by 
reviewing the information provided by the participant. This information should be captured in 
the source document at each visit. 
6.6.2 
Recommended treatment of adverse events 
Treatments for AEs are at the discretion of the investigator or treating physician. Refer to the 
Investigator's Brochure for AEs related to secukinumab. 
Medication used to treat AEs must be recorded on the appropriate eCRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to treat the participant 
safely. Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the system to break a treatment code for a participant, he/she must provide the requested 
participant identifying information and confirm the necessity to break the treatment code for 
the participant. The investigator will then receive details of the investigational drug treatment 
for the specified participant and a fax or email confirming this information. The system will 


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automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name 
• subject number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time. 
Study drug should be discontinued after emergency unblinding. 
6.7 
Preparation and dispensation 
Each study site will be supplied with investigational study drug in packaging as described under 
investigational and control drugs Section 6.1.1. 
Secukinumab solution for s.c. injection or placebo secukinumab solution (active or placebo, 
respectively) will be provided in prefilled syringes (PFS). 
Each participant will require one box with PFS per dose throughout the study: 
· One secukinumab 300 mg (2 x 1.0 mL PFS of 150 mg dose) OR 
· One secukinumab placebo (2 x 1.0 mL PFS)  
All study treatment kits assigned to the participant by IRT during the study will be captured in 
the IRT system. 
The first study treatment administration will occur at the Baseline/Randomization visit after the 
inclusion/exclusion criteria have been confirmed and all study scheduled assessments have been 
performed, including completion of PRO and blood withdrawal. 
All doses of study treatment (secukinumab and/or placebo) will be self-administered by the 
participant/trained caregiver at the study site after the study assessments for the visits have been 
completed. 
At the Baseline visit, participants will be instructed by the site staff on how to self-inject via the 
PFS (Instructions for Use (IFU) containing detailed information about self-administration of 
study treatment should be provided to each participant at the beginning of the study). After 
providing detailed explanations/instructions, participants will then be asked to raise any 
questions. 
Thereafter, they will proceed with self-injection. At Week 1, participants will be asked to refer 
to the IFU and to proceed with self-injection of the study treatment (i.e., without a detailed 
explanation/instruction on handling the syringe). 
A unique medication number is printed on the study medication label. Investigator staff will 
identify the study medication kits to dispense to the participant by contacting the IRT and 


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obtaining the medication number(s). The study medication has a 2-part label (base plus tear-off 
label), immediately before dispensing the medication kit to the participant, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis Country Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The PFS (150 mg active/placebo) sealed in their outer box must be stored in an access 
controlled/locked refrigerator between 2°C and 8°C (36°F and 46°F) (Do Not Freeze) and 
protected from light. They must be carefully controlled in accordance with regulations 
governing investigational medicinal products and local regulations. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
Subcutaneous administration with PFSs 
The study treatment solution must be injected into non-affected areas of the skin. 
The injections will be self-administered into the appropriate site of the body (thighs, arms, 
abdomen), and each injection should be given at a different injection site to reduce the risk of 
reaction. Each new injection should be given at least one inch from the previously used site. If 
participant chooses the abdomen, a 2-inch/5-centimeter area around the navel should be avoided. 
Investigational drug should not be injected into areas where the skin is tender, bruised, red, or 
hard, or where participant has scars or stretch marks. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
Destruction of the unused drug should be done according to local requirements and after 
approval by the Novartis Clinical Team. 
6.7.1.2 
Handling of additional treatment 
The following non-study treatment will be monitored specifically: 
• SoC background therapy, as described in Section 6.1.3 
• Concomitant therapy as described in Section 6.2.1, e.g., anti-malarials, ACE or ARBs 


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7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation) Institutional Review Board (IRB)/IEC-approved informed 
consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant’s source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use - Good Clinical Practice (ICH GCP) 
guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
The study includes two optional components, namely a biomarker component and a 
deoxyribonucleic acid (DNA)/ribonucleic acid (RNA)/Pharmacogenetics component. Each of 
them requires a separate signature if the patient agrees to participate. It is required as part of 
this protocol that the Investigator presents these options to the participants, as permitted by local 
governing regulations. The process for obtaining consent should be exactly the same as 
described above for the main informed consent. 
Declining to participate in these optional assessments (DNA/RNA/Pharmacogenetics or 
biomarkers) will in no way affect the participant’s ability to participate in the main research 
study. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 


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8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(able 8-11or as close to the designated day/time as possible. Missed or rescheduled visits should 
not lead to automatic discontinuation of study investigational treatment or study. Handling of 
participants who discontinue study treatment or study prematurely is described in Section 9.1 
Discontinuation.  


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Table 8-1 
Assessment Schedule 
 


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X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Visit structure given for internal programming purpose only 
2 Screening period will be up to 42 days depending on the MPA Run-in need. The duration of the Screening period must be kept at a minimum. 
3 For participants not yet on MPA at Screening, a Run-in period can optionally be considered 
4 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion criteria are not met are 
captured on the Inclusion/Exclusion eCRF. 
5 Included in Medical History and recorded in the eCRF on the corresponding page. 
6 PPD/QuantiFERON® 
7 not required if chest X-ray, CT or MRI of the chest have been taken in the past three months prior to Screening that show no clinically significant abnormality 
8 Hepatitis B and/or C and/or HIV serology testing performed during Screening period only if required as per local medical practice or regulators prior to initiation of 
therapy. These assessments will be documented in source records only and will not be entered into eCRF 
9 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion criteria are not met 
should be captured on the Inclusion/Exclusion eCRF. After the Baseline visit, the investigator should do an abbreviated physical exam focusing on relevant clinical areas 
10 Body Mass Index (BMI) to be automatically calculated by Novartis 
11 performed locally 
12 To enter the study, participants must have a biopsy demonstrating active glomerulonephritis WHO or ISN/RPS class III or IV LN [excluding III (C), IV-S (C) and IV-G 
(C)]; participants are permitted to have co-existing class V. Renal biopsy must have been performed within 6 months prior to Screening. Otherwise, a new renal biopsy 
must be performed during Screening, once all other eligibility criteria have been confirmed. Any subsequent biopsies (e.g., upon disease flare) may be performed where 
considered appropriate by the investigator  
13 Samples for Lipid panel should be obtained after an overnight fast (10hr or more) 
15 Including central determination of UPCR 
calculation 
16 Site to ensure that a urine container is dispensed at previous site visit 


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17 First morning void urine sample will be collected for 1) local determination of urinary sediment and standard safety evaluation and 2) central determination of UPCR. 
Jugs for the Urine collection will be dispensed at previous visit 
18 Pregnancy tests will be conducted for women of child bearing potential; serum pregnancy test at Screening and Urine pregnancy test at all other time points 
19 SF-36 v2 performed (both PCS and MCS) 
20 AEs/SAEs occurring after the participant has provided informed consent must be reported. 
 
 
 
 
23 Background SoC therapy will be administered during the whole treatment period on a daily basis for MPA and Corticosteroids, cyclophosphamide induction every 2 
weeks for 3 months 
24 for site administration of i.v. corticosteroids only 
25 for site administration of i.v. cyclophosphamide only 
26 planned End of Treatment (EOT) period visit will be performed at Week 104. Participants who discontinue study treatment prematurely for any reason other than 
withdrawal of informed consent before Week 104 will not be considered as discontinued from the study. Please refer to Section 9.1 Discontinuation for detailed 
instructions. 


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X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Visit structure given for internal programming purpose only 
9 These assessments are source documentation only and will not be entered into the eCRF. After the Baseline visit, the investigator should do an abbreviated physical exam 
focusing on relevant clinical areas 
10 Body Mass Index (BMI) to be automatically calculated by Novartis 
11 performed locally 
13 Samples for Lipid panel should be obtained after an overnight fast (10hr or more) 
15 including central determination of UPCR
calculation 
16 site to ensure that a urine container is dispensed at previous site visit 
17 First morning void urine sample will be collected for 1) local determination of urinary sediment and standard safety evaluation and 2) central determination of UPCR. Jugs 
for the Urine collection will be dispensed at previous visit 
18 Pregnancy tests will be conducted for women of childbearing potential; serum pregnancy test at Screening and Urine pregnancy test at all other time points 
19 SF-36 v2 performed (both PCS and MCS) 
20 AEs/SAEs occurring after the participant has provided informed consent must be reported. 
 
 
 
 
23 Background SoC therapy will be administered during the whole treatment period on a daily basis for MPA and Corticosteroids, cyclophosphamide induction every 2 
weeks for 3 months 
26 Planned End of Treatment (EOT) period visit will be performed at Week 104. Participants who discontinue study treatment prematurely for any reason other than 
withdrawal of informed consent before Week 104 will not be considered as discontinued from the study. Please refer to Section 9.1 Discontinuation for detailed instructions 


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8.1 
Screening 
A Screening period of up to 6 weeks will be used to assess participant´s eligibility (Day -42 to 
Day -1). While this duration should provide enough time to evaluate eligibility of the participant, 
including renal biopsy evaluation, it could be extended on a case-by-case basis, to be discussed 
with the Sponsor, to allow for retest of inclusion/exclusion assessments. 
Once eligibility is confirmed, participants elected to receive MPA-based induction SoC therapy 
and not already on this background therapy will be initiated on MPA (MMF or enteric-coated 
MPA sodium) during the run-in period (Day-28 to Day-1). These participants will be initiated 
on an MMF dose of 1 g/day (divided q 12 h.)/equivalent dosage of enteric-coated MPA. Doses 
are to be increased to 2 g/day of MMF/equivalent dosage of enteric-coated MPA in the second 
week and up to 3 g/day of MMF/equivalent dosage of enteric-coated MPA in the third week, if 
tolerability allows. If participants experience adverse effects, which prevent up-titration as 
described, an additional 1 week of titration is permitted. If MMF dose escalation is clinically 
inappropriate as judged by the investigator or inconsistent with local treatment guidelines, 
participants can take a dose of 1.5-2 g/day MMF/equivalent dosage of enteric-coated MPA in 
the absence of observed toxicity. 
All participants evaluated at Screening for eligibility should not be screen failed on the basis of 
a medication requiring washout, unless the participant will be unable to complete the washout 
in the appropriate time frame before Randomization. 
Participants who prematurely withdraw from the study treatment will not be replaced. 
In the case where a safety laboratory assessment at Screening and/or Baseline is outside of the 
range specified in the exclusion criteria, the assessment may be repeated once prior to 
Randomization. If the repeat value remains outside of the specified ranges, the participant must 
be excluded from the study. 
8.1.1 
Information to be collected on Screening failures 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to Randomization will be considered a screen failure. The reason for screen failure should 
be recorded on the appropriate eCRF. The Screening visit date, demographic information, 
informed consent, Inclusion/Exclusion, participant re-screening (for re-screened participants) 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the Screening phase (see SAE Section 10.1.3 for reporting 
details). 
AEs that are not SAEs will be followed up by the investigator and collected only in source data. 
If the participant fails to be randomized, the IRT must be notified within 2 days of the screen 
fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered as early terminated. The reason for early termination should be 
recorded on the appropriate eCRF. If consent was withdrawn during the Screening period before 
the participant was randomized, complete the appropriate eCRF. 


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8.1.2 
Re-screening 
It is permissible to re-screen a participant once if s/he fails the initial Screening; however, each 
case must be discussed and agreed with the Sponsor on a case-by-case basis. 
If a participant re-screens for the study, the participant must sign a new ICF and be issued a 
new subject number prior to any Screening assessments being conducted under the new subject 
number. For all re-screened participants, the investigator/qualified site staff will record if the 
participant was re-screened on the re-screening eCRF and the original Screening number the 
participant was issued prior to the current Screening number. The date of the new informed 
consent signature must be entered in the Informed Consent eCRF corresponding to the new 
subject number. 
For re-screening, all Screening assessments must be performed per protocol, except the 
tuberculosis (TB) work up (if applicable). If the date of the TB work up is less than 12 weeks 
from the projected Baseline date, then it is not required that the TB work up be repeated; 
however, the re-screened participant must repeat PPD skin test or the QuantiFERON TB-Gold 
performed by the central laboratory. 
Participants who are mis-randomized cannot be re-screened. 
8.2 
Participant demographics/other Baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
Baseline characteristics in alignment with eCRF. 
8.2.1 
Demography 
Demographics data to be collected on all participants and recorded in the eCRF include 
• age, 
• sex, 
• race, and ethnicity 
8.2.2 
SLE/LN medical history/diagnosis 
The following information should be collected and entered in the relevant eCRF: 
• the date of first diagnosis for SLE and/or LN 
• SLE/LN family history 
8.2.3 
Prior SLE/LN medications and therapy 
Any treatment for SLE/ LN since initial diagnosis (as determined through medical history 
records or through participant interview) prior to study entry will be collected and recorded in 
the eCRF, along with the duration of the prior therapy, the response to the therapy and the 
reason for discontinuation. 
8.2.4 
Renal biopsy 
An important criterion to be fulfilled for a participant to be randomized within the study is a 
renal biopsy showing active glomerulonephritis WHO or ISN/RPS Class III or IV LN 
[excluding III (C), IV-S (C) and IV-G (C)], with or without co-existing class V features. The 


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biopsy must have been performed within 6 months prior to Screening, or during Screening 
period if not available. 
The local pathologist report confirming Class III or IV LN with active lesions must be kept as 
a source document at the site. In addition, it should be used to complete the Renal Biopsy Report 
eCRF page.  
While the classification of the patient’s LN for randomization will be based on the local 
pathologist report, a central reading of electronic images of the local biopsy slides will be 
performed for confirmation of the classification. The slides used for determination of the 
classification by the local pathologist shall be collected to allow for their digitalization. For this 
purpose, several slides, preferably representing the use of the three most important types of 
staining (e.g., H&E, PAS, silver staining), wherever available, should be collected. Details 
regarding collection of local biopsy slides will be outlined in the Central Laboratory Manual. 
Details regarding central reading of electronic images process, responsibilities and membership 
is described in a separate Central Pathologist Charter. All slides will be returned to the site after 
their digitalization. 
8.2.5 
Standard of care induction therapy 
Before Randomization, during the Screening period, the investigator must define the SoC 
induction therapy that the participant will receive, MPA or CYC-based. (see Section 6.1.3 
Standard of Care background therapy). 
This will ensure that participants can be treated with SoC therapy as per site and/or local 
guidelines, and a balanced repartition within the two treatment arms (secukinumab and placebo). 
The target will be to have a maximum of 25% of randomized participants receiving CYC-based 
induction therapy. 
The choice of SoC induction therapy must be reported in the eCRF and confirmed at time of 
Randomization within the IRT system. 
8.2.6 
Smoking history 
The current and /or previous use of tobacco will be recorded, as well as the estimate number of 
pack-years based on the approximate consumption per year. 
8.2.7 
Cardiovascular medical history 
Protocol-solicited cardiovascular medical history will be collected on the appropriate eCRF 
page. 
8.2.8 
Relevant medical history/ current medical conditions 
Relevant medical history and current medical conditions not related to the study indication, and 
which were present prior to signing of the informed consent, should be recorded in the Medical 
History eCRF. This includes surgical sterilization for females, if applicable. 
Whenever possible, diagnoses and not symptoms should be recorded. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the ICF signature. 


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Significant findings that are observed after the participant has signed the ICF and that meet the 
definition of an AE must be recorded in the AE eCRF. 
8.2.9 
Prior and concomitant medications 
Concomitant medications and prior medications taken over 6 months preceding study 
enrollment for reasons other than SLE/ LN will be captured at the Screening visit and updated 
as necessary in the relevant eCRF. 
Any new medication taken during the course of the study should be collected on the relevant 
eCRF. 
8.2.10 
Determination of the tuberculosis status 
Either a QuantiFERON TB-Gold test or a PPD skin test must be performed at the Screening 
visit for the determination of the participant's tuberculosis status. Participants with a positive 
test may participate in the study if further work up (according to local practice/guidelines) 
establishes conclusively that the participant has no evidence of active tuberculosis, or, if 
presence of latent tuberculosis is established, then treatment according to local country 
guidelines must have been initiated. 
8.2.10.1 QuantiFERON TB-Gold test 
A QuantiFERON TB-Gold test is to be performed at the Screening visit and the results to be 
known prior to Randomization to determine the participant’s eligibility for the trial. The test 
will be used to screen the participant population for latent tuberculosis infection. 
The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual. 
8.2.10.2 PPD skin test 
A PPD skin test is to be performed at the Screening visit and read before Randomization to 
determine the participant’s eligibility for the trial. The test dose is bioequivalent to 5 tuberculin 
units of standard PPD injected intra-dermally, usually into the volar surface of the forearm. The 
site is cleaned and the PPD extract is then injected into the most superficial layer under the skin. 
If given correctly, the injection should raise a small wheal of about 5 mm, which resolves within 
10-15 minutes. 
Because the reaction (induration) will take 48-72 hours to develop, the participants must return 
to the investigators’ site within that time for a proper evaluation of the injection site. This will 
determine whether the participant has had a significant reaction to the PPD test. A reaction is 
measured in millimeters of induration (hard swelling) at the site. A PPD skin induration ≥ 5 mm 
(or according to local practice/guidelines) is interpreted as a positive result. 
8.2.11 
Hepatitis and human immunodeficiency virus (HIV) screen 
Screening for hepatitis and HIV is optional, based on the judgment of the investigator or if 
required by local regulations. If hepatitis testing is performed, testing will include hepatitis B 
surface antigen (HBsAg) and anti-HCV antibodies. If HIV testing is performed, positive HIV 


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screening will be confirmed by a second technique available at the respective local laboratory, 
e.g., Western blot. 
8.2.12 
Electrocardiogram (ECG) 
In this study, local ECG will be used. ECGs must be recorded after 10 minutes rest in the supine 
position to ensure a stable Baseline. A single 12-lead ECG is collected. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions. The original ECGs (on non-
heat-sensitive paper or a certified copy on non-heat sensitive paper), appropriately signed, must 
be collected and archived at the study site. 
The ECG tracing must be labeled with study number, participant initials, subject number, date 
and time, and filed in the study site source documents. Any identifier details must be redacted, 
e.g., obscuring participant initials, date of birth. 
Clinically relevant abnormalities for the Baseline ECG should be recorded on the relevant 
section of the eCRFs capturing medical history/current medical conditions. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. Clinically significant ECG findings at Baseline must be discussed 
with the sponsor before administration of investigational treatment. Clinically significant 
abnormalities must be recorded on the relevant section of the medical history/Current medical 
conditions/AE eCRF as appropriate. 
8.3 
Efficacy 
Clinical efficacy measurements related to primary and secondary objectives are described in 
the subsections below. 
8.3.1 
Complete Renal Response (CRR) 
The CRR will be used to determine efficacy. CRR is a composite endpoint defined as: 
• eGFR ≥ 60 mL/min/1.73m2 or no less than 85% of Baseline 
and 
• 24-hour UPCR ≤ 0.5 mg/mg 
In addition, the estimand definition for primary endpoint is specified in Section 12.4.1. 
8.3.1.1 
Estimated glomerular filtration rate (eGFR) 
The glomerular filtration rate will be estimated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Martínez-Martínez et al 2013) (see 
appendix Section 16.3) based on participant gender, age (years) and serum creatinine (mg/dL). 
Central laboratory serum creatinine values will be used for all renal function data analysis. 
8.3.1.2 
Urine Protein-to-Creatinine Ratio (UPCR) 
Urine Protein-to-Creatinine Ratio (UPCR), expressed in mg/mg, will be determined by a central 
laboratory by dividing the protein concentration by the creatinine concentration as measured in 
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Depending on the objective to be assessed, the UPCR will be determined using one of the 
following two types of urine collection, 24-hour urine collection or first morning void urinary 
sample, as indicated in Section 2, Table 2-1 Objectives and related endpoints. 
Both the 24-hour urine collection and the first morning void will be collected in the participants' 
home. 
8.3.2 
Partial Renal Response (PRR) 
PRR is a composite endpoint defined as: 
• eGFR ≥ 60 mL/min/1.73m2 or no less than 85% of Baseline 
and 
• ≥50 % reduction in 24-hour UPCR to sub-nephrotic level (≤ 3 mg/mg) compared to 
Baseline 
8.3.3 
Average daily dose of corticosteroids 
Average daily dose of oral corticosteroids doses will be used to demonstrate superiority of 
secukinumab compared to placebo in the averaged daily dose of oral corticosteroids 
administered between Week 16 and Week 52. 
8.3.4 
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-
Fatigue©) 
The FACIT-Fatigue© is a 13-item questionnaire (Cella et al 1993), (Yellen et al 1997) that 
assesses self-reported fatigue and its impact upon daily activities and function over the past 
week. The purpose of the FACIT-Fatigue© in this study is to assess the impact of fatigue on 
patients with LN.  
The level of fatigue is measured on a 5-point Likert scale (0 = not at all, 1 = a little bit,  
2 = somewhat, 3 = quite a bit, 4 = very much). 
The purpose of FACIT-Fatigue© in this study is to demonstrate superiority of secukinumab 
compared to placebo on the mean change of score. 
8.3.5 
Short Form Health Survey (SF-36) 
The Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute Form) is a survey 
evaluating individual participants' health status, which also monitors and compares participants' 
disease burden. This has been widely used to assess physical, psychological and social impact 
of chronic disease like LN (Holloway et al 2014). 
It consists of eight subscales that can be scored individually: Physical Functioning, Role-
Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and 
Mental Health (Ware et al 1993). Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed 
(Ware et al 1994). In this trial, SF-36-PCS responder (improvement of ≥ 2.5 points, 
(Lubeck 2004)) will be evaluated. The SF-36 has proven useful in monitoring general and 
specific populations, comparing the relative burden of different disease, differentiating the 
health benefits produced by different treatments, and in screening individual participants. The 


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purpose of the SF-36 in this study is to assess the HRQoL of participants with active LN. Given 
the acute nature of this disease, version 2, with a one-week recall period, will be used in this 
study. 
8.3.6 
Lupus Quality of Life (LupusQoL) 
The LupusQoL is a disease-specific, 34-item, self-report questionnaire designed to measure the 
health-related quality of life (HRQoL) of patients with SLE within 8 domains (i.e., physical 
health (8 items), emotional health (6 items), body image (5 items), pain (3 items), planning (3 
items), fatigue (4 items), intimate relationships (2 items), and burden to others (3 items). 
Responses are based on a 5-point Likert scale where 0 (all of the time) to 4 (never) 
(Yazdany 2011), ( RWS Life). 
Each domain of the LupusQoL is scored separately. 
8.3.7 
Urinary sediment 
Urinary sediment will be determined at site at each visit using the first morning void sample. 
Presence of red blood cells (RBCs), white blood cells (WBCs), epithelial cells, and cellular 
casts (RBC and WBC casts) will be determined by microscopic evaluation or through 
automated evaluation performed at local laboratory. Results must be recorded on the 
appropriate eCRF. 
Active urinary sediment is defined as the presence of cellular casts (RBC or WBC casts), or 
hematuria (> 5 RBCs per high power field or above the laboratory reference range). 
8.3.8 
Appropriateness of efficacy assessments 
The proposed primary endpoint is in line with the CHMP guideline, which recommends that 
studies conducted in patients with LN should be aimed for the control of renal activity with 
primary outcome focusing on renal specific endpoints such as induction of CRR. 
The CRR is demonstrated as a clinically significant improvement of renal function as measured 
by improvement of eGFR ((≥ 60 mL/min/1.73 m2)/return to Baseline eGFR), and a reduction 
in renal injury as measured by reduction in proteinuria (<0.5 mg/mg in 24-hour) 
 
 The urinary sediment was removed from the components of the primary 
endpoint CRR after consultation of Food and Drug Administration (FDA) and European 
Medicines Agency (EMA), due to the difficulty to standardize methods of evaluation for urinary 
sediment across a multicenter study, and because the selection of the appropriate population 
(active class III or IV LN) is ensured by renal biopsies performed within 6 months of enrollment. 
The proposed secondary endpoints, such as the composite PRR, or laboratory indices of the 
activity of renal diseases such as proteinuria, are in line with the CHMP guidelines. 
In addition, both CRR and PRR have been previously used in clinical trials in LN, as a measure 
of renal activity. 
As chronic fatigue and participant's disease burden may interfere with daily activities and 
quality of life, additional patient reported outcome measures (PROs) of physical functioning 
and health-related quality of life (HRQoL) tools will be used for assessing participant's 
perception of the impact of the disease and treatment on daily life. While FACIT-Fatigue© and 


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SF36 PCS are not disease specific, it has been widely used to assess physical, psychological 
and social impact of chronic diseases including SLE. The lupus specific quality of life 
instrument LupusQoL will be evaluated to further evaluate the impact of the disease during the 
study. 
8.4 
Safety 
All blood draws and safety assessments should be done prior to study treatment administration.  
• Physical examination 
• Vital signs 
• Height and weight 
• Laboratory evaluations (Hematology, Clinical Chemistry, Lipid Panel, coagulation panel, 
Urinalysis) 
• Evaluation of AEs/SAEs 
• Local tolerability (Injection site reactions) 
• Pregnancy  
• Tolerability of secukinumab 
 
 
As per Section 4.6, during a public health emergency as declared by local or regional authorities, 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
8.4.1 
Physical examination 
A physical examination, including general appearance, skin, neck, eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, and vascular and neurological systems will be 
performed as indicated in Table 8-1. 
If necessary, based on medical history and/or symptoms, additional exams will be performed at 
the discretion of the investigator. 
Whenever possible, assessments for an individual participant should be performed by the same 
member of the study site staff throughout the study. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study treatment must be 
included in the Medical History eCRF. Significant findings made after signing informed 
consent, which meet the definition of an Adverse Event, must be recorded on the Adverse Event 
eCRF. 
8.4.2 
Vital signs 
Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 8-1. Whenever possible, assessments should be performed 
by the same study site staff member throughout the study. 


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After the participant has been sitting for five minutes, with back supported and both feet placed 
on the floor, heart rate, systolic and diastolic blood pressure will be measured twice 
(measurements separated by 1 to 2 minutes) using a validated device, with an appropriately 
sized cuff. In case the cuff sizes available are not large enough for the participant’s arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used. 
Measurements will be recorded in the source documentation and the average of the two 
measurements will be entered on the Vital Signs eCRF. 
No specific action is pre-defined within this protocol to respond to specific abnormal vital signs, 
as it will be decided by the investigator whether and which specific action needs to be taken to 
respond to any abnormal values, taking into account the overall status of the participant. 
8.4.3 
Height and weight 
Height and body weight will be measured as indicated in Table 8-1. 
Height in centimeter (cm) and body weight (to the nearest 0.1 kilogram (kg)) will be measured 
in indoor clothing, but without shoes. If possible, body weight assessments should be performed 
by the same study site staff member and using the same scale throughout the study. 
8.4.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens listed below, unless noted 
otherwise. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the laboratory manual. Refer to the Laboratory 
Manual for identification of laboratory reference range values and the schema for notification 
of site staff and Novartis for out-of-range values. 
For the identification of clinically notable values, see Section 16.10. All participants with 
laboratory tests containing clinically significant abnormal values are to be followed until the 
values return to normal ranges or until a valid reason, other than treatment related AE, is defined. 
Blood withdrawals and safety assessments should be done prior to study treatment 
administration and should be taken as shown in Table 8-1. 
8.4.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils including bands, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count will be measured. 
8.4.4.1.1 Erythrocyte sedimentation rate (ESR) 
The ESR test will be performed using the ESR Supplies kit provided by the central laboratory. 
A laboratory manual will be provided with detailed information on sample collection and 
handling. ESR results will be reported in the appropriate eCRF page. 
8.4.4.2 
Clinical chemistry 
Serum chemistry will include urea, creatinine, hemoglobin A1c (HbA1c), total bilirubin (TBL), 
AST (serum glutamic oxaloacetic transaminase (SGOT)), ALT (serum glutamic pyruvic 
transaminase (SGPT)), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), 


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sodium, potassium, bicarbonate, calcium, phosphorous, total protein, albumin, lipase, amylase, 
and uric acid. 
High sensitivity C-reactive protein (hsCRP) will also be assessed. In order to preserve the blind, 
results of hsCRP will not be communicated to the study site staff, including the investigator, or 
to Novartis during the study. 
8.4.4.2.1 Lipid panel 
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
cholesterol and triglycerides will be measured from a fasting blood sample. 
8.4.4.2.2 High sensitivity C-reactive protein 
High sensitivity C-reactive protein (hsCRP) will be assessed as indicated in Table 8-1. In order 
to preserve the blind, results of hsCRP will not be communicated to the study site staff, 
including the investigator, or to Novartis during the study. 
8.4.4.3 
Coagulation panel 
Prothrombin time (PT), activated partial thromboplastin time (aPTT) and International 
Normalized Ratio (INR) will be evaluated locally for general safety and additional 
characterization of the disease. 
8.4.4.4 
 Urinalysis 
There will be two types of urinary collection, both performed at participants' home: 
• 24-hour urine collection, corresponding to the 24-hour collection of the urine the day 
preceding the Baseline, Week 12, Week 24, Week 36, Week 52, Week 76 and EOT visits, 
as outlined in Table 8-1. 
• first morning void urine collection on the day of visits as specified in Table 8-1. 
8.4.4.4.1 Local urinalysis 
The participant's first morning void urine sample will be used for local urinalysis assessments 
performed for standard safety evaluation. 
Those standard assessments will include specific gravity, protein, glucose, pH, blood, urine 
blood dipstick (non-hemolyzed), urine blood dipstick (hemolyzed), bilirubin, ketones and WBC. 
Please refer to the central laboratory manual for additional details.  
In addition, participant's first morning void urine sample will also be used for local 
determination of urinary sediment, as outlined in Efficacy Section 8.3.7 and central 
determination of UPCR, as outlined in Efficacy  Section 8.3.1.2. 
Jugs for the first morning void urine collection will be dispensed at participant's previous visit. 
8.4.4.4.2 24-hour urine collection 
A 24-hour urine collection is done at selected time point by collecting urine in a special 
container over a full 24-hour period. 


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Instructions regarding the timing, the collection and the storage of the 24-hour urine collection 
will be detailed within the laboratory manual. 
This 24-hour urine collection will be used for central determination of the UPCR, as mentioned 
in Efficacy Section 8.3.1.2 . 
8.4.4.5 
Autoantibodies 
8.4.4.5.1 ANA and anti-dsDNA 
 
In addition, ANA or anti-dsDNA must be tested positive for a participant being eligible in this 
study in case of confirmed diagnosis of lupus nephritis as the sole criterion as per inclusion 
criteria 2 (refer to Section 5.1 Inclusion criteria). 
 
 
 
8.4.5 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test (serum 
pregnancy test) performed at the Screening visit, and local urine pregnancy tests as indicated in 
Table 8-1. A positive urine pregnancy test requires immediate interruption of study drug until 
serum β-hCG is performed and found to be negative. Additional pregnancy testing might be 
performed if requested by local requirements. 
Secukinumab, MPA, CYC and corticosteroids should not be given to pregnant women; 
therefore, effective methods of birth control must be used for women of childbearing potential 
(see exclusion criteria definitions, Section 5.2). 
In addition, menses will be recorded on the appropriate eCRF page for all pre-menopausal 
women, as indicated in Table 8-1. 


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8.4.6 
Other safety evaluations 
Chest X-ray 
Standard chest X-ray (PA view) will be performed except for those who have had a valid X-ray 
done within 3 months preceding the Screening visit. If participants do not have a chest X-ray, 
CT or MRI obtained within 3 months preceding the Screening visit, a standard chest X-ray (PA 
view) should be performed. In order to minimize unnecessary exposure to radiation, the chest 
X-ray should only be performed after confirming that the participant meets all 
inclusion/exclusion criteria (apart from renal biopsy which would be undertaken after a chest 
x-ray, if applicable). In some sites selected by Novartis, the X-ray assessment may be replaced 
by CT or MRI assessment. 
8.4.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
The other assessments planned for the study are: 
• Clinical Outcome Assessments (COAs): This includes Patient reported outcomes (PRO) 
 
• Trial Feedback Questionnaires 
 
 
 
 
 
 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, COA 
data may be collected remotely (e.g., web portal, telephone interviews) depending on local 
regulations, technical capabilities, and following any applicable training in the required 
process. 
8.5.1 
Patient reported outcomes (PRO) 
Participants will be asked to complete the following PRO measures in e-devices provided by 
the site: 
1. FACIT-Fatigue© 
2. SF-36 v2 
3. LupusQoL 
 
The participant must be given the PRO measure(s) to be completed at the scheduled visit before 
any clinical assessments are conducted. Participant’s refusal to complete all or any part of a 
PRO measure should be documented in the study data capture system and should not be 
captured as a protocol deviation. 


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The participant should be given sufficient space and time to complete the PRO measures. 
The site personnel should check PRO measures for completeness and ask the participant to 
complete any inadvertently missing responses. 
The participant should be made aware that completed measures are not reviewed by the 
investigator/study personnel. 
FACIT-Fatigue©, SF-36 v2 Physical Component Summary and Lupus QoL are already 
described in Efficacy Section 8.3.4, Section 8.3.5, Section 8.3.6, respectively. 


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8.5.3 
Trial Feedback Questionnaire (TFQ) 
This study is including an optional questionnaire, the “Trial Feedback Questionnaire” for trial 
participants to provide feedback on their clinical trial experience. Individual trial participant 
responses will not be reviewed by investigators. Responses may be used by the sponsor 
(Novartis) to understand where improvements can be made in future clinical trial processes. 
This questionnaire does not ask questions about the trial participant's disease, symptoms, 
treatment effect, or AEs, and, therefore is not considered as trial data. 


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8.5.6 
Biomarkers 
This clinical study includes additional, optional biomarker components supported by an 
exploratory objective. These studies are hypothesis generating (i.e., discovery-based research) 
and optional to the participant. 
Exploratory biomarker assessments 
Biomarkers are objectively measured and evaluated indicators of normal biological processes, 
pathogenic processes or pharmacologic responses to a therapeutic intervention (Biomarkers 
Definitions Working Group 2001). This search for biomarkers of disease and drug response 
will involve an integrated molecular approach examining gene expression in blood and protein 
profiles in serum. 
These optional assessments aim to identify potential markers of response and/or loss of response, 
and to characterize molecular mechanisms of treatment with secukinumab. 
Any biomarker samples may be stored for up to 15 years (depending on local regulations) to 
research scientific questions related to secukinumab, LN and related diseases with a potential 
involvement of IL-17A. The material can be destroyed on participant’s request at any time point. 
Any results from these exploratory biomarker assessments will be reported separately. 
 
 The final selection of analytes will be driven by assay availability, new 
information from the public domain, results obtained in other secukinumab clinical studies, as 
well as by hypotheses generated by other exploratory biomarker assessments. In addition, 
selected markers exploring the effect of secukinumab treatment on co-morbidities may be 
assessed. 


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DNA/RNA sampling / Pharmacogenetics 
The study includes an optional genetic research component, which requires a separate informed 
consent signature if the patient agrees to participate as stated in Section 7. As permitted by local 
governing regulations and by IRB/EC, it is required as part of this protocol that the Investigator 
presents these options to the participant. 
The purpose of genetic research is to evaluate the effect of genetic polymorphisms on treatment 
response and to better understand the safety and efficacy of secukinumab. 
As technology changes over time, the most appropriate technology will be used at the time the 
exploratory genetic research is performed. This may include the study of the entire genome. 
Follow instructions for sample collection, numbering, processing, and shipment provided in the 
laboratory manual. 
DNA/RNA samples 
The use of DNA/RNA to search for biomarkers of disease and drug action is exploratory. Any 
results from this DNA/RNA study will not be placed in the participant’s medical records. 
To maximize confidentiality, all samples and the information associated with the samples will 
be double-coded to prevent the exposure of the participant’s information and identity. This 
double-coding process allows Novartis to go back and destroy the sample at the participant’s 
request. In addition, sample information is stored in one secured database while genetic data is 
stored in an independent secured database. 
RNA 
The activity (the expression) of genes will be examined using RNA (or other nucleic acid) 
analytical technologies, which may include expression microarrays, PCR, Nanostring, Next 
Generation Sequencing techniques, or others. These analyses will be used to examine the effect 
of secukinumab on transient RNA expression in serum and may support the identification of 
pathways/markers that characterize the disease or response of treatment with secukinumab.  


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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration, i.e., before Week 100 last planned study treatment 
administration. Discontinuation of study treatment can be initiated by either the participant or 
the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision - participants may choose to discontinue study treatment for 
any reason at any time 
• Pregnancy (see Section 10.1.4 Pregnancy reporting) 
• Participant received a live vaccine 
• Use of prohibited treatment as outlined in Section 6.2.2 prohibited medication 
• Any situation or protocol deviation in which study participation might result in a safety 
risk to the participant 
• Following an emergency unblinding 
• Emergence of the following AEs:  
• Any AE that in the judgment of the investigator, taking into account the 
participant's overall status, prevents the participant from continuing study 
treatment (for example sepsis) 
• Any severe or serious AE that requires treatment with an unacceptable  
co-medication 
• Severe hypersensitivity reaction or anaphylactic reaction 
• Any laboratory abnormalities that in the judgment of the investigator, taking into account 
the participant's overall status, prevents the participant from continuing study treatment 
• Unsatisfactory therapeutic effect 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information in the eCRF. 
Participants who discontinue study treatment prematurely for any reason should NOT be 
considered as discontinued from the study UNLESS they withdrew their consent (see 
Section 9.1.2 Withdrawal of Informed Consent). Where possible, they should continue 
attending site visits. 
All participants who prematurely discontinue study treatment should perform the EOT 
study visit 4 weeks after their last study treatment administration. For example, if study 
treatment discontinuation decision is taken at time of planned Week 16 visit, the participant 
should perform the EOT visit assessments instead of Week 16 visit assessments. 


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Thereafter, different possibilities may arise, for which guidelines are outlined below: 
• Participants unwilling to continue attending further study visits after prematurely 
discontinuing the study treatment should also perform an EOS visit 12 weeks after the last 
administration of the study treatment. 
• Participants willing to continue attending study visits should continue attending all 
subsequent scheduled site visits for clinical and safety study assessments. For the example 
taken above, next visit should be Week 20 during which visit assessments as outlined in 
Visit Schedule Table 8-1 will be performed, except study treatment administration. The 
EOS visit should be performed 12 weeks after the Week 100 visit. 
• Participants initially continuing attending site visits after premature study treatment 
discontinuation may decide to discontinue study at any time. For those participants, the 
EOS visit will be performed at time of study discontinuation. Of note, the EOS visit must 
always be completed at least 12 weeks after the last study treatment administration. 
Finally, if the participant is failing to return for these assessments for unknown reasons, every 
effort (e.g., telephone, e-mail, letter) should be made to contact the participant/pre-designated 
contact as specified in the lost to follow-up section. This contact should preferably be done 
according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the participant’s study withdrawal should be made as detailed in the 
assessment table. 


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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a participant’s samples until the time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g., dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the participant welfare and safety. Should early termination be 
necessary, participants must be contacted by the sites to be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor, depending on the local 
regulation, will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
A participant will be considered to have completed the study when she/he has completed the 
last planned visit in the protocol. 
The investigator must provide follow-up medical care for all participants, including participants 
who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care. 
This care may include initiating another treatment outside of the study, as deemed appropriate 
by the investigator. 


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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a participant or clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade 
mild: usually transient in nature and generally not interfering with normal activities 
moderate: sufficiently discomforting to interfere with normal activities 
severe: prevents normal activities 
2. its relationship to the study treatment and other investigational treatment. If the event is due 
to lack of efficacy or progression of underlying illness (i.e., progression of the study 
indication) the assessment of causality will usually be ‘Not suspected.’ The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying illness 
are not caused by the trial drug, they happen in spite of its administration and/or both lack 
of efficacy and progression of underlying disease can only be evaluated meaningfully by an 
analysis of cohorts, not on a single participant 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 


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6. its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 84 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values, which are considered to be non-typical in patients with 
the underlying disease. Alert ranges for laboratory test abnormalities are included in 
Section 16.10. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
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• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 12 weeks (84 days) following the last administration 
of study treatment, or 30 days after the participant has stopped study participation (whichever 
is later), must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Any SAEs experienced after the 30-day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess the relationship of each SAE to study treatment, complete 
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Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.4 
Pregnancy reporting 
Pregnancies 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 


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Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / AEs have to be considered during the course 
of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate eCRFs 
Please refer to Table 16-1 of appendix Section 16.9 for complete definitions of liver laboratory 
triggers and liver events. 
Every liver event defined in Table 16-2 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (i.e., ALT, AST, TBL, 
PT/INR, ALP and GGT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, 
any local liver chemistry tests previously conducted that are associated with this event 
should have results recorded on the appropriate eCRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Section 9.1.1 Discontinuation of 
study treatment section), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  


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• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist consultancy; obtaining more detailed 
history of symptoms and prior or concurrent diseases, history of concomitant drug use, 
exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess data from the interim analyses, as 
well as the progress of the clinical trial, safety data, and critical efficacy variables and it will 
recommend to the sponsor whether to continue, modify, or terminate the trial. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.2.3 
Steering Committee 
A Steering Committee (SC) will be established comprising disease area experts, investigators 
participating in the trial, i.e., not being members of the DMC, and Novartis representatives from 
the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 Code of Federal Regulation (CFR) Part 11 requirements, 
Investigator site staff will not be given access to the Electronic Data Capture (EDC) system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 


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After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Randomization codes and data about all study treatment(s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer, 
 statistician. Any changes to the database after that time can only be 
made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 


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participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
11.4 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used 
by Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
12 
Data analysis and statistical methods 
Summary statistics for continuous variables include N, mean, standard deviation (SD), 
minimum, lower quartile, median, upper quartile, and maximum. For binary or discrete 
variables, the absolute number of participants in each category and relative frequencies will be 
provided. 
Unless otherwise specified, p-values will be presented as 2-sided p-values and the type I error 
rate (alpha) will be 5%. 
Efficacy and safety data for Treatment Period will be presented by the following two treatment 
groups. 
• Secukinumab 300 mg  
• Placebo 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 


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12.1 
Analysis sets 
The Randomized Analysis Set (RAS) consists of all randomized participants. Unless otherwise 
specified, mis-randomized participants (mis-randomized in IRT) will be excluded from the 
randomized set. 
The Full Analysis Set (FAS) will be comprised of all analyzable participants from the 
randomized set to whom study treatment has been assigned. According to the intent to treat 
principle, participants will be analyzed according to the treatment they have been assigned to 
during the randomization procedure, but according to actual stratum. 
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received. 
12.2 
Subject demographics and other Baseline characteristics 
Summary statistics will be presented for continuous demographic and Baseline characteristic 
variables for each treatment group and for all participants in the randomized set. The number 
and percentage of participants in each category will be presented for categorical variables for 
each treatment group and all participants. 
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term. SLE and LN specific medical history will be 
summarized by treatment group. 
To establish a Baseline level of cardiovascular risk, the number and percentage of participants 
with pre-solicited cardiovascular risk factors will be summarized by treatment group. The 
number of cardiovascular risk factors that each participant has will also be summarized by 
treatment group. If it is unknown whether a participant currently or previously experienced a 
specific cardiovascular risk factor, it will be assumed that cardiovascular risk factor did not 
occur for that participant. 
12.3 
Treatments 
Study treatment 
The analysis of study treatment data will be based on the safety set. The number of active and 
placebo injections received will be presented by treatment group. The duration of exposure to 
study treatment will also be summarized by treatment group. In addition, the number and 
percentage of participants with cumulative exposure levels (e.g., any exposure, ≥ 1 week, ≥ 2 
weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented.  
Prior and concomitant medication 
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to the first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those, 
which were started pre-Baseline and continued into the period where study treatment is 
administered. 


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Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of participants receiving at least one treatment of a particular ATC code and at least 
one treatment in a particular anatomical main group. 
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term. 
The number and percentage of participants receiving prior and concomitant LN therapy will be 
presented by randomized treatment group. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy endpoint is the complete renal response (CRR) at Week 52 with the 
consideration of intercurrent events, which is defined in detail at Section 2.1 .  
12.4.2 
Statistical model, hypothesis, and method of analysis 
The statistical hypothesis tested for the primary objective is that there is “no difference in the 
proportion” of patients fulfilling the response criteria at Week 52 between the secukinumab and 
placebo regimens. 
Let pj denote the proportion of responders at Week 52 for treatment regimens j, j=0, 1 where 
• 0 corresponds to placebo regimen, 
• 1 corresponds to secukinumab, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e., 
H1: secukinumab is not different from placebo regimen with respect to CRR at Week 52 
Logistic regression model adjusting for SoC, race and Baseline UPCR will be used for the 
primary analysis. Difference in marginal response proportions with p-value and respective 95% 
confidence interval will be estimated from the logistic regression model. 
12.4.3 
Handling of intercurrent events of primary estimand 
Major intercurrent events of primary estimand will be addressed with the following strategies 
(considering that these events occur before the assessments at Week 52): 
1. Treatment discontinuation for any reason: non-responder (composite endpoint strategy) 
2. Overuse of corticosteroid (> 10mg/day prednisone equivalent for ≥ 3 consecutive days or ≥ 
7 days in total) between Week 44 and Week 52: non-responder (composite endpoint 
strategy) 
12.4.4 
Handling of missing values not related to intercurrent events  
Participants who do not have the required data to compute CRR at Week 52 will be classified 
as non-responders. 


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12.4.5 
Sensitivity analyses 
The impact of missing data on the analysis results of CRR will be assessed by repeating the 
logistic regression model using different ways to handle missing data. 
These may include, but are not limited to: 
• Multiple imputation 
• Observed data analysis 
• Tipping point analysis 
12.4.6 
Supplementary analyses 
12.4.6.1 Modified complete renal response 
As a supplementary analysis to primary endpoint modified Complete Renal Response (mCRR) 
will be analyzed. 
A participant is defined as a mCRR responder when the following two conditions are met: 
• Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 or no less than 85% of 
Baseline and 
• 24-hour UPCR ≤ 0.7 mg/mg 
Intercurrent events will be handled in the same way as for the primary estimand. 
12.4.6.2 Treatment policy estimand 
A supplementary analysis of the primary endpoint will be performed using a treatment policy 
strategy, i.e., regardless of study treatment discontinuation or corticosteroid overuse.  
12.4.6.3  Components of the primary endpoint 
All components of the endpoint CRR will be tabulated separately by treatment group. This will 
include: 
• Number of participants with eGFR ≥ 60 mL/min/1.73 m2 or no less than 85% of Baseline 
at Week 52 
• Number of participants with 24-hour UPCR ≤ 0.5 mg/mg at Week 52 
• Number of participants without study treatment discontinuation before Week 52 
• Number of participants without corticosteroid overuse before Week 52 
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Secondary efficacy endpoints 
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below.  
H2: Secukinumab 300 mg is not different to placebo with respect to change from Baseline in 
24-hour UPCR at Week 52 compared to Baseline 


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H3: Secukinumab 300 mg is not different to placebo with respect to proportion of patients 
achieving PRR at Week 52 
H4: Secukinumab 300 mg is not different to placebo with respect to average daily dose of oral 
corticosteroids administered between Week 16 and Week 52 
H5: Secukinumab 300 mg is not different to placebo with respect to proportion of patients 
achieving PRR at Week 24 
H6: Secukinumab 300 mg is not different to placebo with respect to time to achieve CRR 
H7: Secukinumab 300 mg is not different to placebo with respect to time to achieve PRR 
H8: Secukinumab 300 mg is not different to placebo with respect to time to achieve first morning 
void UPCR ≤ 0.5 mg/mg 
H9: Secukinumab 300 mg is not different to placebo with respect to FACIT-Fatigue©, mean 
change of score from Baseline at Week 52 
H10: Secukinumab 300 mg is not different to placebo with respect to improvement in SF-36 
PCS mean change from Baseline at Week 52 
H11: Secukinumab 300 mg is not different to placebo with respect to improvement in LupusQoL 
physical health score mean change from Baseline at Week 52 
A sequential testing strategy will be used in order to control for multiplicity of testing. The 
graphical approach of (Bretz et al 2009) for sequentially rejective testing procedures is used to 
illustrate the testing strategy: 


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Figure 12-1 
Testing strategy 
  
The family-wise error will be set to two-sided α = 5% and it will be controlled with the proposed 
hierarchical testing strategy. 
The hypotheses (H1) for the primary objective (CRR at Week 52) for the secukinumab vs. 
placebo will be tested at α. If H1 is rejected, then the hypothesis H2 will be tested at α. If H2 is 
rejected, then the hypothesis H3 will be tested and so on. 
UPCR at Week 52 
For the change in UPCR, analysis will be performed on the loge ratio of the treatment value vs 
Baseline value (calculated by dividing the post-Baseline value by the Baseline value and then 
applying the loge transformation) to normalize the distribution of UPCR at each analysis visit. 
Between-treatment differences in the change in UPCR relative to Baseline will be evaluated 
using MMRM with treatment group, stratification factor (SoC), race, and analysis visit as 
factors and loge Baseline UPCR as continuous covariates. Treatment by analysis visit and loge 
Baseline UPCR by analysis visit will be included as interaction terms in the model. An 
unstructured covariance structure will be assumed for the model. The significance of the 


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treatment effect for secukinumab will be determined from the pairwise comparisons performed 
between secukinumab and placebo at the appropriate analysis visits. 
PRR at Week 24 or at Week 52 
Logistic regression model adjusting for SoC, race and baseline UPCR will be used for the 
analysis. Difference in marginal response proportions with p-value and respective 95% 
confidence interval will be estimated from the logistic regression model. 
Average daily dose of oral corticosteroids administered between Week 16 and Week 52 
Between-treatment differences for average daily dose of oral corticosteroids administered 
between Week 16 and Week 52 will be evaluated with analysis of covariance (ANCOVA) 
model including treatment group, race, Baseline dose and SoC as covariates. Missing data will 
be handled using multiple imputation. 
Time to achieve CRR 
For time to achieve CRR, between treatment differences will be evaluated using log-rank test 
stratified by race and SoC. The hazard ratios for these comparisons for achieving response and 
their corresponding 95% confidence intervals will be computed using a stratified Cox 
proportional hazards regression model with treatment group and loge Baseline UPCR as 
explanatory variable and stratified by race and SoC. Participants who have not achieved 
response up to Week 52 will be considered as censored observations. Kaplan-Meier curves will 
be presented for each treatment. 
Time to achieve PRR 
For time to achieve PRR, between treatment differences will be evaluated using log-rank test 
stratified by race and SoC. The hazard ratios for these comparisons for achieving response and 
their corresponding 95% confidence intervals will be computed using a stratified Cox 
proportional hazards regression model with treatment group and loge Baseline UPCR as 
explanatory variable and stratified by race and SoC. Participants who have not 
achieved response up to Week 52 will be considered as censored observations. Kaplan-Meier 
curves will be presented for each treatment. 
Time to achieve first morning void UPCR ≤ 0.5 mg/mg  
For time to achieve first morning void UPCR ≤ 0.5 mg/mg; between treatment differences will 
be evaluated using log-rank test stratified by race and SoC. The hazard ratios for these 
comparisons for achieving response and their corresponding 95% confidence intervals will be 
computed using a stratified Cox proportional hazards regression model with treatment group 
and loge Baseline UPCR as explanatory variable and stratified by race and SoC. Participants 
who have not achieved response up to Week 52 will be considered as censored observations. 
Kaplan-Meier curves will be presented for each treatment. 
FACIT-Fatigue© change from Baseline at Week 52 
Between-treatment differences in the change from Baseline in FACIT-Fatigue© will be 
evaluated using MMRM with treatment group, stratification factor (SoC), race, and analysis 
visit as factors and Baseline FACIT-Fatigue© as continuous covariates. Treatment by analysis 
visit and Baseline FACIT-Fatigue© by analysis visit will be included as interaction terms in the 
model. An unstructured covariance structure will be assumed for the model. The significance 


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of the treatment effect for secukinumab will be determined from the pairwise comparisons 
performed between secukinumab and placebo at the appropriate analysis visits. 
SF-36 PCS change from Baseline at Week 52 
Between-treatment differences in the change from Baseline in SF-36 PCS will be evaluated 
using MMRM with treatment group, stratification factor (SoC), race, and analysis visit as 
factors and Baseline SF-36 PCS as continuous covariates. Treatment by analysis visit and 
Baseline by analysis visit will be included as interaction terms in the model. An unstructured 
covariance structure will be assumed for the model. The significance of the treatment effect for 
secukinumab will be determined from the pairwise comparisons performed between 
secukinumab and placebo at the appropriate analysis visits. 
LupusQoL physical health score change from Baseline at Week 52 
Between-treatment differences in the change from Baseline in LupusQoL physical health score 
will be evaluated using MMRM with treatment group, stratification factor (SoC), race, and 
analysis visit as factors and Baseline LupusQoL physical health score as continuous covariates. 
Treatment by analysis visit and Baseline LupusQoL physical health score by analysis visit will 
be included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab will be 
determined from the pairwise comparisons performed between secukinumab and placebo at the 
appropriate analysis visits. 
Maintained renal response at Week 104 
A patient with maintained renal response at Week 104 is one who achieves CRR at Week 104 
after already achieving CRR at Week 52. Response rate with 95% confidence interval will be 
presented for the secukinumab group. 
Improved or maintained renal response at Week 104 
A patient with improved or maintained renal response at Week 104 is one who achieves CRR 
or PRR at Week 104 after achieving at least PRR at Week 52. Response rate with 95% 
confidence interval will be presented for the secukinumab group. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.  
Adverse events 
Treatment-emergent adverse events (i.e., events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term and on or before last dose + 84 days) will be summarized. 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of participants having any AE, having an AE in each primary system organ class 
and having each individual AE (preferred term). Summaries will also be presented for AEs by 
severity and for study treatment related AEs. If a participant reported more than one adverse 
event with the same preferred term, the adverse event with the greatest severity will be presented. 


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If a participant reported more than one adverse event within the same primary system organ 
class, the participant will be counted only once with the greatest severity at the system organ 
class level, where applicable. Serious adverse events will also be summarized. 
As appropriate, the incidence of AEs will be presented per 100 participant-years of exposure 
(exposure-adjusted incidence rates). 
Separate summaries will be provided for deaths, SAEs, and AEs leading to study treatment 
discontinuation. 
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented. 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from Baseline 
for each post-Baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from Baseline will only be summarized for 
participants with both Baseline and post-Baseline values. 
12-lead ECG 
Summary statistics will be presented for ECG variables. 
Clinical laboratory evaluations 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from Baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from Baseline will only 
be summarized for participants with both Baseline and post-Baseline values. 
 
 
 
12.6 
Analysis of exploratory endpoints 


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12.6.1 
Patient reported outcomes 
Health-related Quality of Life assessments will be evaluated based on FAS unless otherwise 
specified. 
SF-36 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100) 
• SF-36 PCS and MCS scores (norm-based scores) 
• SF-36 PCS and MCS responder (improvement of ≥ 2.5 points, (Lubeck 2004)) 
For the change in SF-36 summary scores (PCS and MCS), summary statistics will be provided 
using observed data for each treatment regimen. Between-treatment differences will be 
evaluated using MMRM. 
The SF-36 domain scores will be summarized by treatment. 
FACIT-Fatigue© 
For the change in FACIT-Fatigue© scores, summary statistics of observed data by visit and 
change from Baseline in FACIT-Fatigue© will be provided for each treatment. Between-
treatment differences will be evaluated using MMRM. 
LupusQoL 
For the change in LupusQoL domain scores, summary statistics of observed data by visit and 
change from Baseline will be provided for each treatment. Between-treatment differences will 
be evaluated using MMRM. 


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12.6.3 
DNA and RNA 
Exploratory DNA and RNA studies are designed to investigate the association between genetic 
factors (genotypes) and clinical assessments (phenotypes) which are collected during the 
clinical trial. Without prior evidence of a strong association, a number of possible associations 
are evaluated with exploratory analyses. A range of statistical tests is used for the analyses. 
Additional data, from other clinical trials, are often needed to confirm associations. 
Alternatively, if the number of participants enrolled in the study is too small to complete proper 
statistical analyses, the data may be combined, as appropriate, with those from other studies to 
enlarge the dataset for analysis. 
Data generated on hypothesis-free platforms will be reported separately (e.g., CSR addendum). 
12.6.4 
Biomarkers 
Soluble marker panel studies investigate differences in the level of expression of proteins or 
peptides between individuals in a given biofluid. The goal of such studies is to allow the 
identification of potential protein or peptide biomarkers of treatment action or disease and to 
better understand the associated underlying molecular mechanisms. By applying statistical 
analysis methods (e.g., principal component analysis) between participant groups, distinct study 
time points, or between study groups from other clinical trials, it may be possible to identify 
patterns, which are associated with disease state or response to drug treatment. However, the 
exact type of data analysis method will depend on the type of data obtained in the study, and 
thus, the analysis of these data will be data-driven and, hence, not part of the Clinical Study 
Report (CSR). 
 
 
 
 
12.7 
Interim analyses 
12.7.1 
First interim analysis 
The first interim analysis will be performed when approximately 138 participants 
(approximately 35% of the total 400 participants) are expected to complete 52 weeks of 
treatment (including those who discontinue the treatment early). 
Futility analysis 
A futility analysis will be conducted at the first interim analysis. A Go/No-Go decision will be 
taken at this futility analysis based on the predictive probability of achieving statistical 
significance for the primary estimand. Futility stopping rules will be defined in the DMC charter. 


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12.7.2 
Second interim analysis 
Based on the group sequential design applied in the study, the second interim analysis is planned 
when approximately 308 participants (approximately 77 % of the total 400 participants) 
complete 52 weeks of treatment. The results from this interim analysis will support the decision-
making concerning the current clinical study, i.e., to continue or to stop the trial based on 
efficacy (superiority or futility) and/or safety findings. 
Superiority analysis 
A Lan-De Mets alpha spending function (Lan and DeMets 1983) with Pocock type stopping 
boundary (Pocock 1977) (as implemented in the software East 6.5) will be used to maintain the 
overall type-I error rate for the primary and secondary endpoints at Week 52.  
Based on the choice of α-spending function described above, the efficacy boundary in terms of 
p-value scale at the superiority analysis is calculated as p = 0.042 for a two-sided test. The 
observed (i.e., nominal) p-value has to be smaller than 0.042 to conclude superior efficacy at 
the interim analysis. If a hypothesis is not rejected at the superiority analysis, it will be tested 
again at the Week 52 final analysis. The efficacy boundary for the final analysis in terms of p-
value scale is p = 0.024. 
The exact rejecting boundaries will be calculated after the exact number of participants in each 
treatment arm is available. 
A sequential testing hierarchy will be used to test the secondary hypotheses. The secondary 
hypotheses will be tested at the superiority analysis only if the primary hypothesis is rejected. 
This guarantees the 5% overall level of significance for the primary and secondary hypotheses 
(Glimm et al 2010). For Week 52 secondary endpoints the same rejecting boundaries will be 
used as for the primary endpoint. 
Futility analysis 
A second futility analysis will also be conducted at the time of the second interim analysis. 
Futility stopping rules will be specified in the DMC charter. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The total planned sample size is 400 participants. Based on literature (Mysler et al 2013, 
Rovin et al 2012, Furie et al 2020, Rovin et al 2021), the control response rate was assumed to 


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be approximately 25%. Assuming 15% treatment difference with 40% response rate for 
secukinumab, the power for rejecting the null hypothesis for primary endpoint (CRR) is 87%. 
The assumptions are summarized in Table 12-1 below. 
Table 12-1 
Power for primary endpoint 
Analysis 
Control response 
rate 
Secukinumab 
response rate 
Sample size 
Cumulative power for 
primary endpoint 
Superiority Interim 
analysis 
25% 
40% 
308 
79% 
Final analysis 
25% 
40% 
400 
87% 
12.8.2 
Secondary endpoint(s) 
Using published data for control (Mysler et al 2013, Rovin et al 2012, Deng et al 2018, 
Wallace et al 2017, McElhone et al 2016) and assuming given treatment effects for 
secukinumab, a summary for power for secondary efficacy parameters is shown in Table 12-2 
for binary endpoints, Table 12-3 for continuous endpoints and Table 12-4 for time to event 
endpoints. Power for the secondary endpoints was calculated with the group sequential design 
and the total cumulative power, to reject either at the superiority interim or final analysis, is 
presented. 
Table 12-2 
Summary of power for binary secondary endpoints 
Endpoint 
Response rate 
Power 
Secukinumab 300 mg  
(N = 200) 
Placebo 
(N = 200) 
  
PRR at Week 52 
75% 
60% 
87% 
PRR at Week 24 
75% 
60% 
87% 
Table 12-3 
Summary of power or continuous endpoints 
Endpoint 
Mean values 
Common standard 
Power 
  
Secukinumab 300 
mg (N = 200) 
Placebo 
(N = 200) 
deviation 
  
Change from 
baseline in UPCR 
at Week 52 
-3.5 
-2.68 
2.69 
83% 
Average daily dose 
of corticosteroids 
between Week 16 
and Week 52 
5 
5.52 
1.67 
84% 
FACIT-Fatigue© 
change from 
baseline at Week 
52 
7.0 
2.82 
10.0 
98% 
SF-36 PCS change 
from baseline at 
Week 52 
6.1 
3.1 
8.0 
95% 


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Endpoint 
Mean values 
Common standard 
Power 
LupusQoL Physical 
Health change from 
baseline at Week 
52 
9.6 
5.6 
14 
78% 
Table 12-4 
Summary of power for time to event endpoints 
Endpoint 
 Event rates and haza 
rd ratios 
Power 
Placebo (N = 200) 
Event rate at Week 52 
Hazard Ratio Secukinumab (N 
= 200) 
  
Time to CRR  
30% 
1.67 
85% 
Time to PRR  
60% 
1.67 
98% 
Time to UPCR ≤ 
0.5 mg/mg 
35% 
1.67 
89% 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.). 


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately, 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
ACR (2001) Recommendations for the prevention and treatment of glucocorticoid-induced 
osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on 
Glucocorticoid-Induced Osteoporosis. Arthritis Rheum; 44(7):1496-503. 
 
 
Allam R, Anders HJ (2008) The role of innate immunity in autoimmune tissue injury. Curr 
Opin Rheumatol; 20:538-44. 
Appel GB, Contreras G, Dooley MA, et al (2009) Mycophenolate mofetil versus 
cyclophosphamide for induction treatment of lupus nephritis J Am Soc Nephrol; 20:1103-12. 
Bakoush O, Tencer J, Tapia J, et al (2002) Higher urinary IgM excretion in type 2 diabetic 
nephropathy compared to type 1 diabetic nephropathy Kidney International; 61:203-8. 
Bertsias GK, Tektonidou M, Amoura Z, et al (2012) 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. Annals of the Rheumatic Diseases; 71:1771-82 
Bettelli E, Carrier Y, Kuchroo VK (2006) Reciprocal developmental pathways for the 
generation of pathogenic effector TH17 and regulatory T cells. Nature; 441:235-8. 
 
 
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 28:586-604. 
Bruin G, Loesche C, Nyirady J, et al (2017) Population Pharmacokinetic Modeling of 
Secukinumab in Patients With Moderate to Severe Psoriasis. J Clin Pharmacol; 57(7):876-85. 
 
 
 
Cella DF, Tulsky DS, Gray G, et al (1993) The Functional Assessment of Cancer Therapy scale: 
development and validation of the general measure. J. Clin. Oncol; 11(3):570-9. 
Cervera R, Khamashta MA, Font J, et al (2003) Morbidity and mortality in systemic lupus 
erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort 
of 1,000 patients. Medicine (Baltimore); 82(5):299-308. 
Chen DY, Chen YM, Wen MC, et al (2012) The potential role of Th17 cells and Th17-related 
cytokines in the pathogenesis of lupus nephritis. Lupus; 21:1385-96. 


Novartis 
Confidential 
Page 102 of 120 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CAIN457Q12301 
 
 
 
 
Committee for Medicinal Products for Human use (CHMP) (2015) guidance document: 
https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-investigation-
medicinal-products-treatment-systemic-lupus-erythematosus-lupus_en.pdf. 
Costa R, Antunes P, Salvador P, et al (2021) Secukinumab on Refractory Lupus Nephritis. 
Cureus; 13(8): e17198. 
Crispín JC, Oukka M, Bayliss G (2008) Expanded double negative T cells in patients with 
systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol; 
181(12):8761-6. 
Deng J, Luo L, Zhu L, et al (2018) Multitarget therapy versus intravenous cyclophosphamide 
in the induction treatment of lupus nephritis: a metaanalysis of randomized controlled trials. 
Turk J Med Sci; 48(5):901-10. 
FDA 
(2018) 
guidance 
document: 
https:www.fda.gov/downloads/Drugs/Guidances/UCM201790.pdf. 
Faurschou M, Dreyer L, Kamper A, et al (2010) Long-Term Mortality and Renal Outcome in a 
Cohort of 100 Patients With Lupus Nephritis. Arthritis Care Res (Hoboken); 62(6):873–80. 
Feldman CH, Hiraki LT, Winkelmayer WC, et al (2015) Serious infections among adult 
Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis. Arthritis 
Rheumatol; 67(6):1577-85. 
 
 
Furie R, Rovin BH, Houssiau F, et al (2020) Two-Year, Randomized, Controlled Trial of 
Belimumab in Lupus Nephritis. N Engl J Med; 383(12):1117-28. 
 
 
Glimm E, Maurer W, Bretz F (2010) Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med; 29(2):219-28. 
Grootscholten C, Berden JH (2006) Discontinuation of immunosuppression in proliferative 
lupus nephritis: is it possible? Nephrol. Dial. Transplant; 21(6):1465-9. 
Hahn BH, McMahon MA, Wilkinson A, et al (2012) American College of Rheumatology 
guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 
(Hoboken); 64(6):797-808. 
Hirai Y, Masayuki I, Takanori S, et al (2012) IL-17A stimulates granulocyte colony-stimulating 
factor production via ERK1/2 but not p38 or JNK in human renal proximal tubular epithelial 
cells. Am J Physiol Renal Physiol; 302:F244-50. 
Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the 
classification of systemic lupus erythematosus. Arthritis Rheum; 40(9):1725. 


Novartis 
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Page 103 of 120 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CAIN457Q12301 
 
 
Holloway L, Humphrey L, Heron L, et al (2014) Patient-reported outcome measures for 
systemic lupus erythematosus clinical trials: a review of content validity, face validity and 
psychometric performance. Health Qual Life Outcomes; 12:116. 
Houssiau FA, Vasconcelos C, D'Cruz D, et al (2010) The 10-year follow-up data of the Euro-
Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann. 
Rheum. Dis; 69(1):61-4. 
Koga T, Ichinose K, and Tsokos GC (2017) T cells and IL-17 in Lupus Nephritis. Clin 
Immunol; 185:95–9. 
Krebs CF, Schmidt T, Riedel J, et al (2017) T helper type 17 cells in immune-mediated 
glomerular disease. Nat Rev Nephrol; 13(10):647-59. 
Kurts C, Panzer U, Anders H, et al (2013) The immune system and kidney disease: basic 
concepts and clinical implications. Nat Rev Immunol; 13(10):738-53. 
Kwan BC, Tam LS, Lai KB, et al (2009) The gene expression of type 17 T-helper cell-related 
cytokines in the urinary sediment of patients with systemic lupus erythematosus. Rheumatology 
(Oxford); 48(12):1491-7. 
Kyttaris VC, Kampagianni O, Tsokos GC (2013) Treatment with Anti-Interleukin 23 Antibody 
Ameliorates Disease in Lupus-Prone Mice. Biomed Res Int; article ID. 861028. 
Kyttaris VC, Zhang Z, Kuchroo VK, et al (2010) Cutting edge: IL-23 receptor deficiency 
prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol; 184(9):4605-
9. 
Lan KK, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika; 
70:659-63. 
Lichtnekert J, Anders HJ, Lech M (2022) Lupus Nephritis: Current Perspectives and Moving 
Forward. J Inflamm Res; 15:6533-52. 
Levey A, Stevens L, Schmid C, et al (2009) A new equation to estimate glomerular filtration 
rate. Ann Intern Med; 150(9):04-612. 
Lubeck DP (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis. Pharmacoeconomics; 22(2):27-38. 
Markowitz GS, D'Agati VD (2007) The ISN/RPS 2003 classification of lupus nephritis: an 
assessment at 3 years. Kidney Int; 71(6):491-5. 
Martínez-Martínez MU, Mandeville P, Llamzares-Azuara L et al (2013) CKD-EPI is the most 
reliable equation to estimate renal function in patients with systemic lupus erythematosus. 
Nefrologia; 33(1):99-106. 
McElhone K, Abbott J, Sutton C, et al (2016) Sensitivity to Change and Minimal Important 
Differences of the LupusQoL in Patients With Systemic Lupus Erythematosus. Arthritis Care 
Res (Hoboken); 68(10):1505-13. 
Meibohm B, Zhou H (2012) Characterizing the Impact of Renal Impairment on the Clinical 
Pharmacology of Biologics. Journal of Clinical Pharmacology; 52(1):54S-62S. 


Novartis 
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Page 104 of 120 
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Mysler EF, Spindler AJ, Guzman R, et al (2013) Efficacy and safety of ocrelizumab in active 
proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis 
Rheum; 65(9):2368-79. 
Nowling TK, Gilkeson GS (2011) Mechanisms of tissue injury in lupus nephritis. Arthritis Res. 
Ther; 13(6):250. 
Palmer SC, Tunnicliffe DJ, Singh-Grewal D, et al (2017) Induction and Maintenance 
Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis of 
Randomized Trials. Am J Kidney Dis; 70(3):324-36. 
Paust HJ, Turner J, Steinmetz OM, et al (2009) The IL-23/Th17 axis contributes to renal injury 
in experimental glomerulonephritis. J Am Soc Nephrol; 20:969–79. 
Pisitkun P, Ha L, Wang H, et al (2014) Interleukin-17 Cytokines Are Critical in Development 
of Fatal Lupus Glomerulonephritis. Immunity; 37:1104–15. 
Pocock SJ (1977) Group Sequential Methods in the Design and Analysis of Clinical Trials. 
Biometrika; 64(2):191–9. 
RWS Life Sciences LupusQoL: http:www.corptransinc.com/sites/lupusqol/instrument-
information. 
Rovin BH, Furie R, Latinis K, et al (2012) Efficacy and safety of rituximab in patients with 
active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. 
Arthritis Rheum; 64(4):1215-26. 
Rovin BH, Parikh SV (2014) Lupus nephritis: the evolving role of novel therapeutics. Am. J. 
Kidney Dis; 63(4):677-90. 
Rovin BH, Teng YKO, Ginzler EM, et al (2021) Efficacy and safety of voclosporin versus 
placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-
controlled, phase 3 trial. Lancet; 397:2070-80. 
Satoh Y, Nakano K, Yoshinari H, et al (2018) A case of refractory lupus nephritis complicated 
by psoriasis vulgaris that was controlled with secukinumab. Lupus; Lupus; 27(7):1–5. 
Schwartz N, Goilav B, Putterman C (2014) The pathogenesis, diagnosis and treatment of lupus 
nephritis. Curr Opin Rheumatol; 26:502-9. 
Singh JA, Hossain A, Kotb A, et al (2016) Risk of serious infections with immunosuppressive 
drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis. 
BMC Med. 2016; 14(1):137. 
Struemper H, Chen C, Cai W (2013) Population pharmacokinetics of belimumab following 
intravenous administration in patients with Systemic Lupus Erythematosus. The Journal of 
Clinical Pharmacology; 53(7):711–20. 
Summers SA, Odobasic D, Khouri MB, et al (2014) Endogenous interleukin (IL)-17A promotes 
pristane-induced systemic autoimmunity and lupus nephritis induced by pristane. Clin Exp 
Immunol; 176(3):341-50. 
Tan EM, Cohen AS, Fries JF, et al (1982) The 1982 revised criteria for the classification of 
systemic lupus erythematosus. Arthritis Rheum; 25(11):1271-7. 


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Tektonidou MG, Dasgupta A, Ward MM (2016) Risk of End-Stage Renal Disease in Patients 
With Lupus Nephritis, 1971-2015: A Systematic Review and Bayesian Meta-Analysis. Arthritis 
Rheumatol; 68(6):1432-41. 
Waldman M, Madaio MP (2005) Pathogenic autoantibodies in lupus nephritis. Lupus; 14(1):19-
24. 
Wallace DJ, Strand V, Merrill JT, et al (2017) Efficacy and safety of an interleukin 6 
monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging 
randomised controlled trial. Ann. Rheum. Dis; 76(3):534-42. 
Wang H, Ren YL, Chang J, et al (2018) A Systematic Review and Meta-analysis of Prevalence 
of Biopsy-Proven Lupus Nephritis. Arch Rheumatol; 33(1):17-25. 
Ware J, Kosinki M, Gandeck B. (1993) SF-36 Health Survey manual and interpretation guide. 
Boston: The Health Institute, New England Medical Center. 
Ware J, Kosinki M, Gandeck BS (1994) SF-36 Health Survey manual and interpretation guide. 
Update. Boston: The Health Institute, New England Medical Center. 
Weening JJ, D'Agati VD, Schwartz MM, et al (2004) The classification of glomerulonephritis 
in systemic lupus erythematosus revisited. J. Am. Soc. Nephrol; 15(2):241-50. 
Yan J, Li Y, Yang H, et al (2018) Interleukin-17A participates in podocyte injury by inducing 
IL-1b secretion through ROS-NLRP3 inflammasome-caspase-1 pathway. Scand J Immunol; 
87(4):e12645. 
Yazdany J (2011) Health-related quality of life measurement in adult systemic lupus 
erythematosus: Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific 
Quality of Life Questionnaire (SLEQOL), and Systemic Lupus Erythematosus Quality of Life 
Questionnaire (L-QoL). Arthritis Care Res (Hoboken); 63(11):S413-9. 
Yellen SB, Cella DF, Webster K, et al (1997) Measuring fatigue and other anemia-related 
symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J 
Pain Symptom Manage; 13(2):63-74. 
Yu F, Haas M, Glassock R, et al (2017) Redefining lupus nephritis: clinical implications of 
pathophysiologic subtypes. Nat Rev Nephrol; 13(8):483-95. 


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Zhang Z, Kyttaris VC, Tsokos GC (2009) The Role of IL-23/IL-17 Axis in Lupus Nephritis. J 
Immunol; 183(5):3160-9.  
Zickert A, Amoudruz P, Sundström Y, et al (2015) IL-17 and IL-23 in lupus nephritis - 
association to histopathology and response to treatment. BMC Immunol; 16:7. 


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16 
Appendices 
16.1 
ACR Criteria for Diagnosis of SLE 
  


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16.2 
International Society of Nephrology/Renal Pathology Society 
(ISN/RPS) 2003 classification of LN 
  
 


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16.3 
Estimation of eGFR by the CKD-EPI 
The CKD-EPI creatinine equation uses a 2-slope spline to model the relationship between 
estimated GFR and serum creatinine, and a different relationship for age, sex and race. The 
equation was reported to perform better and with less bias than the MDRD Study equation, 
especially in patients with higher GFR. This results in reduced misclassification of CKD 
(Levey et al 2009) 
 
 


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16.4 
Recommended Diagram for administration of Standard of Care 
  


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16.5 
Guidelines for administering PROs 
All questionnaires will be completed on an electronic device at the scheduled study visit prior 
to the participant seeing the investigator for any clinical assessment or evaluation. The study 
coordinator should check the questionnaire for completeness and encourage the participant to 
complete any missing responses. 
The participant should be made aware that completed measures are not reviewed by the 
investigator/study personnel. 
Before trial begin 
Study coordinators should familiarize themselves with the PRO questionnaires in the trial. 
Before completion 
1. Participants should be provided with the correct questionnaire at the appropriate visits, and 
in the appropriate language 
2. Participants should be given sufficient instructions, space, time and privacy to complete 
the questionnaires 
3. Questionnaire should be administered before the clinical examination 
During completion 
1. Administrator may clarify the questions but should not influence the response 
2. Only one response for each question 
3. Also see ‘Addressing Problems and Concerns’ 
After completion 
1. Check for completeness 
2. Check for multiple responses that were made in error 
3. Data should be transcribed from the completed questionnaire to the appropriate web portal 
Addressing Problems and Concerns 
Occasionally a participant may have concerns or questions about the questionnaires 
administered. Guidance related to some of the most common concerns and questions are given 
below. 
The patient does not want to complete the questionnaire(s) 
Tell the participant that completion of the questionnaire(s) is voluntary. The goal is to better 
understand the physical, mental, and social health problems of participants. Emphasize that this 
information is as important as any of the other medical information, and that the 
questionnaire(s) is simple to complete. Suggest that the questionnaire(s) may be different from 
anything the respondent has filled in the past. If the participant still declines, retrieve the 
questionnaires. Record the reason for the decline, and thank the participant. 
The patient is too ill or weak to complete the questionnaire(s) 
In these instances, the coordinator may obtain participant responses by reading out loud each 
question, followed by the corresponding response categories, and entering the participant’s 
response. No help should be provided to the participant by any person other than the designated 


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study coordinator. The coordinator should not influence participant responses. The study 
coordinator cannot translate the question into simpler language and has to be read verbatim. 
The patient wants someone else to complete the questionnaire(s) 
In no case should the coordinator or anyone other than the participant provide responses to the 
questions. Unless specified in the study protocol proxy data are not an acceptable substitute for 
participant self-report. Participants should be discouraged from asking a family member or 
friend for help in completing a questionnaire. 
The patient does not want to finish completing the questionnaire(s) 
If non-completion is a result of the participant having trouble understanding particular items, 
ask the participant to explain the difficulty. Re-read the question for them verbatim, but do not 
rephrase the question. If the respondent is still unable to complete the questionnaire, accept it 
as incomplete. Thank the participant. 
The patient is concerned that someone will look at his/her responses 
Emphasize that all responses are to be kept confidential. Point out that their names do not appear 
anywhere on the questionnaire, so that their results will be linked with an ID number and not 
their name. Tell the participant that his/her answers will be pooled with other participants’ 
answers and that they will be analyzed as a group rather than as individuals. Tell the participant 
that completed forms are not routinely shared with treating staff, and that their responses will 
only be seen by you (to check for completeness), and possibly the investigator. Any response 
which may directly impact on or reflect their medical condition (e.g., noting of severe 
depression) will be communicated by the coordinator to the physician. 
The patient asks the meaning of a question/item 
While completing the questionnaire, some participants might ask the meaning of specific items 
so that they can better understand and respond. If this happens, assist the participant by 
rereading the question for them verbatim. If the participant asks to interpret the meaning of an 
item, do not try to explain it, but suggest that he/she use his/her own interpretation of the 
question. Participants should answer the questions based on what they think the questions mean. 
General information about all questionnaire(s): 
All questionnaires have to be completed by the patients in their local languages using an 
electronic device. The questionnaires should be completed by the patients in a quiet area free 
from disturbance, and before any visit assessments. Patients should receive no help from family 
members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the patient’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 
per question, then this should be brought to patient. Incomplete questions should not be accepted 
without first encouraging the patient to complete unanswered questions. 
The investigator must complete the patient/visit information on the electronic device and ensure 
that the center number, patient’s number and initials are identical to the Case Record Form. As 
there are no source data for this questionnaire, the data queries will be restricted to patient/visit 
information. 


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16.9 
Liver event and Laboratory trigger Definitions and Follow-up 
Requirements 
Table 16-1 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
3 x ULN < ALT / AST ≤ 5 x ULN 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
ALT or AST > 5 × ULN 
  
ALP > 2 × ULN (in the absence of known bone 
pathology) 
  
TBL > 2 × ULN (in the absence of known Gilbert 
syndrome) 
  
ALT or AST > 3 × ULN and INR > 1.5 
  
Potential Hy’s Law cases (defined as ALT or AST > 3 
× ULN and TBL > 2 × ULN [mainly conjugated 
fraction] without notable increase in ALP to > 2 × 
ULN) 
  
Any clinical event of jaundice (or equivalent term) 
  
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, 
or rash with eosinophilia 
  
Any adverse event potentially indicative of a liver 
toxicity* 
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL: total 
bilirubin; ULN: upper limit of normal 
Table 16-2 
Follow up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
1. 
Discontinue the study 
treatment immediately 
2. 
Hospitalize, if clinically 
appropriate 
3. 
Establish causality 
4. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
ALT or AST 
> 8 × ULN 
1. 
Discontinue the study 
treatment immediately 
2. 
Hospitalize if clinically 
appropriate 
3. 
Establish causality 
4. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and INR > 1.5 
1. 
Discontinue the study 
treatment immediately 
2. 
Hospitalize, if clinically 
appropriate 
3. 
Establish causality 
4. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
1. 
Repeat Liver function test 
(LFT) within 48 hours 
2. 
If elevation persists, continue 
follow-up monitoring 
3. 
If elevation persists for more 
than 2 weeks, discontinue 
the study drug 
4. 
Establish causality 
5. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN accompanied by 
symptomsb 
1. 
Discontinue the study 
treatment immediately 
2. 
Hospitalize if clinically 
appropriate 
3. 
Establish causality 
4. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN (patient is 
asymptomatic) 
1. 
Repeat LFT within the next 
week 
2. 
If elevation is confirmed, 
initiate close observation 
of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the absence of 
known bone pathology) 
1. 
Repeat LFT within 48 hours 
2. 
If elevation persists, establish 
causality 
3. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 


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Criteria 
Actions required 
Follow-up monitoring 
TBL (isolated) 
  
  
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
1. 
Repeat LFT within 48 hours 
2. 
If elevation persists, 
discontinue the study 
drug immediately 
3. 
Hospitalize if clinically 
appropriate 
4. 
Establish causality 
5. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic) 
1. 
Repeat LFT within the next 
week 
2. 
If elevation is confirmed, 
initiate close observation 
of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
Jaundice 
1. 
Discontinue the study 
treatment immediately 
2. 
Hospitalize the patient 
3. 
Establish causality 
4. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of a 
liver toxicity* 
1. 
Consider study treatment 
interruption or 
discontinuation 
2. 
Hospitalization if clinically 
appropriate 
3. 
Establish causality 
4. 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN b(General) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia cResolution is defined as an 
outcome of one of the following: (1) return to Baseline values, (2) stable values at three subsequent monitoring 
visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, 
and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.  


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16.10 
Clinically notable laboratory values 
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Clinically notable values will be forwarded to Novartis at the same time that they are sent to 
investigators. Any action based on these laboratory values should be discussed with Novartis 
personnel. 
Table 16-3 
Safety Analyses: Expanded Limits and Notable Criteria 
Notable Criteria 
Laboratory Variable 
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
> 3 x ULN
> 3 x ULN
SGPT (ALT) 
> 3 x ULN
> 3 x ULN
Bilirubin 
> 2 x ULN
> 2 x ULN
Alkaline phosphatase 
> 2.5 x ULN
> 2.5 x ULN
HEMATOLOGY VARIABLES 
Hemoglobin: 20 g/L decrease from Baseline 
Platelet count: < 50 x 10E9/L 
White blood cell count: < 0.8 x LLN 
Neutrophils: < 0.9 x LLN 


Novartis Research and Development 
Secukinumab (AIN457) 
 Clinical Trial Protocol CAIN457Q12301
A two-year, phase III randomized, double-blind, parallel-
group, placebo-controlled trial to evaluate the safety, 
efficacy, and tolerability of 300 mg s.c. secukinumab 
versus placebo, in combination with SoC therapy, in 
patients with active lupus nephritis 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2019-003211-57  
Version number: 
00 (Original Protocol) 
Clinical Trial Phase: 
III 
Release date: 
11-Oct-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.1.1 
Lupus nephritis ...................................................................................... 18 
1.1.2 
Scientific rationale for targeting IL-17 in lupus nephritis ..................... 19 
1.1.3 
Secukinumab ......................................................................................... 20 
1.2 
Purpose .................................................................................................................. 21 
2 
Objectives and endpoints ................................................................................................... 21 
3 
Study design ...................................................................................................................... 25 
4 
Rationale ............................................................................................................................ 27 
4.1 
Rationale for study design ..................................................................................... 27 
4.1.1 
Rationale for choice of background therapy ......................................... 28 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 28 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 29 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 29 
4.5 
Risks and benefits .................................................................................................. 30 
5 
Population .......................................................................................................................... 31 
5.1 
Inclusion criteria .................................................................................................... 31 
5.2 
Exclusion criteria ................................................................................................... 32 
6 
Treatment ........................................................................................................................... 34 
6.1 
Study treatment ...................................................................................................... 34 
6.1.1 
Investigational and control drugs .......................................................... 34 
6.1.2 
Additional study treatments .................................................................. 34 
6.1.3 
SoC background therapy ....................................................................... 35 
6.1.4 
Treatment arms/group ........................................................................... 37 
6.1.5 
Treatment duration ................................................................................ 37 
6.2 
Other treatment(s) .................................................................................................. 37 
6.2.1 
Concomitant therapy ............................................................................. 37 
6.2.2 
Prohibited medication ........................................................................... 39 
6.2.3 
Rescue medication ................................................................................ 39 


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6.3 
Subject numbering, treatment assignment, randomization .................................... 39 
6.3.1 
Subject numbering ................................................................................ 39 
6.3.2 
Treatment assignment, randomization .................................................. 39 
6.4 
Treatment blinding ................................................................................................ 40 
6.5 
Dose escalation and dose modification.................................................................. 41 
6.5.1 
Dose modifications ................................................................................ 41 
6.5.2 
Follow-up for toxicities ......................................................................... 41 
6.6 
Additional treatment guidance ............................................................................... 41 
6.6.1 
Treatment compliance ........................................................................... 41 
6.6.2 
Recommended treatment of adverse events .......................................... 42 
6.6.3 
Emergency breaking of assigned treatment code .................................. 42 
6.7 
Preparation and dispensation ................................................................................. 42 
6.7.1 
Handling of study treatment and additional treatment .......................... 43 
7 
Informed consent procedures ............................................................................................ 44 
8 
Visit schedule and assessments ......................................................................................... 45 
8.1 
Screening ............................................................................................................... 49 
8.1.1 
Information to be collected on Screening failures ................................ 49 
8.1.2 
Re-screening .......................................................................................... 50 
8.2 
Subject demographics/other Baseline characteristics ............................................ 50 
8.2.1 
Demography .......................................................................................... 50 
8.2.2 
SLE/LN medical history/diagnosis ....................................................... 50 
8.2.3 
Prior SLE/LN medications and therapy ................................................ 50 
8.2.4 
Renal biopsy .......................................................................................... 50 
8.2.5 
Standard of care induction therapy ....................................................... 51 
8.2.6 
Smoking history .................................................................................... 51 
8.2.7 
Cardiovascular medical history ............................................................. 51 
8.2.8 
Relevant medical history/ current medical conditions .......................... 51 
8.2.9 
Prior and concomitant medications ....................................................... 52 
8.2.10 
Determination of the tuberculosis status ............................................... 52 
8.2.11 
Hepatitis and human immunodeficiency virus (HIV) screen ................ 52 
8.2.12 
Electrocardiogram (ECG) ..................................................................... 53 
8.3 
Efficacy .................................................................................................................. 53 
8.3.1 
Complete Renal Response (CRR) ......................................................... 53 
8.3.2 
Partial Renal Response (PRR) .............................................................. 54 
8.3.3 
Average daily dose of corticosteroids ................................................... 54 
8.3.4 
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue©) ................................................................................ 54 


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8.3.5 
Short Form Health Survey (SF-36) ....................................................... 54 
8.3.6 
Lupus Quality of Life (LupusQoL) ....................................................... 55 
8.3.7 
Urinary sediment ................................................................................... 55 
8.3.8 
Appropriateness of efficacy assessments .............................................. 55 
8.4 
Safety ..................................................................................................................... 56 
8.4.1 
Physical examination ............................................................................ 56 
8.4.2 
Vital signs.............................................................................................. 56 
8.4.3 
Height and weight ................................................................................. 57 
8.4.4 
Laboratory evaluations .......................................................................... 57 
8.4.5 
Pregnancy and assessments of fertility ................................................. 59 
8.4.6 
Other safety evaluations ........................................................................ 59 
8.4.7 
Appropriateness of safety measurements .............................................. 60 
8.5 
Additional assessments .......................................................................................... 60 
8.5.1 
Patient reported outcomes (PRO).......................................................... 60 
 
 61 
8.5.3 
Trial Feedback Questionnaire (TFQ) .................................................... 62 
 
 63 
 
 63 
8.5.6 
Biomarkers ............................................................................................ 65 
9 
Study discontinuation and completion .............................................................................. 66 
9.1 
Discontinuation ...................................................................................................... 66 
9.1.1 
Discontinuation of study treatment ....................................................... 66 
9.1.2 
Withdrawal of informed consent ........................................................... 68 
9.1.3 
Lost to follow-up ................................................................................... 69 
9.1.4 
Early study termination by the sponsor ................................................. 69 
9.2 
Study completion and post-study treatment .......................................................... 69 
10 Safety monitoring and reporting ........................................................................................ 69 
10.1 
Definition of adverse events and reporting requirements ...................................... 69 
10.1.1 
Adverse events ...................................................................................... 69 
10.1.2 
Serious adverse events .......................................................................... 71 
10.1.3 
SAE reporting........................................................................................ 72 
10.1.4 
Pregnancy reporting .............................................................................. 73 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 73 
10.2 
Additional Safety Monitoring ................................................................................ 74 
10.2.1 
Liver safety monitoring ......................................................................... 74 
10.2.2 
Data Monitoring Committee ................................................................. 74 
10.2.3 
Steering Committee ............................................................................... 75 


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11 Data Collection and Database management ...................................................................... 75 
11.1 
Data collection ....................................................................................................... 75 
11.2 
Database management and quality control ............................................................ 75 
11.3 
Site monitoring ...................................................................................................... 76 
12 Data analysis and statistical methods ................................................................................ 77 
12.1 
Analysis sets .......................................................................................................... 77 
12.2 
Subject demographics and other Baseline characteristics ..................................... 77 
12.3 
Treatments ............................................................................................................. 78 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 78 
12.4.1 
Definition of primary endpoint(s) ......................................................... 78 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 78 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 79 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 79 
12.5 
Analysis of secondary endpoints ........................................................................... 80 
12.5.1 
Testing strategy ..................................................................................... 80 
12.5.2 
Safety endpoints .................................................................................... 84 
12.6 
Analysis of exploratory endpoints ......................................................................... 85 
12.6.1 
Patient reported outcomes ..................................................................... 87 
 
 87 
12.6.3 
DNA and RNA ...................................................................................... 88 
12.6.4 
Biomarkers ............................................................................................ 88 
 
 88 
12.7 
Interim analyses ..................................................................................................... 88 
12.8 
Sample size calculation.......................................................................................... 89 
12.8.1 
Primary endpoint(s) ............................................................................... 89 
12.8.2 
Secondary endpoint(s) ........................................................................... 90 
13 Ethical considerations and administrative procedures ...................................................... 91 
13.1 
Regulatory and ethical compliance ........................................................................ 91 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 91 
13.3 
Publication of study protocol and results............................................................... 91 
13.4 
Quality Control and Quality Assurance ................................................................. 92 
14 Protocol adherence ............................................................................................................ 92 
14.1 
Protocol amendments............................................................................................. 92 
15 References ......................................................................................................................... 93 
16 Appendices ........................................................................................................................ 98 
16.1 
ACR Criteria for Diagnosis of SLE ....................................................................... 98 


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16.2 
International Society of Nephrology/Renal Pathology Society (ISN/RPS) 
2003 classification of LN..................................................................................... 100 
16.3 
Estimation of eGFR by the CKD-EPI ................................................................. 101 
16.4 
Recommended Diagram for administration of Standard of Care ........................ 102 
16.5 
Guidelines for administering PROs ..................................................................... 103 
 
 105 
 
 107 
 
 107 
16.9 
Liver event and Laboratory trigger Definitions and Follow-up Requirements ... 108 
16.10 Clinically notable laboratory values .................................................................... 112 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 21 
Table 6-1 
Investigational and control drug ............................................................ 34 
Table 6-2 
Background therapy .............................................................................. 35 
Table 6-3 
Guidance for corticosteroid (prednisone equivalent) taper ................... 36 
Table 8-1 
Assessment Schedule ............................................................................ 46 
 
 63 
 
 64 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 73 
Table 12-1 
Power for primary endpoint .................................................................. 89 
Table 12-2 
Summary of power for binary secondary endpoints ............................. 90 
Table 12-3 
Summary of power or continuous endpoints ........................................ 90 
Table 12-4 
Summary of power for time to event endpoints .................................... 91 
Table 16-1 
Liver event and laboratory trigger definitions .................................... 108 
Table 16-2 
Follow up requirements for liver events and laboratory triggers ........ 109 
Table 16-3 
Safety Analyses: Expanded Limits and Notable Criteria .................... 112 
List of figures 
Figure 3-1 
Study design .......................................................................................... 26 
Figure 12-1 
Testing strategy ..................................................................................... 81 
 


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List of abbreviations 
 
 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibodies  
ANCOVA 
analysis of covariance 
anti-dsDNA 
Anti-double stranded DNA 
 
 
aPTT 
activated partial thromboplastin time  
AST 
aspartate aminotransferase 
 
  
BMI 
Body Mass Index 
CFR 
Code of Federal Regulation 
CHMP 
Committee for Medicinal Products for Human Use 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
 
  
CNIs 
calcineurin inhibitors 
COAs 
Clinical Outcome Assessments  
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Clinician reported outcomes  
CRR 
Complete Renal Response  
CYC 
cyclophosphamide  
 
  
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate  
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
ERA-EDTA 
European Renal Association – European Dialysis and Transplant Association 
ESRD 
end-stage renal disease 
EULAR 
European League Against Rheumatism 
FACIT-
Fatigue© 
Functional Assessment of Chronic Illness Therapy - Fatigue 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
h 
hour 


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HbA1c 
Hemoglobin A1c 
HDL 
High Density Lipoprotein 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
hsCRP 
High sensitivity C-reactive protein 
i.v. 
intravenous 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
 
 
INR 
International Normalized Ratio  
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISN 
International Society of Neurology  
 
 
LDL 
Low Density Lipoprotein 
LFT 
Liver function test 
 
  
LLN 
lower limit of normal 
LLQ 
lower limit of quantification 
LN 
lupus nephritis 
 
 
mCRR 
modified Complete Renal Response 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
ml 
milliliter(s) 
MMF 
Mycophenolate mofetil  
MMRM 
Mixed-Effect Model Repeated Measure 
MPA 
mycophenolic acid  
 
  
o.d. 
once a day 
p.o. 
per oral 
PCS 
physical component summary  
PD 
pharmacodynamic(s) 
PFS 
Prefilled syringe 
 
 
PK 
pharmacokinetic(s) 
PRR 
partial renal response 
PT 
Prothrombin time  
PY 
Patient Year 
RBC 
red blood cell(s) 


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RNA 
ribonucleic acid 
RPS  
Renal Pathology Society  
s.c. 
subcutaneous 
SAE 
serious adverse event 
SD 
standard deviation 
SF-36 
Medical Outcome Short Form (36) Health Survey 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SLE 
systemic lupus erythematosus 
 
  
SoC 
standard of care 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
total bilirubin 
TEAE 
Treatment-emergent adverse event 
TFQ 
Trial Feedback Questionnaire 
 
 
 
 
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
UPCR 
Urine Protein-to-Creatinine Ratio 
WBC 
white blood cell(s) 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug. 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g., 100 mg 
once a day, 75 mg twice a day) 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Part 
A single component of a study, which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease. 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as Screening, Baseline, titration, washout, etc. 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later. 
Study treatment 
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s) 
Study treatment 
discontinuation 
Point/time when subject permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature subject withdrawal. 
Subject 
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient. 
Subject number 
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc. 
Variable 
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints. 


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Withdrawal of 
consent (WoC) 
Withdrawal of consent from the study is defined as when a subject does not 
want to participate in the study any longer, and does not allow further collection 
of personal data  


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Protocol summary 
 
Protocol 
number 
 
CAIN457Q12301 
Full Title 
A two-year, phase III randomized, double-blind, parallel-group, placebo-
controlled trial to evaluate the safety, efficacy, and tolerability of 300 mg s.c. 
secukinumab versus placebo, in combination with SoC therapy, in patients with 
active lupus nephritis 
Brief title 
Study of safety, efficacy and tolerability of secukinumab versus placebo, in 
combination with SoC therapy, in patients with active lupus nephritis 
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation 
type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this trial is to evaluate the efficacy and safety of subcutaneous 
secukinumab 300 mg compared to placebo, in combination with standard of care 
therapy (SoC), in subjects with active lupus nephritis (ISN/RPS Class III or IV, 
with or without co-existing class V features). Background SoC will consist of 
induction therapy with mycophenolic acid (MPA) (which refers to Mycophenolate 
mofetil (MMF) (Cellcept® or generic equivalent), or enteric-coated MPA sodium 
(Myfortic® or generic equivalent) at equivalent doses (oral), or 
Cyclophosphamide (CYC) (i.v.), followed by maintenance therapy with MPA 
(MMF, enteric-coated MPA sodium, or their generics). In addition, all subjects 
will receive i.v. and/or oral corticosteroids. 
The aim of the study is to demonstrate the efficacy and safety of secukinumab in 
LN that will enable registration for the indication of lupus nephritis. 
Primary 
Objective(s)  
The primary objective is to demonstrate that secukinumab 300 mg is superior to 
placebo in Complete Renal Response (CRR) rate at Week 52 in active lupus 
nephritis (ISN/RPS Class III or IV, with or without co-existing Class V features) 
subjects on a background of SoC therapy 
Secondary 
Objectives 
Objective 1: To demonstrate superiority of secukinumab compared to placebo in 
change from Baseline in 24-hour UPCR at Week 52 
Objective 2: To demonstrate superiority of secukinumab compared to placebo in 
proportion of subjects achieving partial renal response (PRR) at Week 52 
Objective 3: To demonstrate superiority of secukinumab compared to placebo in 
average daily dose of oral corticosteroids administered between Week 16 and 
Week 52 
Objective 4: To demonstrate superiority of secukinumab compared to placebo in 
proportion of subjects achieving PRR at Week 24 
Objective 5: To demonstrate superiority of secukinumab compared to placebo in 
time to achieve CRR 
Objective 6: To demonstrate superiority of secukinumab compared to placebo in 
time to achieve PRR 


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Objective 7: To demonstrate superiority of secukinumab compared to placebo in 
time to achieve first morning void Urine Protein-to-Creatinine Ratio (UPCR) ≤ 0.5 
mg/mg 
Objective 8: To demonstrate superiority of secukinumab compared to placebo in 
change in Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-
Fatigue©) score at Week 52 
Objective 9: To demonstrate superiority of secukinumab compared to placebo in 
patient’s health related quality of life via Medical Outcome Short Form Health 
Survey (SF-36 Physical Component Summary (PCS)) score at Week 52 
Objective 10: To demonstrate superiority of secukinumab compared to placebo in 
change of LupusQoL (Physical Health) score at Week 52 
Objective 11: To evaluate the safety and tolerability of secukinumab s.c. as an 
add-on therapy to Standard of Care in lupus nephritis subjects 
Objective 12: To estimate the proportion of subjects with maintained renal 
response at Week 104 
Objective 13: To estimate the proportion of subjects with improved or maintained 
renal response at Week 104 
Study design 
This is a pivotal, randomized, double-blind, placebo controlled trial evaluating at 
Week 52 the efficacy and safety of secukinumab versus placebo in subjects with 
active lupus nephritis also receiving background SoC regimen. In addition, long-
term efficacy, safety and tolerability will be collected up to 2 years. 
Population 
The study population will be comprised of adult male and female subjects in the 
age range of 18-75 years with a renal biopsy (results current or within the 6 months 
prior to Screening) showing active glomerulonephritis WHO or ISN/RPS Class III 
or IV LN [excluding III (C), IV-S (C) and IV-G (C)], with or without co-existing class 
V features, who are inadequately controlled with previous SoC defined as having 
UPCR ≥1 and active urinary sediment (presence of cellular casts which are 
granular casts or red blood cells) or hematuria (>5 red blood cells per high power 
field)). 
Approximately 460 subjects, randomized into two treatment arms (1:1 active: 
placebo), are planned. At randomization, subjects will be stratified on the basis of 
the SoC induction therapy they will receive during the study, MPA or CYC-based, 
to ensure a balanced representation in each of the treatment arms (secukinumab 
or placebo). The target will be to have a maximum of 25% of randomized subjects 
receiving CYC-based induction therapy. 
Key Inclusion 
criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Adult male and female subjects aged 18 - 75 years old at the time of Baseline 
2. Confirmed diagnosis of: 
· SLE with documented history of at least 4 of the 11 criteria for SLE as defined 
by the American College of Rheumatology (ACR). [NOTE: The 4 criteria do not 
have to be present at the time of Screening], 
OR 
· Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA 
antibodies. 
3. Active lupus nephritis, as defined by meeting the 4 following criteria: 


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· Biopsy within 6 months prior to Screening visit indicating active 
glomerulonephritis WHO or ISN/RPS Class III or IV LN [excluding III (C), IV-S (C) 
and IV-G (C)]; subjects are permitted to have co-existing Class V. If no biopsy was 
performed within 6 months of Screening, a biopsy will need to be performed during 
the Screening period, after all other inclusion/exclusion criteria would have been 
verified. 
· UPCR ≥1 at Screening 
· Estimated eGFR >30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) 
· Active urinary sediment (presence of cellular casts (granular or red blood cell 
casts) or hematuria (>5 red blood cells per high power field)) 
4. Subjects must be currently on, or willing to initiate SoC induction therapy for LN 
according to the institutional practices using MPA (MMF or enteric-coated MPA 
sodium) or low-dose CYC in addition to corticosteroids. 
5. If the subject is on cholesterol-lowering agents, the dose must be stable for at 
least 7 days prior to Randomization. 
6. Subjects must be treated with anti-malarials (e.g., hydroxychloroquine), unless 
contra-indicated, and the dose must be stable for at least 10 days prior to 
Randomization. 
7. Able to provide signed informed consent. 
Key Exclusion 
criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this 
study. 
1. Severe renal impairment as defined by i.) Stage 4 CKD, or ii.) presence of 
oliguria (defined as a documented urine volume < 400 mL/24 hrs), or iii.) ESRD 
requiring dialysis or transplantation 
2. Known intolerance/hypersensitivity to MPA (MMF or enteric-coated MPA 
sodium), or oral corticosteroids, or any component of the study treatment 
3. Subjects having received any other biologic immunomodulatory therapy within 
6 months prior to Screening, excluding belimumab where 3 months are acceptable 
4. Previous exposure to secukinumab (AIN457) or any other biologic drug 
targeting IL-17 or the IL-17 receptor 
5. Subjects having received any investigational drug within 1 month or five times 
the half-life, whichever is longer 
6. Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) 
within the 12 weeks prior to Baseline 
7. Treatment with a systemic calcineurin inhibitor (e.g., cyclosporine, tacrolimus) 
within 12 weeks prior to Baseline 
8. CYC use (i.v. or oral) within the month prior to Baseline 
9. Subjects requiring dialysis within the previous 12 months before Screening 
10. History of renal transplant 
11. Any severe progressive or uncontrolled concurrent medical condition, 
including recent severe thromboembolic events, that, in the opinion of the principal 
investigator, renders the subject unsuitable for the trial 


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12. Active ongoing inflammatory diseases that might confound the evaluation of 
the benefit of secukinumab therapy, including inflammatory bowel disease 
13. Presence of investigator-identified significant medical problems which at the 
investigator’s discretion will prevent the subject from participating in the study, 
including but not limited to the following: myocarditis, pericarditis, poorly controlled 
seizure disorder, acute confusional state, depression, severe manifestations of 
neuropsychiatric SLE (NPSLE) 
14. Chest X-ray, computerized tomography (CT) scan, or MRI with evidence of 
ongoing infectious or malignant process, obtained within 12 weeks prior to 
Randomization and evaluated by a qualified physician 
15. History of chronic, recurrent systemic infections, active tuberculosis infection, 
or active systemic infections during the last two weeks (exception: common cold) 
prior to Randomization 
16. Known infection with human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C at Screening or Randomization 
17. History of lymphoproliferative disease or any known malignancy or history of 
malignancy of any organ system treated or untreated within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases (except 
for skin Bowen’s disease or basal cell carcinoma or actinic keratoses that have 
been treated with no evidence of recurrence in the past 12 weeks, carcinoma in 
situ of the cervix or non-invasive malignant colon polyps that have been removed) 
18. Any of the following abnormal laboratory values on Screening evaluations as 
reported by Central Laboratory : 
· Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase 
> 2.5xULN 
· Hemoglobin <8g/dL 
· Neutrophils <1.0 x 109/L 
· Platelet count <50 x 109/L 
19. Inability or unwillingness to undergo repeated venipuncture (e.g., because of 
poor tolerability or lack of venous access) 
20. History or evidence of ongoing alcohol or drug abuse, within the last six months 
before Randomization 
21. Pregnant or lactating women 
22. Women of childbearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective methods of 
contraception during the entire study or longer if required by locally approved 
prescribing information (e.g., in European Union (EU) 20 weeks) 
Study 
treatment 
At Baseline, all eligible subjects will be randomized to one of the two treatment 
arms in a 1:1 ratio via Interactive Response Technology (IRT): 
• 
Arm 1: approximately 230 LN subjects will receive secukinumab 300 mg s.c. 
(2 x 1.0 mL PFS of 150 mg dose) at Randomization, Weeks 1, 2 and 3, and 
every 4 weeks from Week 4 until week 100 
• 
Arm 2: approximately 230 LN subjects will receive placebo s.c. (2 x 1.0 mL 
PFS of 0 mg dose) at Randomization, Weeks 1, 2 and 3, and every 4 weeks 
from Week 4 until week 100 


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At Randomization, subjects will be stratified on the basis of the SoC induction 
therapy they will receive during the study, MPA or CYC-based, to ensure a 
balanced representation in each of the treatment arms (secukinumab or placebo). 
Efficacy 
assessments 
• 
Assessment of CRR, defined as eGFR within the normal range or no less 
than 85% of Baseline AND 24-hour UPCR ≤ 0.5 mg/mg 
• 
Time to achieve UPCR ≤ 0.5 mg/mg 
• 
Assessment of PRR, defined as ≥50% reduction in 24-hour UPCR to sub-
nephrotic levels AND normal eGFR or no less than 85% of Baseline 
• 
Average daily dose of oral corticosteroids 
• 
Time to achieve CRR 
• 
Time to achieve PRR 
• 
FACIT-Fatigue© score 
• 
SF-36 PCS score 
• 
LupusQoL Physical Health score 
Key safety 
assessments 
• 
Physical examinations 
• 
Vital signs 
• 
Height and weight 
• 
Laboratory evaluations (hematology, clinical chemistry, coagulation panel, 
local urinalysis, 24-hour urine collection, lipid panel, 
 
 and 
pregnancy test) 
• 
Chest X-ray 
• 
Evaluation of AEs and SAEs 
Other 
assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Biomarkers (urine and serum) 
• 
Pharmacogenetics; DNA and RNA analysis 
Data analysis 
The primary efficacy endpoint is the CRR at Week 52. 
The statistical hypothesis tested for the primary objective is that there is no 
difference in the proportion of subjects fulfilling the response criteria at Week 52 
between the secukinumab regimen and placebo regimens. 
Let pj denote the proportion of responders at Week 52 for treatment 
regimens j, j=0, 1 where 
· 0 corresponds to placebo regimen, 
· 1 corresponds to secukinumab , 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e., 


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H1: secukinumab is not different to placebo regimen with respect to CRR at Week 
52 
Logistic regression model adjusting for SoC, race and Baseline UPCR will be used 
for the primary analysis. Difference in marginal response proportions with p-value 
and respective 95% confidence interval will be estimated from the logistic 
regression model. 
Safety analyses will include summaries of AEs, laboratory measurements, and 
vital signs. 
Full details of all data analyses will be specified in statistical analysis plan. 
Key words 
Systemic Lupus Erythematosus (SLE), Lupus Nephritis (LN), secukinumab, renal 
biopsy, estimated glomerular filtration rate (eGFR), Urine Protein-to-Creatinine 
Ratio (UPCR), Standard of care (SoC) background therapy 


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1 
Introduction 
1.1 
Background 
1.1.1 
Lupus nephritis 
Lupus nephritis is estimated to affect more than one-half of SLE patients and is a severe 
manifestation in SLE (Cervera et al 2003). 
Immune complex formation in LN related to a plethora of autoantibodies, especially                
anti-dsDNA and anti-nucleosome antibodies, is the result of systemic autoimmunity and is a 
hallmark of the disease (Waldman and Madaio 2005), (Nowling and Gilkeson 2011) that is 
generally treated by systemic immunosuppression. Once formed, immune complexes activate 
complement, which can injure renal cells leading to either mesangial LN (class I, II), 
proliferative LN (class III, IV), membranous LN (class V) and advanced sclerotic LN (class 
VI). However, pathogenesis of LN is complex and involves both the innate and adaptive 
immune systems; various cytokines, immune tissues and cell types are involved in its 
pathogenesis. Intra-renal inflammation is maintained via local cytokine and chemokine 
production, and by cells of the innate immune system such as neutrophils, that are attracted into 
the glomerulus and interstitium. Targeting local release of proinflammatory cytokines by 
blocking single cytokine pathways may enhance treatment efficacy in autoimmunity without 
increasing systemic immunosuppression (Allam and Anders 2008), (Yu et al 2017). 
Lupus nephritis is characterized by glomerular endothelium, podocyte, tubulointerstitial and 
vascular injury. Specific leukocyte subsets, including IL-17-producing T helper type 17 (TH17) 
cells, drive inflammation and contribute to renal immunopathology (Yu et al 2017). 
Lupus nephritis is categorized histologically into 6 classes by the International Society of 
Nephrology/Renal Pathology Society (ISN/RPS) classification system (Weening et al 2004), 
(Markowitz and D'Agati 2007). Treatments include management with corticosteroids together 
with anti-malarials for lower stage disease, followed by more aggressive immunosuppressive 
therapies for more severe disease, and ultimately renal transplant. 
Class III and IV LN are detected in approximately 39 to 71.9 % of LN patients, and from the 
deposition of immune complexes in the subendothelial space of the glomerular capillaries 
(Wang et al 2018). Both these classes of LN are considered to have similar lesions that differ 
by severity and distribution. Class IV diffuse LN is distinguished from class III on the basis of 
involvement of more than 50% of glomeruli with endocapillary lesions. Patients with class III 
and IV LN require aggressive therapy with glucocorticoids and immunosuppressive agents 
cyclophosphamide (CYC), mycophenolate mofetil (MMF), rituximab as well as calcineurin 
inhibitors (CNIs) (Hahn et al 2012). 
Lupus nephritis is associated with significant morbidity and mortality, even with current 
treatments. With current induction and maintenance therapies, the risk of developing LN-related 
end-stage renal disease (ESRD) at 5, 10, and 15 years remained at 11%, 17%, and 22%, 
respectively for the last decade (Tektonidou et al 2016), (Faurschou et al 2010). In addition, 
current immunosuppressive therapies carry substantial infectious as well as other mid/long-
term toxicity risks. 


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Despite recent advances in treatment for several autoimmune diseases, there are currently no 
specific Food and Drug Administration (FDA) or European Medicines Agency (EMA)-
approved therapies for LN. Current treatments are non-specific, aimed at slowing progression 
with general immunosuppression. Renal response rates remain suboptimal, underscoring the 
persistent high unmet medical need in the treatment of patients with LN. Thus, there is still a 
substantial proportion of LN patients with ESRD within 5 years (Houssiau et al 2010). 
The European League Against Rheumatism (EULAR)/European Renal Association – European 
Dialysis and Transplant Association (ERA-EDTA) and ACR guidelines are uniform in their 
recommendations for therapy for class III and IV LN and include a sequence of induction and 
maintenance phases. For patients with class III or IV proliferative glomerulonephritis, the 
guidelines recommend induction therapy with MPA (MMF or enteric-coated MPA sodium) or 
intravenous (i.v.) CYC, with or without initial pulses of i.v. methylprednisolone. With current 
induction regimens, less than 60% of class III to V patients achieve a complete or 
partial response (Appel et al 2009). Among those who attain a complete renal response (CRR) 
with current standard-of-care (SoC), nearly half of the patients had a relapse. The incidence rate 
of 
relapse 
in 
these 
patients 
was 
5 
to 
15 
per 
100 
patient 
year 
(PY) 
(Grootscholten and Berden 2006). 
Despite the aggressive nature of SoC treatment, only up to 40% of patients achieve a CRR after 
1 year (Rovin and Parikh 2014). In addition, current LN treatment regimens have substantial 
side effects from glucocorticoids and prolonged immunosuppression (Schwartz et al 2014). 
Immunosuppressed LN patients are at significant risk of developing serious infections. In a 
multiethnic Medicaid cohort, the incidence rate of serious infections was more than 2-fold 
higher in LN than in SLE patients (Feldman et al 2015). 
Given the severity of the condition and the lack of approved therapy, there is a high unmet 
medical need for efficacious therapies, which also have a favorable benefit:risk profile, for the 
treatment of LN patients. 
1.1.2 
Scientific rationale for targeting IL-17 in lupus nephritis 
Animal model studies have demonstrated that the IL-17 and upstream IL-23 pathways 
contribute to renal injury in experimental models of LN or glomerulonephritis. IL-23 receptor 
deficiency decreased the number of IL-17A-producing double-negative (DN) T cells, produced 
less anti-DNA antibodies and prevented glomerulonephritis in lupus-prone C57BL/6-lpr/lpr 
mice (Kyttaris et al 2010); treatment with an anti-IL-23 antibody in the same mouse model 
ameliorated nephritis and was accompanied by a reduction of IL-17A produced by in 
vitro stimulated splenocytes post-treatment (Kyttaris et al 2013). Both IL-23p19 and IL-17A 
knock-out mice developed less severe nephritis in a T cell-mediated murine model of 
nephrotoxic nephritis (Paust et al 2009). Elevated expression of IL-17A was observed in   
lupus-prone Fcgr2b knock-out mice, which develop fatal lupus glomerulonephritis, while mice 
lacking IL-17 displayed increased survival and protection from glomerulonephritis 
(Pisitkun et al 2014). Additional support for a role of IL-17A in LN has been provided in the 
pristane-induced LN mouse model, in which absence of IL-17A led to decreased renal 
inflammation and renal injury, along with reduced levels of anti-DNA antibodies 
(Summers et al 2014). In this model, macrophages as well as neutrophils were the main 


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producers of IL-17A. Thus, based on these animal data, blocking IL-17A in LN may prove 
beneficial in limiting glomerular inflammation and renal damage. 
A growing number of studies in patients with LN indicate that IL-17A and Th17 cells play 
important roles in the pathogenesis of LN, contributing to glomerular injury and the persistence 
of inflammation and renal damage (Zhang et al 2009), (Crispín and Tsokos 2008). High levels 
of IL-17 predict poor histopathological outcomes after immunosuppressive therapy in patients 
with LN (Zickert et al 2015). A subset of T cells infiltrates the kidneys of patients with LN and 
represent the major source for IL-17 (Crispín and Tsokos 2008). IL-17 has the potential to 
induce the production of additional inflammatory cytokines and chemokines and to promote 
recruitment of inflammatory cells such as monocytes and neutrophils to inflamed organs. 
Higher levels of glomerular IL-17 and IL-23 expression are observed in renal biopsies from 
class IV LN patients as compared with those from minimal change nephropathy patients and 
normal controls. Both glomerular IL-17 and IL-23 expression levels positively correlate with 
renal histological activity index scores for LN patients (Chen et al 2012). The urinary 
expression of Th17-related genes, including those for IL-17 and IL-23, is increased and 
associated with the activity of LN (Kwan et al 2009). 
Additional evidence shows that neutrophil recruitment to the kidney starts several hours after 
the induction of nephrotoxic nephritis and is partly mediated by IL-17A-producing γδ T cells 
(Kurts et al 2013). 
Th17 
cells 
promote 
intra-renal 
IL-17A 
expression 
in 
LN 
(Crispín and Tsokos 2008). IL-17 can also drive T cells away from maturing into a regulatory 
T cell phenotype that can suppress autoantibody production and attenuate the systemic immune 
response (Bettelli et al 2006). 
An imbalance between inflammatory Th17 and regulatory T cells and the secretion of 
inflammatory cytokines including IL-17A amplify the immune response in LN by inducing the 
local production of chemokines and cytokines, as well as the recruitment of neutrophils and 
monocytes. This ultimately contributes to persistent inflammation and kidney damage in LN 
(Koga et al 2017). IL-17A can also act directly on kidney cells such as mesangial cells 
(Paust et al 2009), tubular epithelial cells (Hirai et al 2012) and podocytes (Yan et al 2018), 
thereby increasing inflammation, T cell and neutrophil infiltration, and disruption of renal 
function leading to proteinuria. Therefore, a pathogenic model for glomerulonephritis is 
emerging in which Th17 cells infiltrate the kidney and IL-17A (as well as potentially other 
cytokines) produced by Th17 cells acts directly on resident kidney cells to induce cytokines and 
chemokines that lead to further recruitment of Th17 cells and neutrophils into the tissue, 
resulting in renal tissue damage (Krebs et al 2017).  
A recent report of a patient with refractory LN and concomitant psoriasis vulgaris suggests that 
treatment with the IL-17A inhibitor secukinumab may have contributed to an improvement in 
renal function and a decrease in urine protein levels in this patient (Satoh et al 2018).  
1.1.3 
Secukinumab 
Secukinumab is a recombinant high-affinity fully human monoclonal anti-human IL-17A 
antibody of the IgG1/kappa isotype. 
Secukinumab is currently approved in more than 94 countries worldwide. The product is 
indicated for the treatment of three inflammatory/autoimmune diseases, moderate to severe 


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plaque psoriasis (PSO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), and is being 
evaluated in other inflammatory conditions such as non-radiographic axial spondyloarthritis, 
juvenile idiopathic arthritis and pediatric psoriasis. 
The outcome of the extensive Novartis clinical program comprising more than 25 Phase III 
studies and at least 17,000 subjects studied over a period up to 5 years in these indications has 
shown that secukinumab offers robust and clinically meaningful efficacy to these patients and 
is complemented by a consistently favorable benefit:risk profile. The safety profile of 
secukinumab was indeed consistent and comparable across PsO, PsA and AS, supporting its 
long-term use in these chronic inflammatory conditions. 
Based on the available data suggesting that IL-17 is an appropriate therapeutic target for patients 
with LN, secukinumab has the potential to be an effective therapy for the active LN patients 
(ISN/RPS Class III or IV, with or without co-existing Class V features), when used in 
combination with SoC therapy. 
1.2 
Purpose 
The purpose of this trial is to evaluate the efficacy and safety of subcutaneous secukinumab  
300 mg compared to placebo, in combination with standard of care therapy (SoC), in subjects 
with active lupus nephritis (ISN/RPS Class III or IV, with or without co-existing class V 
features). 
Background SoC will consist of induction therapy with mycophenolic acid (MPA) (which refers 
to Mycophenolate mofetil (MMF) (Cellcept® or generic equivalent), or enteric-coated MPA 
sodium (Myfortic® or generic equivalent) at equivalent doses (oral), or Cyclophosphamide 
(CYC) (i.v.), followed by maintenance therapy with MPA. In addition, all subjects will receive 
i.v. and/or oral corticosteroids. 
The aim of the study is to demonstrate the efficacy and safety of secukinumab in LN that will 
enable registration for the indication of lupus nephritis. 
Within this document, at each time MPA will be mentioned without further information, 
it will refer to Cellcept®, Myfortic® or generic equivalent at equivalent doses. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary 
objective(s) 
• 
To demonstrate that secukinumab 300 mg is superior to 
placebo in Complete Renal Response (CRR) rate at 
Week 52 in active lupus nephritis (ISN/RPS Class III or 
IV, with or without co-existing Class V features) subjects 
on a background of SoC therapy. 
• 
Proportion of subjects 
achieving CRR at Week 52 
CRR is a composite endpoint 
defined as meeting the 
following: 
• 
Estimated glomerular 
filtration rate (eGFR) within 


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Objective(s) 
Endpoint(s) 
the normal range or no 
less than 85% of Baseline 
and 
• 
24-hour urine protein-to-
creatinine ratio (UPCR) 
≤0.5 mg/mg 
 
 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To demonstrate superiority of secukinumab 
compared to placebo in change from baseline 
in 24-hour UPCR at Week 52 
• 
Change from Baseline in 24-hour UPCR 
at Week 52 
• 
To demonstrate superiority of secukinumab 
compared to placebo in proportion of subjects 
achieving partial renal response (PRR) at Week 
52 
• 
Proportion of subjects achieving PRR at 
Week 52 defined as: 
• 
≥50% reduction in 24-hour UPCR to 
sub-nephrotic levels 
and 
• 
Normal eGFR or no less than 85% 
of Baseline 
• 
To demonstrate superiority of secukinumab 
compared to placebo in average daily dose of 
oral corticosteroids administered between 
Week 16 and Week 52 
• 
Average daily dose of oral corticosteroids 
administered between Week 16 and 
Week 52 compared to placebo 
• 
To demonstrate superiority of secukinumab 
compared to placebo in proportion of subjects 
achieving PRR at Week 24 
• 
Proportion of subjects achieving PRR at 
Week 24 defined as: 
• 
≥50% reduction in 24-hour UPCR to 
sub-nephrotic levels 
and 
• 
Normal eGFR or no less than 85% 
of Baseline 
• 
To demonstrate superiority of secukinumab 
compared to placebo in time to achieve CRR 
• 
Time to achieve CRR up to Week 52 
• 
To demonstrate superiority of secukinumab 
compared to placebo in time to achieve PRR 
• 
Time to achieve PRR up to Week 52 
• 
To demonstrate superiority of secukinumab 
compared to placebo in time to achieve first 
morning void UPCR ≤ 0.5 mg/mg 
• 
Time to achieve first morning void UPCR 
≤ 0.5 mg/mg up to Week 52 
• 
To demonstrate superiority of secukinumab 
compared to placebo in change in Functional 
Assessment of Chronic Illness Therapy – 
Fatigue (FACIT-Fatigue©) score at Week 52  
• 
Improvement in FACIT-Fatigue© mean 
change of score from Baseline at Week 
52 compared to placebo 
• 
To demonstrate superiority of secukinumab 
compared to placebo in patient’s health related 
quality of life via Medical Outcome Short Form 
Health Survey (SF-36 Physical Component 
Summary (PCS)) score at Week 52 
• 
Improvement in SF-36 PCS mean 
change from Baseline at Week 52 
compared to placebo  


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Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To demonstrate superiority of secukinumab 
compared to placebo in change of LupusQoL 
(Physical Health) score at Week 52 
 
• 
To evaluate the safety and tolerability of 
secukinumab s.c. as an add-on therapy to 
Standard of Care in lupus nephritis subjects 
• 
Improvement in LupusQoL Physical 
Health mean change of score from 
Baseline at Week 52 compared to 
placebo 
• 
Incidence of Treatment-emergent AEs 
(TEAEs) / SAEs from Baseline to Week 
52; vital signs and body measurements, 
standard chemistry and hematology up 
to Week 52 
• 
To estimate the proportion of subjects with 
maintained renal response at Week 104 
• 
Estimate the proportion of subjects with 
CRR at Week 104 within subjects who 
had achieved CRR at Week 52 in the 
secukinumab group 
• 
To estimate the proportion of subjects with 
improved or maintained renal response at 
Week 104 
• 
Estimate the proportion of subjects with 
improved or maintained response (PRR 
or CRR) in subjects who had achieved at 
least PRR at Week 52 in the 
secukinumab group 
 
 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
 


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• 
To perform exploratory 
pharmacogenomic analysis 
based on blood samples for 
DNA and RNA analysis (optional 
assessments) 
• 
Evaluate the relationship of genetic polymorphisms and 
transcriptomic data with treatment response 
3 
Study design 
This is a pivotal, randomized, double-blind, placebo controlled trial evaluating at Week 52 the 
efficacy and safety of secukinumab versus placebo in subjects with active LN also receiving 
background SoC regimen. Long-term efficacy, safety and tolerability will be collected up to 2 
years.  
The SoC regimen will consist of induction therapy with MPA or CYC, followed by maintenance 
therapy with MPA. The choice of background SoC induction therapy will be at investigator's 
discretion. At Randomization, subjects will be stratified on the basis of the SoC induction 
therapy they will receive during the study, MPA or CYC-based, to ensure a balanced 
representation in each of the treatment arms (secukinumab or placebo). The target will be to 
have a maximum of 25% of randomized subjects receiving CYC-based induction therapy. 
In addition, steroids will be administered through i.v. pulses followed by oral daily doses as 
described in Section 6.1.3 SoC background therapy. 
The primary endpoint analysis will be performed after all subjects have completed the visit 
associated with the primary endpoint (Week 52). Although the unblinding of selected members 
of the Novartis Global Clinical Team will occur after the Week 52 database lock, original 
randomization to active treatment versus placebo will continue to remain blinded to all 
investigators, site personnel, subjects, and monitors until the final database lock and analyses 
are completed. 
 
 


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The study consists of the following parts: 
a. Screening (up to 42 days/6 weeks) 
b. Run-in period (optional): For subjects who will receive MPA as SoC induction therapy as 
per investigator's decision and who are not already on MPA at Screening, MPA dosing 
will be initiated during a run-in period before Randomization (for up to 4 weeks prior to 
the first dose of secukinumab) 
c. Treatment Period: Duration of 104 weeks of treatment with secukinumab/placebo in 
addition to SoC treatment (with last dose given at Week 100) 
d. Follow-up period: Duration of 8 weeks (last visit performed 12 weeks after last dose of 
study medication) 
Figure 3-1 
Study design 
 
Screening to Randomization (Screening and Run-in period): 
A Screening period of up to 6 weeks will be used to assess subject´s eligibility and to adjust for 
concomitant medication(s) (-42 to -1 day). This flexible duration will provide enough time to 
evaluate eligibility of the subject, including renal biopsy evaluation. If subjects do not have a 
renal biopsy obtained within 6 months of the Screening visit, a renal biopsy should be 
performed. This renal biopsy should be performed after confirming that the subject meets all 
other inclusion/exclusion criteria. 
Subjects who will receive MPA-based SoC induction therapy for the treatment of active LN as 
per investigator's decision, and not already on MPA when entering Screening, will be initiated 
on MPA during the run-in period (-28 to -1) as described in Section 6.1.3 SoC background 
therapy. 
Treatment period: Treatment period covers time between Randomization (Baseline) through 
EOT. 
At Baseline, eligible subjects will be randomized in a 1:1 ratio to secukinumab 300 mg s.c. or 
placebo. Approximately 230 subjects will be randomized to each of the two treatment arms. A 
blinded, weekly, s.c. secukinumab or placebo loading regimen will be administered for the first 
4 weeks followed by a monthly maintenance dose in all randomized subjects thereafter. At the 


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end of the treatment period at Week 104, the planned End of Treatment (EOT) visit will be 
performed.  
Subjects who discontinue study treatment prematurely for any reason other than withdrawal of 
informed consent before Week 104 will not be considered as discontinued from the 
study. Those subjects should perform the EOT study visit 4 weeks after their last study 
treatment administration. Thereafter, subjects should continue attending all subsequent 
scheduled site visits for study assessments. Subjects who are unwilling to continue attending 
further study visits after prematurely discontinuing the study treatment, should attend the End 
of Study (EOS) visit 12 weeks after the last administration of study treatment. Please refer to 
Section 9.1.1 Discontinuation of study treatment for further details. 
In addition, starting at Week 52, subjects who are not deemed, by the investigator, to achieve 
the desired benefit from the study treatment, should be considered for rescue medication. In 
case a prohibited medication (as defined in Section 6.2.2 Prohibited medication) is used as 
rescue medication, the subject should be discontinued from study treatment. 
Follow-up period: An EOS visit is to be done for all subjects. The EOS visit will be performed 
12 weeks after last study treatment administration for all subjects who complete the 104 weeks 
treatment period, or who discontinue prematurely study treatment and study. For subjects who 
discontinue study treatment prematurely but continue attending study visits, please refer to 
Section 9.1.1 Discontinuation of study treatment for detailed guidelines. 
Safety assessments will include physical examinations, vital signs, standard clinical laboratory 
evaluations, hematology (including blood coagulation assays), blood chemistry, urinalysis, 
adverse and serious adverse event monitoring. 
4 
Rationale 
4.1 
Rationale for study design 
The double-blind, randomized, placebo-controlled, parallel-group design will enable the 
evaluation of the benefit-risk of the proposed secukinumab dose regimen in an adequate and 
well-controlled setting, minimizing potential bias in reporting of safety and efficacy data. 
A recommended steroid tapering regimen will be initiated in all randomized subjects during the 
treatment period. The tapering schedule (timing and dose decrease) will depend on the Baseline 
corticosteroid dose. The tapering regimen, as described in Section 6.1.3 SoC Background 
therapy, is in alignment with common medical practice in LN and is designed to minimize 
steroid-related toxicity and avoid confounding the primary efficacy assessment. 
CRR is a preferred primary outcome for induction and maintenance therapy in LN. It is 
demonstrated as clinically significant improvement of renal function during the induction 
phase, shown by improvement of eGFR and signs and symptoms of renal injury like protein 
excretion. The primary endpoint assessment is planned at Week 52 as recommended by various 
guidelines. The two-year duration (104 weeks) will provide additional safety and efficacy data 
as well as the durability of response. 
An assessment of PRR will be conducted as a secondary endpoint in the trial and will evaluate 
the proportion of subjects who improved while not achieving a CRR. Considering the long 


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duration of the study (104 weeks), maintenance of CRR and prevention of renal flares are also 
secondary outcomes that may be evaluated.
 
 
 
4.1.1 
Rationale for choice of background therapy 
The SoC background therapy that all subjects will receive was selected as it corresponds to the 
treatment recommendations of the ACR and EULAR/ERA-EDTA guidelines for induction and 
maintenance therapy for subjects with ISN/RPS Class III or IV LN, with or without co-existing 
class V features, (Bertsias et al 2012), (Hahn et al 2012), (Palmer et al 2017). 
The choice of background SoC regimen for induction will be left at investigator's discretion, 
with a maximum of 25% of randomized subjects receiving CYC-based induction therapy 
(stratification at Randomization will ensure balanced representation in both groups, 
secukinumab or placebo). SoC background regimen will consist of induction therapy with MPA 
or low-dose CYC regimen, followed by maintenance therapy with MPA, along with 
glucocorticoids: 
• MPA and CYC are considered equivalent for the induction of remission in patients with 
ISN/RPS Class III or IV LN, with or without co-existing class V features 
• The low dose intravenous CYC regimen for induction was selected, as it presents a better 
efficacy/toxicity ratio than high-dose intravenous CYC 
• Corticosteroid administration as per the above mentioned guidelines are considered a 
mainstay in LN treatment 
4.2 
Rationale for dose/regimen and duration of treatment 
Secukinumab dosing will start with initial dosing of 300 mg s.c. injections at Baseline, Weeks 
1, 2, 3, and 4, followed by dosing every 4 weeks. This dosing regimen is approved for treatment 
of other autoimmune diseases (PsO, PsA). Available data in PsO and PsA strongly suggest that 
secukinumab operates at the plateau of the dose-exposure-response curve in these autoimmune 
diseases, which is one of the reasons to select this dose level in LN as well. As clearly 
demonstrated in the development program for PsO, it is expected that the initial weekly dosing 
during the first month will enable rapid achievement of effective drug concentrations and lead 
to a more rapid onset of clinical response. 
It has to be noted that due to kidney damage, proteinuria is commonly observed in patients with 
LN. The effect of renal impairment on the PK of biologics is dependent on the ability of the 
compound to undergo glomerular filtration, which is largely driven by molecular weight (MW). 
Secukinumab has a MW of ca. 148 kDa, and renal clearance usually plays a minimal role in the 
elimination of biologics with MW greater than 69 kDa (Meibohm and Zhou H 2012). An 
association between increased Baseline proteinuria and increased clearance was observed in the 
population PK analysis of belimumab (a human mAb that inhibits B-cell activating factor, 
BAFF) in SLE (Struemper et al 2013). Also, there is evidence that in some forms of renal 
disease, such as diabetic nephropathy, there may be an increase in the renal elimination of IgGs 
(Bakoush et al 2002). However, slight changes in distribution volume or increased clearance of 
secukinumab in LN patients will probably not dramatically change the PK characteristics of 
secukinumab.  


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In addition, the secukinumab dosing regimen used in the study is associated with a reassuring 
safety profile, as confirmed in multiple clinical trials (up to 5 years) and in the post-marketing 
setting. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
A placebo arm is included for the whole duration of the study treatment. Due to the nature of 
the disease and the primary outcome measure used (CRR), a placebo arm is necessary to obtain 
reliable efficacy measurements for comparison between the active treatment and the placebo. 
In addition, all subjects, including those assigned to the placebo arm, will receive background 
SoC therapy as recommended within the EULAR/ERA-EDTA and ACR guidelines for the 
induction and maintenance treatment of patients with active ISN/RPS class III or IV LN 
[excluding III (C), IV-S (C) and IV-G (C)] ,with or without co-existing class V features.  
As recommended by the same guidelines, all subjects will also receive hydroxychloroquine 
(HCQ) as adjunctive medication unless contraindicated. Treatment with lipid-lowering statin 
and of renin-angiotensin-aldosterone system inhibitors (ACE inhibitors /ARBs) is allowed. 
The FDA (FDA 2018) and the Committee for Medicinal Products for Human Use (CHMP) 
recommend double blind, parallel-group, randomized trial designs. Per the CHMP guideline 
(Committee for Medicinal Products for Human use (CHMP) 2015), a superiority trial design 
against an active comparator or placebo is preferred in LN. Placebo-controlled trials are 
acceptable provided that placebo is given as add-on to SoC therapy. 
4.4 
Purpose and timing of interim analyses/design adaptations 
The study team, site staff, investigators and subjects will remain blinded to the interim data and 
results of the analysis for both the futility and interim analysis described below. 
In addition to those interim analysis, the primary endpoint analysis will be performed after all 
subjects have completed the visit associated with the primary endpoint (Week 52). At time of 
the primary endpoint analysis, although the unblinding of selected members of the Novartis 
Global Clinical Team will occur, investigators/site personnel, subjects and monitors will remain 
blinded until the final study analyses are completed. 
Futility Analysis 
A futility analysis will be performed when approximately 30% of the subjects have completed 
the first 52 weeks of treatment. A Go/No-Go decision will be taken at this futility analysis based 
on predictive probability calculated from the CRR achieved at Week 52. 
The analysis will be conducted by an independent statistician and programmer supporting an 
independent data monitoring committee (DMC). Futility stopping rules will be defined in the 
DMC charter. 
 
 
 
  


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Interim analysis 
Based on the group sequential design applied in the study, an Interim Analysis is planned when 
2/3 or approximately 67% subjects complete 52 weeks of treatment. The interim analysis will 
be performed by independent DMC. The results from this interim analysis will support the 
decision to continue or to stop the trial based on efficacy and/or safety findings. 
4.5 
Risks and benefits 
To date, no evidence-based, systemic therapy has been available for lupus nephritis patients. 
Current standard of care therapies comprise conventional immunosuppressants which are not 
fully efficacious in all patients and associated with significant toxicities. Based on the scientific 
rationale for targeting IL-17 pathway in lupus, and the data available on secukinumab, IL-17 
inhibition by secukinumab has a potential therapeutic benefit for lupus nephritis patients who 
are clinically active despite standard of care treatment. 
Secukinumab has demonstrated positive benefit risk in the treatment of multiple chronic 
inflammatory diseases, including PsA, AS and PsO. 
Secukinumab therapy has a well-established and well-described safety profile based on 
extensive post-marketing experience and continued clinical trial patient exposure since its 
approval for the first indication of moderate to severe plaque psoriasis. Details of the risk and 
benefits are outlined in the current version of the Investigator's Brochure (IB). 
The safety and tolerability of secukinumab as an add-on to SoC will be evaluated. Based on the 
favorable safety profile of secukinumab and the known safety profile of the SoC treatments for 
LN, it is unlikely that the addition of secukinumab to the LN SoC regimens will result in 
unacceptably high risks, particularly for serious infections. In a pooled analysis of clinical trial 
data, including multiple indications and nearly 18,000 patients exposed to any dose of 
secukinumab, the crude incidence of severe AEs of infections was 2.7% [PSUR – data on file]. 
In comparison, a recent meta-analysis found that, in patients with lupus nephritis treated, the 
crude incidence rates of serious infections have been reported at 26.7% with high-dose 
glucocorticoids, 15.1% with cyclophosphamide, and 11.6% with MMF (Singh et al 2016). 
Additionally, in secukinumab trials, the exposure-adjusted incidence rate of SAEs of infections 
have been reported at 1.6/100 PY [PSUR – data on file], while the risk of serious infections 
with a combined regimen of MMF and corticosteroids was reported at 19/100 PY 
(Rovin et al 2012), (Mysler et al 2013). 
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, and periodic review of safety data 
by an independent DMC. Additional information can be found in the IB for secukinumab. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and must agree that in 
order to participate in the study, they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the subject will not reliably comply, they 
should not be entered or continue in the study. 


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From the standpoint of the overall risk-benefit assessment, the current trial with secukinumab 
is justified. 
5 
Population 
The study population will be comprised of adult male and female subjects in the age range of 
18-75 years with a renal biopsy (current or within the 6 months prior to Screening) showing 
active glomerulonephritis WHO or ISN/RPS Class III or IV LN [excluding III (C), IV-S (C) 
and IV-G (C)], with or without co-existing class V features, who are inadequately controlled 
with previous SoC defined as having UPCR ≥1 and active urinary sediment (presence of cellular 
casts which are granular casts or red blood cells or hematuria (>5 red blood cells per high power 
field)). 
Approximately 460 subjects, randomized into two treatment arms (1:1 active: placebo), are 
planned. At Randomization, subjects will be stratified on the basis of the SoC induction therapy 
they will receive during the study, MPA or CYC-based, to ensure a balanced representation in 
each of the treatment arms (secukinumab or placebo). The target will be to have a maximum of 
25% of randomized subjects receiving CYC-based induction therapy. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Adult male and female subjects aged 18 - 75 years old at the time of Baseline. 
2. Confirmed diagnosis of: 
• SLE with documented history of at least 4 of the 11 criteria for SLE as defined by the 
American 
College 
of 
Rheumatology 
(ACR) 
(Tan et al 1982) 
revised 
by 
(Hochberg 1997). [NOTE: The 4 criteria do not have to be present at the time of 
Screening], 
OR 
• LN as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. 
3. Active lupus nephritis, as defined by meeting the 4 following criteria: 
• Biopsy within 6 months prior to Screening visit indicating active glomerulonephritis 
WHO or ISN/RPS Class III or IV LN [excluding III (C), IV-S (C) and IV-G (C)]; 
subjects are permitted to have co-existing Class V. If no biopsy was performed within 
6 months of Screening, a biopsy will need to be performed during the Screening period, 
after all other inclusion/exclusion criteria would have been verified. 
• UPCR ≥1 at Screening. 
• Estimated eGFR >30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI). 
• Active urinary sediment (presence of cellular casts (granular or red blood cell casts) 
or hematuria (>5 red blood cells per high power field)). 
4. Subjects must be currently on, or willing to initiate SoC induction therapy for LN according 
to the institutional practices using MPA or low-dose CYC in addition to corticosteroids. For 
guidance, see published guidelines such as by (Bertsias et al 2012), (Hahn et al 2012). 


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5. If the subject is on cholesterol-lowering agents, the dose must be stable for at least 7 days 
prior to Randomization. 
6. Subjects must be treated with anti-malarials (e.g., hydroxychloroquine), unless         
contra-indicated, and the dose must be stable for at least 10 days prior to Randomization. 
7. Able to provide signed informed consent. 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Severe renal impairment as defined by i.) Stage 4 CKD, or ii.) presence of oliguria (defined 
as a documented urine volume < 400 mL/24 hrs), or iii.) ESRD requiring dialysis or 
transplantation. 
2. Known intolerance/hypersensitivity to MPA, or oral corticosteroids, or any component of 
the study drug(s). 
3. Subjects having received any other biologic immunomodulatory therapy within 6 months 
prior to Screening, excluding belimumab where 3 months are acceptable. 
4. Previous exposure to secukinumab (AIN457) or any other biologic drug targeting IL-17 or 
the IL-17 receptor. 
5. Subjects having received any investigational drug within 1 month or five times the half-life 
of enrollment, whichever is longer. 
6. Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) within the 
12 weeks prior to Baseline. 
7. Treatment with a systemic calcineurin inhibitor (e.g., cyclosporine, tacrolimus) within 12 
weeks prior to Baseline 
8. CYC use (i.v. or oral) within the month prior to Baseline. 
9. Subjects requiring dialysis within the previous 12 months before Screening. 
10. History of renal transplant. 
11. Any severe progressive or uncontrolled concurrent medical condition, including recent 
severe thromboembolic events, that, in the opinion of the principal investigator, renders the 
subject unsuitable for the trial. 
12. Active ongoing inflammatory diseases that might confound the evaluation of the benefit of 
secukinumab therapy, including inflammatory bowel disease. 
13. Presence of investigator-identified significant medical problems which at the investigator’s 
discretion will prevent the subject from participating in the study, including but not limited 
to the following: myocarditis, pericarditis, poorly controlled seizure disorder, acute 
confusional state, depression, severe manifestations of neuropsychiatric SLE (NPSLE). 
14. Chest X-ray, computerized tomography (CT) scan, or MRI with evidence of ongoing 
infectious or malignant process, obtained within 12 weeks prior to Randomization and 
evaluated by a qualified physician. 
15. History of chronic, recurrent systemic infections, active tuberculosis infection, or active 
systemic infections during the last two weeks (exception: common cold) prior to 
Randomization. 
16. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at 
Screening or Randomization. 


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17. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system treated or untreated within the past 5 years, regardless of whether there 
is evidence of local recurrence or metastases (except for skin Bowen’s disease or basal cell 
carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the 
past 12 weeks, carcinoma in situ of the cervix or non-invasive malignant colon polyps that 
have been removed). 
18. Any of the following abnormal laboratory values on Screening evaluations as reported by 
Central Laboratory: 
• 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase > 2.5xULN 
• 
Hemoglobin <8g/dL 
• 
Neutrophils <1.0 x 109/L 
• 
Platelet count <50 x 109/L 
19. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of venous access). 
20. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
Randomization. 
21. Pregnant or lactating women. 
22. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
the entire study or longer if required by locally approved prescribing information (e.g., in 
European Union (EU) 20 weeks). 
Highly effective contraception methods include: 
• Total abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy [with or without 
hysterectomy], total hysterectomy or tubal ligation at least six weeks before taking 
study treatment). In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment. 
• Male sterilization (at least 6 months prior to Screening). The vasectomized male partner 
should be the sole partner for that subject. 
• Barrier methods of contraception: Condom or occlusive cap (diaphragm or 
cervical/vault 
caps). 
NOTE: 
for 
United 
Kingdom: 
with 
spermicidal 
foam/gel/film/cream/vaginal suppository. 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS). In case of use of oral contraception, women should have been stable on the same 
treatment for a minimum of 3 months prior to Randomization. 
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the informed consent form (ICF). 


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Note: Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks prior to enrollment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment is she considered not of childbearing potential. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Novartis Global Clinical Supply (GCS) will supply the following study treatments:  
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
AIN457 150mg / 
1mL 
Solution for 
Injection 
Subcutaneous 
use 
Double blinded 
prefilled syringes 
(PFS) 
Novartis Pharma 
AG 
AIN457 0 mg / 
1mL (Placebo) 
Solution for 
Injection 
Subcutaneous 
use 
Double blinded 
prefilled syringes 
(PFS) 
Novartis Pharma 
AG 
The PFSs are packed in a double blinded fashion and do not need to be prepared. 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. The investigational treatment packaging has a 2-part label. A unique 
Randomization number is printed on each part of this label, which corresponds to placebo or 
active treatment.  
The study treatments will be labeled as follows: Double blind secukinumab and placebo PFS 
will be labeled AIN457 150 mg/1 mL/Placebo 
6.1.2 
Additional study treatments 
 No other study treatment beyond investigational drug and control drug are included in this trial. 
 
 
 
 


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6.1.3 
SoC background therapy 
All subjects will receive SoC background regimen for induction and maintenance therapy.  
Table 6-2 
Background therapy 
Name of the 
medication 
Dosage Form 
Route of 
administration 
Availability 
MMF/MPA 
Tablet 
Oral 
Open-label subject 
packs 
CYC 
Powder for solution for 
infusion 
Intravenous 
Open-label subject 
packs 
Corticosteroids 
Tablets and/or 
Solution for injection 
Oral and/or 
Intravenous use 
Open-label subject 
packs 
Background SoC medications will NOT be provided by Novartis GCS and must be handled at 
the country level. 
6.1.3.1 
Induction therapy 
The induction therapy will consists of either MPA or low-dose CYC, in combination with 
corticosteroids. The choice of the induction SoC therapy, MPA or low-dose CYC will be left at 
the investigator's discretion. To ensure a balanced representation in both treatment arms 
(secukinumab or placebo), subjects will be stratified at time of Randomization according to 
their SoC induction therapy. A maximum of 25% of subjects receiving CYC-based SoC 
induction therapy will be allowed to be randomized in the study (maximum of 116 subjects in 
the study). 
MPA: 
Target dose during the first six-month treatment period (MPA induction period) is 2 g/day of 
MMF or equivalent dosage of enteric-coated MPA of 1440 mg/day. If required, a dose up to 3 
g/day of MMF or equivalent dosage of enteric-coated MPA of 2160 mg/day is allowed, based 
on Investigator’s judgement. A reduction of MPA dose is only allowed in case of toxicity, as 
per Investigator's decision. 
Optional Run-in period 
Subjects not already on MPA at study entry will be initiated, after verification of eligibility, on 
an MMF dose of 1 g/day (divided q 12 hrs) or an equivalent dosage of enteric-coated MPA of 
720 mg/day. The dose must be increased to 2 g/day of MMF or equivalent dosage of           
enteric-coated MPA in the second week, and up to 3 g/day of MMF or equivalent dosage of 
enteric-coated MPA in the third week when required. If subjects experience adverse effects that 
prevent up-titration as described, an additional 1 week of titration is permitted. If MMF/MPA 
dose escalation is clinically inappropriate as judged by the investigator, or inconsistent with 
local treatment guidelines, subjects can take a dose of 1-2 g/day MMF or equivalent dosage of 
enteric-coated MPA in the absence of observed toxicity. 
Low-dose CYC: 
The low-dose CYC induction treatment consists of 6 administrations of 500 mg i.v. CYC every 
2 weeks. All i.v. CYC administration will be performed according to the site and /or local 


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guidelines, including the administration of any medication for prophylaxis of potential 
toxicities. 
The first i.v. CYC administration will be performed at Baseline visit, after all 
inclusion/exclusion criteria would have been verified. 
Corticosteroids: 
Pulse i.v. corticosteroid should be initiated at Baseline visit (500–1000 mg methylprednisolone 
daily) for a maximum of 3 doses. This will be followed by daily administration of oral 
glucocorticoids at initial dose of 0.3 to 0.5 mg/kg/day to be tapered within 16 weeks to the 
minimal dose necessary to control disease (see recommended guidance on Table 6-3). 
Subjects who cannot take the pulse i.v. corticosteroid therapy should directly start on 0.3-0.5 
mg/kg/day oral dose of glucocorticoid followed by the above-described tapering. 
Subjects having already received pulse i.v. corticosteroids up to a cumulative dose of 3000 mg 
within 12 weeks prior to Baseline do not need to repeat the i.v. pulse. For these subjects already 
on corticosteroids at Baseline, a predefined steroid taper regimen (see Table 6-3) should be 
implemented. 
In all cases, from Week 16 onward, the target dose of oral corticosteroids is 5 mg daily 
(prednisone equivalent). 
Table 6-3 
Guidance for corticosteroid (prednisone equivalent) taper 
Initial Dose 
40 mg 
30 mg 
20 mg 
Week 2 
30 
25 
15 
Week 4 
25 
20 
15 
Week 6 
20 
15 
10 
Week 8 
15 
10 
10 
Week 12 
10 
10 
10 
Week 16 and 
thereafter maintain at 
5 mg where possible 
* acceptable dose 
range 
5 
*7.5 – 2.5 
5 
*7.5 – 2.5 
5 
*7.5 – 2.5 
6.1.3.2 
Maintenance therapy 
After the induction period (6 months for MPA-based induction; 12 weeks for CYC-based 
induction), all subjects must receive MPA-based maintenance therapy. 
The target dose during the maintenance period is 1-2 g/day of MMF or of equivalent dosage of 
enteric-coated MPA. Further reduction of MMF to 0.5 g/day or of equivalent dosage of    
enteric-coated MPA is allowed as per Investigator's decision. 
In addition, all subjects will receive a maintenance dose of oral corticosteroids as per             
Table 6-3 above, with a target dose of 5 mg/day prednisone equivalent (2.5-7.5 mg/day 
acceptable dose range) from Week 16. 


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A recommended diagram for administration of SoC background therapy from the Run-In period 
until Week 24 is provided in Appendix 16.4. 
6.1.4 
Treatment arms/group 
At Baseline, all eligible subjects will be randomized to one of the two treatment arms in a 1:1 
ratio via Interactive Response Technology (IRT): 
• Arm 1: approximately 230 LN subjects will receive secukinumab 300 mg s.c. (2 x 1.0 mL 
PFS of 150 mg dose) at Randomization (i.e., Baseline). 
• Arm 2: approximately 230 LN subjects will receive placebo s.c. (2 x 1.0 mL PFS of 0 mg 
dose) at Randomization (i.e., Baseline). 
At Randomization, subjects will be stratified on the basis of the SoC induction therapy they will 
receive during the study, MPA or CYC-based, to ensure a balanced representation in each of 
the treatment arms (secukinumab or placebo).  
6.1.5 
Treatment duration 
Subjects will receive investigational treatment at Baseline, Weeks 1, 2 and 3, followed by 
administration every 4 weeks starting at Week 4, until Week 100. Subjects will self-administer 
all secukinumab or placebo doses at the investigational site. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate Case Report Form (CRF). 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Guidelines for the use of specific medications are provided below. 
Subjects may continue on the concomitant medication listed below provided they are on a stable 
dosage from seven days prior to Screening to the end of study. However investigators may 
change the dose of concomitant medications during the study for safety reasons based on their 
clinical judgement. Each concomitant medication should be captured/recorded in the eCRF at 
every visit, including the dose changes when appropriate. 
Anti-malarials 
Subjects will remain on one stable background anti-malarial medication (e.g., 
hydroxychloroquine) in addition to the SoC medication. Subjects who have not taken previously 
anti-malarial medication should be initiated on an anti-malarial at least 10 days prior to 


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Randomization (unless contraindicated) and remain on a stable dose throughout the trial. Refer 
to Section 5.1 Inclusion Criteria. 
 
Anti-hypertensive medication 
Subjects already taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin 
receptor blockers (ARBs) at Screening should remain on the same dose throughout the study 
unless precluded by toxicity or if dose adjustment is required for hypertensive control. 
Combination therapy with an ACE inhibitor and an ARB will not be allowed. For subjects not 
already receiving one of these agents, it is recommended that treatment with an ACE inhibitor 
or ARB should be initiated during Screening (unless contraindicated) and be given at a stable 
dose for at least 7 days prior to Randomization. These therapies should not be initiated after 
study Baseline. 
Cholesterol-lowering drugs 
Concomitant treatment with cholesterol-lowering drugs (e.g., statins) will continue if prescribed 
prior to the study and will be recorded in the eCRF. Statin treatment can be initiated during the 
course of the study if considered required by the Investigator. 
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 
NSAIDs may have impact upon renal function and therefore should only be used during the 
trial if deemed necessary by the Investigator, e.g. in cases such as the following: 
• treatment of pleuritis and pericarditis. 
• treatment of arthritis pain that is unresponsive to other treatment modalities (e.g., 
analgesics) 
Osteoporosis Prevention /Treatment 
Subjects not already taking vitamin D (400 IU/day) and calcium supplements (1200 mg/day of 
calcium citrate or 1500 mg/day calcium carbonate) are allowed to start these medications, at the 
investigator’s discretion (see ACR 2001). 
Other Permitted Therapy 
• Low dose aspirin for cardio-protection may be used at Investigator’s discretion. 
• Subjects who use oral contraceptives or hormone-replacement therapy should continue 
their use. 
• Any prophylaxis for CYC-induced toxicities, as per site and or local guidelines, if patient 
is to receive low-dose CYC-based induction treatment. 
All other concomitant medications deemed necessary will be reviewed by the Investigator and 
decisions made on a case-by-case basis. 
Note: Concomitant medications will not be provided by Novartis and must be supplied by the 
study center. 


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6.2.2 
Prohibited medication 
The following treatments are prohibited after Screening and during the course of the trial due 
to their mechanisms of action that can confound the study results. If administered, the subject 
is to be withdrawn from the study treatment:  
• Initiation of CYC treatment (oral or i.v.) outside of the protocol planned low-dose CYC 
induction therapy for subjects elected to receive CYC-based induction 
• Initiation of rituximab or belimumab therapy 
• Use of any other systemic biologic /non-biologic immunomodulatory treatment 
• Administration of live vaccines 
6.2.3 
Rescue medication 
Rescue medication is defined as any new medication used because the subject's disease is not 
adequately controlled by the investigational study treatment in addition to the SoC background 
therapy. 
Although no subject will be restricted from receiving necessary rescue medications for lack of 
benefit or worsening of the disease (e.g., experiencing a renal flare), subjects will be 
discontinued from the study treatment if they are treated with prohibited medications (as 
described in Section 6.2.2). The choice of the rescue medication will be based on the treating 
Investigator's assessment and applicable regulatory guidelines. 
Subjects who discontinue investigational treatment can continue to attend all subsequent 
scheduled visit assessments unless informed consent is withdrawn as described in Section 9.1.1 
Discontinuation of study treatment. If study investigational treatment is discontinued, subjects 
may take study-prohibited medication under the investigator's guidance and as per locally 
approved prescribing information. 
Use of rescue medication must be recorded on the appropriate eCRF page. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for Screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available. 
6.3.2 
Treatment assignment, randomization 
At Baseline visit, all eligible subjects will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the subject, which will be used to link the subject to a treatment arm 


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and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment. 
Randomization will be stratified by the SoC induction therapy subjects will receive (MPA or 
CYC-based). A maximum of 25% of the randomized subjects will receive low-dose CYC 
induction therapy (up to 58 subjects per treatment arm). This will ensure that subjects can be 
treated with SoC therapy as per site and/or local guidelines, and a balanced repartition within 
the two treatment arms. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
This is a double-blind, randomized treatment trial. 
Subjects, investigator staff, persons performing the assessments will remain blinded to the 
identity of the treatment from the time of Randomization until final database lock, using the 
following methods: 
(1) Randomization data are kept strictly confidential until the time of unblinding and will not 
be accessible by anyone else involved in the study with the following exceptions: 
• Specific vendors whose role in the clinical trial requires their unblinding (e.g., IRT) 
• Global Clinical Supply 
• The designated Novartis study team members involved in the primary endpoint analysis 
 
 
(2) The identity of the treatments will be concealed by the use of study treatments in the form 
of PFS, filled with secukinumab or placebo, that are all identical in packaging, labeling, 
appearance and schedule of administration. 
 
 
 
 
As the primary endpoint analysis will be performed at Week 52, there will be a database lock 
when all subjects have completed Week 52 assessments. Summary results may be shared 
internally and externally; however, individual unblinded subject data will not be disclosed. For 
details regarding the planned Interim Analyses, refer to Section 4.4 Purpose and timing of 
interim analyses/design adaptation, and Section 12.7 Interim analyses. 


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A final database lock will occur when all subjects have completed the study. After the Week 
104 analysis has been conducted, the Novartis clinical team will notify the investigative staff 
and the IRT system and site personnel and the subject will be unblinded to the originally 
assigned treatment arms. 
The high sensitivity C-reactive protein (hsCRP) results from samples collected during the 
treatment period will be revealed only after database lock and analyses are completed. 
6.5 
Dose escalation and dose modification 
Investigational study treatment dose adjustments are not permitted. 
6.5.1 
Dose modifications 
Study treatment interruption is only permitted if, in the opinion of the investigator, a subject is 
deemed to be placed at a significant safety risk unless dosing is temporarily interrupted. In such 
cases, study treatment should be interrupted only during the time that this risk is present and 
ongoing. Study treatment can be restarted at the next scheduled visit after resolution of the 
safety risk. 
Any study treatment interruption must be recorded on the appropriate eCRF. 
6.5.2 
Follow-up for toxicities 
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant abnormal laboratory value, must be followed up in accordance with what 
is clinically indicated per the investigator until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrist, etc., should be consulted as deemed necessary. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
6.6.1.1 
Study treatment compliance 
Administration of study treatment will occur at the study site through Week 100. The first study 
treatment administration will occur at the Baseline/Randomization visit only after eligibility 
criteria have been confirmed, all study Baseline assessments have been performed, and the 
scheduled blood samples have been drawn. 
Compliance is expected to be 100% unless temporary interruption is needed for safety reasons 
as described in Section 6.5.1. Compliance will also be assessed by a Novartis monitor using 
information provided by authorized site personnel. 
All doses of study treatment administration will be recorded on the appropriate eCRF page. 
6.6.1.2 
Standard of care treatment compliance 
All intravenous administration of SoC, like CYC or pulses of glucocorticoids as specified in 
Section 6.1.3 SoC background therapy, must be administered at the study site under the 


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supervision of appropriate personnel. Doses administered and dates should be recorded on the 
appropriate eCRF pages. 
Oral doses of MPA or corticosteroids, as specified in Section 6.1.3, will be taken by the patient 
at home. 
The investigator must promote compliance by instructing the subject to take the SoC treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the SoC treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit by reviewing the information provided 
by the subject. This information should be captured in the source document at each visit. 
6.6.2 
Recommended treatment of adverse events 
Treatment for AEs are at the discretion of the investigator or treating physician. Refer to the 
Investigator's Brochure for AEs related to secukinumab. 
Medication used to treat AEs must be recorded on the appropriate eCRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time. 
Study drug should be discontinued after emergency unblinding. 
6.7 
Preparation and dispensation 
Each study site will be supplied with investigational study drug in packaging as described under 
investigational and control drugs Section 6.1.1. 


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Secukinumab solution for s.c. injection or placebo secukinumab solution (active or placebo, 
respectively) will be provided in prefilled syringes (PFS). 
Each subject will require one box with PFS per dose throughout the study: 
· One secukinumab 300 mg (2 x 1.0 mL PFS of 150 mg dose) OR 
· One secukinumab placebo (2 x 1.0 mL PFS)  
All study treatment kits assigned to the subject by IRT during the study will be captured in the 
IRT system. 
The first study treatment administration will occur at the Baseline/Randomization visit after the 
inclusion/exclusion criteria have been confirmed and all study scheduled assessments have been 
performed, including completion of PRO and blood withdrawal. 
All doses of study treatment (secukinumab and/or placebo) will be self-administered by the 
subject/trained caregiver at the study site after the study assessments for the visits have been 
completed. 
At the Baseline visit, subjects will be instructed by the site staff on how to self-inject via the 
PFS (Instructions for Use (IFU) containing detailed information about self-administration of 
study treatment should be provided to each subject at the beginning of the study). After 
providing detailed explanations/instructions, subjects will then be asked to raise any questions. 
Thereafter, they will proceed with self-injection. At Week 1, subjects will be asked to refer to 
the IFU and to proceed with self-injection of the study treatment (i.e., without a detailed 
explanation/instruction on handling the syringe). 
A unique medication number is printed on the study medication label. Investigator staff will 
identify the study medication kits to dispense to the subject by contacting the IRT and obtaining 
the medication number(s). The study medication has a 2-part label (base plus tear-off label), 
immediately before dispensing the medication kit to the subject, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis Country Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The PFS (150 mg active/placebo) sealed in their outer box must be stored in a access 
controlled/locked refrigerator between 2°C and 8°C (36°F and 46°F) (Do Not Freeze) and 


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protected from light. They must be carefully controlled in accordance with regulations 
governing investigational medicinal products and local regulations. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
 
Subcutaneous administration with PFSs 
The study treatment solution must be injected into non-affected areas of the skin. 
The injections will be self-administered into the appropriate site of the body (thighs, arms, 
abdomen), and each injection should be given at a different injection site to reduce the risk of 
reaction. Each new injection should be given at least one inch from the previously used site. If 
subject chooses the abdomen, a 2-inch area around the navel should be avoided. Investigational 
drug should not be injected into areas where the skin is tender, bruised, red, or hard, or where 
subject has scars or stretch marks. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
Destruction of the unused drug should be done according to local requirements and after 
approval by the Novartis Clinical Team. 
6.7.1.2 
Handling of additional treatment 
The following non-study treatment will be monitored specifically: 
• SoC background therapy, as described in Section 6.1.3 
• Concomitant therapy as described in Section 6.2.1, e.g., anti-malarials, ACE or ARBs 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use - Good Clinical Practice (ICH GCP) 
guidelines and regulatory requirements and is considered appropriate for this study. Any 


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changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
The study includes two optional components, namely a biomarker component and a 
deoxyribonucleic acid (DNA)/ribonucleic acid (RNA)/Pharmacogenetics component. Each of 
them requires a separate signature if the subject agrees to participate. It is required as part of 
this protocol that the Investigator presents these options to the subjects, as permitted by local 
governing regulations. The process for obtaining consent should be exactly the same as 
described above for the main informed consent. 
Declining to participate in these optional assessments (DNA/RNA/Pharmacogenetics or 
biomarkers) will in no way affect the subject’s ability to participate in the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 
8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the designated day/time as possible. Missed or rescheduled visits should not 
lead to automatic discontinuation of study investigational treatment or study. Handling of 
subjects who discontinue study treatment or study prematurely is described in Section 9.1 
Discontinuation.  


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Table 8-1 
Assessment Schedule 
 


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X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Visit structure given for internal programming purpose only 
2 Screening period will be up to 42 days depending on the MPA Run-in need. The duration of the Screening period must be kept at a minimum. 
3 For subjects not yet on MPA at Screening, a Run-in period is necessary 
4 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion criteria are not met are captured on the Inclusion/Exclusion eCRF. 
5 Included in Medical History and recorded in the eCRF on the corresponding page. 
6 PPD/QuantiFERON® 
7 not required if chest X-rays have been taken in the past 12 weeks that show no clinically significant abnormality 
8 Hepatitis B and/or C and/or HIV serology testing performed during Screening period only if required as per local medical practice or regulators prior to initiation of therapy. These assessments will be documented in source records only and will not be entered 
into eCRF 
9 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion criteria are not met are captured on the Inclusion/Exclusion eCRF. After the Baseline visit, the investigator should 
do an abbreviated physical exam focusing on relevant clinical areas 
10 Body Mass Index (BMI) to be automatically calculated by Novartis 
11 performed locally 
12 To enter the study, subjects must have a biopsy demonstrating active glomerulonephritis WHO or ISN/RPS class III or IV LN [excluding III (C), IV-S (C) and IV-G (C)]; subjects are permitted to have co-existing class V. Renal biopsy must have been 
performed within 6 months prior to Screening. Otherwise, a new renal biopsy must be performed during Screening, once all other eligibility criteria have been confirmed. Any subsequent biopsies (e.g., upon disease flare) may be performed where considered 
appropriate by the investigator  
13 Samples for Lipid panel should be obtained after an overnight fast (10hr or more) 
15 Including central determination of UPCR 
calculation 
16 Site to ensure that a urine container is dispensed at previous site visit 
17 First morning void urine sample will be collected for 1) local determination of urinary sediment and standard safety evaluation and 2) central determination of UPCR. Jugs for the Urine collection will be dispensed at previous visit 
18 Pregnancy tests will be conducted for women of child bearing potential; serum pregnancy test at Screening and Urine pregnancy test at all other time points 
19 SF-36 v2 performed (both PCS and MCS), SF-36-PCS responder will be evaluated 
20 AEs/SAEs occurring after the patient has provided informed consent must be reported. 
21 at pre-dose 
 
23 Background SoC therapy will be administered during the whole treatment period on a daily basis for MPA and Corticosteroids, cyclophosphamide induction every 2 weeks for 3 months 
24 for site administration of i.v. corticosteroids only 
25 for site administration of i.v. cyclophosphamide only 
26 planned End of Treatment (EOT) period visit will be performed at Week 104. Subjects who discontinue study treatment prematurely for any reason other than withdrawal of informed consent before Week 104 will not be considered as discontinued from the 
study. Please refer to Section 9.1 Discontinuation for detailed instructions. 
 


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X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Visit structure given for internal programming purpose only 
9 These assessments are source documentation only and will not be entered into the eCRF. After the Baseline 
visit, the investigator should do an abbreviated physical exam focusing on relevant clinical areas 
10 Body Mass Index (BMI) to be automatically calculated by Novartis 
11 performed locally 
13 Samples for Lipid panel should be obtained after an overnight fast (10hr or more) 
15 including central determination of UPCR
calculation 
16 site to ensure that a urine container is dispensed at previous site visit 
17 First morning void urine sample will be collected for 1) local determination of urinary sediment and standard 
safety evaluation and 2) central determination of UPCR. Jugs for the Urine collection will be dispensed at 
previous visit 
18 Pregnancy tests will be conducted for women of childbearing potential; serum pregnancy test at 
Screening and Urine pregnancy test at all other time points 
19 SF-36 v2 performed (both PCS and MCS), SF-36-PCS responder will be evaluated 
20 AEs/SAEs occurring after the patient has provided informed consent must be reported. 
21 at pre-dose 
 Background SoC therapy will be administered during the whole treatment period on a daily basis for 
MPA and Corticosteroids, cyclophosphamide induction every 2 weeks for 3 months 
26 Planned End of Treatment (EOT) period visit will be performed at Week 104. Subjects who discontinue 
study treatment prematurely for any reason other than withdrawal of informed consent before Week 104 
will not be considered as discontinued from the study. Please refer to Section 9.1 Discontinuation for 
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8.1 
Screening 
A Screening period of up to 6 weeks will be used to assess subject´s eligibility (-42 to -29). This 
flexible duration will provide enough time to evaluate eligibility of the subject, including renal 
biopsy evaluation. 
Once eligibility is confirmed, subjects elected to receive MPA-based induction SoC therapy 
and not already on this background therapy will be initiated on MPA (MMF or enteric-coated 
MPA sodium) during the run-in period (-28 to -1). These subjects will be initiated on an MMF 
dose of 1 g/day (divided q 12 hrs.)/equivalent dosage of enteric-coated MPA. Doses are to be 
increased to 2 g/day of MMF/equivalent dosage of enteric-coated MPA in the second week and 
up to 3 g/day of MMF/equivalent dosage of enteric-coated MPA in the third week, if tolerability 
allows. If subjects experience adverse effects, which prevent up-titration as described, an 
additional 1 week of titration is permitted. If MMF dose escalation is clinically inappropriate 
as judged by the investigator or inconsistent with local treatment guidelines, subjects can take 
a dose of 1.5-2 g/day MMF/equivalent dosage of enteric-coated MPA in the absence of 
observed toxicity. 
All subjects evaluated at Screening for eligibility should not be screen failed on the basis of a 
medication requiring washout, unless the subject will be unable to complete the washout in the 
appropriate time frame before Randomization. 
Subjects who prematurely withdraw from the study treatment will not be replaced. 
In the case where a safety laboratory assessment at Screening and/or Baseline is outside of the 
range specified in the exclusion criteria, the assessment may be repeated once prior to 
Randomization. If the repeat value remains outside of the specified ranges, the subject must be 
excluded from the study. 
8.1.1 
Information to be collected on Screening failures 
Subjects who sign an informed consent form and are subsequently found to be ineligible prior 
to Randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate eCRF. The Screening visit date, demographic information, 
informed consent, Inclusion/Exclusion, subject re-screening (for re-screened subjects) pages 
must also be completed for screen failure subjects. No other data will be entered into the clinical 
database for subjects who are screen failures, unless the subject experienced a serious adverse 
event during the Screening phase (see SAE Section 10.1.3 for reporting details). 
AEs that are not SAEs will be followed up by the investigator and collected only in source data. 
If the subject fails to be randomized, the IRT must be notified within 2 days of the screen fail 
that the subject was not randomized. 
Subjects who are randomized and fail to start treatment, e.g., subjects randomized in error, will 
be considered as early terminated. The reason for early termination should be recorded on the 
appropriate eCRF. If consent was withdrawn during the Screening period before the subject 
was randomized, complete the appropriate eCRF. 


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8.1.2 
Re-screening 
It is permissible to re-screen a subject once if s/he fails the initial Screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis. 
If a subject re-screens for the study, the subject must sign a new ICF and be issued a new subject 
number prior to any Screening assessments being conducted under the new subject number. For 
all re-screened subjects, the investigator/qualified site staff will record if the subject was re-
screened on the re-screening eCRF and the original Screening number the subject was issued 
prior to the current Screening number. The date of the new informed consent signature must be 
entered in the Informed Consent eCRF corresponding to the new subject number. 
For re-screening, all Screening assessments must be performed per protocol, except the 
tuberculosis (TB) work up (if applicable). If the date of the TB work up is less than 12 weeks 
from the projected Baseline date, then it is not required that the TB work up be repeated; 
however, the re-screened subject must repeat PPD skin test or the QuantiFERON TB-Gold 
performed by the central laboratory. 
Subjects who are mis-randomized cannot be re-screened. 
8.2 
Subject demographics/other Baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
Baseline characteristics in alignment with eCRF. 
8.2.1 
Demography 
Demographics data to be collected on all subjects and recorded in the eCRF include 
• age, 
• sex, 
• race, and ethnicity 
• source of referral 
8.2.2 
SLE/LN medical history/diagnosis 
The following information should be collected and entered in the relevant eCRF: 
• the date of first diagnosis for SLE and/or LN 
• SLE/LN family history 
8.2.3 
Prior SLE/LN medications and therapy 
Any treatment for SLE/ LN since initial diagnosis (as determined through medical history 
records or through subject interview) prior to study entry will be collected and recorded in the 
eCRF, along with the duration of the prior therapy, the response to the therapy and the reason 
for discontinuation. 
8.2.4 
Renal biopsy 
An important criteria to be fulfilled for a subject to be randomized within the study is a renal 
biopsy showing active glomerulonephritis WHO or ISN/RPS Class III or IV LN [excluding III 


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(C), IV-S (C) and IV-G (C)], with or without co-existing class V features. The biopsy must have 
been performed within 6 months prior to Screening, or during Screening period if not available. 
The local pathologist report confirming Class III or IV LN with active lesions must be kept as 
a source document at the site. In addition, it should be used to complete the Renal Biopsy Report 
eCRF page.  
While the classification of the subject's LN for randomization will be based on the local 
pathologist report, a central reading of electronic images of the local biopsy slides will be 
performed for confirmation of the classification. For this purpose, the slides used for 
determination of the classification by the local pathologist, representing at least the three most 
important types of staining (H&E, PAS, silver staining) will be collected to allow for their 
digitalization. Details regarding collection of local biopsy slides will be outlined in the Central 
Laboratory Manual. Details regarding central reading of electronic images process, 
responsibilities and membership is described in a separate Central Biopsy Reading Charter. All 
slides will be returned to the site after their digitalization. 
8.2.5 
Standard of care induction therapy 
Before Randomization, during the Screening period, the investigator must define the SoC 
induction therapy that the subject will receive, MPA or CYC-based. (see Section 6.1.3 Standard 
of Care background therapy). 
This will ensure that subjects can be treated with SoC therapy as per site and/or local guidelines, 
and a balanced repartition within the two treatment arms (secukinumab and placebo). 
The target will be to have a maximum of 25% of randomized subjects receiving CYC-based 
induction therapy. 
The choice of SoC induction therapy must be reported in the eCRF and confirmed at time of 
Randomization within the IRT system. 
8.2.6 
Smoking history 
The current and /or previous use of tobacco will be recorded, as well as the estimate number of 
pack-years based on the approximate consumption per year. 
8.2.7 
Cardiovascular medical history 
Protocol-solicited cardiovascular medical history will be collected on the appropriate eCRF 
page. 
8.2.8 
Relevant medical history/ current medical conditions 
Relevant medical history and current medical conditions not related to the study indication, and 
which were present prior to signing of the informed consent, should be recorded in the Medical 
History eCRF. This includes surgical sterilization for females, if applicable. 
Whenever possible, diagnoses and not symptoms should be recorded. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the ICF signature. 


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Significant findings that are observed after the subject has signed the ICF and that meet the 
definition of an AE must be recorded in the AE eCRF. 
8.2.9 
Prior and concomitant medications 
Concomitant medications and prior medications taken over 6 months preceding study 
enrollment for reasons other than SLE/ LN will be captured at the Screening visit, and updated 
as necessary in the relevant eCRF. 
Any new medication taken during the course of the study should be collected on the relevant 
eCRF. 
8.2.10 
Determination of the tuberculosis status 
Either a QuantiFERON TB-Gold test or a PPD skin test must be performed at the Screening 
visit for the determination of the subject's tuberculosis status. Subjects with a positive test may 
participate in the study if further work up (according to local practice/guidelines) establishes 
conclusively that the subject has no evidence of active tuberculosis, or, if presence of latent 
tuberculosis is established, then treatment according to local country guidelines must have been 
initiated. 
8.2.10.1 QuantiFERON TB-Gold test 
A QuantiFERON TB-Gold test is to be performed at the Screening visit and the results to be 
known prior to Randomization to determine the subject’s eligibility for the trial. The test will 
be used to screen the subject population for latent tuberculosis infection. 
The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual. 
8.2.10.2 PPD skin test 
A PPD skin test is to be performed at the Screening visit and read before Randomization to 
determine the subject’s eligibility for the trial. The test dose is bioequivalent to 5 tuberculin 
units of standard PPD injected intra-dermally, usually into the volar surface of the forearm. The 
site is cleaned and the PPD extract is then injected into the most superficial layer under the skin. 
If given correctly, the injection should raise a small wheal of about 5 mm, which resolves within 
10-15 minutes. 
Because the reaction (induration) will take 48-72 hours to develop, the subjects must return to 
the investigators’ site within that time for a proper evaluation of the injection site. This will 
determine whether the subject has had a significant reaction to the PPD test. A reaction is 
measured in millimeters of induration (hard swelling) at the site. A PPD skin induration ≥5 mm 
(or according to local practice/guidelines) is interpreted as a positive result. 
8.2.11 
Hepatitis and human immunodeficiency virus (HIV) screen 
Screening for hepatitis and HIV is optional, based on the judgment of the investigator or if 
required by local regulations. If hepatitis testing is performed, testing will include hepatitis B 
surface antigen (HBsAg) and anti-HCV antibodies. If HIV testing is performed, positive HIV 


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screening will be confirmed by a second technique available at the respective local laboratory, 
e.g., Western blot. 
8.2.12 
Electrocardiogram (ECG) 
In this study, local ECG will be used. ECGs must be recorded after 10 minutes rest in the supine 
position to ensure a stable Baseline. A single 12-lead ECG is collected. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions. The original ECGs (on         
non-heat-sensitive paper or a certified copy on non-heat sensitive paper), appropriately signed, 
must be collected and archived at the study site. 
The ECG tracing must be labeled with study number, subject initials, subject number, date and 
time, and filed in the study site source documents. Any identifier details must be redacted, e.g., 
obscuring subject initials, date of birth. 
Clinically relevant abnormalities for the Baseline ECG should be recorded on the relevant 
section of the eCRFs capturing medical history/current medical conditions. 
For any ECGs with subject safety concerns, two additional ECGs must be performed to confirm 
the safety finding. Clinically significant ECG findings at Baseline must be discussed with the 
sponsor before administration of investigational treatment. Clinically significant abnormalities 
must be recorded on the relevant section of the medical history/Current medical conditions/AE 
eCRF as appropriate. 
8.3 
Efficacy 
Clinical efficacy measurements related to primary and secondary objectives are described in 
the subsections below. 
8.3.1 
Complete Renal Response (CRR) 
The CRR will be used to determine efficacy. CRR is a composite endpoint defined as: 
• eGFR is within the normal range or no less than 85% of Baseline 
and 
• 24-hour UPCR ≤ 0.5 mg/mg 
In addition, the estimand definition for primary endpoint is specified in Section 12.4.1. 
8.3.1.1 
Estimated glomerular filtration rate (eGFR) 
The glomerular filtration rate will be estimated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Martínez-Martínez et al 2013) (see 
appendix Section 16.3) based on subject gender, age (years) and serum creatinine (mg/dL). 
Central laboratory serum creatinine values will be used for all renal function data analysis. 
8.3.1.2 
Urine Protein-to-Creatinine Ratio (UPCR) 
Urine Protein-to-Creatinine Ratio (UPCR), expressed in mg/mg, will be determined by a central 
laboratory by dividing the protein concentration by the creatinine concentration as measured in 
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Depending on the objective to be assessed, the UPCR will be determined using one of the 
following two types of urine collection, 24-hour urine collection or first morning void urinary 
sample, as indicated in Section 2, Table 2-1 Objectives and related endpoints. 
Both the 24-hour urine collection and the first morning void will be collected in the subjects' 
home. 
8.3.2 
Partial Renal Response (PRR) 
PRR is a composite endpoint defined as: 
• eGFR is within the normal range or no less than 85% of Baseline 
and 
• ≥50 % reduction in 24-hour UPCR to sub-nephrotic level compared to Baseline 
8.3.3 
Average daily dose of corticosteroids 
Average daily dose of oral corticosteroids doses will be used to demonstrate superiority of 
secukinumab compared to placebo in the averaged daily dose of oral corticosteroids 
administered between Week 16 and Week 52. 
8.3.4 
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-
Fatigue©) 
The FACIT-Fatigue© is a 13-item questionnaire (Cella et al 1993), (Yellen et al 1997) that 
assesses self-reported fatigue and its impact upon daily activities and function over the past 
week. The purpose of the FACIT-Fatigue© in this study is to assess the impact of fatigue on 
subjects with LN.  
The level of fatigue is measured on a 5-point Likert scale (0 = not at all, 1 = a little bit,                     
2 = somewhat, 3 = quite a bit, 4 = very much). 
The purpose of FACIT-Fatigue© in this study is to demonstrate superiority of secukinumab 
compared to placebo on the mean change of score. 
8.3.5 
Short Form Health Survey (SF-36) 
The Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute Form) is a survey 
evaluating individual subjects' health status, which also monitors and compares subjects' disease 
burden. This has been widely used to assess physical, psychological and social impact of 
chronic disease like LN (Holloway et al 2014). 
It consists of eight subscales that can be scored individually: Physical Functioning,                 
Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and 
Mental Health (Ware et al 1993). Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed 
(Ware et al 1994). In this trial, SF-36-PCS responder (improvement of ≥ 2.5 points, 
(Lubeck 2004)) will be evaluated. The SF-36 has proven useful in monitoring general and 
specific populations, comparing the relative burden of different disease, differentiating the 
health benefits produced by different treatments, and in screening individual subjects. The 
purpose of the SF-36 in this study is to assess the HRQoL of subjects with active LN. Given 


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the acute nature of this disease, version 2, with a one-week recall period, will be used in this 
study. 
8.3.6 
Lupus Quality of Life (LupusQoL) 
The LupusQoL is a disease-specific, 34-item, self-report questionnaire designed to measure the 
health-related quality of life (HRQoL) of subjects with SLE within 8 domains (i.e., physical 
health (8 items), emotional health (6 items), body image (5 items), pain (3 items), planning       
(3 items), fatigue (4 items), intimate relationships (2 items), and burden to others (3 items). 
Responses are based on a 5-point Likert scale where 0 (all of the time) to 4 (never) 
(Yazdany 2011), (RWS Life). 
Each domain of the LupusQoL is scored separately. 
8.3.7 
Urinary sediment 
Urinary sediment will be determined at site at each visit using the first morning void sample. 
Presence of red blood cells (RBCs), white blood cells (WBCs), epithelial cells, and cellular 
casts will be determined by microscopic evaluation and recorded on the appropriate eCRF. 
Active urinary sediment is defined as the presence of cellular casts which are granular casts or 
red blood cells, or hematuria (>5 RBCs per high power field). 
8.3.8 
Appropriateness of efficacy assessments 
The proposed primary endpoint is in line with the CHMP guideline, which recommends that 
studies conducted in patients with LN should be aimed for the control of renal activity with 
primary outcome focusing on renal specific endpoints such as induction of CRR. 
The CRR is demonstrated as a clinically significant improvement of renal function as measured 
by improvement of eGFR (normalization/return to Baseline eGFR), and a reduction in renal 
injury as measured by reduction in proteinuria (<0.5 mg/mg in 24-hour) 
 
. The urinary sediment was removed from the components of the primary endpoint 
CRR after consultation of Food and Drug Administration (FDA) and European Medicines 
Agency (EMA), due to the difficulty to standardize methods of evaluation for urinary sediment 
across a multicenter study, and because the selection of the appropriate population (active class 
III or IV LN) is ensured by renal biopsies performed within 6 months of enrollment. 
The proposed secondary endpoints, such as the composite PRR, or laboratory indices of the 
activity of renal diseases such as proteinuria, are in line with the CHMP guidelines. 
In addition, both CRR and PRR have been previously used in clinical trials in LN, as measure 
of the renal activity. 
As chronic fatigue and subject's disease burden may interfere with daily activities and quality 
of life, additional patient reported outcome measures (PROs) of physical functioning and 
health-related quality of life (HRQoL) tools will be used for assessing subject's perception of 
the impact of the disease and treatment on daily life. While FACIT - Fatigue and SF36 PCS are 
not disease specific, it has been widely used to assess physical, psychological and social impact 
of chronic diseases including SLE. The lupus specific quality of life instrument LupusQoL will 
be evaluated to further evaluate the impact of the disease during the study. 


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8.4 
Safety 
All blood draws and safety assessments should be done prior to study treatment administration. 
Appropriate safety assessments (e.g., evaluation of AEs and SAEs) should be repeated after the 
dose is administered. 
• Physical examination 
• Vital signs 
• Height and weight 
• Laboratory evaluations (Hematology, Clinical Chemistry, Lipid Panel, coagulation panel, 
Urinalysis) 
• Evaluation of AEs/SAEs 
• Local tolerability (Injection site reactions) 
• Pregnancy and assessment of fertility 
• Tolerability of secukinumab 
 
 
8.4.1 
Physical examination 
A physical examination, including general appearance, skin, neck, eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, and vascular and neurological systems 
will be performed as indicated in Table 8-1. 
If necessary, based on medical history and/or symptoms, additional exams will be performed at 
the discretion of the investigator. 
Whenever possible, assessments for an individual subject should be performed by the same 
member of the study site staff throughout the study. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study treatment must be 
included in the Medical History eCRF. Significant findings made after signing informed 
consent, which meet the definition of an Adverse Event, must be recorded on the Adverse Event 
eCRF. 
8.4.2 
Vital signs 
Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 8-1. Whenever possible, assessments should be performed 
by the same study site staff member throughout the study. 
After the subject has been sitting for five minutes, with back supported and both feet placed on 
the floor, heart rate, systolic and diastolic blood pressure will be measured twice (measurements 
separated by 1 to 2 minutes) using a validated device, with an appropriately sized cuff. In case 
the cuff sizes available are not large enough for the subject’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. Measurements will be 
recorded in the source documentation and the average of the two measurements will be entered 
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No specific action is pre-defined within this protocol to respond to specific abnormal vital signs, 
as it will be decided by the investigator whether and which specific action needs to be taken to 
respond to any abnormal values, taking into account the overall status of the subject. 
8.4.3 
Height and weight 
Height and body weight will be measured as indicated in Table 8-1. 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg)) will be measured 
in indoor clothing, but without shoes. If possible, body weight assessments should be performed 
by the same study site staff member and using the same scale throughout the study. 
8.4.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens listed below, unless noted 
otherwise. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the laboratory manual. Refer to the Laboratory 
Manual for identification of laboratory reference range values and the schema for notification 
of site staff and Novartis for out of range values. 
For the identification of clinically notable values, see Section 16.10. All subjects with 
laboratory tests containing clinically significant abnormal values are to be followed until the 
values return to normal ranges or until a valid reason, other than treatment related AE, is 
defined. 
Blood withdrawals and safety assessments should be done prior to study treatment 
administration and should be taken as shown in Table 8-1. 
8.4.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils including bands, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count will be measured. 
8.4.4.1.1 Erythrocyte sedimentation rate (ESR) 
The ESR test will be performed using the ESR Supplies kit provided by the central laboratory. 
A laboratory manual will be provided with detailed information on sample collection and 
handling. ESR results will be reported in the appropriate eCRF page. 
8.4.4.2 
Clinical chemistry 
Serum chemistry will include urea, creatinine, hemoglobin A1c (HbA1c), total bilirubin (TBL), 
AST (serum glutamic oxaloacetic transaminase (SGOT)), ALT (serum glutamic pyruvic 
transaminase (SGPT)), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), 
sodium, potassium, bicarbonate, calcium, phosphorous, total protein, albumin, lipase, amylase, 
and uric acid. 
High sensitivity C-reactive protein (hsCRP) will also be assessed. In order to preserve the blind, 
results of hsCRP will not be communicated to the study site staff, including the investigator, or 
to Novartis during the study. 


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8.4.4.2.1 Lipid panel 
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
cholesterol and triglycerides will be measured from a fasting blood sample. 
8.4.4.2.2 High sensitivity C-reactive protein 
High sensitivity C-reactive protein (hsCRP) will be assessed using a fasting blood sample as 
indicated in Table 8-1. In order to preserve the blind, results of hsCRP will not be 
communicated to the study site staff, including the investigator, or to Novartis during the study. 
8.4.4.3 
Coagulation panel 
Prothrombin time (PT), activated partial thromboplastin time (aPTT) and International 
Normalized Ratio (INR) will be evaluated locally for general safety and additional 
characterization of the disease. 
8.4.4.4 
Urinary analysis 
There will be two types of urinary collection, both performed at subjects' home: 
• 24-hour urine collection, corresponding to the 24-hour collection of the urine the day 
preceding the Baseline, Week 12, Week 24, Week 36, Week 52, Week 76 and EOT visits, 
as outlined in Table 8-1. 
• first morning void urine collection on the day of visits as specified in Table 8-1. 
8.4.4.4.1 Local urinalysis 
The subject's first morning void urine sample will be used for local urinalysis assessments 
performed for standard safety evaluation. 
Those standard assessments will include specific gravity, protein, glucose, pH, blood, urine 
blood dipstick (non-hemolyzed), urine blood dipstick (hemolyzed), bilirubin, ketones and 
WBC. 
Please refer to the central laboratory manual for additional details.  
In addition, subject's first morning void urine sample will also be used for local determination 
of urinary sediment, as outlined in Efficacy Section 8.3.7 and central determination of UPCR, 
as outlined in Efficacy Section 8.3.1.2. 
Jugs for the first morning void urine collection will be dispensed at subject's previous visit. 
8.4.4.4.2 24-hour urine collection 
A 24-hour urine collection is done at selected time point by collecting urine in a special 
container over a full 24-hour period. 
Instructions regarding the timing, the collection and the storage of the 24-hour urine collection 
will be detailed within the laboratory manual. 
This 24-hour urine collection will be used for central determination of the UPCR, as mentioned 
in Efficacy Section 8.3.1.2 . 


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8.4.4.5 
Autoantibodies 
8.4.4.5.1 ANA and anti-dsDNA 
 
In addition, ANA or anti-dsDNA must be tested positive for a patient being eligible in this study 
in case of confirmed diagnosis of lupus nephritis as the sole criterion as per inclusion criteria 2 
(refer to Section 5.1 Inclusion criteria). 
 
              
8.4.5 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test (serum 
pregnancy test) performed at the Screening visit, and local urine pregnancy tests as indicated in 
Table 8-1. A positive urine pregnancy test requires immediate interruption of study drug until 
serum β-hCG is performed and found to be negative. Additional pregnancy testing might be 
performed if requested by local requirements. 
Secukinumab, MPA, CYC and corticosteroids should not be given to pregnant women; 
therefore, effective methods of birth control must be used for women of childbearing potential 
(see exclusion criteria definitions, Section 5.2). 
In addition, menses will be recorded on the appropriate eCRF page for all pre-menopausal 
women, as indicated in Table 8-1. 
8.4.6 
Other safety evaluations 
Chest X-ray 
Standard chest X-ray (PA view) will be performed except for those who have had a valid X-ray 
done within 3 months of first dosing. If subjects do not have a chest X-ray obtained within 3 
months preceding the Screening visit, a chest X-ray should be performed. In order to minimize 
unnecessary exposure to radiation, the chest X-ray should only be performed after confirming 
that the subject meets all inclusion/exclusion criteria. In some sites selected by Novartis, the   
X-ray assessment may be replaced by MRI assessment. 


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8.4.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/subject population. 
8.5 
Additional assessments 
The other assessments planned for the study are: 
• Clinical Outcome Assessments (COAs): This includes Patient reported outcomes (PRO) 
 
• Trial Feedback Questionnaires 
 
 
 
 
• Optional Biomarkers 
8.5.1 
Patient reported outcomes (PRO) 
Subjects will be asked to complete the following PRO measures in e-devices provided by the 
site: 
1. FACIT-Fatigue© 
2. SF-36 v2 
3. LupusQoL 
 
The subject must be given the PRO measure(s) to be completed at the scheduled visit before 
any clinical assessments are conducted. Subject’s refusal to complete all or any part of a PRO 
measure should be documented in the study data capture system and should not be captured as 
a protocol deviation. 
The subject should be given sufficient space and time to complete the PRO measures. 
The site personnel should check PRO measures for completeness and ask the subject to 
complete any inadvertently missing responses. 
The patient should be made aware that completed measures are not reviewed by the 
investigator/study personnel. 
FACIT-Fatigue©, SF-36 v2 Physical Component Summary and Lupus QoL are already 
described in Efficacy Section 8.3.4, Section 8.3.5, Section 8.3.6, respectively. 
 
 
 


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8.5.3 
Trial Feedback Questionnaire (TFQ) 
This study is including an optional questionnaire, the “Trial Feedback Questionnaire” for trial 
subjects to provide feedback on their clinical trial experience. Individual trial subject responses 
will not be reviewed by investigators. Responses may be used by the sponsor (Novartis) to 
understand where improvements can be made in future clinical trial processes. This 
questionnaire does not ask questions about the trial subject's disease, symptoms, treatment 
effect, or AEs, and, therefore is not considered as trial data. 


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8.5.6 
Biomarkers 
This clinical study includes additional, optional biomarker components supported by an 
exploratory objective. These studies are hypothesis generating (i.e., discovery based research) 
and optional to the subject. 
Exploratory biomarker assessments 
Biomarkers are objectively measured and evaluated indicators of normal biological processes, 
pathogenic processes or pharmacologic responses to a therapeutic intervention (Biomarkers 
Definitions Working Group 2001). This search for biomarkers of disease and drug response 
will involve an integrated molecular approach examining gene expression in blood and protein 
profiles in serum. 
These optional assessments aim to identify potential markers of response and/or loss of 
response, and to characterize molecular mechanisms of treatment with secukinumab. 
Any biomarker samples may be stored for up to 15 years (depending on local regulations) to 
research scientific questions related to secukinumab, LN and related diseases with a potential 
involvement of IL-17A. The material can be destroyed on subject’s request at any time point. 
Any results from these exploratory biomarker assessments will be reported separately. 
 
 The final selection of analytes will be driven by assay availability, new 
information from the public domain, results obtained in other secukinumab clinical studies, as 
well as by hypotheses generated by other exploratory biomarker assessments. In addition, 
selected markers exploring the effect of secukinumab treatment on co-morbidities may be 
assessed. 


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DNA/RNA sampling / Pharmacogenetics 
The study includes an optional genetic research component, which requires a separate informed 
consent signature if the subject agrees to participate as stated in Section 7. As permitted by local 
governing regulations and by IRB/EC, it is required as part of this protocol that the Investigator 
presents these options to the subject. 
The purpose of genetic research is to evaluate the effect of genetic polymorphisms on treatment 
response and to better understand the safety and efficacy of secukinumab. 
As technology changes over time, the most appropriate technology will be used at the time the 
exploratory genetic research is performed. This may include the study of the entire genome. 
Follow instructions for sample collection, numbering, processing, and shipment provided in the 
laboratory manual. 
DNA/RNA samples 
The use of DNA/RNA to search for biomarkers of disease and drug action is exploratory. Any 
results from this DNA/RNA study will not be placed in the subject’s medical records. 
To maximize confidentiality, all samples and the information associated with the samples will 
be double-coded to prevent the exposure of the subject’s information and identity. This    
double-coding process allows Novartis to go back and destroy the sample at the subject’s 
request. In addition, sample information is stored in one secured database while genetic data is 
stored in an independent secured database. 
RNA 
The activity (the expression) of genes will be examined using RNA (or other nucleic acid) 
analytical technologies, which may include expression microarrays, PCR, Nanostring, Next 
Generation Sequencing techniques, or others. These analyses will be used to examine the effect 
of secukinumab on transient RNA expression in serum and may support the identification of 
pathways/markers that characterize the disease or response of treatment with secukinumab.  
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, i.e., before Week 100 last planned study treatment 


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administration. Discontinuation of study treatment can be initiated by either the subject or the 
investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Subject/guardian decision - subjects may choose to discontinue study treatment for any 
reason at any time 
• Pregnancy (see Section 10.1.4 Pregnancy reporting) 
• Patient received a live vaccine 
• Use of prohibited treatment as outlined in Section 6.2.2 prohibited medication 
• Any situation or protocol deviation in which study participation might result in a safety 
risk to the subject 
• Following an emergency unblinding 
• Emergence of the following AEs:  
• Any AE that in the judgment of the investigator, taking into account the subject's 
overall status, prevents the subject from continuing study treatment (for example 
sepsis) 
• Any severe or serious AE that requires treatment with an unacceptable              
co-medication 
• Severe hypersensitivity reaction or anaphylactic reaction 
• Any laboratory abnormalities that in the judgment of the investigator, taking into account 
the subject's overall status, prevents the subject from continuing study treatment 
• Unsatisfactory therapeutic effect 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information in the eCRF. 
Subjects who discontinue study treatment prematurely for any reason should NOT be 
considered as discontinued from the study UNLESS they withdrew their consent (see 
Section 9.1.2 Withdrawal of Informed Consent). Where possible, they should continue 
attending site visits. 
All subjects who prematurely discontinue study treatment should perform the EOT study 
visit 4 weeks after their last study treatment administration. For example, if study treatment 
discontinuation decision is taken at time of planned Week 16 visit, the subject should perform 
the EOT visit assessments instead of Week 16 visit assessments. 
Thereafter, different possibilities may arise, for which guidelines are outlined below: 
• Subjects unwilling to continue attending further study visits after prematurely 
discontinuing the study treatment should also perform an EOS visit 12 weeks after the last 
administration of the study treatment. 
• Subjects willing to continue attending study visits should continue attending all 
subsequent scheduled site visits for clinical and safety study assessments. For the example 


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taken above, next visit should be Week 20 during which visit assessments as outlined in 
Visit Schedule Table 8-1 will be performed, except study treatment administration. The 
EOS visit should be performed 12 weeks after the Week 100 visit. 
• Subjects initially continuing attending site visits after premature study treatment 
discontinuation may decide to discontinue study at any time. For those subjects, the EOS 
visit will be performed at time of study discontinuation. Of note, the EOS visit must always 
be completed at least 12 weeks after the last study treatment administration. 
Finally, if the subject is failing to return for these assessments for unknown reasons, every effort 
(e.g., telephone, e-mail, letter) should be made to contact the subject/pre-designated contact as 
specified in the lost to follow-up section. This contact should preferably be done according to 
the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
9.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 


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For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be contacted by the sites to be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on the local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last subject finishes their Study Completion visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
A subject will be considered to have completed the study when she/he has completed the last 
planned visit in the protocol. 
The investigator must provide follow-up medical care for all subjects, including subjects who 
are prematurely withdrawn from the study, or must refer them for appropriate ongoing care. 
This care may include initiating another treatment outside of the study, as deemed appropriate 
by the investigator. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 


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Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs also may be detected when they are volunteered by the subject during or 
between visits or through physical examination findings, laboratory test findings, or other 
assessments. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade 
mild: usually transient in nature and generally not interfering with normal activities 
moderate: sufficiently discomforting to interfere with normal activities 
severe: prevents normal activities 
2. its relationship to the study treatment and other investigational treatment. If the event is 
due to lack of efficacy or progression of underlying illness (i.e., progression of the study 
indication) the assessment of causality will usually be ‘Not suspected.’ The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single subject 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 


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Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values, which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory test abnormalities are included in 
Section 16.10. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 


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• is medically significant, e.g., defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the   
ICH-E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 12 weeks (84 days) following the last administration of 
study treatment, or 30 days after the subject has stopped study participation (whichever is later),  
must be reported to Novartis safety within 24 hours of learning of its occurrence. Detailed 
instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Any SAEs experienced after the 30-day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess the relationship of each SAE to study treatment, complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 


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investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.4 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 


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10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / AEs have to be considered during the course 
of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate eCRFs 
Please refer to Table 16-1 of appendix Section 16.9 for complete definitions of liver laboratory 
triggers and liver events. 
Every liver event defined in Table 16-2 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (i.e., ALT, AST, TBL, 
PT/INR, ALP and GGT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate eCRF. 
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Section 9.1.1 Discontinuation of 
study treatment section), if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess data from interim analysis, as well 


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as the progress of the clinical trial, safety data, and critical efficacy variables and it will 
recommend to the sponsor whether to continue, modify, or terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.2.3 
Steering Committee 
A Steering Committee (SC) will be established comprising disease area experts, investigators 
participating in the trial, i.e., not being members of the DMC, and Novartis representatives from 
the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 Code of Federal Regulation (CFR) Part 11 requirements, 
Investigator site staff will not be given access to the Electronic Data Capture (EDC) system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 


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AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Randomization codes and data about all study treatment(s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 


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12 
Data analysis and statistical methods 
Summary statistics for continuous variables include N, mean, standard deviation (SD), 
minimum, lower quartile, median, upper quartile, and maximum. For binary or discrete 
variables, the absolute number of subjects in each category and relative frequencies will be 
provided. 
Unless otherwise specified, p-values will be presented as 2-sided p-values and the type I error 
rate (alpha) will be 5%. 
Efficacy and safety data for Treatment Period will be presented by the following two treatment 
groups. 
• Secukinumab 300 mg  
• Placebo 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Randomized Analysis Set (RAS) consists of all randomized subjects. Unless otherwise 
specified, mis-randomized subjects (mis-randomized in IRT) will be excluded from the 
randomized set. 
The Full Analysis Set (FAS) will be comprised of all analyzable subjects from the randomized 
set to whom study treatment has been assigned. According to the intent to treat principle, 
subjects will be analyzed according to the treatment they have been assigned to during the 
randomization procedure, but according to actual stratum. 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received. 
12.2 
Subject demographics and other Baseline characteristics 
Summary statistics will be presented for continuous demographic and Baseline characteristic 
variables for each treatment group and for all subjects in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects. 
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term. SLE and LN specific medical history will be 
summarized by treatment group. 
To establish a Baseline level of cardiovascular risk, the number and percentage of subjects with 
pre-solicited cardiovascular risk factors will be summarized by treatment group. The number 
of cardiovascular risk factors that each subject has will also be summarized by treatment group. 
If it is unknown whether a subject currently or previously experienced a specific cardiovascular 
risk factor, it will be assumed that cardiovascular risk factor did not occur for that subject. 


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12.3 
Treatments 
Study treatment 
The analysis of study treatment data will be based on the safety set. The number of active and 
placebo injections received will be presented by treatment group. The duration of exposure to 
study treatment will also be summarized by treatment group. In addition, the number and 
percentage of subjects with cumulative exposure levels (e.g., any exposure, ≥ 1 week, ≥ 2 
weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented.  
Prior and concomitant medication 
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those, 
which were started pre-Baseline and continued into the period where study treatment is 
administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group. 
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term. 
The number and percentage of subjects receiving prior and concomitant LN therapy will be 
presented by randomized treatment group. 
12.4 
Analysis of the primary endpoint(s) 
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy endpoint is the complete renal response at Week 52. 
The estimand definition for the primary endpoint is as follows: 
1. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
LN population 
2. Variable: composite of remaining on the study and on randomized treatment through 52 
weeks and achieving CRR response at 52 weeks 
3. Intercurrent event: the intercurrent event is captured through the variable definition 
4. Population-level summary: difference in proportions of responders between the 
secukinumab and placebo arms 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The statistical hypothesis tested for the primary objective is that there is no difference in the 
proportion of subjects fulfilling the response criteria at Week 52 between the secukinumab  and 
placebo regimens. 
 


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Let pj denote the proportion of responders at Week 52 for treatment regimens j, j=0, 1 where 
• 0 corresponds to placebo regimen, 
• 1 corresponds to secukinumab, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e., 
H1: secukinumab is not different to placebo regimen with respect to CRR at Week 52 
Logistic regression model adjusting for SoC, race and Baseline UPCR will be used for the 
primary analysis. Difference in marginal response proportions with p-value and respective 95% 
confidence interval will be estimated from the logistic regression model. 
12.4.3 
Handling of missing values/censoring/discontinuations 
Non-responder imputation will be used for handling missing data for the primary endpoint and 
other binary endpoints. For the continuous secondary and exploratory variables Mixed-Effect 
Model Repeated Measure (MMRM) model, which is valid under the missing at random 
assumption, will be used. For average daily dose of oral corticosteroids multiple imputation will 
be used for handling missing data. 
12.4.4 
Sensitivity and Supportive analyses 
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence that 
the results seen from the primary analysis are robust. These analyses will center on the 
deviations in model assumptions and the treatment of missing data. 
Sensitivity analyses 
The impact of missing data on the analysis results of CRR will be assessed as well by repeating 
the logistic regression model using different ways to handle missing data. 
These may include, but are not limited to: 
• Multiple imputation 
• Observed data analysis 
• Tipping point analysis 
Supportive analyses 
As a sensitivity analysis to primary endpoint modified Complete Renal Response (mCRR) will 
be analyzed. 
A subject is defined as a mCRR responder when the following two conditions are met: 
· Estimated glomerular filtration rate (eGFR) is within the normal range or no less than 85% of 
Baseline and 
· 24-hour UPCR ≤ 0.7 mg/mg 


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12.5 
Analysis of secondary endpoints 
12.5.1 
Testing strategy 
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below.  
H2: Secukinumab 300mg is not different to placebo with respect to change from Baseline in  
24-hour UPCR at Week 52 compared to Baseline 
H3: Secukinumab 300mg is not different to placebo with respect to proportion of subjects 
achieving PRR at Week 52 
H4: Secukinumab 300mg is not different to placebo with respect to average daily dose of oral 
corticosteroids administered between Week 16 and Week 52 
H5: Secukinumab 300mg is not different to placebo with respect to proportion of subjects 
achieving PRR at Week 24 
H6: Secukinumab 300mg is not different to placebo with respect to time to achieve CRR, 
H7: Secukinumab 300mg is not different to placebo with respect to time to achieve PRR 
H8: Secukinumab 300mg is not different to placebo with respect to time to achieve first morning 
void UPCR ≤ 0.5 mg/mg 
H9:Secukinumab 300mg is not different to placebo with respect to FACIT-Fatigue©, mean 
change of score from Baseline at Week 52 
H10: Secukinumab 300mg is not different to placebo with respect to improvement in SF-36 PCS 
mean change from Baseline at Week 52 
H11: Secukinumab 300mg is not different to placebo with respect to improvement in LupusQoL 
physical health score mean change from Baseline at Week 52 
A sequential testing strategy will be used in order to control for multiplicity of testing. The 
graphical approach of (Bretz et al 2009) for sequentially rejective testing procedures is used to 
illustrate the testing strategy: 


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Figure 12-1 
Testing strategy 
  
The family-wise error will be set to two-sided α=5% and it will be controlled with the proposed 
hierarchical testing strategy. 
The hypotheses (H1) for the primary objective (CRR at Week 52) for the secukinumab vs. 
placebo will be tested at α. If H1 is rejected, then the hypothesis H2 will be tested at α. If H2 is 
rejected, then the hypothesis H3 will be tested and so on. 
Estimand definitions for the secondary variables 
Estimand definition for the secondary binomial variables is the following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
LN population, unless otherwise specified. 
B. Variable: composite of remaining on the study and on randomized treatment through 16 
weeks and achieving variable (e.g., PRR) response at 52 (or 24) weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: Difference in marginal response proportions between treatments 


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The estimand of binary variables is (secukinumab vs placebo) obtained from a logistic 
regression model adjusting for covariates in the FAS population. Difference in marginal 
response proportions will be computed for comparisons of secukinumab vs. placebo regimen 
utilizing the logistic regression model fitted. In the analysis subjects dropping out or being 
unblinded before the time point of interest or having missing response data at the time point of 
interest are considered as non-responders. 
Estimand definition for the secondary continuous variables except average daily dose of oral 
corticosteroids is the following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
LN population 
B. Variable: variable (e.g., change from Baseline in UPCR) of interest 
C. Intercurrent event: had no intercurrent events occurred before Week 52 
D. Population-level summary: difference in variable means between the treatment conditions 
The estimand of continuous variables at Week 52 is (secukinumab vs placebo) obtained from a 
repeated measures model in the FAS population assuming subjects dropping out or having 
missing data at Week 52 are missing-at-random (MAR). 
Estimand definition for the average daily dose of oral corticosteroids is the following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
LN population 
B. Variable: variable (e.g., average daily dose of oral corticosteroids) of interest 
C. Intercurrent event: observed data regardless of intercurrent events 
D. Population-level summary: difference in variable means between the treatment conditions 
Estimand definition for the secondary time-to-event variables is the following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
LN population 
B. Variable: time to response of interest (e.g., CRR) 
C. Intercurrent event: had no intercurrent events occurred before Week 52 
D. Population-level summary: hazard ratio of secukinumab vs placebo 
For all secondary endpoints, supplementary estimands of interest may be specified in statistical 
analysis plan. 
UPCR at Week 52 
For the change in UPCR analysis will be performed on the loge ratio of the treatment value vs 
Baseline value (calculated by dividing the post-Baseline value by the Baseline value and then 
applying the loge transformation) to normalize the distribution of UPCR at each analysis visit. 
Between-treatment differences in the change in UPCR relative to Baseline will be evaluated 
using MMRM with treatment group, stratification factor (SoC), race, and analysis visit as 
factors and loge Baseline UPCR as continuous covariates. Treatment by analysis visit and loge 
Baseline UPCR by analysis visit will be included as interaction terms in the model. An 


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unstructured covariance structure will be assumed for the model. The significance of the 
treatment effect for secukinumab regimens at different analysis visits will be determined from 
the pairwise comparisons performed between secukinumab and placebo at the appropriate 
analysis visits 
PRR at Week 24 or at Week 52 
Logistic regression model adjusting for SoC, race and baseline UPCR will be used for the 
analysis. Difference in marginal response proportions with p-value and respective 95% 
confidence interval will be estimated from the logistic regression model. 
Average daily dose of oral corticosteroids administered between Week 16 and Week 52 
Between-treatment differences for average daily dose of oral corticosteroids administered 
between Week 16 and Week 52 will be evaluated with analysis of covariance (ANCOVA) 
model including treatment group, race, Baseline dose and SoC as covariates. Missing data will 
be handled using multiple imputation. 
Time to achieve CRR 
For time to achieve CRR between treatment differences will be evaluated using log-rank test 
stratified by race and SoC. The hazard ratios for these comparisons for achieving response and 
their corresponding 95% confidence intervals will be computed using a stratified Cox 
proportional hazards regression model with treatment group and loge Baseline UPCR as 
explanatory variable and stratified by race and SoC. Subjects who have not achieved response 
up to Week 52 will be considered as censored observations. Kaplan-Meier curves will be 
presented for each treatment. 
Time to achieve PRR 
For time to achieve PRR between treatment differences will be evaluated using log-rank test 
stratified by race and SoC. The hazard ratios for these comparisons for achieving response and 
their corresponding 95% confidence intervals will be computed using a stratified Cox 
proportional hazards regression model with treatment group and loge Baseline UPCR as 
explanatory variable and stratified by race and SoC. Subjects who have not achieved response 
up to Week 52 will be considered as censored observations. Kaplan-Meier curves will be 
presented for each treatment. 
Time to achieve first morning void UPCR ≤ 0.5 mg/mg  
For time to achieve first morning void UPCR ≤ 0.5 mg/mg between treatment differences will 
be evaluated using log-rank test stratified by race and SoC. The hazard ratios for these 
comparisons for achieving response and their corresponding 95% confidence intervals will be 
computed using a stratified Cox proportional hazards regression model with treatment group 
and loge Baseline UPCR as explanatory variable and stratified by race and SoC. Subjects who 
have not achieved response up to Week 52 will be considered as censored 
observations.  Kaplan-Meier curves will be presented for each treatment. 
FACIT-Fatigue© change from Baseline at Week 52 
Between-treatment differences in the change from Baseline in FACIT-Fatigue© will be 
evaluated using MMRM with treatment group, stratification factor (SoC), race, and analysis 
visit as factors and Baseline FACIT-Fatigue© as continuous covariates. Treatment by analysis 


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visit and Baseline FACIT-Fatigue© by analysis visit will be included as interaction terms in the 
model. An unstructured covariance structure will be assumed for the model. The significance 
of the treatment effect for secukinumab regimens at different analysis visits will be determined 
from the pairwise comparisons performed between secukinumab and placebo at the appropriate 
analysis visits. 
SF-36 PCS change from Baseline at Week 52 
Between-treatment differences in the change from Baseline in SF-36 PCS will be evaluated 
using MMRM with treatment group, stratification factor (SoC), race, and analysis visit as 
factors and Baseline SF-36 PCS as continuous covariates. Treatment by analysis visit and 
Baseline by analysis visit will be included as interaction terms in the model. An unstructured 
covariance structure will be assumed for the model. The significance of the treatment effect for 
secukinumab regimens at different analysis visits will be determined from the pairwise 
comparisons performed between secukinumab and placebo at the appropriate analysis visits. 
LupusQoL physical health score change from Baseline at Week 52 
Between-treatment differences in the change from Baseline in LupusQoL physical health score 
will be evaluated using MMRM with treatment group, stratification factor (SoC), race, and 
analysis visit as factors and Baseline LupusQoL physical health score as continuous covariates. 
Treatment by analysis visit and Baseline LupusQoL physical health score by analysis visit will 
be included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens at 
different analysis visits will be determined from the pairwise comparisons performed between 
secukinumab and placebo at the appropriate analysis visits. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.  
Adverse events 
Treatment-emergent adverse events (i.e., events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term and on or before last dose + 84 days) will be summarized. 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of subjects having any AE, having an AE in each primary system organ class and 
having each individual AE (preferred term). Summaries will also be presented for AEs by 
severity and for study treatment related AEs. If a subject reported more than one adverse event 
with the same preferred term, the adverse event with the greatest severity will be presented. If 
a subject reported more than one adverse event within the same primary system organ class, the 
subject will be counted only once with the greatest severity at the system organ class level, 
where applicable. Serious adverse events will also be summarized. 
As appropriate, the incidence of AEs will be presented per 100 subject-years of exposure 
(exposure-adjusted incidence rates). 


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Separate summaries will be provided for deaths, SAEs, other significant AEs leading to 
discontinuation and AEs leading to study treatment discontinuation. 
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented. 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from Baseline 
for each post-Baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from Baseline will only be summarized for subjects 
with both Baseline and post-Baseline values. 
12-lead ECG 
Summary statistics will be presented for ECG variables. 
Clinical laboratory evaluations 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from Baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from Baseline will only 
be summarized for subjects with both Baseline and post-Baseline values. 
 
 
 
12.6 
Analysis of exploratory endpoints 


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12.6.1 
Patient reported outcomes 
Health-related Quality of Life assessments will be evaluated based on FAS unless otherwise 
specified. 
SF-36 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100) 
• SF-36 PCS and MCS scores (norm-based scores) 
• SF-36 PCS and MCS responder (improvement of ≥ 2.5 points, (Lubeck 2004)) 
For the change in SF-36 summary scores (PCS and MCS), summary statistics will be provided 
using observed data for each treatment regimen. Between-treatment differences will be 
evaluated using MMRM. 
The SF-36 domain scores will be summarized by treatment. 
 
FACIT-Fatigue 
For the change in FACIT-Fatigue scores, summary statistics of observed data by visit and 
change from Baseline in FACIT will be provided for each treatment. Between-treatment 
differences will be evaluated using MMRM. 
LupusQoL 
For the change in LupusQoL domain scores, summary statistics of observed data by visit and 
change from Baseline will be provided for each treatment. Between-treatment differences will 
be evaluated using MMRM. 
 
 
 


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12.6.3 
DNA and RNA 
Exploratory DNA and RNA studies are designed to investigate the association between genetic 
factors (genotypes) and clinical assessments (phenotypes) which are collected during the 
clinical trial. Without prior evidence of a strong association, a number of possible associations 
are evaluated with exploratory analyses. A range of statistical tests is used for the analyses. 
Additional data, from other clinical trials, are often needed to confirm associations. 
Alternatively, if the number of subjects enrolled in the study is too small to complete proper 
statistical analyses, the data may be combined, as appropriate, with those from other studies to 
enlarge the dataset for analysis. 
Data generated on hypothesis-free platforms will be reported separately (e.g., CSR addendum). 
12.6.4 
Biomarkers 
Soluble marker panel studies investigate differences in the level of expression of proteins or 
peptides between individuals in a given biofluid. The goal of such studies is to allow the 
identification of potential protein or peptide biomarkers of treatment action or disease and to 
better understand the associated underlying molecular mechanisms. By applying statistical 
analysis methods (e.g., principal component analysis) between subject groups, distinct study 
time points, or between study groups from other clinical trials, it may be possible to identify 
patterns, which are associated with disease state or response to drug treatment. However, the 
exact type of data analysis method will depend on the type of data obtained in the study, and 
thus, the analysis of these data will be data-driven and, hence, not part of the Clinical Study 
Report (CSR). 
12.7 
Interim analyses 
Futility Analysis 
A futility analysis will be performed when approximately 30% of subjects will have completed 
the first 52 weeks of treatment. A Go/No-Go decision will be taken at this futility analysis based 
on predictive probability calculated from the CRR achieved at Week 52. The analysis will be 
conducted by an independent statistician and programmer supporting an external DMC. Futility 
stopping rules will be defined in the DMC charter. 
 
 
 
 
 
 


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Interim analysis 
Based on the group sequential design applied in the study, an interim analysis is planned when 
2/3 or 67% of the subjects complete 52 weeks of treatment. The results from this interim 
analysis will support the decision-making concerning the current clinical study, i.e., to continue 
or to stop the trial based on efficacy and/or safety findings. 
A Lan-De Mets alpha spending function with O’Brien Fleming type stopping boundary (as 
implemented in the software East 6.3) will be used to maintain the overall type-I error rate for 
the primary and secondary endpoints at Week 52 (O'Brien and Fleming 1979). 
Based on the choice of α-spending function described above, the efficacy boundary in terms of 
p-value scale at the interim analysis is calculated as p=0.012 for a two-sided test. The observed 
(i.e., nominal) p-value has to be smaller than 0.012 to conclude superior efficacy at the interim 
analysis. If a hypothesis is not rejected at the interim analysis, it will be tested again at the Week 
52 analysis. The efficacy boundary for the final analysis in terms of p-value scale is p=0.046. 
The exact rejecting boundaries will be calculated after the exact number of subjects in each 
treatment arm is available. 
A sequential testing hierarchy will be used to test the secondary hypotheses. The secondary 
hypotheses will be tested at the interim analysis only if the primary hypothesis is rejected. This 
guarantees the 5% overall level of significance for the primary and secondary hypotheses 
(Glimm et al 2010). For Week 52 secondary endpoints the same rejecting boundaries will be 
used as for the primary endpoint. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The total planned sample size is 460 subjects. Based on literature (Mysler et al 2013), 
(Rovin et al 2012) the control response rate was assumed approximately 30%. Assuming 15% 
treatment difference with 45% response rate for secukinumab, the power for rejecting the null 
hypothesis for primary endpoint (CRR) is 92%. The assumptions are summarized in the          
Table 12-1 below. 
Table 12-1 
Power for primary endpoint 
Analysis 
Control 
response rate 
Secukinumab 
response rate 
Sample size 
Cumulative power for 
primary endpoint 
Interim analysis 
30% 
45% 
306 
60% 
Final analysis 
30% 
45% 
460 
92% 


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12.8.2 
Secondary endpoint(s) 
Using published data for control (Mysler et al 2013), (Rovin et al 2012), (Deng et al 2018) 
(Wallace et al 2017), (McElhone et al 2016) and assuming given treatment effects for 
secukinumab, a summary for power for secondary efficacy parameters is shown in Table 12-2 
for binary endpoints, Table 12-3 for continuous endpoints and Table 12-4 for time to event 
endpoints. Power for the secondary endpoints was calculated with the group sequential design 
and the total cumulative power, to reject either at the interim or final analysis, is presented. 
 
Table 12-2 
Summary of power for binary secondary endpoints 
Endpoint 
Response rate 
Power 
Secukinumab 300 mg  
(N = 230) 
Placebo 
(N = 230) 
  
PRR at Week 52 
75% 
60% 
93% 
PRR at Week 24 
75% 
60% 
93% 
 
Table 12-3 
Summary of power or continuous endpoints 
Endpoint 
Mean values 
Common 
standard 
Power 
  
Secukinumab 
300 mg (N = 230) 
Placebo 
(N = 230) 
deviation 
  
Change from 
baseline in UPCR 
at Week 52 
-3.5 
-2.68 
2.69 
90% 
Average daily 
dose of 
corticosteroids 
between Week 
16 and Week 52 
5 
5.52 
1.67 
91% 
FACIT-Fatigue© 
change from 
baseline at Week 
52 
7.0 
2.82 
10.0 
99% 
SF-36 PCS 
change from 
baseline at Week 
52 
6.1 
3.1 
8.0 
98% 
LupusQoL 
Physical Health 
change from 
baseline at Week 
52 
9.6 
5.6 
14 
86% 
 
 
 
 
 


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Table 12-4 
Summary of power for time to event endpoints 
Endpoint 
 Event rates and hazard ratios 
Power 
Placebo (N = 230) 
Event rate at Week 52 
Hazard Ratio 
Secukinumab (N = 230) 
  
Time to CRR  
30% 
1.67 
92% 
Time to PRR  
60% 
1.67 
99% 
Time to UPCR ≤ 
0.5 mg/mg 
35% 
1.67 
95% 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately, 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
ACR (2001) Recommendations for the prevention and treatment of glucocorticoid-induced 
osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on 
Glucocorticoid-Induced Osteoporosis. Arthritis Rheum; 44(7):1496-503. 
 
Allam R, Anders HJ (2008) The role of innate immunity in autoimmune tissue injury. Curr 
Opin Rheumatol; 20:538-44. 
Appel GB, Contreras G, Dooley MA, et al (2009) Mycophenolate mofetil versus 
cyclophosphamide for induction treatment of lupus nephritis J Am Soc Nephrol; 20:1103-12. 
Bakoush O, Tencer J, Tapia J, et al (2002) Higher urinary IgM excretion in type 2 diabetic 
nephropathy compared to type 1 diabetic nephropathy Kidney International; 61:203-8. 
Bertsias GK, Tektonidou M, Amoura Z, et al (2012) 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. Annals of the Rheumatic Diseases; 71:1771-82 
Bettelli E, Carrier Y, Kuchroo VK (2006) Reciprocal developmental pathways for the 
generation of pathogenic effector TH17 and regulatory T cells. Nature; 441:235-8. 
 
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 28:586-604. 
Bruin G, Loesche C, Nyirady J, et al (2017) Population Pharmacokinetic Modeling of 
Secukinumab in Patients With Moderate to Severe Psoriasis. J Clin Pharmacol; 57(7):876-85. 
 
 
Cella DF, Tulsky DS, Gray G, et al (1993) The Functional Assessment of Cancer Therapy 
scale: development and validation of the general measure. J. Clin. Oncol; 11(3):570-9. 
Cervera R, Khamashta MA, Font J, et al (2003) Morbidity and mortality in systemic lupus 
erythematosus during a 10-year period: a comparison of early and late manifestations in a 
cohort of 1,000 patients. Medicine (Baltimore); 82(5):299-308. 
Chen DY, Chen YM, Wen MC, et al (2012) The potential role of Th17 cells and Th17-related 
cytokines in the pathogenesis of lupus nephritis. Lupus; 21:1385-96. 


Novartis 
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Protocol No. CAIN457Q12301 
 
 
 
Committee for Medicinal Products for Human use (CHMP) (2015) guidance document: 
https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-investigation-
medicinal-products-treatment-systemic-lupus-erythematosus-lupus_en.pdf. 
Crispín JC, Oukka M, Bayliss G (2008) Expanded double negative T cells in patients with 
systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol; 
181(12):8761-6. 
Deng J, Luo L, Zhu L, et al (2018) Multitarget therapy versus intravenous cyclophosphamide 
in the induction treatment of lupus nephritis: a metaanalysis of randomized controlled trials. 
Turk J Med Sci; 48(5):901-10. 
FDA (2018) guidance document: 
https://www.fda.gov/downloads/Drugs/Guidances/UCM201790.pdf. 
Faurschou M, Dreyer L, Kamper A, et al (2010) Long-Term Mortality and Renal Outcome in 
a Cohort of 100 Patients With Lupus Nephritis. Arthritis Care Res (Hoboken); 62(6):873–80. 
Feldman CH, Hiraki LT, Winkelmayer WC, et al (2015) Serious infections among adult 
Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis. Arthritis 
Rheumatol; 67(6):1577-85. 
 
 
 
Glimm E, Maurer W, Bretz F (2010) Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med; 29(2):219-28. 
Grootscholten C, Berden JH (2006) Discontinuation of immunosuppression in proliferative 
lupus nephritis: is it possible? Nephrol. Dial. Transplant; 21(6):1465-9. 
Hahn BH, McMahon MA, Wilkinson A, et al (2012) American College of Rheumatology 
guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 
(Hoboken); 64(6):797-808. 
Hirai Y, Masayuki I, Takanori S, et al (2012) IL-17A stimulates granulocyte colony-
stimulating factor production via ERK1/2 but not p38 or JNK in human renal proximal tubular 
epithelial cells. Am J Physiol Renal Physiol; 302:F244-50. 
Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for 
the classification of systemic lupus erythematosus. Arthritis Rheum; 40(9):1725. 
Holloway L, Humphrey L, Heron L, et al (2014) Patient-reported outcome measures for 
systemic lupus erythematosus clinical trials: a review of content validity, face validity and 
psychometric performance. Health Qual Life Outcomes; 12:116. 


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Houssiau FA, Vasconcelos C, D'Cruz D, et al (2010) The 10-year follow-up data of the Euro-
Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. 
Ann. Rheum. Dis; 69(1):61-4. 
Koga T, Ichinose K, and Tsokos GC (2017) T cells and IL-17 in Lupus Nephritis. Clin 
Immunol; 185:95–9. 
Krebs CF, Schmidt T, Riedel J, et al (2017) T helper type 17 cells in immune-mediated 
glomerular disease. Nat Rev Nephrol; 13(10):647-59. 
Kurts C, Panzer U, Anders H, et al (2013) The immune system and kidney disease: basic 
concepts and clinical implications. Nat Rev Immunol; 13(10):738-53. 
Kwan BC, Tam LS, Lai KB, et al (2009) The gene expression of type 17 T-helper cell-related 
cytokines in the urinary sediment of patients with systemic lupus erythematosus. 
Rheumatology (Oxford); 48(12):1491-7. 
Kyttaris VC, Kampagianni O, Tsokos GC (2013) Treatment with Anti-Interleukin 23 
Antibody Ameliorates Disease in Lupus-Prone Mice. Biomed Res Int; article ID. 861028. 
Kyttaris VC, Zhang Z, Kuchroo VK, et al (2010) Cutting edge: IL-23 receptor deficiency 
prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol; 
184(9):4605-9. 
Levey A, Stevens L, Schmid C, et al (2009) A new equation to estimate glomerular filtration 
rate. Ann Intern Med; 150(9):04-612. 
Levin A, Stevens PE, Bilous RW, et al (2013) 'Kidney disease: Improving global outcomes 
(KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and 
management of chronic kidney disease' Kidney International Supplements; 3(1):1-150. 
Lubeck DP (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis. Pharmacoeconomics; 22(2):27-38. 
Markowitz GS, D'Agati VD (2007) The ISN/RPS 2003 classification of lupus nephritis: an 
assessment at 3 years. Kidney Int; 71(6):491-5. 
Martínez-Martínez MU, Martínez-Martínez MU, Mandeville P, et al (2013) CKD-EPI is the 
most reliable equation to estimate renal function in patients with systemic lupus 
erythematosus. Nefrologia; 33(1):99-106. 
McElhone K, Abbott J, Sutton C, et al (2016) Sensitivity to Change and Minimal Important 
Differences of the LupusQoL in Patients With Systemic Lupus Erythematosus. Arthritis Care 
Res (Hoboken); 68(10):1505-13. 
Meibohm B, Zhou H (2012) Characterizing the Impact of Renal Impairment on the Clinical 
Pharmacology of Biologics. Journal of Clinical Pharmacology; 52(1):54S-62S. 
Mysler EF, Spindler AJ, Guzman R, et al (2013) Efficacy and safety of ocrelizumab in active 
proliferative lupus nephritis: results from a randomized, double-blind, phase III study. 
Arthritis Rheum; 65(9):2368-79. 


Novartis 
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Protocol No. CAIN457Q12301 
 
Nowling TK, Gilkeson GS (2011) Mechanisms of tissue injury in lupus nephritis. Arthritis 
Res. Ther; 13(6):250. 
O'Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics; 
35(3):549-56. 
Palmer SC, Tunnicliffe DJ, Singh-Grewal D, et al (2017) Induction and Maintenance 
Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis of 
Randomized Trials. Am J Kidney Dis; 70(3):324-36. 
Paust HJ, Turner J, Steinmetz OM, et al (2009) The IL-23/Th17 axis contributes to renal 
injury in experimental glomerulonephritis. J Am Soc Nephrol; 20:969–79. 
Pisitkun P, Ha L, Wang H, et al (2014) Interleukin-17 Cytokines Are Critical in Development 
of Fatal Lupus Glomerulonephritis. Immunity; 37:1104–15. 
RWS Life Sciences LupusQoL: http://www.corptransinc.com/sites/lupusqol/instrument-
information. 
Rovin BH, Furie R, Latinis K, et al (2012) Efficacy and safety of rituximab in patients with 
active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. 
Arthritis Rheum; 64(4):1215-26. 
Rovin BH, Parikh SV (2014) Lupus nephritis: the evolving role of novel therapeutics. Am. J. 
Kidney Dis; 63(4):677-90. 
Satoh Y, Nakano K, Yoshinari H, et al (2018) A case of refractory lupus nephritis 
complicated by psoriasis vulgaris that was controlled with secukinumab. Lupus; Lupus; 
27(7):1–5. 
Schwartz N, Goilav B, Putterman C (2014) The pathogenesis, diagnosis and treatment of 
lupus nephritis. Curr Opin Rheumatol; 26:502-9. 
Singh JA, Hossain A, Kotb A, et al (2016) Risk of serious infections with immunosuppressive 
drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis. 
BMC Med. 2016; 14(1):137. 
Struemper H, Chen C, Cai W (2013) Population pharmacokinetics of belimumab following 
intravenous administration in patients with Systemic Lupus Erythematosus. The Journal of 
Clinical Pharmacology; 53(7):711–20. 
Summers SA, Odobasic D, Khouri MB, et al (2014) Endogenous interleukin (IL)-17A 
promotes pristane-induced systemic autoimmunity and lupus nephritis induced by pristane. 
Clin Exp Immunol; 176(3):341-50. 
Tan EM, Cohen AS, Fries JF, et al (1982) The 1982 revised criteria for the classification of 
systemic lupus erythematosus. Arthritis Rheum; 25(11):1271-7. 
Tektonidou MG, Dasgupta A, Ward MM (2016) Risk of End-Stage Renal Disease in Patients 
With Lupus Nephritis, 1971-2015: A Systematic Review and Bayesian Meta-Analysis. 
Arthritis Rheumatol; 68(6):1432-41. 
Waldman M, Madaio MP (2005) Pathogenic autoantibodies in lupus nephritis. Lupus; 
14(1):19-24. 


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Wallace DJ, Strand V, Merrill JT, et al (2017) Efficacy and safety of an interleukin 6 
monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-
ranging randomised controlled trial. Ann. Rheum. Dis; 76(3):534-42. 
Wang H, Ren YL, Chang J, et al (2018) A Systematic Review and Meta-analysis of 
Prevalence of Biopsy-Proven Lupus Nephritis. Arch Rheumatol; 33(1):17-25. 
Ware J, Kosinki M, Gandeck B. (1993) SF-36 Health Survey manual and interpretation guide. 
Boston: The Health Institute, New England Medical Center. 
Ware J, Kosinki M, Gandeck BS (1994) SF-36 Health Survey manual and interpretation 
guide. Update. Boston: The Health Institute, New England Medical Center. 
Weening JJ, D'Agati VD, Schwartz MM, et al (2004) The classification of glomerulonephritis 
in systemic lupus erythematosus revisited. J. Am. Soc. Nephrol; 15(2):241-50. 
Yan J, Li Y, Yang H, et al (2018) Interleukin-17A participates in podocyte injury by inducing 
IL-1b secretion through ROS-NLRP3 inflammasome-caspase-1 pathway. Scand J Immunol; 
87(4):e12645. 
Yazdany J (2011) Health-related quality of life measurement in adult systemic lupus 
erythematosus: Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific 
Quality of Life Questionnaire (SLEQOL), and Systemic Lupus Erythematosus Quality of Life 
Questionnaire (L-QoL). Arthritis Care Res (Hoboken); 63(11):S413-9. 
Yellen SB, Cella DF, Webster K, et al (1997) Measuring fatigue and other anemia-related 
symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J 
Pain Symptom Manage; 13(2):63-74. 
Yu F, Haas M, Glassock R, et al (2017) Redefining lupus nephritis: clinical implications of 
pathophysiologic subtypes. Nat Rev Nephrol; 13(8):483-95. 
Zhang Z, Kyttaris VC, Tsokos GC (2009) The Role of IL-23/IL-17 Axis in Lupus Nephritis. J 
Immunol; 183(5):3160-9.  
Zickert A, Amoudruz P, Sundström Y, et al (2015) IL-17 and IL-23 in lupus nephritis - 
association to histopathology and response to treatment. BMC Immunol; 16:7. 


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16 
Appendices 
16.1 
ACR Criteria for Diagnosis of SLE 
  


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16.2 
International Society of Nephrology/Renal Pathology Society 
(ISN/RPS) 2003 classification of LN 
  
 
 
 


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16.3 
Estimation of eGFR by the CKD-EPI 
The CKD-EPI creatinine equation uses a 2-slope spline to model the relationship between 
estimated GFR and serum creatinine, and a different relationship for age, sex and race. The 
equation was reported to perform better and with less bias than the MDRD Study equation, 
especially in patients with higher GFR. This results in reduced misclassification of CKD 
(Levey et al 2009) 
 
 
 


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16.4 
Recommended Diagram for administration of Standard of Care 
  


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16.5 
Guidelines for administering PROs 
All questionnaires will be completed on an electronic device at the scheduled study visit prior 
to the subject seeing the investigator for any clinical assessment or evaluation. The study 
coordinator should check the questionnaire for completeness and encourage the subject to 
complete any missing responses. 
The subject should be made aware that completed measures are not reviewed by the 
investigator/study personnel. 
Before trial begin 
Study coordinators should familiarize themselves with the PRO questionnaires in the trial. 
Before completion 
1. Subjects should be provided with the correct questionnaire at the appropriate visits, and in 
the appropriate language 
2. Subjects should be given sufficient instructions, space, time and privacy to complete the 
questionnaires 
3. Questionnaire should be administered before the clinical examination 
During completion 
1. Administrator may clarify the questions but should not influence the response 
2. Only one response for each question 
3. Also see ‘Addressing Problems and Concerns’ 
After completion 
1. Check for completeness 
2. Check for multiple responses that were made in error 
3. Data should be transcribed from the completed questionnaire to the appropriate web portal 
Addressing Problems and Concerns 
Occasionally a subject may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below. 
The patient does not want to complete the questionnaire(s) 
Tell the subject that completion of the questionnaire(s) is voluntary. The goal is to better 
understand the physical, mental, and social health problems of subjects. Emphasize that this 
information is as important as any of the other medical information, and that the 
questionnaire(s) is simple to complete. Suggest that the questionnaire(s) may be different from 
anything the respondent has filled in the past. If the subject still declines, retrieve the 
questionnaires. Record the reason for the decline, and thank the subject. 
The patient is too ill or weak to complete the questionnaire(s) 
In these instances, the coordinator may obtain subject responses by reading out loud each 
question, followed by the corresponding response categories, and entering the subject’s 
response. No help should be provided to the subject by any person other than the designated 
study coordinator. The coordinator should not influence subject responses. The study 
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The patient wants someone else to complete the questionnaire(s) 
In no case should the coordinator or anyone other than the subject provide responses to the 
questions. Unless specified in the study protocol proxy data are not an acceptable substitute for 
subject self-report. Subjects should be discouraged from asking a family member or friend for 
help in completing a questionnaire. 
The patient does not want to finish completing the questionnaire(s) 
If non-completion is a result of the subject having trouble understanding particular items, ask 
the subject to explain the difficulty. Re-read the question for them verbatim, but do not rephrase 
the question. If the respondent is still unable to complete the questionnaire, accept it as 
incomplete. Thank the subject. 
The patient is concerned that someone will look at his/her responses 
Emphasize that all responses are to be kept confidential. Point out that their names do not appear 
anywhere on the questionnaire, so that their results will be linked with an ID number and not 
their name. Tell the subject that his/her answers will be pooled with other subjects’ answers and 
that they will be analyzed as a group rather than as individuals. Tell the subject that completed 
forms are not routinely shared with treating staff, and that their responses will only be seen by 
you (to check for completeness), and possibly the investigator. Any response which may 
directly impact on or reflect their medical condition (e.g., noting of severe depression) will be 
communicated by the coordinator to the physician. 
The patient asks the meaning of a question/item 
While completing the questionnaire, some subjects might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the subject by rereading the 
question for them verbatim. If the subject asks to interpret the meaning of an item, do not try to 
explain it, but suggest that he/she use his/her own interpretation of the question. Subjects should 
answer the questions based on what they think the questions mean. 
General information about all questionnaire(s): 
All questionnaires have to be completed by the patients in their local languages using an 
electronic device. The questionnaires should be completed by the patients in a quiet area free 
from disturbance, and before any visit assessments. Patients should receive no help from family 
members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the patient’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 
per question, then this should be brought to patient. Incomplete questions should not be accepted 
without first encouraging the patient to complete unanswered questions. 
The investigator must complete the patient/visit information on the electronic device and ensure 
that the center number, patient’s number and initials are identical to the Case Record Form. As 
there are no source data for this questionnaire, the data queries will be restricted to patient/visit 
information. 


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16.9 
Liver event and Laboratory trigger Definitions and Follow-up 
Requirements 
Table 16-1 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
3 x ULN < ALT / AST ≤ 5 x ULN 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
ALT or AST > 5 × ULN 
  
ALP > 2 × ULN (in the absence of known bone 
pathology) 
  
TBL > 2 × ULN (in the absence of known Gilbert 
syndrome) 
  
ALT or AST > 3 × ULN and INR > 1.5 
  
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and TBL > 2 × ULN [mainly 
conjugated fraction] without notable increase in 
ALP to > 2 × ULN) 
  
Any clinical event of jaundice (or equivalent 
term) 
  
ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia 
  
Any adverse event potentially indicative of a liver 
toxicity* 
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal 


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Table 16-2 
Follow up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
1. Discontinue the study 
treatment immediately 
2. Hospitalize, if clinically 
appropriate 
3. Establish causality 
4. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
1. Discontinue the study 
treatment immediately 
2. Hospitalize if clinically 
appropriate 
3. Establish causality 
4. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and INR > 1.5 
1. Discontinue the study 
treatment immediately 
2. Hospitalize, if clinically 
appropriate 
3. Establish causality 
4. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
1. Repeat Liver function test 
(LFT) within 48 hours 
2. If elevation persists, 
continue follow-up 
monitoring 
3. If elevation persists for 
more than 2 weeks, 
discontinue the study 
drug 
4. Establish causality 
5. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN accompanied by 
symptomsb 
1. Discontinue the study 
treatment immediately 
2. Hospitalize if clinically 
appropriate 
3. Establish causality 
4. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN (patient is 
asymptomatic) 
1. Repeat LFT within the next 
week 
2. If elevation is confirmed, 
initiate close 
observation of the 
patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the absence of 
known bone pathology) 
1. Repeat LFT within 48 
hours 
2. If elevation persists, 
establish causality 
3. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
TBL (isolated) 
  
  
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
1. Repeat LFT within 48 
hours 
2. If elevation persists, 
discontinue the study 
drug immediately 
3. Hospitalize if clinically 
appropriate 
4. Establish causality 
5. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic) 
1. Repeat LFT within the next 
week 
2. If elevation is confirmed, 
initiate close 
observation of the 
patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 


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Criteria 
Actions required 
Follow-up monitoring 
Jaundice 
1. Discontinue the study 
treatment immediately 
2. Hospitalize the patient 
3. Establish causality 
4. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
1. Consider study treatment 
interruption or 
discontinuation 
2. Hospitalization if clinically 
appropriate 
3. Establish causality 
4. Record the AE and 
contributing factors 
(e.g., conmeds, med 
hx, lab) in the 
appropriate CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to Baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.  


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16.10 
Clinically notable laboratory values 
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Clinically notable values will be forwarded to Novartis at the same time that they are sent to 
investigators. Any action based on these laboratory values should be discussed with Novartis 
personnel. 
Table 16-3 
Safety Analyses: Expanded Limits and Notable Criteria 
  
  
Notable Criteria 
Laboratory Variable 
  
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
  
>3 x ULN 
>3 x ULN 
SGPT (ALT) 
  
>3 x ULN 
>3 x ULN 
Bilirubin 
  
>2 x ULN 
>2 x ULN 
Alkaline phosphatase 
  
>2.5 x ULN 
>2.5 x ULN 
HEMATOLOGY VARIABLES 
Hemoglobin: 20 g/L decrease from Baseline 
Platelet count: < 50 x 10E9/L 
White blood cell count: < 0.8 x LLN 
Neutrophils: < 0.9 x LLN 

SAP_001.pdf: 
   Clinical Development 
Secukinumab (AIN457) 
CAIN457Q12301 / NCT04181762
A two-year, phase III randomized, double-blind, parallel-group, placebo-
controlled trial to evaluate the safety, efficacy, and tolerability of 300 mg 
s.c. secukinumab versus placebo, in combination with SoC therapy, in
patients with active lupus nephritis 
Statistical Analysis Plan (SAP) 
Amendment 3 
Author: 
 
, 
, Trial Statisticians 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
09-Oct-2023
Number of pages: 
46 
Property of Novartis 
Confidential May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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SAP Amendment 3 
 
Secukinumab/AIN457Q12301 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
20-
Oct- 
2020 
 
FDA 
feedback 
on protocol 
Added Kaplan-Meier analysis for time 
to study treatment discontinuation 
2.4.3 Time to 
study treatment 
discontinuation 
 
 
 
Added treatment policy estimand for 
primary objective, added analysis of 
components of the estimands for 
primary objective. 
2.3.4.2 
Supportive 
analyses 
 
 
 
Added treatment policy estimand as 
supplementary estimand for secondary 
objectives with binary variables 
Added treatment policy and composite 
estimands as supplementary estimands 
for 
secondary 
objectives 
with 
continuous variables. 
2.6.2 Statistical 
hypothesis, 
model 
and 
method 
of 
analysis 
 
 
 
Added methodology for trimmed 
means 
5.4.1.4 
Trimmed 
means 
15-
Mar-
2023 
Prior to 
DBL of 
interim 
analysis 
1 
To 
align 
with 
protocol 
amendment 
1 
Stated SAP amendment 2 is to align 
with protocol amendment 1. 
1 
 
 
 
Mentioned the total sample size is 
changed to 400.  
1.1 
 
 
 
Explained the study now has two 
interim analyses and one final primary 
endpoint analysis. 
 
 
 
 
Added the table of objectives and 
endpoints. 
1.2 
 
 
 
Added the estimand framework. 
 
 
 
 
Clarified 
the 
normal 
range 
of 
estimated glomerular filtration rate 
(eGFR). 
 
 
 
 
Clarified the components of the 
primary endpoint. 
2.5 


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SAP Amendment 3 
 
Secukinumab/AIN457Q12301 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
 
 
 
Amended the intercurrent events for 
the 
primary 
estimand 
and 
the 
strategies to handle them. 
 
 
 
 
Updated the strategies to handle 
missing data not related to intercurrent 
events. 
 
 
 
 
Revised the sensitivity analyses and 
the supportive analyses for the 
primary objective. 
 
 
 
 
Clarified the two Week 104 analyses 
and mentioned they are not in the 
testing hierarchy.  
2.6 
 
 
 
Updated the supportive analyses for 
the secondary objectives. 
 
 
 
 
Categorized the interim analyses into 
the first (with approximately 138 
participants) 
and 
second 
(with 
approximately 
308 
participants) 
interim analysis. 
2.14 
 
 
 
Changed the alpha spending function 
from O’Brien-Fleming to Pocock for 
the superiority analysis in the second 
interim analysis. 
 
 
 
 
Added a futility analysis in the second 
interim analysis. 
 
 
 
 
Changed the total sample size from 
460 to 400 based on an updated 
response rate of placebo. 
3 
 
 
 
Re-calculated the powers for the 
primary 
and 
secondary 
efficacy 
analyses. 
 
 
 
 
Incorporated the intercurrent events 
and the strategies to handle them in the 
definition of efficacy variables. 
5.1 
 
 
 
Updated the definition of active 
urinary sediment. 
 


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Page 4 
SAP Amendment 3 
 
Secukinumab/AIN457Q12301 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
 
 
 
Created two visit window groups 
specifically for eGFR and 24h UPCR. 
5.3 
 
 
 
Amended the details of logistic 
regression. 
5.4 
 
 
 
Updated reference. 
6 
21-
Aug-
2023 
Prior to 
the 
final 
DBL of 
the 
study 
The 
purpose of 
this 
amendment 
is to update 
the analysis 
plan due to 
the 
early 
termination 
of the study 
Various changes to reflect the updated 
analysis due to early termination. 
Entire 
Document 
 


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SAP Amendment 3 
 
Secukinumab/AIN457Q12301 
 
Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design .......................................................................................... 10 
1.2 
Study objectives and endpoints ............................................................. 12 
1.2.1 
Primary estimand .................................................................................. 16 
1.2.2 
Secondary estimands ............................................................................. 17 
2 
Statistical methods ............................................................................................................. 18 
2.1 
Data analysis general information ......................................................... 18 
2.2 
Analysis sets .......................................................................................... 18 
2.2.1 
Treatment groups .................................................................................. 19 
2.2.2 
Subgroup of interest .............................................................................. 19 
2.3 
Patient disposition, demographics and other baseline characteristics ... 19 
2.3.1 
Patient disposition ................................................................................. 19 
2.3.2 
Background and demographic characteristics ....................................... 19 
2.3.3 
Medical history...................................................................................... 20 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) ....................................................................................................... 20 
2.4.1 
Study treatment / compliance ................................................................ 20 
2.4.2 
Prior, concomitant and post therapies ................................................... 21 
2.4.3 
Time to study treatment discontinuation ............................................... 21 
2.5 
Analysis of the primary objective ......................................................... 21 
2.5.1 
Primary endpoint ................................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.5.3 
Handling of intercurrent events of primary estimand ........................... 22 
2.5.4 
Handling of missing values not related to intercurrent events .............. 22 
2.5.5 
Sensitivity analyses ............................................................................... 22 
2.5.6 
Supplementary analyses ........................................................................ 22 
2.6 
Analysis of secondary objectives .......................................................... 22 
2.6.1 
Secondary efficacy endpoints ............................................................... 22 
2.6.2 
Handling of intercurrent events of secondary estimands ...................... 25 
2.6.3 
Handling of missing values not related to intercurrent events .............. 25 
2.6.4 
Sensitivity analyses ............................................................................... 25 
2.6.5 
Supplementary analyses ........................................................................ 25 


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2.7 
Analysis of exploratory objectives ........................................................ 25 
2.8 
Safety analyses ...................................................................................... 25 
2.8.1 
Adverse events (AEs) ............................................................................ 26 
2.8.2 
Laboratory data ..................................................................................... 27 
2.8.3 
Other safety data ................................................................................... 29 
 
 30 
 
 30 
2.11 
Patient reported outcomes (PROs) ........................................................ 30 
2.12 
Biomarkers ............................................................................................ 31 
2.13 
Other Exploratory analyses ................................................................... 31 
2.14 
Interim analysis ..................................................................................... 31 
2.14.1 
First interim analysis ............................................................................. 31 
2.14.2 
Second interim analysis ......................................................................... 32 
3 
Sample size calculation ..................................................................................................... 32 
3.1.1 
Primary endpoint(s) ............................................................................... 32 
3.1.2 
Secondary endpoint(s) ........................................................................... 33 
4 
Change to protocol specified analyses .............................................................................. 34 
5 
Appendix ........................................................................................................................... 35 
5.1 
Description of additional efficacy variables ......................................... 35 
5.2 
Description of health-related quality of life variables ........................... 35 
5.3 
Visit Windows ....................................................................................... 36 
5.4 
Statistical methodology and assumptions ............................................. 40 
5.4.1 
Analysis of continuous data .................................................................. 40 
5.4.2 
Analysis of binary and categorical data ................................................ 41 
5.4.3 
Kaplan-Meier analysis .......................................................................... 42 
5.4.4 
Imputation methods ............................................................................... 43 
5.4.5 
Crude incidence and related risk estimates ........................................... 43 
5.4.6 
Exposure adjusted incidence rate and related risk estimates ................ 44 
6 
Reference ........................................................................................................................... 45 
 
 


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List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 13 
Table 2-1 
Overview of analyses on some safety endpoints................................... 26 
Table 2-2 
CTCAE grades for laboratory parameters to be analyzed .................... 27 
Table 2-3 
Liver-related events ............................................................................... 29 
Table 2-4 
Criteria for notable vital sign abnormalities .......................................... 30 
Table 3-1 
Power for primary endpoint .................................................................. 33 
Table 3-2 
Summary of power for binary secondary endpoints ............................. 33 
Table 3-3 
Summary of power or continuous endpoints ........................................ 33 
Table 3-4 
Summary of power for time to event endpoints .................................... 34 
Table 5-1 
Analysis visit windows ......................................................................... 38 
Table 5-2 
Rules for flagging variables .................................................................. 40 
Table 5-3 
Examples for calculating exposure time for incidence rates (IR) ......... 45 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 12 
Figure 2-1 
Testing strategy ..................................................................................... 24 
 


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List of abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
Body Mass Index 
BSL 
Baseline 
CKD 
chronic kidney disease 
 
 
Cmax 
Maximum concentration  
Cmin 
Minimum concentration 
CO 
Country Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRP 
C-Reactive Protein 
CRR 
Complete Renal Response  
cs-DMARD  
conventional synthetic DMARD 
CSR 
Clinical Study Report 
CTCAE 
Common Criteria for Adverse Events 
Ctrough 
trough concentration 
CYC 
Cyclophosphamide 
 
 
DMARD 
Disease Modifying Anti-rheumatic Drug 
DMC 
Data monitoring committee 
DNA 
DeoxyriboNucleic Acid 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eGFR 
estimated glomerular filtration rate 
ESR 
Erythrocyte sedimentation rate  
ESRD 
end-stage renal disease 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GGT 
gamma glutamyl transferase 
H 
Hour 
HDL 
High Density Lipoprotein 
HLA 
Human Leukocyte Antigen  
hsCRP 
high sensitivity C-Reactive Protein 
i.v. 
Intravenous 
 
 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LDL 
Low Density Lipoprotein 


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LFT 
Liver function test 
LLN 
lower limit of normal 
 
 
LN 
Lupus Nephritis 
LOCF 
Last Observation Carried Forward 
LupusQoL 
Lupus Nephritis Quality of Life questionnary 
MAR 
missing at random 
MCS 
Mental Component Summary 
MedDRA 
Medical dictionary for regulatory activities 
Mg 
milligram(s) 
Ml 
milliliter(s) 
MMRM 
Mixed effect Model for Repeated Measurements 
MPA 
mycophenolic acid 
PRR 
partial renal response 
PCS 
Physical Component Summary 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PRN 
as needed 
PRO 
Patient Reported Outcome 
q4w 
Every 4 weeks 
QoL 
Quality of Life  
SAE 
serious adverse event 
SD 
standard deviation 
SF-36 
Medical Outcome Short Form (36) Health Survey  
SF-36 PCS 
Short Form-36 Physical Component Summary 
SLE 
systemic lupus erythematosus 
 
  
SoC 
Standard of Care 
SPP 
Safety Profiling Plan 
 
 
ULN 
upper limit of normal 
 
 
UPCR 
Urine Protein-to-Creatinine Ratio 
 
  
vs 
Versus 
 
 
 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) is for study CAIN457Q12301, “A two-year, phase III 
randomized, double-blind, parallel-group, placebo-controlled trial to evaluate the safety, 
efficacy, and tolerability of 300 mg s.c. secukinumab versus placebo, in combination with SoC 
therapy, in patients with active lupus nephritis (SELUNE)”.  
Data was originally planned to be analyzed by Novartis according to the data analysis Section 
12 of the clinical study protocol CAIN457Q12301-Protocol-V1.0 17 Feb 2023 (protocol 
amendment 1). However, the study has been terminated early by Novartis due to futile results 
from interim analysis 1. There have been no safety related reasons for early termination or 
concerns for the participants in this study. Due to the program termination, protocol version 1.0 
dated 17-Feb-2023 was not approved globally yet resulting in a mix of approved protocol 
version 1.0 dated 17-Feb-2023 and protocol version 00 dated 11-Oct-2019 across countries. 
The purpose of this version of SAP (SAP amendment 3) is to provide details on the 
implementation of analyses to be reported in the abbreviated Clinical Study Report (abbreviated 
CSR).  
Analyses based on this SAP will be executed after all patients complete their planned visits 
based on the early termination plan.  
Data analysis will be performed by 
 according to this SAP. 
Data analyses for Data Monitoring Committee (DMC) meetings are specified in a separate 
DMC SAP. 
The statistical methodology is described below and any deviations from Protocol-V1.0 are 
documented. Additional detailed information regarding the analysis methodology is contained 
in the Appendix section. 
1.1 
Study design 
This is a Phase III, randomized, double-blind, placebo-controlled trial evaluating at Week 52 
the efficacy and safety of secukinumab versus placebo in subjects with active Lupus Nephritis 
(LN) also receiving background Standard of Care (SoC) regimen. Long-term efficacy, safety 
and tolerability will be collected up to 2 years.  
The SoC regimen will consist of induction therapy with mycophenolic acid (MPA) (which 
refers to Mycophenolate mofetil (MMF) (Cellcept® or generic equivalent), or enteric-coated 
MPA sodium (Myfortic® or generic equivalent) at equivalent doses (oral), or 
Cyclophosphamide (CYC) (i.v.), followed by maintenance therapy with MPA. The choice of 
background SoC induction therapy will be at investigator's discretion. At Randomization, 
subjects will be stratified on the basis of the SoC induction therapy they will receive during the 
study, MPA or CYC-based, to ensure a balanced representation in each of the treatment arms 
(secukinumab or placebo). The target will be to have a maximum of 25% of randomized 
subjects receiving CYC-based induction therapy. 
In addition, steroids will be administered through i.v. pulses followed by oral daily doses as 
described in study protocol. 


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The study previously included three major analyses: two interim analyses and a final primary 
endpoint analysis. The first interim analysis was conducted when approximately 138 
participants (approximately 35% of the total 400 participants) are expected to complete 52 
weeks of treatment (including those who discontinue the treatment early). This interim 
analysis contains a futility analysis and a PK analysis. The second interim analysis will be 
performed when approximately 308 participants (approximately 77% of all 400 participants) 
complete 52 weeks of treatment (including those who discontinue the treatment early). The 
results from this interim analysis will support the decision-making concerning the current 
clinical study, i.e., to continue or to stop the trial based on efficacy (superiority or futility) 
and/or safety findings. The final primary endpoint analysis will be conducted when all 400 
participants complete 52 weeks of treatment (including those who discontinue the treatment 
early). Additional safety analyses may be performed between the second interim analysis and 
the Week 52 final analysis if needed to support health authority interactions following a 
statistically significant result at the second interim analysis. 
Nevertheless, since the study is terminated early due to the futile outcomes from the first interim 
analysis, the second interim analysis will be discarded, and the final analysis will be performed 
with all available patients by the time of study termination. Recruitment in this study was 
stopped on 26-May-2023 with 276 participants randomized. Last patient last visit (LPLV) was 
on 13-SEP-2023, Moreover, due to early termination of the study, only the primary efficacy 
analysis will be conducted with formal statistical inference. Secondary efficacy analyses will 
be summarized within each treatment descriptively and exploratory efficacy analyses will not 
be performed. An abbreviated CSR will be generated after the final database lock. 
It was initially planned that unblinding of selected members of the Novartis Global Clinical 
Team will occur after the Week 52 database lock, original randomization of active treatment 
versus placebo would continue to remain blinded to all investigators, site personnel, subjects, 
and monitors until the final database lock and analyses are completed. Due to early termination 
of the trial, no unblinding of selected members of the Novartis Global Clinical Team occurred 
before final database lock.  
 
The study consists of the following parts: 
• Screening (up to 42 days/6 weeks) 
• Run-in period (optional): For subjects who will receive MPA as SoC induction therapy as 
per investigator's decision and who are not already on MPA at Screening, MPA dosing 
will be initiated during a run-in period before Randomization (for up to 4 weeks prior to 
the first dose of secukinumab) 
• Treatment Period: Duration of 104 weeks of treatment with secukinumab/placebo in 
addition to SoC treatment (with last dose given at Week 100) 
• Follow-up period: Duration of 8 weeks (last visit performed 12 weeks after last dose of 
study medication) 


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Figure 1-1 
Study design 
 
Screening to Randomization (Screening and Run-in period): 
A Screening period of up to 6 weeks will be used to assess subject´s eligibility and to adjust for 
concomitant medication(s) (-42 to -1 day). This flexible duration will provide enough time to 
evaluate eligibility of the subject, including renal biopsy evaluation.  
Treatment period: Treatment period covers time between Randomization (Baseline) through 
EOT. 
At Baseline, eligible subjects will be randomized in a 1:1 ratio to secukinumab 300 mg s.c. or 
placebo. Approximately 200 subjects were planned to be randomized to each of the two 
treatment arms. A blinded, weekly, s.c. secukinumab or placebo loading regimen will be 
administered for the first 4 weeks followed by a monthly maintenance dose in all randomized 
subjects thereafter. At the end of the treatment period at Week 104, the planned End of 
Treatment (EOT) visit will be performed.  
Subjects who discontinue study treatment prematurely for any reason other than withdrawal of 
informed consent before Week 104 will not be considered as discontinued from the study.  
Safety assessments will include physical examinations, vital signs, standard clinical laboratory 
evaluations, hematology (including blood coagulation assays), blood chemistry, urinalysis, 
adverse and serious adverse event monitoring. 
1.2 
Study objectives and endpoints 
Table 1-1 shows the objectives and related endpoints as defined in Protocol-V01. Due to the 
early termination of the study: only the primary objective will be analyzed with formal statistical 
inference, secondary objectives will be summarized with descriptive statistics, and exploratory 
objectives will not be analyzed. 
 


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Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To demonstrate that secukinumab 300 mg 
is superior to placebo in Complete Renal 
Response (CRR) rate at Week 52 in 
active lupus nephritis (ISN/RPS Class III 
or IV, with or without co-existing Class V 
features) patients on a background of 
SoC therapy. 
• 
Proportion of participants achieving CRR at Week 
52 
CRR at Week 52 is an endpoint defined as 
meeting all of the following: 
• 
Estimated glomerular filtration rate (eGFR) ≥ 
60 mL/min/1.73 m2 or no less than 85% of 
Baseline 
• 
24-hour urine protein-to-creatinine ratio 
(UPCR) ≤ 0.5 mg/mg 
• 
No treatment discontinuation before Week 
52 
• 
The participant did not receive more than 10 
mg/day prednisone equivalent for ≥ 3 
consecutive days or for ≥ 7 days in total 
during Week 44 through Week 52 
 
Secondary objective(s) 
Endpoint(s) for secondary objective(s)* 
• 
To demonstrate superiority of 
secukinumab compared to placebo in 
change from baseline in 24-hour UPCR at 
Week 52 
• 
Change from Baseline in 24-hour UPCR at Week 
52  
• 
To demonstrate superiority of 
secukinumab compared to placebo in 
proportion of patients achieving partial 
renal response (PRR) at Week 52 
• 
Proportion of participants achieving PRR at Week 
52 defined as: 
• 
≥ 50% reduction in 24-hour UPCR to sub-
nephrotic levels (≤ 3 mg/mg) 
and 
• 
eGFR ≥ 60 mL/min/1.73 m2 or no less than 
85% of Baseline 
 
• 
To demonstrate superiority of 
secukinumab compared to placebo in 
average daily dose of oral corticosteroids 
administered between Week 16 and 
Week 52 
• 
Average daily dose of oral corticosteroids 
administered between Week 16 and Week 52 
compared to placebo 
 
• 
To demonstrate superiority of 
secukinumab compared to placebo in 
proportion of patients achieving PRR at 
Week 24 
• 
Proportion of participants achieving PRR at Week 
24 defined as: 
• 
≥ 50% reduction in 24-hour UPCR to sub-
nephrotic levels (≤ 3 mg/mg) 
and 
• 
eGFR ≥ 60 mL/min/1.73 m2 or no less than 
85% of Baseline 
 
• 
To demonstrate superiority of 
secukinumab compared to placebo in time 
to achieve CRR 
• 
Time to achieve CRR up to Week 52 
 


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Objective(s) 
Endpoint(s) 
• 
To demonstrate superiority of 
secukinumab compared to placebo in time 
to achieve PRR 
• 
Time to achieve PRR up to Week 52 
 
• 
To demonstrate superiority of 
secukinumab compared to placebo in time 
to achieve first morning void UPCR ≤ 0.5 
mg/mg 
• 
Time to achieve first morning void UPCR ≤ 0.5 
mg/mg up to Week 52 
 
• 
To demonstrate superiority of 
secukinumab compared to placebo in 
change in Functional Assessment of 
Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue©) score at Week 52  
• 
Improvement in FACIT-Fatigue© mean change of 
score from Baseline at Week 52 compared to 
placebo 
 
• 
To demonstrate superiority of 
secukinumab compared to placebo in 
patient’s health related quality of life via 
Medical Outcome Short Form Health 
Survey (SF-36 Physical Component 
Summary (PCS)) score at Week 52 
• 
Improvement in SF-36 PCS mean change from 
Baseline at Week 52 compared to placebo  
 
• 
To demonstrate superiority of 
secukinumab compared to placebo in 
change of LupusQoL (Physical Health) 
score at Week 52 
 
• 
To evaluate the safety and tolerability of 
secukinumab s.c. as an add-on therapy to 
Standard of Care in lupus nephritis 
patients  
• 
Improvement in LupusQoL Physical Health mean 
change of score from Baseline at Week 52 
compared to placebo 
 
• 
Incidence of Treatment-emergent AEs (TEAEs) / 
SAEs from Baseline to Week 52; vital signs and 
body measurements, standard chemistry and 
hematology up to Week 52 
• 
To estimate the proportion of patients with 
maintained renal response at Week 104 
• 
Estimate the proportion of participants with CRR 
at Week 104 within participants who had 
achieved CRR at Week 52 in the secukinumab 
group 
• 
To estimate the proportion of patients with 
improved or maintained renal response at 
Week 104 
• 
Estimate the proportion of participants with 
improved or maintained response (PRR or CRR) 
at Week 104 in participants who had achieved at 
least PRR at Week 52 in the secukinumab group 
 
 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 


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Objective(s) 
Endpoint(s) 


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*Intercurrent events of the secondary efficacy endpoints and the strategies to handle these are specified 
in Section 1.2.2. 
1.2.1 
Primary estimand 
The primary clinical question of interest to be answered in the trial is:  
What is the effect of subcutaneous secukinumab 300 mg compared with placebo on achieving 
CRR at Week 52, in patients with active LN (ISN/RPS Class III or IV, with or without co-
existing class V features), on a background of SoC therapy? 
CRR is defined as 
1. eGFR ≥ 60 mL/min/1.73m2 or no less than 85% of Baseline 
AND 
2. 24-hour UPCR ≤ 0.5 mg/mg 
Objective(s) 
Endpoint(s) 
• 
To perform exploratory pharmacogenomic 
analysis based on blood samples for DNA 
and RNA analysis (optional assessments) 
• 
Evaluate the relationship of genetic 
polymorphisms and transcriptomic data with 
treatment response 


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This question gives rise to the primary estimand, which has the following attributes with respect 
to the primary question: 
• Population: Participants with active LN (ISN/RPS Class III or IV, with or without co-
existing class V features), as defined by the inclusion and exclusion criteria of the study 
protocol amendment 1 Section 5.  
• Treatment: The randomized treatment (the investigational therapy subcutaneous 
secukinumab 300 mg or the placebo), in combination with SoC. More details about the 
treatment are provided in protocol amendment 1 Section 6. 
• Endpoint: An endpoint meeting all of the following: 
• CRR at Week 52; 
• If the participant discontinues the treatment (for reasons other than “study terminated 
by sponsor”) before Week 52, then the participant will be considered as a non-
responder (composite endpoint strategy); 
• If the participant has overuse of corticosteroid (> 10 mg/day prednisone equivalent for 
≥ 3 consecutive days or ≥ 7 days in total) between Week 44 and Week 52, then the 
participant will be considered as a non-responder (composite endpoint strategy). 
• Treatment discontinuation due to “study terminated by sponsor” will not be considered 
as an intercurrent event. 
Summary measure: Difference in marginal response proportions of achieving CRR at Week 
52, between secukinumab and placebo. 
1.2.2 
Secondary estimands 
Due to the early termination of the study, the secondary efficacy objectives previously defined 
under the testing hierarchy in Protocol-V01 will be summarized descriptively using observed 
data. Below is the list of the secondary endpoints: 
 
1. Change from Baseline in 24-hour UPCR at Week 52 
2. Proportion of patients achieving PRR at Week 52 
3. Average daily dose of oral corticosteroids administered between Week 16 and Week 52 
compared to placebo 
4. Proportion of patients achieving PRR at Week 24 
5. Time to achieve CRR up to Week 52 
6. Time to achieve PRR up to Week 52 
7. Time to achieve first morning void UPCR ≤ 0.5 mg/mg up to Week 52 
8. Improvement in FACIT-Fatigue© mean change from Baseline at Week 52 
9. Improvement in SF-36 PCS mean change from Baseline at Week 52 
10. Improvement in LupusQoL Physical Health mean change from Baseline at Week 52 
In addition, the following three objectives will be assessed as secondary analyses as well:  
11. To evaluate the safety and tolerability of secukinumab s.c. as an add-on therapy to 
Standard of Care in lupus nephritis subjects 
12. To estimate the proportion of subjects with maintained renal response at Week 104 


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13. To estimate the proportion of subjects with improved or maintained renal response at 
Week 104 
  
2 
Statistical methods 
2.1 
Data analysis general information 
This SAP guides the statistical analysis for the abbreviated CSR after all patients enrolled in the 
study complete their planned visits based on the study’s early termination plan. 
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in the number and percent of subjects in each category. Kaplan-Meier estimates 
of the probability to experience an event will be calculated from baseline along with 95% 
confidence intervals using Greenwood’s formula. The cumulative probability to flare will be 
plotted against time. The default level of significance will be set to 5% (two-sided, family-wise 
type-I-error). For group sequential testing an alpha spending function was used to ensure control 
of type 1 error. 
Two-sided p-value will only be provided for the primary analysis. Two-sided unadjusted 
confidence intervals will be displayed for the primary and select secondary analyses. 
Data analyses will be presented by treatment regimen. Efficacy and safety data will be presented 
by the 2 treatment groups: AIN457 300 mg and placebo. The 2 treatment groups represent the 
regimens that subjects were randomized to for the study. 
Comparative efficacy data 
Comparative efficacy analyses (i.e., inferential efficacy comparisons with placebo) will focus 
on the primary analysis. Comparative efficacy will be performed based on the Full Analysis Set 
2 (FAS2) population using the randomized treatment.  
Efficacy data following study treatment discontinuation 
Subjects may continue performing the study visits and assessments after permanent 
discontinuation of study treatment. Efficacy data for inferential analyses will be handled 
according the estimand definitions for the primary endpoint. For summary tables efficacy data 
will be presented separately after permanent treatment discontinuation. 
2.2 
Analysis sets 
The following analysis sets will be used in this trial: 
The Randomized Analysis Set (RAS) consists of all randomized subjects. Regardless of 
whether they actually received study medication. Subject were analyzed according to the 
treatment assigned at randomization.  
The Full Analysis Set (FAS) will be comprised of all analyzable subjects from the randomized 
set to whom study treatment has been assigned. According to the intent to treat principle, 
subjects will be analyzed according to the treatment they have been assigned to during the 


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randomization procedure, but according to actual stratum. Mis-randomized subjects (mis-
randomized in IRT) will be excluded from the FAS. 
The Full Analysis Set 2 (FAS2) will be comprised of all analyzable subjects from the 
randomized set to whom study treatment has been assigned and who would have had a chance 
to reach 52 weeks of treatment at the study termination. According to the intent to treat principle, 
subjects will be analyzed according to the treatment they have been assigned to during the 
randomization procedure, but according to actual stratum. FAS2 will be used as the primary 
analysis set for the primary estimand analysis. 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received. 
 
 
 
2.2.1 
Treatment groups 
Efficacy and safety data for Treatment Period will be presented by the following two treatment 
groups. 
1. AIN457 300 mg  
2. Placebo 
2.2.2 
Subgroup of interest 
Will not be done for the abbreviated CSR.  
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number of subjects screened will be presented. In addition, the reasons for screen failures 
will be provided. The number and percentage of subjects in the randomized set who completed 
the study periods and who discontinued the study or treatment prematurely (including the reason 
for discontinuation) will be presented for each treatment group and all subjects. 
For each protocol deviation (PD), the number and percentage of subjects for whom the PD 
applies will be tabulated. 
 
2.3.2 
Background and demographic characteristics 
The following common background and demographic variables will be summarized: 
Continuous variables: 
• Age  
• Height 


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• Weight 
• Body mass index (BMI) = (body weight in kilograms) / (height in meters)2 
For BMI, height and body weight, the last value prior to randomization is used. If there is no 
weight recorded prior to administration of study drug, BMI will be missing. 
Categorical variables: 
• Age categories (< 30 yr, ≥30 yr) 
• Gender 
• Race 
• Ethnicity 
• Smoking status at baseline 
Baseline disease characteristics will also be summarized for the following variables: 
• 
Patient’s global assessment of disease activity, UPCR, eGFR, Serum creatinine(mg/dl), 
C3(mg/dl), C4(mg/dl), Anti-dsDNA (geometric mean IU/ml), Standard of care induction 
therapy, corticosteroids (mg/day) at screening, time since first diagnosis of SLE and LN 
(years), and renal biopsy LN classification 
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group and for all subjects (total) in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects (total) in the randomized set.  
Unless otherwise specified, analyses will be based on the randomized set. 
2.3.3 
Medical history 
Any condition entered on the Relevant medical history / current medical conditions CRF will 
be coded using the MedDRA dictionary. They will be summarized by system organ class (SOC) 
and preferred term (PT) of the MedDRA dictionary. Summaries for cardiovascular medical 
history and SLE/LN medical history will also be provided. 
To establish a baseline level of cardiovascular risk, the number and percentage of subjects with 
pre-solicited cardiovascular risk factors will be summarized by treatment group. The number 
of cardiovascular risk factors that each subject has will also be summarized by treatment group. 
If it is unknown whether or not a subject currently or previously experienced a specific 
cardiovascular risk factor, it will be assumed that cardiovascular risk factor did not occur for 
that subject. Unless otherwise specified, analyses will be based on the randomized set. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The analysis of study treatment data will be based on the safety set. The number of active and 
placebo s.c. administrations received will be presented by treatment group. The duration of 
exposure to study treatment will also be summarized by treatment group. In addition, the 


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number and percentage of subjects with cumulative exposure levels (e.g., any exposure, ≥ 4 
weeks, ≥ 8 weeks, etc.) will be presented. 
Duration of exposure will be defined as the time from first dose of study treatment to the time 
of minimum of (last dose of the treatment + 84 days) and (last visit date). For subjects who 
discontinue treatment, this will be the subject’s last visit in the corresponding treatment period.  
Duration of exposure (years) = duration of exposure (days) / 365.25 
Duration of exposure (100 subject years) = duration of exposure (years) / 100 
The analyses of duration of exposure described above will be done for the entire study treatment 
period. 
2.4.2 
Prior, concomitant and post therapies 
Prior medications will be presented in listing. Concomitant medications will be summarized in 
separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and within 84 days after last dose will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group (the 1st level of the ATC codes). Tables 
will show the overall number and percentage of subjects receiving at least one treatment of a 
particular ATC code and at least one treatment in a particular anatomical main group. 
Significant concomitant non-drug therapies and procedures will be summarized by primary 
system organ class and MedDRA preferred term. 
Any non-drug therapies and procedures done between the day of first dose of study treatment 
and within 84 days after last dose will be defined as concomitant non-drug therapies and 
procedures, including those which were started pre-baseline and continued into the period 
where study treatment is administered. 
Concomitant medication will be identified by comparing recorded or imputed start and end 
dates of medication taken to the reference start date. 
2.4.3 
Time to study treatment discontinuation 
Will not be done for the abbreviated CSR. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary efficacy endpoint is the complete renal response (CRR) at Week 52 with the 
consideration of intercurrent events, which is defined in detail at Section 1.2.1.  


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2.5.2 
Statistical hypothesis, model, and method of analysis 
The statistical hypothesis tested for the primary objective is that there is “no difference in the 
proportion” of patients fulfilling the response criteria at Week 52 between the secukinumab and 
placebo regimens. 
Let pj denote the proportion of responders at Week 52 for treatment regimens j, j=0, 1 where 
• 0 corresponds to placebo regimen, 
• 1 corresponds to secukinumab, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e., 
H1: secukinumab is not different from placebo regimen with respect to CRR at Week 52. 
Logistic regression model adjusting for SoC, race (White/Non-White) and Baseline First 
Morning Void UPCR will be used for the primary analysis. Difference in marginal response 
proportions with p-value and respective 95% confidence interval will be estimated from the 
logistic regression model (see Section 5.4.2.2). 
2.5.3 
Handling of intercurrent events of primary estimand 
Major intercurrent events of primary estimand will be addressed with the following strategies 
(considering that these events occur before the assessments at Week 52): 
1. Treatment discontinuation (for reasons other than “study terminated by sponsor”) for any 
reason: non-responder (composite endpoint strategy) 
2. Overuse of corticosteroid (> 10mg/day prednisone equivalent for ≥ 3 consecutive days or ≥ 
7 days in total) between Week 44 and Week 52: non-responder (composite endpoint strategy) 
Note that treatment discontinuation due to “study terminated by sponsor” is not considered as 
an intercurrent event for the primary estimand. 
2.5.4 
Handling of missing values not related to intercurrent events 
The primary estimand analysis will be performed on FAS2. Participants in FAS2 who do not 
have the required data to compute CRR at Week 52 will be classified as non-responders. 
2.5.5 
Sensitivity analyses 
Will not be done for the abbreviated CSR.  
2.5.6 
Supplementary analyses 
A supplementary analysis of the primary endpoint will be summarizing CRR descriptively with 
observed data without considering any intercurrent events. This analysis will be performed 
using FAS population. 
2.6 
Analysis of secondary objectives 
2.6.1 
Secondary efficacy endpoints 
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below. However, due to the early termination of the study, the ten listed secondary efficacy 


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analyses above will no longer be in the testing hierarchy and will be summarized with 
descriptive statistics using observed data.  
H2: Secukinumab 300mg is not different to placebo with respect to change from Baseline in  
24-hour UPCR at Week 52 compared to Baseline 
H3: Secukinumab 300mg is not different to placebo with respect to proportion of patients 
achieving PRR at Week 52 
H4: Secukinumab 300mg is not different to placebo with respect to average daily dose of oral 
corticosteroids administered between Week 16 and Week 52 
H5: Secukinumab 300mg is not different to placebo with respect to proportion of patients 
achieving PRR at Week 24 
H6: Secukinumab 300mg is not different to placebo with respect to time to achieve CRR, 
H7: Secukinumab 300mg is not different to placebo with respect to time to achieve PRR 
H8: Secukinumab 300mg is not different to placebo with respect to time to achieve first morning 
void UPCR ≤ 0.5 mg/mg 
H9: Secukinumab 300mg is not different to placebo with respect to FACIT-Fatigue©, mean 
change of score from Baseline at Week 52 
H10: Secukinumab 300mg is not different to placebo with respect to improvement in SF-36 PCS 
mean change from Baseline at Week 52 
H11: Secukinumab 300mg is not different to placebo with respect to improvement in LupusQoL 
physical health score mean change from Baseline at Week 52 
A sequential testing strategy in combination with the group sequential testing was planned in 
order to control for multiplicity of testing. The graphical approach of (Bretz et al 2009) for 
sequentially rejective testing procedures was planned for the testing strategy: 


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Figure 2-1 
Testing strategy 
 
Moreover, there are two additional secondary efficacy endpoints not included in the previous 
testing hierarchy that will also be analyzed descriptively: 
• Estimate the proportion of subjects with CRR at Week 104 within subjects who had 
achieved CRR at Week 52 in the secukinumab group 
• Estimate the proportion of subjects with improved or maintained response (PRR or CRR) 
at Week 104 in subjects who had achieved at least PRR at Week 52 in the secukinumab 
group 
Secondary efficacy variables will be analyzed using the FAS population: 
• 
UPCR at Week 52 
• 
PRR at Week 24 or at Week 52 
• 
Average daily dose of oral corticosteroids administered between Week 16 and Week 52 
• 
Time to achieve CRR: Kaplan-Meier curves will be presented for each treatment. 
• 
Time to achieve PRR: Kaplan-Meier curves will be presented for each treatment. 


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• 
Time to achieve first morning void UPCR ≤ 0.5 mg/mg: Kaplan-Meier curves will be 
presented for each treatment. 
• 
FACIT-Fatigue© change from Baseline at Week 52 
• 
SF-36 PCS change from Baseline at Week 52 
• 
LupusQoL physical health score change from Baseline at Week 52 
• 
Maintained renal response at Week 104: A patient with maintained renal response at 
Week 104 is one who achieves CRR at Week 104 after already achieving CRR at Week 
52. Response rate with 95% confidence interval will be presented for the secukinumab 
group. 
• 
Improved or maintained renal response at Week 104: A patient with improved or 
maintained renal response at Week 104 is one who achieves CRR or PRR at Week 104 
after achieving at least PRR at Week 52. Response rate with 95% confidence interval 
will be presented for the secukinumab group. 
   
2.6.2 
Handling of intercurrent events of secondary estimands 
Not applicable. 
2.6.3 
Handling of missing values not related to intercurrent events 
Binary, continuous, and time to event variables will be analyzed using observed data.     
2.6.4 
Sensitivity analyses 
Will not be done for the abbreviated CSR. 
2.6.5 
Supplementary analyses 
Will not be done for the abbreviated CSR. 
 
2.7 
Analysis of exploratory objectives 
Exploratory analyses will not be performed for the abbreviated CSR due to the early termination 
of the study. 
2.8 
Safety analyses 
  Summary will be performed for the entire treatment period. The analyses of the follow-up 
period will be limited to summaries for treatment-emergent adverse events, serious adverse 
events and risks based on adverse events. 
Safety analyses will be performed on treatment received or actual treatment as described below: 
The actual treatment or treatment received for summaries of safety data will differ to the 
treatment assigned at randomization only if a subject received the wrong treatment during the 
entire study. 


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2.8.1 
Adverse events (AEs) 
The crude incidence of treatment emergent adverse events (i.e., events started after the first dose 
of study treatment or events present prior to the first dose of study treatment but increased in 
severity based on preferred term and on or before last dose date + 84 days) will be summarized 
by primary system organ class and preferred term. Confidence intervals for the crude rate will 
be derived as described in Section 5.4.5. In addition, exposure time-adjusted incidence rates 
including 95% confidence intervals will be provided for the entire treatment period (see Section 
5.4.6).  
Adverse events reported will be presented in descending frequency according to its incidence 
in the secukinumab group starting from the most common event. Summaries (crude incidences 
only) will also be presented for AEs by severity and for study treatment related AEs. If a 
particular AE ‘severity’ is missing, this variable will be listed as missing and treated as missing 
in summaries. If a subject reported more than one adverse event with the same preferred term, 
the adverse event with the greatest severity will be presented. If a subject reported more than 
one adverse event within the same primary system organ class, the subject will be counted only 
once with the greatest severity at the system organ class level, where applicable.  
Separate summaries will be provided for adverse events suspected to be related to study drug, 
deaths, serious adverse events, and adverse events leading to discontinuation and adverse events 
requiring concomitant medication. 
The crude incidence rate will be provided without treatment information. For SAEs occurred 
during screening a listing will be prepared for all subjects screened including screening failures. 
An overview of the safety analyses which will be performed for treatment emergent AEs, labs 
and vital signs for each analysis period is described in Table 2-1.  
Table 2-1 
Overview of analyses on some safety endpoints 
Analysis 
period 
AEs & SAEs 
& Safety 
topics of 
interest AEs 
AEs by 
severity 
Study drug 
related AEs 
Notables for 
(vitals), lab 
criteria 
Entire 
Treatment  
 
• crude 
incidence 
• exposure 
time 
adjusted 
incidence 
• crude 
incidence 
 
• crude 
incidence 
 
• crude 
incidence 
 
Safety topics of interest included as the safety risks as defined in the Risk Management Plan 
(RMP) as well as those that are not listed in the RMP but are deemed important and relevant; 
these topics are also defined in the Program Case Retrieval Sheet.  
The crude incidence and exposure-adjusted incidence rates for the safety topics of interest AEs 
will be summarized. In addition, separate listings will be provided for SAEs.. 
Algorithms for date imputations will be provided in Programming Datasets Specifications. 


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2.8.2 
Laboratory data 
The summary of lab data will only include treatment emergent data, which are defined as those 
lab assessments after the first dose of study treatment and on or before last dose + 84 days. 
Reported laboratory assessments with either a less than or greater than sign (“<” or “>”) will be 
used for analysis after removal of the sign and conversion to standard unit. These laboratory 
data will be displayed in listings using the standard unit with the reported sign (“<” or “>”). 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, chemistry and urinalysis).  
For urinalysis, frequency table will be presented. 
Descriptive summary statistics for the change from baseline to each study visit will be presented. 
These descriptive summaries will be presented by laboratory test and treatment group. Change 
from baseline will only be summarized for subjects with both baseline and post baseline values 
and will be calculated as: 
change from baseline = post baseline value – baseline value 
 The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-2: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG). 
These summaries will be split into hematology and chemistry. 
Table 2-2 
CTCAE grades for laboratory parameters to be analyzed 
CTCAE v4.0 Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
HGB decreased 
(Anemia) 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L 
See note below 
Platelet count 
decreased 
<LLN – 75.0 x10e9 /L 
<75.0 - 50.0 x10e9 /L 
<50.0 – 25.0 x10e9 /L 
<25.0 x 10e9 /L 
White blood cell 
decreased 
<LLN - 3.0 x 10e9 /L 
<3.0 - 2.0 x 10e9 /L 
<2.0 - 1.0 x 10e9 /L 
<1.0 x 10e9 /L 
Neutrophil count 
decreased 
<LLN - 1.5 x 10e9 /L 
<1.5 - 1.0 x 10e9 /L 
<1.0 - 0.5 x 10e9 /L 
<0.5 x 10e9 /L 
Lymphocyte count 
decreased 
<LLN - 0.8 x 10e9/L 
<0.8 - 0.5 x 10e9 /L 
 
<0.5 - 0.2 x 10e9 /L 
<0.2 x 10e9 /L 
Creatinine increased* 
 
>1 - 1.5 x baseline;  
>ULN - 1.5 x ULN 
>1.5 - 3.0 x 
baseline; >1.5 - 3.0 x 
ULN 
>3.0 baseline;  
>3.0 - 6.0 x ULN 
>6.0 x ULN 
TBL increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
GGT increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALT increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
AST increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALP increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Glucose increased 
(Hyperglycemia )  
;  
>ULN - 8.9 mmol/L 
>8.9 - 13.9 mmol/L 
>13.9 - 27.8 mmol/L 
>27.8 mmol/L 
Glucose decreased 
(Hypoglycemia) 
<LLN - 3.0 mmol/L 
<3.0 - 2.2 mmol/L 
<2.2 - 1.7 mmol/L 
<1.7 mmol/L 
Cholesterol high 
>ULN - 7.75 mmol/L 
>7.75 - 10.34 mmol/L 
>10.34 - 12.92 mmol/L 
>12.92 mmol/L 
Hypertriglyceridemia 
1.71 - 3.42 mmol/L 
>3.42 - 5.7mmol/L 
>5.7 - 11.4 mmol/L 
>11.4 mmol/L 


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Note: Grade 4 Hemoglobin events are defined as life-threatening anemia events and will not be displayed in the table, as a 
numerical range is not provided in the CTCAE. 
*Note: for “creatinine increased” the baseline criteria do not apply. 
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase (either initial or entire) 
analyzed. Of note, baseline will be defined as last assessment prior to first dosing in initial 
treatment phase. Subjects with abnormal laboratory values will be listed and values outside the 
normal ranges will be flagged. 
Summaries for newly occurring or worsening clinically notable lipid abnormalities will also be 
provided cumulatively for each of the following parameters and categories: 
• HDL: 
• <=LLN 
• <0.8 x LLN 
• LDL, cholesterol, triglycerides: 
• >=ULN  
• >1.5 x ULN  
• >2.5 x ULN 
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given in Table 2-3: 


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Table 2-3 
Liver-related events 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN 
AST 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
TBL 
>1.5xULN, >2xULN, >3xULN, 
ALP 
>2xULN, >3xULN. >5xULN 
ALT or AST & 
TBL 
ALT or AST>3xULN & TBL >2xULN; 
ALT or AST >5xULN & TBL >2xULN; 
ALT or AST >8xULN & TBL >2xULN; 
ALT or AST >10xULN & TBL >2xULN 
ALP & TBL 
ALP >3xULN & TBL >2xULN 
ALP >5xULN & TBL >2xULN 
ALT or AST & 
TBL & ALP 
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law) 
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean 
that cases of ALT or AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result 
in severe DILI. 
Notes: 
In studies which enroll subjects with pre-existing liver disease, baseline LFT may be increased above 
ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the abnormality 
criteria 
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN. 
Individual subject data listings will be provided for subjects with abnormal laboratory data. 
Data of subjects with newly occurring or worsening liver enzyme abnormalities will be listed 
in an additional listing. 
Boxplots over time will be presented for selected laboratory parameters (neutrophils, liver and 
lipid parameters). 
2.8.3 
Other safety data 
2.8.3.1 
Vital signs 
The summary of vital signs will only include treatment emergent data, which are defined as 
those vital sign measurements after the first dose of study treatment and on or before last dose 
+ 84 days. 
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 
presented by vital sign and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values and will be calculated as: 
change from baseline = post-baseline value – baseline value 


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The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-4: 
Table 2-4 
Criteria for notable vital sign abnormalities 
Vital sign (unit) 
Notable abnormalities 
Systolic blood pressure (mmHg) 
>= 140 mmHg or < 90 mmHg 
Diastolic blood pressure (mmHg) 
>=90 mmHg or <60 mmHg 
Pulse (bpm) 
> 100 bpm or <60 bpm 
2.11 
Patient reported outcomes (PROs) 
Health-related Quality of Life assessments will be evaluated based on FAS unless otherwise 
specified. 
SF-36 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100) 
• SF-36 PCS and MCS scores (norm-based scores) 
• SF-36 PCS and MCS responder (improvement of ≥ 2.5 points, (Lubeck 2004)) 


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For the change in SF-36 summary scores (PCS and MCS), summary statistics will be provided 
using observed data for each treatment regimen.  
The SF-36 domain scores will be summarized by treatment. 
FACIT-Fatigue 
For the change in FACIT-Fatigue scores, summary statistics of observed data by visit and 
change from Baseline in FACIT will be provided for each treatment.  
LupusQoL 
For the change in LupusQoL domain scores, summary statistics of observed data by visit and 
change from Baseline will be provided for each treatment.  
2.12 
Biomarkers 
The analysis of biomarker data will be data-driven and, hence, not part of the Clinical Study 
Report (CSR). 
2.13 
Other Exploratory analyses 
Not applicable. 
2.14 
Interim analysis 
Two interim analyses were planned for the study. However, since the futility analysis from the 
first interim analysis shows futile outcomes, the study is terminated early and the second interim 
analysis will not be conducted. 
2.14.1 
First interim analysis 
The first interim analysis will be performed when approximately 138 participants 
(approximately 35% of the total 400 participants) are expected to complete 52 weeks of 
treatment (including those who discontinue the treatment early). 
Futility Analysis 
A futility analysis will be conducted at the first interim analysis. A Go/No-Go decision will be 
taken at this futility analysis based on the predictive probability of achieving statistical 
significance for the primary estimand. Futility stopping rules will be defined in the DMC charter 
and DMC SAP. 
 
 
 
 
 
 
 
 
 


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2.14.2 
Second interim analysis 
Based on the group sequential design applied in the study, the second interim analysis is planned 
when approximately 308 participants (approximately 77 % of the total 400 participants) 
complete 52 weeks of treatment (including those who discontinue the treatment early). The 
results from this interim analysis will support the decision-making concerning the current 
clinical study, i.e., to continue or to stop the trial based on efficacy (superiority or futility) and/or 
safety findings. 
Superiority analysis 
A Lan-De Mets alpha spending function (Lan and DeMets 1983) with Pocock type stopping 
boundary (Pocock 1977) (as implemented in the software East 6.5) will be used to maintain the 
overall type-I error rate for the primary and secondary endpoints at Week 52. 
Based on the choice of α-spending function described above, the efficacy boundary in terms of 
p-value scale at the superoprity analysis is calculated as p=0.042 for a two-sided test. The 
observed (i.e., nominal) p-value has to be smaller than 0.042 to conclude superior efficacy at 
the superiority interim analysis. If a hypothesis is not rejected at the superiority interim analysis, 
it will be tested again at the Week 52 final analysis. The efficacy boundary for the final analysis 
in terms of p-value scale is p=0.024. 
The exact rejecting boundaries will be calculated after the exact number of participants in each 
treatment arm is available. 
A sequential testing hierarchy will be used to test the secondary hypotheses. The secondary 
hypotheses will be tested at the superiority analysis only if the primary hypothesis is rejected. 
This guarantees the 5% overall level of significance for the primary and secondary hypotheses 
(Glimm 2010). For Week 52 secondary endpoints the same rejecting boundaries will be used 
as for the primary endpoint. 
Futility analysis 
A second futility analysis will also be conducted at the time of the second interim analysis. 
Futility stopping rules will be specified in the DMC charter. 
3 
Sample size calculation 
3.1.1 
Primary endpoint(s) 
The total planned sample size is 400 participants. Based on literature (Mysler et al 2013), 
(Rovin et al 2012), (Furie et al 2020), (Rovin et al 2021), the control response rate was assumed 
to be approximately 25%. Assuming 15% treatment difference with 40% response rate for 
secukinumab, the power for rejecting the null hypothesis for primary endpoint (CRR) is 87%. 
The assumptions are summarized in Table 3-1 below. 


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Table 3-1 
Power for primary endpoint 
Analysis 
Control 
response 
rate 
Secukinumab 
response rate 
Sample size 
Cumulative power for 
primary endpoint 
Superiority 
Interim 
analysis 
25% 
40% 
308 
79% 
Final 
analysis 
25% 
40% 
400 
87% 
3.1.2 
Secondary endpoint(s) 
Using published data for control (Mysler et al 2013), (Rovin et al 2012), (Deng et al 2018) 
(Wallace et al 2017), (McElhone et al 2016) and assuming given treatment effects for 
secukinumab, a summary for power for secondary efficacy parameters is shown in Table 3-2 
for binary endpoints, Table 3-3 for continuous endpoints and Table 3-4 for time to event 
endpoints. Power for the secondary endpoints was calculated with the group sequential design 
and the total cumulative power, to reject either at the superiority interim or final analysis, is 
presented. 
Table 3-2 
Summary of power for binary secondary endpoints 
Endpoint 
Response rate 
Power 
Secukinumab 300 mg  
(N = 200) 
Placebo 
(N = 200) 
  
PRR at Week 52 
75% 
60% 
87% 
PRR at Week 24 
75% 
60% 
87% 
Table 3-3 
Summary of power or continuous endpoints 
Endpoint 
Mean values 
Common 
standard 
Power 
  
Secukinumab 
300 mg (N = 200) 
Placebo 
(N = 200) 
deviation 
  
Change from 
baseline in UPCR 
at Week 52 
-3.5 
-2.68 
2.69 
83% 
Average daily 
dose of 
corticosteroids 
between Week 
16 and Week 52 
5 
5.52 
1.67 
84% 
FACIT-Fatigue© 
change from 
baseline at Week 
52 
7.0 
2.82 
10.0 
98% 


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Endpoint 
Mean values 
Common 
standard 
Power 
SF-36 PCS 
change from 
baseline at Week 
52 
6.1 
3.1 
8.0 
95% 
LupusQoL 
Physical Health 
change from 
baseline at Week 
52 
9.6 
5.6 
14 
78% 
 
 
 
 
 
Table 3-4 
Summary of power for time to event endpoints 
Endpoint 
 Event rates and hazard ratios 
Power 
Placebo (N = 200) 
Event rate at Week 52 
Hazard Ratio 
Secukinumab (N = 200) 
  
Time to CRR  
30% 
1.67 
85% 
Time to PRR  
60% 
1.67 
98% 
Time to UPCR ≤ 
0.5 mg/mg 
35% 
1.67 
89% 
4 
Change to protocol specified analyses 
 The following significant changes from Protocol-V01 are implemented in this SAP: 
1. Terminate the study early due to the futile outcomes from the first interim analysis. 
2. Change the Clinical Study Report type from full to abbreviated. 
3. Remove the second interim analysis. 
4. Indicate the CRO 
 will carry out the final analysis. 
5. Exclude treatment discontinuation due to “study terminated by sponsor” as an 
intercurrent event for the primary objective. 
6. Update FAS2 as patients with chance to reach Week 52 and use it as the analysis set for 
the  primary analysis in the final analysis. 
7. Remove subgroup analyses for the primary and secondary endpoints. 
8. Remove the sensitivity analyses for the primary objective. 
9. Only have the observed “no intercurrent event” analysis for the supplementary analysis 
of the primary objective. 
10. Change hierarchical secondary efficacy analyses from formal comparisons to 
descriptive summaries. 
11. Remove the intercurrent events and their strategies for the secondary efficacy objectives. 
Secondary efficacy objectives will be summarized with observed data. 


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12. Remove the sensitivity and supplementary analyses for the secondary objectives. 
13. Remove all exploratory analyses. 
14. Remove the initial period (Week 1 - 52) and keep the entire treatment period safety 
analyses. 
15. Remove some safety analyses. 
16. Add safety topics of interest AEs for safety analyses. 
. 
18. Indicate biomarker analyses are not part of the CSR. 
5 
Appendix 
5.1 
Description of additional efficacy variables 
Estimated glomerular filtration rate (eGFR) 
The glomerular filtration rate will be estimated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Martínez-Martínez et al 2013) based on 
subject gender, age (years) and serum creatinine (mg/dL). 
Central laboratory serum creatinine values will be used for all renal function data analysis. 
5.2 
Description of health-related quality of life variables 
SF-36 
The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to 
measure health-related quality of life among healthy subjects and patients with acute and 
chronic conditions. It consists of eight subscales (domains) that can be scored individually: 
Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, 
Role- Emotional, and Mental Health. Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-
36 has proven useful in monitoring general and specific populations, comparing the relative 
burden of different disease, differentiating the health benefits produced by different treatments, 
and in screening individual patients. The eight domains are based on a scale from 0-100 while 
PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. 
Quality metric uses weighted maximum likelihood estimation, a modified version of item 
response theory (IRT) to estimate scale scores when a respondent is missing multiple 
items.  The PCS summary score measure requires scores for seven scales, one of which must 
be the PF scale and the MCS score also requires scores for seven scales, one of which must be 
the MH scale.  Only one item is needed for each of the multi-item domains.  
FACIT-Fatigue 
The FACIT-Fatigue© is a 13-item questionnaire that assesses self-reported fatigue and its 
impact upon daily activities and function. The purpose of FACIT-Fatigue in this study is to 


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assess the impact of treatment on fatigue and daily activities and function.in patients with 
axSpA.  
Subjects respond to each item on a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = 
somewhat; 3 = quite a bit; 4 = very much) based on their experience of fatigue during the past 
2 weeks. The scale score is computed by summing the item scores, after reversing those items 
that are worded in the negative direction. Numbering the questions from 1 to 13, it is evident 
that questions 7 and 8 are worded in the positive direction (4 indicates a desirable response) and 
all other questions are worded in the negative directions (4 indicates an undesirable response). 
Thus, it is necessary to reverse the responses for questions 7 and 8 (i.e. original response of 0 
gets mapped to 4, 1=3, 2=2, 3=1, and 4=0) for scoring purposes. 
When there are missing item scores, the scale score was computed by summing the non-missing 
item scores, multiplying by 13 (the total number of items in the scale) and dividing by the 
number of non-missing items (i.e. normalizing the results). The latter rule applied only when at 
least half of the items (seven or more) are non-missing.  
FACIT Fatigue scale score range from 0 to 52, where higher scores represent less fatigue (Cella 
D et al. 1993). 
Lupus Quality of Life (LupusQoL) 
The LupusQoL is a disease-specific, 34-item, self-report questionnaire designed to measure the 
health-related quality of life (HRQoL) of subjects with SLE within 8 domains (i.e., physical 
health (8 items), emotional health (6 items), body image (5 items), pain (3 items), planning       
(3 items), fatigue (4 items), intimate relationships (2 items), and burden to others (3 items). 
Responses are based on a 5-point Likert scale where 0 (all of the time) to 4 (never) 
(Yazdany 2011), (RWS Life). 
Each domain of the LupusQoL is scored separately 
5.3 
Visit Windows 
Baseline and post-baseline definitions 
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. A post-baseline value refers to a measurement taken after the first 
dose of study treatment.  
Analysis visit windows 
Analysis visit windows will be used for the data that is summarized by visit; they are based on 
the study visit and evaluation schedule and comprise a set of days around the nominal visit day. 
For any assessment, there are protocol defined scheduled visits around which analysis visit 
windows were created to cover the complete range of days within the study.  
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 46 instead 
of on Day 29, it will be re-aligned to visit window Week 8. In the case of major deviations from 
the visit schedule, or due to unscheduled visits, several assessments of a subject may fall in a 


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particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below.  
For lab/vital signs, follow-up (F/U) visit is excluded from analysis visit mapping window. Only 
assessments that come as F/U nominal visit will be directly assigned as analysis F/U visit. Other 
assessments that are beyond the last on-treatment visit window (W104) or after nominal F/U 
visit date won't be mapped to any analysis visit. F/U visit will not be included in the summary 
tables by visit. 
Of note, subjects are allowed to have gaps in visits.  


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Table 5-1 
Analysis visit windows 
 
Analysis 
Visit 
 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Group 6 
Group 7 
 
Group 8 
 
Group 9 
Group 
10 
Group 11 
Baseline 
 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 1 
 
8 
2-11 
2-11 
 
 
 
 
 
 
 
 
2-11 
 
Week 2 
 
15 
12-18 
12-18 
 
 
 
 
 
 
 
 
12-18 
 
Week 3 
 
22 
19-25 
19-25 
 
 
 
 
 
 
 
 
19-25 
 
Week 4 
 
29 
26-43 
26-43 
 
 
 
 
2-57 
 
 
2-57 
26-43 
 
Week 8 
 
57 
44-71 
44-71 
2-71 
2-71 
 
 
 
 
 
 
44-64 
 
Week 12 
 
85 
72-99 
72-99 
72-127 
72-127 
2-127 
 
58-99 
2-127 
2-127 
58-127 
65-106 
65-148 
Week 16 
 
113 
100-127 
100-127 
 
 
 
 
100-141 
 
 
 
107-127 
 
Week 20 
 
141 
128-155 
128-155 
 
 
 
 
 
 
 
 
128-148 
 
Week 24 
 
169 
156-183 
156-183 
128-267 
128-211 
128-211 
2-267 
142-211 
128-267 
128-267 
128-267 
149-190 
149-232 
Week 28 
 
197 
184-211 
184-211 
 
 
 
 
 
 
 
 
191-211 
 
Week 32 
 
225 
212-239 
212-239 
 
 
 
 
 
 
 
 
212-232 
 
Week 36 
 
253 
240-267 
240-267 
 
212-309 
212-309 
 
212-309 
 
 
 
233-274 
233-344 
Week 40 
 
281 
268-295 
268-295 
 
 
 
 
 
 
 
 
275-295 
 
Week 44 
 
309 
296-323 
296-323 
 
 
 
 
 
 
 
 
296-323 
 
Week 48 
 
337 
324-351 
324-351 
 
 
 
 
 
 
 
 
324-344 
 
Week 52 
 
365 
352-379 
352-379 
268-449 
310-449 
310-449 
268-547 
310-547 
310-547 
268-449 
268-449 
345-386 
345-512 
Week 56 
 
393 
380-407 
380-407 
 
 
 
 
 
 
 
 
387-407 
 
Week 60 
 
421 
408-435 
408-435 
 
 
 
 
 
 
 
 
408-435 
 
Week 64 
 
449 
436-463 
436-463 
 
 
 
 
 
 
 
 
436-463 
 
Week 68 
 
477 
464-491 
464-491 
 
 
 
 
 
 
 
 
464-491 
 


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Analysis 
Visit 
 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Group 6 
Group 7 
 
Group 8 
 
Group 9 
Group 
10 
Group 11 
Week 72 
 
505 
492-519 
492-519 
 
 
 
 
 
 
 
 
492-512 
 
Week 76 
 
533 
520-547 
520-547 
450-631 
450-631 
450-631 
 
 
 
450-631 
450-631 
513-554 
513-708 
Week 80 
 
561 
548-575 
548-575 
 
 
 
 
 
 
 
 
555-575 
 
Week 84 
 
589 
576-603 
576-603 
 
 
 
 
 
 
 
 
576-603 
 
Week 88 
 
617 
604-631 
604-631 
 
 
 
 
 
 
 
 
604-631 
 
Week 92 
 
645 
632-659 
632-659 
 
 
 
 
 
 
 
 
632-659 
 
Week 96 
 
673 
660-687 
660-687 
 
 
 
 
 
 
 
 
660-687 
 
Week 100 
 
701 
688-715 
688-715 
 
 
 
 
 
 
 
 
688-708 
 
Week 104 
 
729 
≥716 
≥716 
≥632 
≥632 
≥632 
≥548 
≥548 
≥548 
≥632 
≥632 
≥709 
≥709 
 
Group 1: Physical Examination, Body Weight, Hematology, Clinical Chemistry (exclude eGFR), Coagulation Panel, Urinalysis,Vital Signs 
Group 2: Lipids 
Group 3: hsCRP, ESR 
Group 4: Anti-dsDNA antibody and ANA, 
 
 FACIT-Fatigue, SF-36, LupusQoL 
 
 
 
Group 8: Serum collection for optional biomarkers 
Group 9: Urine collection for optional biomarkers 
Group 10: eGFR  
Group 11: 24-hr urine collection 
If the participant has received treatment from the extension study, then the assessment values will not be included in the visits of this core study. 
 
 


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The mapping described above applies to all visits (not just scheduled visits).  Repeat and/or 
unscheduled visits (which will be numbered in the database according to new NCDS standards) 
will be mapped for analysis purposes in the same way as scheduled visits. This leaves the 
possibility, then, for multiple measurements within an analysis window. The following 
conventions will be used to determine the appropriate measurement to be summarized in the 
event of multiple measurements within a visit window. 
Table 5-2 
Rules for flagging variables 
Timing of measurement 
Type of data 
Rule 
Baseline 
All data 
The last measurement made prior to administration of the first dose of study 
treatment – note this may include measurements taken on the day of 
randomization (e.g., lab). Baseline assessments scheduled for and captured on 
Day 1 will be considered baseline measurements regardless of the time of 
assessment. If a patient did not receive any dose of study treatment then the 
randomization date will be used. 
Only the date part will be considered if there is only one assessment on Day 1 
but if there are multiple assessments on Day 1, then the following rules will 
apply: 
1. If time of assessment exist, 
• 
select the last available measurement prior to the reference start 
date/time considering time 
• 
if no measurement prior to the reference start date/time then 
considering time select the earliest measurement post reference start 
date/time 
2. If time of assessment does not exist the measurement from the lowest 
CRF visit number will be used. 
Post-baseline efficacy 
All data 
The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g., 1 day before target date and 1 
day after) the first one will be used.  
Cases where the same parameter is recorded more than once on the same 
date will be handled as follows: 
• 
If time of completion exists the earliest measurement will be use 
• 
If time does not exist the measurement from the lowest CRF visit 
number will be used 
Post-baseline safety 
Summary visit 
information (e.g., 
lab, etc.) 
The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g., 1 day before target date and 1 
day after) the first one will be used.  
Cases where the same parameter is recorded more than once on the same 
date will be handled as follows: 
• 
If time of completion exists the earliest measurement will be used 
• 
If time does not exist the measurement from the lowest CRF visit 
number will be used 
• 
If CRF visit number is the same the average value will be used 
Post-baseline safety  
Notable 
abnormalities 
(e.g., lab) 
The most extreme measurement in the window will be used. Note this means 
a patient can have a notably high and notably low measurement within a 
window 
5.4 
Statistical methodology and assumptions 
5.4.1 
Analysis of continuous data 
5.4.1.1 
Summary statistics for continuous data 
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by visit and treatment group.  


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5.4.2 
Analysis of binary and categorical data 
5.4.2.1 
Summary statistics for binary and categorical data 
Summary statistics for discrete variables will be presented in contingency tables and will 
include count and frequency in each category. If applicable, confidence intervals will be derived 
as well based on the score method including continuity correction (Newcombe 1998): 
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z = probit(1-α/2), n as total 
number of subjects (i.e. number of subjects in the denominator), p as estimated crude incidence 
(number of subjects with event / n) and q = 1-p 
Then the lower limit is 
(
)
(
)










+
+
+
−
−
−
−
+
×
=
2
2
2
2
1
4
1
2
1
2
,0
max
100
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is 
(
)
(
)










+
−
+
−
+
+
+
+
×
=
2
2
2
2
1
4
1
2
1
2
,1
min
100
z
n
nq
p
n
z
z
z
np
U
. 
In addition, if L > p then L = p and if U < p then U = p. 
For binary response variables the placebo-adjusted response rates including 95% confidence 
interval will be derived. 
SAS code for risk difference: 
proc freq data=; 
        tables response* treatment / riskdiff; 
run; 
Note the response value should be sorted with ‘1’ ahead of ‘0’. 
5.4.2.2 
Logistic regression 
Certain binary outcome variables, e.g., response outcomes, will be evaluated using a logistic 
regression model with treatment,  stratification factor (SoC), and race (Black vs. Non-Black) as 
factors and baseline score (if applicable. e.g. baseline UPCR) as covariates. The marginal 
standardization method will be used to calculate the mean response rate in each treatment group 
as well as their difference. This method uses the same fitted logistic model, but involves using 
the model to predict, for each patient in the study, the mean outcome assuming assignment to 
each particular treatment group in turn, assuming each patient’s observed values for the other 
baseline covariates (i.e., disease condition and weight). Averaging these predictions for each 
treatment group provides the estimate of the mean response rate for each treatment group. Then 


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the difference will be derived based on the estimated mean response rates comparing 
secukinumab i.v. regimen vs placebo. 
The macro Margins (Predictive margins and average marginal effects) will be used. 
SAS code example as the following, 
%Margins(data = mydata, 
                  class = treatment strata, 
                  response = response,  
                  roptions = event='1', 
                  model  = treatment strata, 
                  dist = binomial, 
                  margins = treatment,  
                  options = cl diff) 
For cases where the convergence status indicates that the model did not reach appropriate 
convergence (conv_status is not 0), no risk difference or p-value will be presented from that 
model. 
However, if the issue relates to the primary timepoint of Week 52 then the following steps will 
be followed: 
1. Change race categorization from “Black vs. Non-Black” to “White vs. Non-White”. If 
there are still issues, perform step 2. 
2. Remove race from the model. If there are still issues, perform step 3. 
3. Remove  FMV baseline score from the model. If there are still issues, perform step 4. 
4. Remove strata from the model. If there are still issues, perform step 5.  
5. Use Fisher’s exact test as described below. 
When Fisher’s exact test is applied, only a p-value for a test of equal response in the two groups 
will be presented. 
ods output fishersexact=fisher; 
proc freq data=mydata; 
        by visit; 
        table treatment*response / fisher; 
run; 
Input dataset should only contain data from the two treatment groups to be compared. 
5.4.3 
Kaplan-Meier analysis 
The SAS procedure PROC LIFETEST is used to obtain Kaplan-Meier estimates of the 
proportion of patients with disease flare. 


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• The Kaplan-Meier estimate for the cumulative Failure (1-survival) rate along with the 
corresponding 95% confidence interval, using Greenwood’s formula to compute the estimate 
of the standard error, at specific time points,  
•median (95% confidence interval) and the estimate of the event rate at the end of the Treatment 
Period 2 (Week 52) will be provided. 
The SAS procedure PROC LIFETEST will be used to obtain Kaplan-Meier estimates of the 
time to event variables. 
The Kaplan-Meier estimate will be derived along with the corresponding 95% confidence 
interval, using Greenwood’s formula to compute the estimate and the standard error, at specific 
time points, 
5.4.4 
Imputation methods 
Missing values for the primary objective’s main analysis will be imputed with non-responder 
imputation. 
5.4.5 
Crude incidence and related risk estimates  
5.4.5.1 
Crude incidence and 100*(1-α)% confidence interval 
For n subjects, each at risk to experience a certain event with probability π, the crude incidence 
is estimated as p=x/n, where x is the number of subjects with the event. 
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction (Newcombe 1998).  
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z = PROBIT(1-α/2), n as 
total number of subjects (i.e. number of subjects in the denominator), and p as estimated crude 
incidence (number of subjects with event / n) it is q=1-p. 
Then the lower limit is 
(
)
(
)










+
+
+
−
−
−
−
+
=
2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is 
(
)
(
)










+
−
+
−
+
+
+
+
=
2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
. 
In addition, if L > p then L = p and if U < p then U = p. 
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson, 1934) will be 
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement. 


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However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses. 
5.4.5.2 
Odds ratio and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event with probability π1 and π0 respectively, the odds ratio is estimated as 
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p
−
−
 with p1= x1/n1 and p0=x0/n0. A conditional exact 100*(1-α)% confidence interval 
can be obtained by using the SAS procedure PROC FREQ with statement EXACT OR. 
However, to be able to adjust for covariates odds ratios will primarily be obtained from PROC 
LOGISTIC. 
5.4.5.3 
Risk difference and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event, the risk difference is estimated as p1-p0 with p1= x1/n1 and p0=x0/n0.  
Exact unconditional confidence limits for the risk difference can be obtained with SAS 
procedure PROC FREQ and option RISKDIFF in the TABLES statement, specifying the 
RISKDIFF option also in the EXACT statement.   
5.4.6 
Exposure adjusted incidence rate and related risk estimates 
5.4.6.1 
Exposure adjusted incidence rate and 100*(1-α)% confidence interval 
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 
∑
=
=
n
j
jt
T
1
 and D is the number of subjects with 
at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson 
variable with parameter θT and observed value D can be obtained based on (Garwood 1936), 
from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai 
1993; Ulm 1990): 
Lower confidence limit   
T
c
L
D
2
,
2
/
5
.
0
α
=
 for D>0, 0 otherwise, 
Upper confidence limit 
T
c
U
D
2
2
,
2
/
1
5
.
0
+
−
=
α
 
Where cα,k is the αth quantile of the Chi-square distribution with k degrees of freedom. 
The example below shows how this should be handled for cases where subjects switch treatment. 
In particular for summarizing ‘Any AIN’ as a group, one should take into consideration the 
sequence of treatments while calculating exposure time for subjects.  a 
 


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Table 5-3 
Examples for calculating exposure time for incidence rates (IR) 
1st treatment / total 
exposure time 
2nd treatment / total 
exposure time 
AE event onset (in days 
from study start) 
Exposure for IR 
Placebo / 100 days 
AIN457 150 mg / 200 days 
Day 50 (during 1st 
treatment) 
Day 110 (10 days into 2nd 
treatment) 
Placebo:  50 days 
AIN457 150 mg: 10 days 
Any AIN: 10 days 
6 
Reference 
Bretz F, Maurer W, Brannath W, et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 28(4):586-604. 
Bruin G, Loesche C, Nyirady J, et al (2017) Population Pharmacokinetic Modeling of 
Secukinumab in Patients With Moderate to Severe Psoriasis. J Clin Pharmacol; 57(7):876-85. 
Cella DF, Tulsky DS, Gray G et al. (1993) The Functional Assessment of Cancer Therapy 
(FACT) scale: Development and validation of the general measure. Journal of Clinical 
Oncology; 11(3):570-579. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika, 26; 404–413. 
Deng J, Luo L, Zhu L, et al (2018) Multitarget therapy versus intravenous cyclophosphamide 
in the induction treatment of lupus nephritis: a metaanalysis of randomized controlled trials. 
Turk J Med Sci; 48(5):901-10. 
FDA 
Guidance 
for 
Industry: 
Population 
Pharmacokinetics 
p. 
https://www.fda.gov/media/71364/download. 
Furie R, Rovin BH, Houssiau F, et al (2020) Two-Year, Randomized, Controlled Trial of 
Belimumab in Lupus Nephritis. N Engl J Med; 383(12):1117-28. 
Garwood F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453. 
Glimm, E., Maurer, W., and Bretz, F. (2010) Hierarchical testing of multiple endpoints in 
group-sequential trials. Statistics in Medicine 29, 219-228 
Heinze G (2006). A comparative investigation of methods for logistic regression with separated 
or nearly separated data. Statistics in Medicine; 25:4216–4226 
Koch GG, Tangen CM, Jung JW, et al. (1998) Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Statistics in Medicine; 17:1863-92. 
Lan KK, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika; 
70:659-63. 
Levin A, Stevens PE, Bilous RW, et al (2013) 'Kidney disease: Improving global outcomes 
(KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and 
management of chronic kidney disease' Kidney International Supplements; 3(1):1-150. 
Lubeck, DP. (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis.  Pharmacoeconomics 22(1): 27-38. 


Novartis 
Confidential 
Page 46 
SAP Amendment 3 
 
Secukinumab/AIN457Q12301 
 
 
Martínez-Martínez MU, Mandeville P, Llamzares-Azuara L et al (2013) CKD-EPI is the most 
reliable equation to estimate renal function in patients with systemic lupus erythematosus. 
Nefrologia; 33(1):99-106. 
McElhone K, Abbott J, Sutton C, et al (2016) Sensitivity to Change and Minimal Important 
Differences of the LupusQoL in Patients With Systemic Lupus Erythematosus. Arthritis Care 
Res (Hoboken); 68(10):1505-13. 
Mysler EF, Spindler AJ, Guzman R, et al (2013) Efficacy and safety of ocrelizumab in active 
proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis 
Rheum; 65(9):2368-79. 
Newcombe, RG. (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-872. 
Pocock SJ (1977) Group Sequential Methods in the Design and Analysis of Clinical Trials. 
Biometrika; 64(2):191–9. 
Predictive margins and average marginal effects: http://support.sas.com/kb/63/038.html 
Permutt T, Li F(2017). Trimmed means for symptom trials with dropouts. Pharmaceutical 
statistics.;16(1):20-8. 
RWS Life Sciences LupusQoL: http://www.corptransinc.com/sites/lupusqol/instrument-
information. 
Rovin BH, Furie R, Latinis K, et al (2012) Efficacy and safety of rituximab in patients with 
active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. 
Arthritis Rheum; 64(4):1215-26. 
Rovin BH, Teng YKO, Ginzler EM, et al (2021) Efficacy and safety of voclosporin versus 
placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-
controlled, phase 3 trial. Lancet; 397:2070-80. 
Rubin, DB (1987). Multiple imputation for nonresponse in surveys. John Wiley & Sons. 
Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867 
Ulm K (1990). A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373-375 
Wallace DJ, Strand V, Merrill JT, et al (2017) Efficacy and safety of an interleukin 6 
monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging 
randomised controlled trial. Ann. Rheum. Dis; 76(3):534-42. 
Yazdany J (2011) Health-related quality of life measurement in adult systemic lupus 
erythematosus: Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific 
Quality of Life Questionnaire (SLEQOL), and Systemic Lupus Erythematosus Quality of Life 
Questionnaire (L-QoL). Arthritis Care Res (Hoboken); 63(11):S413-9.