Clinical trial NCT03021499
Conditions: Lupus Nephritis
Keywords: lupus nephritis calcineurin inhibitors voclosporin
Sponsor: Aurinia Pharmaceuticals Inc.
Start date: 2017-05-17; Completion date: 2019-10-10
Enrollment: 358 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy of voclosporin compared with placebo in achieving renal response after 52 weeks of therapy in subjects with active lupus nephritis.

Detailed description:
The aim of the current study is to investigate whether voclosporin, added to the standard of care treatment in active lupus nephritis (LN), is able to reduce disease activity over a treatment period of 52 weeks. The background therapy will be mycophenolate mofetil (MMF) and initial treatment with IV methylprednisolone, followed by a reducing course of oral corticosteroids. Subjects with active, flaring LN will be eligible to enter the study. They are required to have a diagnosis of LN according to established diagnostic criteria and clinical and biopsy features suggestive of active nephritis. Efficacy will be assessed by the ability of the drug combination to reduce the level of proteinuria (as measured by Urine Protein Creatinine Ratio (UPCR)) while demonstrating an acceptable safety profile.

Arms: arm 1: oral, 23.7 mg twice daily (BID) arm 2: Voclosporin placebo, oral, 3 capsules twice daily (BID)
Interventions: intervention 1: Voclosporin intervention 2: Placebo Oral Capsule
Intervention descriptions: intervention 1: calcineurin inhibitor intervention 2: matching placebo capsule

Protocol documents:
Prot_002.pdf: 
 
This trial will be conducted in compliance with this protocol, ICH GCP and applicable regulatory requirements. 
The information contained in this document is proprietary to Aurinia Pharmaceuticals, Inc. and is not to be copied, disclosed or 
otherwise distributed by an outside authority to any person or persons without the prior written permission of Aurinia. 
 
 
A Randomized, Controlled Double-blind Study Comparing the 
Efficacy and Safety of Orelvo (voclosporin) (23.7 mg Twice 
Daily) with Placebo in Achieving Renal Response in Subjects 
with Active Lupus Nephritis 
 
Clinical Protocol Number: 
AUR-VCS-2016-01 
 
 
Study Name: 
AURORA (AURinia Orelvo Renal 
Assessments) 1: Aurinia Renal Response in 
Active Lupus with Orelvo (voclosporin) 
 
 
Date: 
04 May 2017 
 
 
Version Number: 
2.0 (Amendment 1) 
 
 
IND Number: 
114577 
 
 
EudraCT Number: 
2016-004045-81 
 
 
 


 
 
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NAMES AND ADDRESSES 
Lead Investigator 
Name: 
 
 
Address: 
 
 
 
 
Tel: 
 
 
Fax: 
 
 
Email: 
 
 
Sponsor 
Name: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
24 Hour: 
 
 
Medical Monitor 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 


 
 
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Regulatory Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Trial Statistician 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 




 
 
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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: A Randomized, Controlled Double-blind Study 
Comparing the Efficacy and Safety of Orelvo (voclosporin) (23.7 mg Twice Daily) with 
Placebo in Achieving Renal Response in Subjects with Active Lupus Nephritis. 
Version Number/Date: 2.0/04 May 2017 
I agree to comply with the current International Council for Harmonisation Guidelines on Good 
Clinical Practice and applicable regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• me (including, if applicable, my spouse (or legal partner) and dependent children); 
• my sub-investigators 
before the start of the study and to report any changes that affect my financial disclosure status 
for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Aurinia Pharmaceuticals Inc. 
Signature by the Investigator on this form documents review, agreement and approval of the 
requirements contained within this protocol. 
 
 
 
Signature 
 
Date (e.g., DD Month Year) 
 


 
 
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SYNOPSIS 
Title: 
A Randomized, Controlled Double-blind Study Comparing the Efficacy and Safety 
of Orelvo (voclosporin) (23.7 mg Twice Daily) with Placebo in Achieving Renal 
Response in Subjects with Active Lupus Nephritis. 
Short Title: 
AURORA (AURinia Orelvo Renal Assessments) 1: Aurinia Renal Response in 
Active Lupus with Voclosporin 
Study Product: 
Orelvo (voclosporin) 
Indication: 
Active lupus nephritis 
Phase: 
3 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VCS-2016-01 
Objectives: 
Primary Objective: 
• To assess the efficacy of Orelvo (voclosporin) compared with placebo in 
achieving renal response after 52 weeks of therapy in subjects with active lupus 
nephritis (LN) 
Secondary Objective: 
• To assess the safety and tolerability of Orelvo over 52 weeks compared with 
placebo in subjects with active LN 
Design: 
Prospective, randomized, placebo-controlled, double-blind, parallel-group, 52-week, 
international, multicenter, 2-arm comparison study of Orelvo versus matching 
placebo. 
Treatment: 
Investigational Treatment: 
Orelvo softgel capsules containing 7.9 mg drug. Approximately 324 subjects will be 
randomized to Orelvo (23.7 mg twice daily (BID)) or matching placebo (162 subjects 
per arm). 
All subjects will receive an initial treatment of intravenous (IV) methylprednisolone, 
followed by a reducing taper of oral corticosteroid. Additionally, all subjects will 
receive background therapy with mycophenolate mofetil (MMF).   
All subjects who complete participation and study treatment through 52 weeks and 
provide consent will have the opportunity to enroll into a continuation study (design 
pending finalization). 
Inclusion Criteria: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 (or legal age of consent 
if >18 years) to 75 years of age, inclusive, at the time of screening (Visit 1). 
3. Previous diagnosis of systemic lupus erythematosus (SLE) according to the 
American College of Rheumatology criteria (1997; see Appendix 5).  
 


 
 
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4. Subjects with evidence of active nephritis, defined as follows: 
Kidney biopsy result within 2 years prior to screening indicating Class III, 
IV-S, IV-G (alone or in combination with Class V), or Class V LN (see 
Appendix 3) with a doubling or greater increase of urine protein creatinine 
ratio (UPCR) within the last 6 months to a minimum of ≥1.5 mg/mg for 
Class III/IV or to a minimum of ≥2 mg/mg for Class V at screening. Biopsy 
results over 6 months prior to screening must be reviewed with a medical 
monitor to confirm eligibility. 
OR 
Kidney biopsy result within 6 months prior to screening indicating Class III, 
IV-S, or IV-G (alone or in combination with Class V) LN with a UPCR of 
≥1.5 mg/mg at screening.  
OR 
Kidney biopsy result within 6 months prior to screening indicating Class V LN 
and a UPCR of ≥2 mg/mg at screening. 
A biopsy can be performed during screening, if not available. The above 
criteria must be fulfilled at baseline. 
5. In the opinion of the Investigator, subject requires high-dose corticosteroids and 
immunosuppressive therapy. 
6. Subject is willing to take oral MMF for the duration of the study, either by 
continuing current MMF therapy or by initiating it on or before the Baseline 
Visit. 
7. Women of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline. Two effective forms 
of contraception must be used simultaneously unless abstinence is the chosen 
method. Subjects must use effective contraception during the study (see 
Section 5.4, Adequate/Effective Contraception). 
Exclusion Criteria: 
1. Subjects unable or unwilling to give written informed consent and/or to comply 
with study procedures. 
2. Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney 
Disease Epidemiology Collaboration equation of ≤45 mL/minute/1.73 m2 at 
screening confirmed before randomization. 
3. Currently taking or known need for any of the medications listed in Section 7.8, 
Prohibited Therapy and Concomitant Treatment at screening or during the study. 
This includes prohibited medications prior to screening as specified in 
Section 7.8.1, Prohibited Medications. 
4. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or 
expected to require dialysis during the study period. 
5. A previous kidney transplant or planned transplant within study treatment 
period. 


 
 
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6. Any known hypersensitivity or contraindication to MMF, mycophenolic acid, 
cyclosporine, corticosteroids or any components of these drug products. 
7. Current or medical history of: 
• 
Congenital or acquired immunodeficiency. 
• 
In the opinion of the Investigator, clinically significant drug or alcohol abuse 
within 2 years prior to screening. 
• 
Malignancy within 5 years of screening, with the exception of basal and 
squamous cell carcinomas treated by complete excision. Subjects with 
cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been 
treated with conization or loop electrosurgical excision procedure and have 
had a normal repeat Papanicolaou test are allowed. 
• 
Lymphoproliferative disease or previous total lymphoid irradiation. 
• 
Severe viral infection (e.g., cytomegalovirus, hepatitis B virus, hepatitis C 
virus) within 3 months of screening; or known HIV infection. Severe viral 
infection is defined as active disease requiring antiviral therapy. 
• 
Active tuberculosis (TB), or known history of TB/evidence of old TB if not 
taking prophylaxis with isoniazid (see Section 9.2.1, Screening Visit 
Procedures). 
8. Other known clinically significant active medical conditions, such as: 
• 
Severe cardiovascular disease including congestive heart failure, history of 
cardiac dysrhythmia or congenital long QT syndrome. QT interval duration 
corrected for heart rate using method of Fridericia exceeding 480 msec in the 
presence of a normal QRS interval (<110 msec) at time of screening will result 
in exclusion. 
• 
Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or 
bilirubin ≥2.5 times the upper limit of normal) at screening and, if abnormal at 
screening, then confirmed that the levels have returned to <2.5 times upper 
limit of normal before randomization. 
• 
Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• 
Bone marrow insufficiency unrelated to active SLE (according to Investigator 
judgment) with white blood cell count <2,500/mm3; absolute neutrophil count 
<1.3 × 103/μL; thrombocytopenia (platelet count <50,000/mm3). 
• 
Active bleeding disorders. 
• 
Current infection requiring IV antibiotics. 
9. Any overlapping autoimmune condition for which the condition or the treatment 
of the condition may affect the study assessments or outcomes (e.g., scleroderma 
with significant pulmonary hypertension; any condition for which additional 
immunosuppression is indicated). Overlapping conditions for which the 
condition or treatment is not expected to affect assessments or outcomes (e.g., 
Sjögren’s syndrome) are not excluded. 


 
 
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10. No vaccines using live organisms, virus or bacterial, are allowed during 
screening and while taking the study treatment. 
11. Other major physical or psychiatric illness or major traumatic injury within 
6 months prior to screening that may affect study conduct or interfere with study 
assessments or outcome. 
12. Any other medical condition which, in the Investigator’s judgment, may be 
associated with increased risk to the subject or may interfere with study 
assessments or outcomes. 
13. Subjects who are pregnant, breast feeding or, if of childbearing potential, not 
using adequate contraceptive precautions. 
14. Participation in another interventional clinical study within 4 weeks prior to 
screening and/or receipt of investigational drugs within 4 weeks or 5 half-lives 
of the drug (whichever is longer) prior to screening. 
15. Subjects randomized and treated in a previous voclosporin clinical study. 
Primary Endpoint: 
Renal response at Week 52 will be adjudicated by the Clinical Endpoints Committee 
based on the following parameters: 
• 
UPCR of ≤0.5 mg/mg, and 
• 
eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR 
of >20%, and 
• 
Received no rescue medication for LN (see Section 7.8, Prohibited Therapy 
and Concomitant Treatment), and 
• 
Did not receive more than 10 mg prednisone for ≥3 consecutive days or for 
≥7 days in total during Weeks 44 through 52, just prior to the renal response 
assessment. 
Subjects who withdraw from the study prior to the Week 52 assessment will be 
defined as non responders. 
Secondary 
Endpoints: 
• 
Time to UPCR of ≤0.5 mg/mg. 
• 
Partial renal response as defined by 50% reduction from baseline in UPCR 
at Weeks 24 and 52. 
• 
Time to 50% reduction in UPCR from baseline.  
• 
Renal response at Week 52 (based on definition of primary endpoint). 
• 
Duration of UPCR ≤0.5 mg/mg. 
• 
Proportion of subjects experiencing a confirmed >30% decrease from 
baseline in eGFR at each timepoint. 
• 
Change from baseline in UPCR at each time point. 
• 
Change from baseline in serum creatinine, urine protein, and eGFR. 


 
 
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• 
Change from screening in immunology parameters (complement 3 (C3), C4, 
and anti-double-stranded DNA). 
• 
Renal response with low-dose steroids (defined as renal response in the 
presence of corticosteroids of ≤2.5 mg between Weeks 16 to 24 and 
Weeks 44 to 52). 
• 
Change from baseline in health-related quality of life at Weeks 12, 24, and 
52. 
• 
Health Resource Utilization at Weeks 24 and 52. 
• 
Change from baseline in the Safety of Estrogens in Lupus Erythematosus 
National Assessment - Systemic Lupus Erythematosus Disease Activity 
(SELENA-SLEDAI) Index score at Weeks 24 and 52. 
Procedures: 
See Schedule of Events for full details of protocol required procedures and applicable 
visits (and timings). Subjects who have provided signed and dated informed consent 
will be screened for entry into this study. Baseline proteinuria level is determined by 
a mean of 2 first morning void urine samples taken during the screening period. If a 
subject has not had a kidney biopsy within the required timeframe for study 
eligibility, one may be performed to assess eligibility into the study, provided consent 
is in place and provided the results are received before randomization. Subjects 
meeting the required eligibility criteria will be randomized in a ratio of 1:1 to receive 
either Orelvo (23.7 mg BID) or matching placebo starting on Day 1. All subjects will 
receive initial treatment with 0.5 to 1.0 g IV methylprednisolone. In consultation with 
the Medical Monitor, and if it is in the subject’s best interest, IV methylprednisolone 
may 
be 
started 
during 
the 
screening 
period. 
Subjects 
receiving 
IV 
methylprednisolone in the 3 months prior to screening must be discussed with the 
Medical Monitor prior to initiating further IV methylprednisolone. For subjects who 
are not already taking prescribed MMF prior to randomization, the dosing of MMF 
will start at 500 mg BID for a total daily dose of 1 g/day for the first week, increasing 
to 1 g BID for a total daily dose of 2 g/day for the second and subsequent weeks (i.e., 
beginning on Day 8).  
All subjects will complete dosing through 52 weeks of study treatment. Subjects who 
permanently discontinue study treatment before the Week 52 visit will return for all 
remaining study visits and assessments unless they have withdrawn consent. All 
subjects who complete participation and study treatment through 52 weeks and 
provide consent will have the opportunity to enroll into a continuation study for 
which the details are not yet finalized. 
Sample Size: 
A 2 group continuity corrected Chi square test with a 0.05 two-sided significance 
level will have 80% power to detect the difference between a placebo response rate 
of 20.0% and an Orelvo response rate of 34.4% (odds ratio=2.1) when the sample 
size in each group is 162 (total N=324). While the effect of withdrawals will be 
investigated, subjects withdrawing for any reason will be counted as non-responders 
in the primary analysis and therefore no adjustment of sample size for withdrawals is 
necessary. 


 
 
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Statistical Methods: 
Analysis: 
All statistical analyses will be undertaken at study closure and will incorporate all 
Week 24 and Week 52 endpoints. 
Populations: 
The efficacy analysis will be based on the intent-to-treat (ITT) principles and will 
consist of all randomized subjects. 
The per-protocol set will be a subset of subjects in the ITT population who do not 
have any major protocol violations (to be defined prior to unblinding). 
The safety analysis set will consist of all subjects who receive at least 1 dose of study 
treatment. 
Methods: 
The primary analysis of the primary endpoint, renal response at Week 52, will be 
conducted on the ITT population. The relative renal response for Orelvo compared 
to placebo will be determined using logistic regression. The logistic regression model 
will include terms for treatment, baseline UPCR, biopsy class, and MMF use at 
baseline. Results of this logistic regression will be displayed as odds ratios and a 
2-sided confidence interval (CI) (Orelvo compared to placebo). The proportion of 
subjects exhibiting renal response at Weeks 24 and 52 will be summarized by 
treatment group. 
The analyses of the secondary endpoints are described below: 
Other binary endpoints will be analyzed in a similar manner to the primary endpoint. 
Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Orelvo will be compared to placebo using a Cox proportional hazard 
model. The model will include terms for treatment and appropriate baseline 
assessments. Median time-to-event along with 2-sided CIs will be displayed. 
Other endpoints will be summarized by visit and differences between baseline and 
on-treatment values at weeks up to and including Week 52 will be analyzed using 
Mixed Effect Model Repeated Measures (MMRM). The MMRM model will include 
terms for treatment, visit, treatment by visit interaction and baseline. Results will be 
expressed as differences between treatment arms (along with associated 95% CI).  
Safety Endpoints: 
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables. 
Laboratory values (based on results from the central laboratory), vital signs and other 
safety parameters will be summarized by visit as absolute values and change from 
baseline. Laboratory values outside of defined normal ranges will be summarized. 
The impact of withdrawals on primary endpoint will be investigated with a tipping 
point analysis. 
 
 






 
 
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Visit(1) 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visits 
4-8 
Visit 
9 
Visit 10 
Visits 
11-13 
Visit 14 
Visit 15 
End of 
Treatment/ 
Early 
Termination(2) 
Visit 16 
Safety 
Follow-up(3) 
Day/Week 
Day -30 to 
Day -1 
Day 1 
 
Day 2 
Wks 2, 
4, 8, 12, 
16 
±3 days 
Wk 20 
±3 days 
Wk 24 
±10 days 
Wks 30, 
36, 42 
±10 days 
Wk 48 
±10 days 
Wk 52  
±10 days 
Wk 56 
±10 days 
Pregnancy test(12) 
 
 
 
 
 
 
 
 
 
 
AEs(13) 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications(14) 
 
 
 
 
 
 
 
 
 
 
SELENA-SLEDAI 
 
 
 
 
 
 
 
 
 
 
SF-36 and LupusPro(15) 
 
 
 
(7) 
 
 
 
 
 
 
Healthcare Resource 
Utilization(16) 
 
 
 
 
 
 
 
 
 
 
Dispense study 
treatment/compliance 
 
 
 
 
 
 
 
 
(17) 
 
First dose of study 
treatment (at the study 
site)(18) 
 
 
 
 
 
 
 
 
 
 
MMF dispensing(19) 
 
 
 
 
 
 
 
 
 
 
IV methylprednisolone 
administration(20) 
 
 
 
 
 
 
 
 
 
 
Oral corticosteroid 
tapering(21) 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1 
Unscheduled visits/assessments can be done as needed. Adverse events, concomitant medications and verbal compliance check is needed. 
2 
Subjects who discontinue study treatment or terminate the study early, are to attend an Early Termination Visit and have the assessments listed performed. Subjects who complete study 
treatment will attend the End of Treatment at Week 52 and have the assessments listed performed.  
3 
Subjects who do not enroll into the continuation study will have a follow up safety visit 4 weeks after the last dose of study treatment. 
4 
If a subject has not had a recent kidney biopsy, one may be performed to assess eligibility for the study provided informed consent has been given and results are 
received prior to randomization. If one is performed as part of standard of care after randomization, the results will be recorded in the electronic case report form. 
5 
Complete physical examination at screening, abbreviated examination at all other applicable visits. Height is measured at screening only. 
6 
During the study, and after screening, in the event that a subject is noted to have a QTcF value exceeding 500 msec, or >60 msec more than baseline, the ECG 
will be repeated; see Section 9.1.4.1, Procedures to Manage a Treatment-Emergent Increase in QTc. Electrocardiograms will be recorded digitally after the 
subject has been in a resting, supine position for at least 5 minutes. 
7 
Week 12 only. 
8 
Laboratory assessments will be performed according to the schedule in Section 9.1.1, Laboratory Assessments; subjects must be fasting for at least 8 to 12 hours 
at baseline and end of study/early termination. 
9 
Blood samples will be collected at 0 and 2 hours post dose for pharmacokinetics. 
10 
Two FMV specimens, to be performed and resulted before baseline. 
11 
24-hour urine collection should begin 2 days prior to the scheduled study visit in order not to coincide with the FMV sampling due on the day of the study visit. 
12 
Serum pregnancy test to be evaluated at central laboratory at screening, Week 24, and Week 52; urine pregnancy test will be performed locally at all other 
applicable visits. 
13 
Adverse events will be recorded after the subject signs the ICF; AEs which occur during screening or prior to the first dose of study treatment will not be 
considered TEAEs. 
14 
Concomitant medications include all herbal medicines and supplements taken by the subject. 
15 
For details on HRQoL assessments, see Section 9.3.1, Health-related Quality of Life Assessments (HRQoL). 
16 
For details on Healthcare Resource Utilization, see Section 9.3.2, Healthcare Resource Utilization Assessment. 
17 
Compliance only. 
18 All scheduled procedures must be done prior to first dose, including IV methylprednisolone and MMF. 
19 
For subjects not on MMF during screening, will start receiving MMF therapy at the Baseline Visit and return for local complete blood count assessments at 
Weeks 1 and 3 after randomization (see Section 7 2 2 3, Mycophenolate Mofetil (Background Therapy)). 
20 
IV methylprednisolone administered 0.5 g on baseline and Day 2. If IV corticosteroids must be administered during screening then the FMV urine specimens 
will be collected prior to the infusion (see Section 7.2.2.2, Corticosteroids). 
21 
See Section 7.2.2.2, Corticosteroids. 
Notes: Subjects who discontinue therapy will attend their regularly scheduled study visits to the end of the study. Subjects who withdraw consent and terminate the 
study early or discontinue treatment early should be advised to attend both Visit 15 and the Safety Follow up Visit (Visit 16). 
Abbreviations: AE=adverse event; BP=blood pressure; CBC=complete blood count; ECG=electrocardiogram; FMV=first morning void; HRQoL=health-related quality of life; IV=intravenous; 
LN=lupus nephritis; MMF=mycophenolate mofetil; QTcF=QT interval duration corrected for heart rate using method of Fridericia; SAE=serious adverse event; SELENA-SLEDAI=Safety of 
Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index; SLE=systemic lupus erythematosus. 


 
 
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TABLE OF CONTENTS 
Page 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................4 
INVESTIGATOR AGREEMENT FORM ............................................................................5 
SYNOPSIS ................................................................................................................................6 
SCHEMA ................................................................................................................................12 
AUR-VCS-2016-01 SCHEDULE OF EVENTS ..................................................................13 
TABLE OF CONTENTS ......................................................................................................16 
LIST OF TABLES .................................................................................................................21 
LIST OF APPENDICES .......................................................................................................21 
LIST OF ABBREVIATIONS ...............................................................................................22 
1. 
INTRODUCTION AND BACKGROUND ..................................................................25 
1.1 
Background of the Disease and Treatment Options – Lupus Nephritis .......................25 
1.1.1 
Limitations of Current Treatment .............................................................................25 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Lupus Nephritis ............................27 
1.2.1 
Mechanism of Action................................................................................................27 
1.2.2 
Use of Immunosuppression in Lupus Nephritis .......................................................27 
1.2.3 
Clinical Studies of Calcineurin Inhibitors in Lupus Nephritis .................................28 
1.2.4 
Voclosporin ...............................................................................................................29 
1.2.4.1 
Pharmacokinetic Considerations ............................................................................29 
1.2.4.2 
Lupus Nephritis Clinical Development .................................................................30 
1.2.5 
Potential Toxicities ...................................................................................................31 
2. 
RATIONALE .................................................................................................................33 
2.1 
Dose Rationale .............................................................................................................33 
3. 
STUDY OBJECTIVES ..................................................................................................35 
3.1 
Primary Objective ........................................................................................................35 
3.2 
Secondary Objective ....................................................................................................35 
3.3 
Endpoints .....................................................................................................................35 
3.3.1 
Primary Endpoint ......................................................................................................35 
3.3.2 
Secondary Endpoints ................................................................................................35 
3.3.2.1 
Key Secondary Endpoints ......................................................................................35 
3.3.2.2 
Other Secondary Endpoints ...................................................................................36 
4. 
INVESTIGATIONAL PLAN .......................................................................................37 


 
 
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4.1 
Overall Study Design ...................................................................................................37 
4.2 
Duration of Subject Participation and Study ...............................................................37 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ................................................................................38 
5.1 
Number of Subjects......................................................................................................38 
5.2 
Inclusion Criteria .........................................................................................................38 
5.3 
Exclusion Criteria ........................................................................................................39 
5.4 
Adequate/Effective Contraception ...............................................................................41 
5.5 
Withdrawal of Subjects ................................................................................................42 
5.6 
Discontinuation of Study Treatment ............................................................................42 
5.6.1 
Discontinuation from Study Treatment Due to Early Non-response to Therapy .....42 
5.6.2 
Discontinuation of Study Treatment Due to an Adverse Event................................43 
6. 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ..............44 
6.1 
Randomization .............................................................................................................44 
6.2 
Blinding........................................................................................................................44 
6.3 
Unblinding ...................................................................................................................44 
7. 
STUDY TREATMENTS ...............................................................................................46 
7.1 
Dosage Forms/Formulation .........................................................................................46 
7.1.1 
Orelvo– Study Treatment..........................................................................................46 
7.1.2 
Placebo Control.........................................................................................................46 
7.1.3 
Background Therapy.................................................................................................46 
7.1.3.1 
Mycophenolate Mofetil ..........................................................................................46 
7.1.3.2 
Corticosteroids .......................................................................................................46 
7.2 
Drug Dosage and Administration ................................................................................46 
7.2.1 
Treatment Arms ........................................................................................................46 
7.2.2 
Dosing Guidelines.....................................................................................................47 
7.2.2.1 
Orelvo/Placebo – Study Treatment ........................................................................47 
7.2.2.2 
Corticosteroids .......................................................................................................47 
7.2.2.3 
Mycophenolate Mofetil (Background Therapy) ....................................................49 
7.3 
Package and Labeling ..................................................................................................50 
7.4 
Study Treatment Allocation .........................................................................................51 
7.5 
Site Supply, Storage, Accountability ...........................................................................51 
7.5.1 
Site Supply ................................................................................................................51 
7.5.2 
Storage ......................................................................................................................51 
7.5.3 
Accountability ...........................................................................................................51 
7.6 
Orelvo/Placebo Dose Modification..............................................................................52 
7.6.1 
Deterioration in Renal Function ...............................................................................52 
7.6.1.1 
Decrease in eGFR >30% and eGFR <60 mL/min/1.73 m2 ....................................52 
7.6.1.2 
Decrease in eGFR ≤30% and eGFR <60 mL/min/1.73 m2 ....................................53 


 
 
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7.6.1.3 
Recovery of eGFR .................................................................................................53 
7.7 
Procedures for Overdose ..............................................................................................53 
7.8 
Prohibited Therapy and Concomitant Treatment .........................................................53 
7.8.1 
Prohibited Medications .............................................................................................54 
7.8.2 
Allowed Concomitant Medications ..........................................................................55 
7.9 
Increased Blood Pressure .............................................................................................55 
8. 
RISKS/PRECAUTIONS ...............................................................................................56 
9. 
STUDY PROCEDURES ...............................................................................................57 
9.1 
Description of Study Assessments ...............................................................................57 
9.1.1 
Laboratory Assessments ...........................................................................................57 
9.1.1.1 
Evaluation of Biomarkers ......................................................................................59 
9.1.2 
Physical Examinations ..............................................................................................59 
9.1.3 
Vital Signs.................................................................................................................60 
9.1.3.1 
Blood Pressure Management .................................................................................60 
9.1.4 
Standard 12-lead Electrocardiogram ........................................................................60 
9.1.4.1 
Procedures to Manage a Treatment-Emergent Increase in QTc ............................61 
9.1.5 
Lupus Disease Activity Assessments .......................................................................61 
9.1.6 
Orelvo Pharmacokinetics ..........................................................................................61 
9.2 
Schedule of Assessments .............................................................................................61 
9.2.1 
Screening Visit Procedures .......................................................................................62 
9.2.2 
Treatment Procedures ...............................................................................................62 
9.2.3 
End of Study (or Early Discontinuation) Procedures ...............................................64 
9.2.4 
Follow-up Procedures ...............................................................................................65 
9.2.5 
Unscheduled Visit .....................................................................................................65 
9.3 
Study Specific Assessment Procedures .......................................................................66 
9.3.1 
Health-related Quality of Life Assessments (HRQoL) .............................................66 
9.3.1.1 
Short Form Health Survey (SF-36) ........................................................................66 
9.3.1.2 
LupusPRO ..............................................................................................................66 
9.3.2 
Healthcare Resource Utilization Assessment ...........................................................66 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............67 
10.1 
Definitions....................................................................................................................67 
10.1.1 
Adverse Event ...........................................................................................................67 
10.1.2 
Adverse Drug Reaction .............................................................................................67 
10.1.3 
Serious Adverse Event ..............................................................................................67 
10.1.4 
Suspected Unexpected Serious Adverse Reaction....................................................68 
10.2 
Adverse Event Descriptors ..........................................................................................68 
10.2.1 
Intensity/Severity Categorization .............................................................................68 
10.2.2 
Causal Relationship Categorization ..........................................................................69 
10.2.3 
Outcome Categorization ...........................................................................................69 


 
 
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10.2.4 
Symptoms of the Disease Under Study ....................................................................70 
10.2.5 
Clinical Laboratory Evaluations ...............................................................................70 
10.2.6 
Abuse, Misuse, Overdose and Medication Error ......................................................70 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................70 
10.3.1 
Adverse Events .........................................................................................................70 
10.3.2 
Serious Adverse Events ............................................................................................71 
10.3.3 
Pregnancy..................................................................................................................73 
11. CLINICAL ENDPOINTS COMMITTEE ..................................................................74 
12. DATA AND SAFETY MONITORING BOARD PROCEDURES ...........................75 
13. STATISTICAL ANALYSIS .........................................................................................76 
13.1 
Statistical Methods .......................................................................................................76 
13.2 
Sample Size and Power Calculations ...........................................................................76 
13.3 
Populations ...................................................................................................................76 
13.3.1 
Intent-to-Treat Set .....................................................................................................76 
13.3.2 
Safety Set ..................................................................................................................77 
13.3.3 
Per-protocol Set ........................................................................................................77 
13.4 
Background and Demographic Characteristics ............................................................77 
13.5 
Study Treatment ...........................................................................................................77 
13.6 
Concomitant Therapy...................................................................................................77 
13.7 
Efficacy Evaluations ....................................................................................................77 
13.7.1 
Primary Endpoint ......................................................................................................77 
13.7.2 
Secondary Endpoints ................................................................................................78 
13.7.2.1 
Key Secondary Endpoints ......................................................................................78 
13.7.2.2 
Other Secondary Endpoints ...................................................................................78 
13.8 
Statistical and Analytical Methods ..............................................................................79 
13.8.1 
Primary Efficacy Analysis ........................................................................................79 
13.8.2 
Sensitivity Analyses ..................................................................................................79 
13.8.3 
Secondary Efficacy Analysis ....................................................................................79 
13.8.3.1 
Response Endpoints ...............................................................................................79 
13.8.3.2 
Time to Endpoints ..................................................................................................80 
13.8.3.3 
Change from Baseline Endpoints...........................................................................80 
13.8.3.4 
Health Resource Utilization ...................................................................................81 
13.8.4 
Multiplicity ...............................................................................................................81 
13.9 
Safety Evaluations .......................................................................................................81 
13.10 Interim Analyses ..........................................................................................................82 
13.11 Other Evaluations.........................................................................................................82 
13.11.1 Pharmacokinetics ......................................................................................................82 
14. ETHICAL CONDUCT OF THE STUDY ...................................................................83 
14.1 
Informed Consent.........................................................................................................83 


 
 
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14.2 
Institutional Review Board or EC/IEC ........................................................................83 
15. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................84 
16. ADMINISTRATIVE PROCEDURES .........................................................................85 
16.1 
Sponsor’s Responsibilities ...........................................................................................85 
16.1.1 
Study Supplies ..........................................................................................................85 
16.1.2 
Insurance ...................................................................................................................85 
16.1.3 
Study Monitoring ......................................................................................................85 
16.2 
Investigator’s Responsibilities .....................................................................................86 
16.2.1 
Reporting and Recording of Data .............................................................................86 
16.2.2 
Investigator Training.................................................................................................86 
16.2.3 
Source Documentation ..............................................................................................86 
17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .............................................................................88 
17.1 
Protocol Waivers, Deviations and Violations ..............................................................88 
17.2 
Study Termination .......................................................................................................88 
18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................89 
19. REFERENCES ...............................................................................................................90 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Dosing Schedule for IV Methylprednisolone and Daily Oral 
Prednisone (mg) ...............................................................................................49 
Table 2 
Review of Laboratory Assessments .................................................................57 
Table 3 
Orelvo Response Rates Required to Maintain a Minimum 80% Power ..........76 
 
LIST OF APPENDICES 
Page 
Appendix 1 
Drug Therapy for the Treatment of Hypertension ...........................................93 
Appendix 2 
Measurement of Blood Pressure ......................................................................94 
Appendix 3 
International Society of Nephrology and the Renal Pathology Society 
(ISN/RPS) 2003 Classification of Lupus Nephritis .........................................95 
Appendix 4 
Conversion Table for Oral Corticosteroids ......................................................97 
Appendix 5 
1997 Update of the 1982 American College of Rheumatology Revised Criteria 
for the Classification of Systemic Lupus Erythematosus ................................98 
Appendix 6 
Systemic Lupus Erythematosus Disease Activity Measure 
(SELENA-SLEDAI) ......................................................................................100 
Appendix 7 
Expanded List of Allowed Concomitant Medications ...................................102 
Appendix 8 
Summary of Treatment and Food Restrictions ..............................................104 
Appendix 9 
Short Form Health Survey (SF-36) HRQoL Assessment ..............................105 
Appendix 10 LupusPRO (v1.7) HRQoL Assessment .........................................................111 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
ACE 
Angiotensin converting enzyme 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALMS 
Aspreva Lupus Management Study 
ANC 
Absolute neutrophil count 
ARB 
Angiotensin receptor blocker 
AUC0-12 
Area under the curve between 0 and 12 hours 
AUC0-24 
Area under the curve between 0 and 24 hours 
AURA-LV 
Aurinia Urinary protein Reduction Active – Lupus with 
Voclosporin 
AURION 
Aurinia early Urinary protein ReductION Predicts Response 
AURORA 
AURinia Orelvo Renal Assessments 
Aurinia 
Aurinia Pharmaceuticals Inc. 
AZA 
Azathioprine 
BID 
Twice daily 
BP 
Blood pressure 
C3 / C4 
Complement 3 / complement 4 
CEC 
Clinical Endpoints Committee 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum concentration 
CNI 
Calcineurin inhibitor 
CsA 
Cyclosporine A 
CYP3A4/5 
Cytochrome P450 3A4/5 
DMC 
Data Monitoring Committee 
dsDNA 
Double-stranded deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 


 
 
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EDC 
Electronic data capture 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HCP 
Health care professional 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVC 
Intravenous cyclophosphamide 
IWRS 
Interactive web response system 
LN 
Lupus nephritis 
MMF 
Mycophenolate mofetil 
MMRM 
Mixed Effect Model Repeated Measures 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Odds ratio 
Orelvo 
Voclosporin (for Phase 3 lupus nephritis indication) 
P-gp 
P-glycoprotein 


 
 
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PK 
Pharmacokinetic 
QTc 
Corrected QT interval 
QTcF 
QT interval duration corrected for heart rate using method of 
Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SELENA 
Safety of Estrogens in Lupus Erythematosus National Assessment 
SLE 
Systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
t1/2 
Terminal elimination half-life 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
UPCR 
Urine protein creatinine ratio 
 
 
WHO 
World Health Organization 


 
 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options – Lupus 
Nephritis 
Lupus nephritis (LN) is the most common serious manifestation of systemic lupus 
erythematosus (SLE). Lupus nephritis is divided into different classes according to the level of 
treatment required, using a classification system for renal biopsy pathology originally 
developed by the World Health Organization (WHO). The classification of LN has evolved 
and the “International Society of Nephrology/Renal Pathology Society 2003 Classification of 
Lupus Nephritis” is now widely used and has a higher level of inter-observer reproducibility 
than the original classification (see Appendix 3). For subjects with Class III, IV (proliferative), 
or V (membranous), or combinations of these forms of LN, the standard of care is treatment 
with corticosteroids and immunosuppressive therapy. 
Lupus nephritis manifests as diverse patterns of immune complex-mediated renal disease 
affecting glomerular, tubulointerstitial, and vascular compartments. It can lead to permanent 
and irreversible tissue damage within the kidney, resulting in end-stage renal disease (ESRD), 
and thus making LN a serious and potentially life-threatening condition. In subjects with LN, 
renal damage results in proteinuria and/or hematuria and a decrease in renal function as 
evidenced by reduced creatinine clearance and estimated glomerular filtration rate (eGFR), and 
increased serum creatinine levels. 
In LN as in other serious renal diseases, the main clinical outcomes are progression to ESRD 
(i.e., the need for long-term dialysis or transplantation) and death. The current standard of care 
for LN, corticosteroids and immunosuppressants, has improved the prognosis of the disease 
considerably. Incidence rates of ESRD in LN, however, appear to have been stable over recent 
years, possibly reflecting the limits of effectiveness of current treatments or lack of adherence 
to treatments by subjects. The most recent studies have reported 10-year survival rates of over 
90% and, although the overall risk of developing ESRD in subjects with LN is approximately 
15%, the 5-year risk of developing ESRD has been found to be as low as 5% [1]. Recently, 
10-year follow-up data of LN subjects treated with intravenous cyclophosphamide (IVC) for 
active disease followed by maintenance treatment with azathioprine (AZA) found rates of 
ESRD to be approximately 7% [2]. 
1.1.1 Limitations of Current Treatment 
The current treatment paradigm for LN includes 2 goals, based on the severity of disease. The 
first goal of treatment in subjects with active LN is intended to bring the disease under control 
as quickly as possible to limit the potential for extensive renal scarring or loss of life. This 
phase of treatment is particularly critical for those subjects at highest risk for ESRD (i.e., 
subjects with clinical or laboratory indicators of active nephritis, such as biopsy evidence of 


 
 
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proliferative nephritis, active urinary sediment, elevated serum creatinine, and/or proteinuria). 
In subjects with severe LN, the achievement of complete or partial remission, as demonstrated 
by stabilization or improvement in renal function, improvement in proteinuria, and 
normalization of active urinary sediment, has been shown to be associated with better patient 
and renal survival. Treatment of active LN (i.e., induction treatment) typically consists of high 
doses of both corticosteroids and immunosuppressants. 
The second goal of treatment, after the patient successfully responds to treatment, is to 
maintain remission by preventing renal flares and any resulting deterioration in renal function. 
In this second phase of treatment, lower doses of both corticosteroids and immunosuppressants 
are used. 
Corticosteroids are the cornerstone of treatment in SLE, and have been the standard since the 
1950s to treat both renal and non-renal manifestations. Intravenous (IV) steroid pulse therapy 
is widely used to rapidly treat relapsing LN, but does not provide long-term management. Oral 
corticosteroids taken for prolonged periods and at high doses are often needed, but have 
potentially severe, and at times irreversible adverse effects including risk of infection, 
hyperlipidemia, hypertension, osteoporosis, diabetes, and accelerated atherosclerosis. 
Induction treatment recommendations advocate the use of immunosuppressants in conjunction 
with high-dose oral corticosteroids, to enable a rapid taper to a lower maintenance dose of 
steroids. Steroid-sparing therapies are needed in order to treat disease activity and also 
minimize cumulative and high-dose steroid exposure. 
Intravenous cyclophosphamide, while classically considered the standard of care for induction 
therapy, is still associated with significant potentially life-threatening toxicities, such as the 
increased risk of severe infections including sepsis, malignancy, and major morbidity, such as 
permanent gonadal failure. 
Recent studies have shown that induction treatment with mycophenolate mofetil (MMF) has 
similar efficacy to that of IVC. The authors of a recent meta-analysis concluded that MMF is 
as efficacious as IVC and is not associated with the risk of infertility, which is a significant 
toxicity of IVC in this patient population [3]. In the Aspreva Lupus Management Study 
(ALMS), a comparison of MMF and IVC in the treatment of active LN, 50.4% subjects with 
active LN entering the study had nephrotic-range proteinuria (>3 g/day) [4]. Intravenous 
cyclophosphamide and MMF reduced proteinuria to a similar extent. However, even after 
24 weeks of therapy with either MMF or IVC in the setting of a clinical study, subjects had 
substantial residual proteinuria. At the end of 24 weeks of therapy, normal (<500 mg/24 hours) 
protein excretion levels were observed in only 27% of subjects who received IVC and 23.8% 
of subjects who received MMF [5]. The findings from ALMS indicate that there exists a 
substantial unmet medical need for more effective treatments for active LN with heavy 
proteinuria. 


 
 
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The importance of proteinuria and reduction of proteinuria as prognostic factors for renal 
flares, ESRD and death in subjects with LN is well documented. Proteinuria in itself is related 
to progression of renal disease through effects on the glomerulus and tubulointerstitium [6]. In 
observational studies, proteinuria has been shown to be a predictor of adverse renal outcomes, 
cardiovascular disease, and mortality in subjects with non-diabetic proteinuric 
nephropathies [7]. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Lupus Nephritis 
1.2.1 Mechanism of Action 
Calcineurin inhibitors (CNIs) are a class of immunosuppressants which reversibly inhibit 
immunocompetent lymphocytes, particularly T-lymphocytes in the G0 and G1 phase of the 
cell-cycle, and also reversibly inhibit the production and release of lymphokines. Voclosporin, 
a CNI, mediates its suppressive effects by binding to an ubiquitous intracellular protein 
cyclophilin. This complex, in turn, inhibits the calcium- and calmodulin-dependent 
serine/threonine phosphatase activity of the enzyme calcineurin. Calcineurin inhibition then 
prevents the activation of various transcription factors necessary for the induction of cytokine 
genes during T-cell activation, such as interleukin-2, interleukin-4, tumor necrosis factor-α, 
granulocyte-macrophage colony stimulating factor, and interferon-γ. 
1.2.2 Use of Immunosuppression in Lupus Nephritis 
Calcineurin inhibitors are standard treatment to prevent acute rejection in subjects who have 
received transplants. Since the development of cyclosporine in the early 1980s, standard 
immunosuppression regimens to prevent rejection post-transplantation have included steroids 
and a CNI; more recently other immunosuppressants, such as MMF, have been added to 
standard therapy. The rationale for use of CNIs in autoimmune diseases include potent effects 
on T-cell activation and immunomodulatory effects. AT-cell mediated immune response is an 
important feature of the pathogenesis of many of these diseases, including LN. Calcineurin 
inhibitors also have specific anti-proteinuric effects. The podocyte is a key cell in the 
glomerular capillary wall that maintains the integrity of the filtration barrier and prevents the 
development of proteinuria in healthy individuals, while being the primary target of injury in 
proteinuric kidney disease. Podocyte injury is an important factor in the progression of LN. It 
typically occurs due to immune complex deposition but may also occur in the absence of this 
histologic feature [8]. Podocyte function depends on a complex and unique structure that, in 
turn, depends on a tightly regulated actin cytoskeleton. Synaptopodin acts as a key stabilizer 
of the actin cytoskeleton in podocytes. When synaptopodin is phosphorylated, it binds to 
another protein, 14-3-3, and is thus protected from degradation. Calcineurin dephosphorylates 
synaptopodin allowing its degradation, thus promoting proteinuria by destabilization of the 
podocyte actin cytoskeleton. Expression of activated calcineurin in podocytes leads to 
proteinuria. By inhibiting activated calcineurin, tacrolimus thus exerts a specific 


 
 
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anti-proteinuric effect by preventing the degradation of the podocyte-stabilizing protein 
synaptopodin. Taken together, these data suggest that the anti-proteinuric effects of CNIs may 
be explained by their direct effect on the podocyte actin cytoskeleton as well as 
immunomodulatory effects on T-lymphocytes [9]. 
1.2.3 Clinical Studies of Calcineurin Inhibitors in Lupus Nephritis 
Bao et al, 2008 [10] performed an open-label study in 40 subjects with Class V+IV LN. 
Subjects were randomized to either IVC and prednisolone or “multi-target therapy” with MMF 
plus tacrolimus (4 mg/day) and prednisolone. In the multi-target group, 50% achieved 
complete remission compared with 5% in the standard IVC group at 6 months. Estimated 
glomerular filtration rate normalized in both groups, but there was a significantly larger 
reduction in proteinuria in the multi-target therapy group.  
Miyasaka et al, 2009 [11] evaluated the efficacy and safety of tacrolimus in 63 subjects 
receiving glucocorticoid therapy for LN in a double-blind, placebo-controlled, randomized 
trial. Subjects with persistent nephritis requiring 10 mg/day prednisone were randomized to 
receive 28 weeks of treatment with tacrolimus (3 mg/day) or placebo. There was a statistically 
significant improvement in the primary endpoint, the Lupus Nephritis Disease Activity Index, 
in the tacrolimus group compared to the placebo group. Daily urinary protein excretion (the 
percentage of subjects with urine protein <0.3 g/day at the final evaluation) also showed a 
significant decrease in the tacrolimus group. However, measures of glucose intolerance were 
more frequent in tacrolimus-treated subjects. The authors concluded that tacrolimus should be 
considered one of the options to treat LN. On the basis of the results of this study, tacrolimus 
was approved for the treatment of LN in Japan. 
In an observational study conducted by Cortes-Hernandez et al, 2010 [12], 70 subjects who 
had received MMF as continuous therapy were followed over a 5-year period. Tacrolimus was 
added as rescue therapy in 17 subjects who were treatment failures or had renal flares on 
treatment with MMF. The authors reported a significant reduction in proteinuria at 3 months, 
and after 2 years of follow-up, it was concluded that tacrolimus was a safe and effective 
treatment for MMF non-responsive cases. 
Several smaller pilot studies and case series in subjects with LN, including subjects with 
membranous nephropathy, have suggested a treatment benefit of tacrolimus with or without 
MMF [13-19]. 
The available data suggest a plausible mechanism of action by which CNIs may provide 
treatment benefits in LN. The clinical evidence is suggestive of improvement in measures of 
response in active LN and improvement in extrarenal manifestations of SLE and immunologic 
parameters. 


 
 
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1.2.4 Voclosporin 
Voclosporin is a next-generation CNI developed for the treatment of autoimmune diseases and 
for use in the prevention of organ graft rejection. Voclosporin is structurally similar to 
cyclosporine A (CsA) except for a novel modification of a functional group on the amino acid 1 
residue of the molecule. This alteration has changed the binding of voclosporin to calcineurin 
leading to a 3- to 5-fold increase in potency when compared to CsA. This modification has 
also shifted metabolism away from amino acid 1, the major site of metabolism for CsA, thus 
altering the metabolic profile. This in turn has led to faster elimination of metabolites resulting 
in lower measured metabolite exposure as compared to CsA. The combination of increased 
potency and decreased measured metabolite exposure, for voclosporin as compared to CsA, 
has led to better pharmacokinetic (PK)/ pharmacodynamic predictability. 
During the development of this investigational product the legacy names of voclosporin, VCS, 
 are referenced in discussions related to historical usage. However, for the LN Phase 3 
clinical development program, the name of the investigational product will be referred to as 
Orelvo, the proposed trade name. These legacy names should all be considered interchangeable 
unless specifically identified as different. 
Prior to the LN clinical development program, approximately 2,200 subjects received 
investigational products containing voclosporin in 14 Phase 1 and 10 Phase 2/3 clinical studies 
in the indications of transplant rejection, psoriasis and non-infectious uveitis. Detailed data for 
these clinical studies are presented in the Investigator’s Brochure (IB).  
1.2.4.1 Pharmacokinetic Considerations 
Voclosporin approximates linear multiexponential PKs. Exposure to voclosporin was 
dose-related with maximum concentrations occurring ≤2 hours with a terminal elimination 
half-life (t1/2) of ≥30 hours. Drug accumulation was minor with accumulation factors of 
approximately 2 hours after twice daily (BID) dosing. Administration of voclosporin oral 
solution with either low- or high-fat meals decreased both the rate and extent of absorption 
which appeared to be related to the fat content of the meal. It is therefore recommended that 
Orelvo (voclosporin) be administered on an empty stomach to ensure adequate absorption. 
Voclosporin has been shown to be a substrate of cytochrome P450 3A4/5 (CYP3A4/5). 
Concomitant administration of ketoconazole, a strong CYP3A4/5 inhibitor, led to a 6-fold 
increase in maximum concentration (Cmax) and an 18-fold increase in area under the curve 
between 0 and 12 hours (AUC0-12) for voclosporin. Concomitant administration of rifampin, 
an inducer of CYP3A4/5, resulted in a decrease in exposure to voclosporin. Maximum 
concentration decreased approximately 70%, the area under the concentration curve decreased 
approximately 90%, and t1/2 decreased 85%. Consequently, both ketoconazole and rifampin 
are contraindicated with Orelvo (voclosporin). Concomitant administration of voclosporin and 


 
 
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midazolam, a model substrate of CYP3A4/5 and potential inhibitor of CYP3A4/5, did not 
result in statistically significant changes in the rate or extent of exposure to midazolam or 
α-hydroxy-midazolam. 
Voclosporin is both a substrate for and an inhibitor of P-glycoprotein (P-gp). Concomitant 
administration of verapamil, a known inhibitor of P-gp, demonstrated an approximate 3-fold 
increase in Cmax and AUC0-12 of voclosporin. Concomitant administration of digoxin, a P-gp 
substrate, resulted in statistically significant increases in digoxin Cmax and area under the curve 
between 0 and 24 hours (AUC0-24) and a decrease in clearance. Therefore concomitant 
administration of P-gp substrates with voclosporin would be expected to result in increased 
exposure to the substrate. Clinicians are advised to consider the benefit/risk of concomitant 
P-gp substrate drugs carefully. 
1.2.4.2 Lupus Nephritis Clinical Development 
The AURA-LV study (Protocol AUR-VCS-2012-01) is a randomized, controlled, 
double-blind Phase 2 study comparing the efficacy and safety of voclosporin (23.7 mg BID or 
39.5 mg BID) with placebo in achieving remission in patients with active LN. The duration of 
the study is 48 weeks and is ongoing. All patients received background therapy with MMF and 
corticosteroid taper. The primary endpoint of complete remission was defined as: urine protein 
creatinine ratio (UPCR) of ≤0.5 mg/mg at 24 weeks (using first morning void) and eGFR 
≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of ≥20%. In addition, 
patients could not receive rescue medications for LN (defined as >10 mg prednisone/day 
for >3 consecutive days or >7 days total from Weeks 16-24) to be considered for complete 
remission.  
A total of 265 subjects were randomized into the AURA-LV study. The 24-week primary 
endpoint assessment for the AURA-LV clinical study demonstrated that the groups were 
generally well balanced for age, gender and race, with a trend to higher proteinuria and lower 
eGFR data in the low-dose voclosporin arm. The low dose achieved a statistically significant 
benefit over placebo for the primary efficacy assessment of complete remission at 24 weeks 
(odds ratio (OR) [95% CI] = 2.03, [1.01, 4.05], p=0.045), without a statistically significant 
improvement seen in the high dose. The results were confirmed by 24 hour urine collections 
(p=0.047). Both the low- and high-dose voclosporin were statistically superior to placebo in 
partial remission, time to complete remission, and time to partial remission. A mean reduction 
in serum creatinine was seen in both arms (0.2 mg/dL low, 0.1 high; p<0.001). In the 
voclosporin groups, eGFR fell by a median of 8-9 mL/min by Week 4 and then stabilized over 
the course of the study. Blood pressure did not vary by group. The correlation of 24-hour urine 
protein and using the first morning void was assessed from the results of the AURA-LV study 
demonstrating a high degree of correlation (Pearson Correlation Coefficient = 0.92). 


 
 
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Over 90% of subjects experienced at least 1 adverse event (AE); the most common being 
infectious disease (56.2% low-dose, 63.6% high-dose and 50.0% placebo), GI disorders 
(41.6% low-dose, 52.3% high-dose and 36.4% placebo). More serious adverse events (SAEs) 
occurred in the voclosporin groups (25.8% low-dose, 25.0% high-dose, 15.8% placebo), and 
were consistent with those observed in LN patients. There were 13 deaths (4.9%) during the 
study. There were more deaths in the voclosporin low-dose arm (10) than in either the 
voclosporin high-dose (2) or placebo (1) arms, with the majority (11/13) occurring in Asia. All 
deaths were assessed by the Investigators as unrelated to study treatment.  
In summary, no unexpected safety signals were observed with the use of voclosporin in LN 
subjects; voclosporin was generally well tolerated. The overall safety profile is consistent with 
the expectations for the class of drug, the patient population, and concomitant therapies.  
The AURION study (protocol AUR-VCS-2014-01) is an exploratory open-label Phase 2 study 
assessing the short-term predictors of remission of voclosporin 23.7 mg BID in combination 
with standard of care in patients with active LN. The duration of the study is 48 weeks with 
10 subjects randomized. All subjects received background therapy with MMF and 
corticosteroids. At 24 weeks, 4/7 (57.1%) subjects continued to be in complete remission as 
measured by a UPCR of ≤0.5 mg/mg, eGFR within 20% of baseline, and concomitant steroid 
dose of less than 5 mg/day. Within these 7 AURION patients, there was a 54% mean reduction 
in proteinuria at 24 weeks compared to pre-treatment levels along with consistent 
improvements in complement 3 (C3), C4 and anti-double-stranded DNA. Renal function as 
measured by eGFR remained stable. Voclosporin was well tolerated with no unexpected safety 
signals observed.  
1.2.5 Potential Toxicities 
Voclosporin has been studied in numerous disease states. When examining LN, there were a 
small proportion of voclosporin treated subjects that experienced an early drop of ≥30% in 
eGFR, however that proportion then remains stable over time. None of these treatment-
emergent adverse events (TEAEs) were classed as serious. The majority of TEAEs of 
decreased GFR were classed as mild or moderate, and resulted in permanent discontinuation 
of study drug in 1 (1.1%) placebo subject, 6 (6.7%) voclosporin low-dose subjects and 5 (5.6%) 
voclosporin high-dose subjects. There were more TEAEs of hypertension seen in the 
voclosporin-treated patients compared to placebo however, overall mean systolic and diastolic 
blood pressure (BP) decreased in all groups, without statistically significant differences seen 
between groups. Overall, only 1 (1.1%) subject, in the voclosporin high-dose group, had a 
TEAE of hypertension that resulted in permanent discontinuation of study drug.  
There was evidence of an increased incidence of TEAEs over placebo and with increased dose 
of voclosporin in the System Organ Classes of Infections and Infestations, Gastrointestinal 
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There were more deaths in the voclosporin low-dose arm (10) than in either the voclosporin 
high-dose (2) or placebo (1) arms, with the majority (11/13) occurring in South-East Asia. All 
deaths were assessed by the Investigator and Data and Safety Monitoring Board (DSMB) as 
unrelated to study treatment. A full description of adverse events can be found in the IB. 


 
 
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2. RATIONALE 
The rationale for the development of Orelvo and the choice of doses is to introduce a novel 
CNI to the LN patient population, with meaningful efficacy while minimizing toxicities 
common to other CNIs. In clinical studies, a favorable efficacy/safety profile for Orelvo has 
been demonstrated in the prevention of renal transplant rejection. 
As evaluated in nonclinical and clinical studies (healthy volunteers, moderate to severe 
psoriasis, renal transplantation, and uveitis) Orelvo is well tolerated and exhibits AEs that are 
typical of other CNIs yet seen to a lesser extent than that seen historically with other CNIs. 
The aim of the current study is to investigate whether Orelvo, added to the standard of care 
treatment in active LN, is able to reduce disease activity over a treatment period of 52 weeks. 
The background therapy will be MMF at a dose of at least 1 g/day and initial treatment with 
IV methylprednisolone, followed by a reducing course of oral corticosteroids. Subjects with 
active, flaring LN will be eligible to enter the study. They are required to have a diagnosis of 
LN according to established diagnostic criteria (American College of Rheumatology) and 
clinical and biopsy features suggestive of active nephritis. Efficacy will be assessed by the 
ability of the drug combination to reduce the level of proteinuria (as measured by urine 
protein/creatinine ratio (UPCR)) while demonstrating an acceptable safety profile. Normally, 
most subjects will respond to treatment by 6 months, but the optimal short-term predictor of 
long-term renal function is the response to treatment by 12 months (as observed in the 
AURA-LV study). Therefore, the primary endpoint of the Phase 3 study will be complete renal 
response at 52 weeks. 
2.1 
Dose Rationale 
This Phase 3 study is designed to evaluate the treatment benefit of Orelvo 23.7 mg BID versus 
placebo. Orelvo and/or placebo are herein referred to as study treatment. The selection of 
Orelvo dose in this study (see Section 7, Study Treatments) was based on the previous 
experience with this drug in the Phase 2 study (AURA-LV). In AURA-LV, subjects were 
administered voclosporin 23.7 mg BID, 39.5 mg BID, or matching placebo. Low-dose 
voclosporin was significantly superior to placebo in the proportion of subjects achieving 
complete renal response at Week 24 (p=0.045). There was no increase in efficacy with the 
higher dose and no significant differences between the 2 voclosporin groups in achievement 
of renal response.  
Orelvo 23.7 mg BID will be administered as a fixed dose without the use of therapeutic drug 
monitoring. Population PK analyses of voclosporin concentrations from the clinical 
development program (including healthy subjects, subjects with renal impairment, subjects 
with hepatic impairment, renal transplant, and plaque psoriasis) demonstrated that weight did 
not have a significant effect on the PKs of voclosporin. The protocol contains provisions for 


 
 
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management of dose based on safety concerns, in particular, BP and renal function. The safety 
data from the use of voclosporin demonstrates that these risks are dose-related, reversible, and 
can be managed by dose reduction and temporary interruption.   


 
 
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the efficacy of Orelvo (voclosporin) compared with placebo in achieving renal 
response after 52 weeks of therapy in subjects with active LN 
3.2 
Secondary Objective 
• To assess the safety and tolerability of Orelvo over 52 weeks compared with placebo in 
subjects with active LN 
3.3 
Endpoints 
3.3.1 Primary Endpoint 
Renal response at Week 52 will be adjudicated by the Clinical Endpoints Committee (CEC) 
based on the following parameters: 
• UPCR of ≤0.5 mg/mg, and 
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, 
and 
• Received no rescue medication for LN (see Section 7.8, Prohibited Therapy and 
Concomitant Treatment), and 
• Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in 
total during Weeks 44 through 52, just prior to the renal response assessment 
Subjects who withdraw from the study prior to the Week 52 assessment will be defined as 
non-responders. 
3.3.2 Secondary Endpoints 
3.3.2.1 Key Secondary Endpoints 
• Time to UPCR of ≤0.5 mg/mg 
• Partial renal response as defined by 50% reduction from baseline in UPCR at Weeks 24 
and 52 
• Time to 50% reduction in UPCR from baseline 
• Renal response at Week 52 (based on definition of primary endpoint) 


 
 
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• Duration of UPCR ≤0.5 mg/mg 
• Proportion of subjects experiencing a confirmed >30% decrease from baseline in eGFR 
at each timepoint 
3.3.2.2 Other Secondary Endpoints 
• Change from baseline in UPCR at each time point 
• Change from baseline in serum creatinine, urine protein, and eGFR 
• Change from screening in immunology parameters (complement 3 (C3), C4, and anti- 
double-stranded deoxyribonucleic acid (dsDNA)) at Weeks 24 and 52 
• Renal response with low-dose steroids (defined as renal response in the presence of 
corticosteroids of ≤2.5 mg/day between Weeks 16 to 24 and Weeks 44 to 52) 
• Change from baseline in health-related quality of life (HRQoL) at Weeks 12, 24, and 
52 
• Health Resource Utilization at Weeks 24 and 52 
• Change from baseline in the Safety of Estrogens in Lupus Erythematosus National 
Assessment - Systemic Lupus Erythematosus Disease Activity (SELENA-SLEDAI) 
Index score at Weeks 24 and 52 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 3, multicenter, randomized, prospective, double-blind, parallel-group, 
placebo-controlled, 2-arm comparison study of Orelvo versus matching placebo. Subjects who 
have provided a signed and dated informed consent will be screened into the study up to 
30 days before randomization. During the screening period, eligibility criteria will be assessed. 
A kidney biopsy may be performed, provided the subject has given consent and provided the 
results can be obtained and reviewed before baseline. Subjects who meet all of the inclusion 
criteria and none of the exclusion criteria will be eligible for randomization into the study. 
Baseline assessments will be performed before the first dose of study treatment is administered 
on Day 1. The baseline assessments of the serum creatinine and urine protein laboratory 
parameters will be established by using the mean of the 2 pre-randomization values. Using an 
interactive web response system (IWRS), eligible subjects will be randomized to receive either 
oral Orelvo 23.7 mg BID or matching placebo for 52 weeks. All subjects should receive 
0.5 g/day IV methylprednisolone on Days 1 and 2 before changing to a reducing course of oral 
corticosteroid therapy on Day 3. (For additional details and exceptions, see Section 7.2.2.2, 
Corticosteroids). Starting at the Baseline Visit, all subjects will also receive background 
therapy with MMF (see Section 7.2.2.3, Mycophenolate Mofetil (Background Therapy). 
All subjects will return for assessment of efficacy and safety at Day 2 and Weeks 2, 4, 8, 12, 
16, 20, 24, 30, 36, 42, 48, and 52. See Schedule of Events, for detailed information regarding 
visits. In addition, subjects not on MMF during screening, will start receiving MMF at the 
Baseline Visit and will return for local complete blood count assessments at Weeks 1 and 3 
after randomization. 
All subjects, completed or withdrawn, will complete the End of Treatment/Early Termination 
assessments (Visit 15) at Week 52 or at the time of early termination. Subjects who do not 
enroll in the continuation study will attend the Safety Follow-up Visit (Visit 16) at Week 56 to 
collect any new AEs and concomitant medications. At the follow-up visit, UPCR and eGFR 
will be assessed as well. For subject withdrawal procedures and criteria, see Section 5.5, 
Withdrawal of Subjects. 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is approximately 60 weeks. The screening 
period is up to 30 days and the treatment duration is 52 weeks, with a further follow-up visit 
4 weeks after last dose (completion or early termination) if not participating in the continuation 
study. 


 
 
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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
It is anticipated that approximately 324 subjects (162 in the Orelvo 23.7 mg BID treatment 
group and 162 subjects in the placebo group) will be randomized in this study.  
5.2 
Inclusion Criteria 
The following inclusion criteria must be met for each subject: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 (or legal age of consent if >18 years) 
to 75 years of age, inclusive, at the time of screening (Visit 1). 
3. Previous diagnosis of SLE according to the American College of Rheumatology criteria 
(1997; see Appendix 5). 
4. Subjects with evidence of active nephritis, defined as follows: 
Kidney biopsy result within 2 years prior to screening indicating Class III, IV-S, IV-G 
(alone or in combination with Class V), or Class V LN (see Appendix 3) with a doubling 
or greater increase of UPCR within the last 6 months to a minimum of ≥1.5 mg/mg for 
Class III/IV or to a minimum of ≥2 mg/mg for Class V at screening. Biopsy results over 
6 months prior to screening must be reviewed with a medical monitor to confirm 
eligibility. 
OR 
Kidney biopsy result within 6 months prior to screening indicating Class III, IV-S, or 
IV-G (alone or in combination with Class V) LN with a UPCR of ≥1.5 mg/mg at 
screening. 
OR 
Kidney biopsy result within 6 months prior to screening indicating Class V LN and a 
UPCR of ≥2 mg/mg at screening.  
A biopsy can be performed during screening, if not available. The above criteria must be 
fulfilled at baseline. 


 
 
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5. In the opinion of the Investigator, subject requires high-dose corticosteroids and 
immunosuppressive therapy. 
6. Subject is willing to take oral MMF for the duration of the study, either by continuing 
current MMF therapy or by initiating it on or before the Baseline Visit. 
7. Women of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline. Two effective forms of contraception must 
be used simultaneously unless abstinence is the chosen method. Subjects must use effective 
contraception during the study (see Section 5.4, Adequate/Effective Contraception). 
5.3 
Exclusion Criteria 
1. Subjects unable or unwilling to give written informed consent and/or to comply with study 
procedures. 
2. eGFR as calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) 
equation 
of 
≤45 mL/min/1.73 m2 
at 
screening 
confirmed 
before 
randomization. 
3. Currently taking or known need for any of the medications listed in Section 7.8, Prohibited 
Therapy and Concomitant Treatment at screening or during the study. This includes 
prohibited medications prior to screening as specified in Section 7.8.1, Prohibited 
Medications. 
4. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to 
require dialysis during the study period. 
5. A previous kidney transplant or planned transplant within study treatment period. 
6. Any known hypersensitivity or contraindication to MMF, mycophenolic acid, 
cyclosporine, corticosteroids or any components of these drug products. 
7. Current or medical history of: 
• Congenital or acquired immunodeficiency. 
• In the opinion of the Investigator, clinically significant drug or alcohol abuse within 
2 years prior to screening. 


 
 
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• Malignancy within 5 years of screening, with the exception of basal and squamous cell 
carcinomas treated by complete excision. Subjects with cervical dysplasia that is 
cervical intraepithelial neoplasia 1, but have been treated with conization or loop 
electrosurgical excision procedure, and have had a normal repeat Papanicolaou test are 
allowed. 
• Lymphoproliferative disease or previous total lymphoid irradiation. 
• Severe viral infection (e.g., cytomegalovirus, hepatitis B virus, hepatitis C virus) within 
3 months of screening; or known HIV infection. Severe viral infection is defined as 
active disease requiring antiviral therapy. 
• Active TB, or known history of TB/evidence of old TB if not taking prophylaxis with 
isoniazid (see Section 9.2.1, Screening Visit Procedures). 
8. Other known clinically significant active medical conditions, such as: 
• Severe cardiovascular disease including congestive heart failure, history of cardiac 
dysrhythmia or congenital long QT syndrome. QT interval duration corrected for heart 
rate using method of Fridericia (QTcF) exceeding 480 msec in the presence of a normal 
QRS interval (<110 msec) at time of screening will result in exclusion. 
• Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or bilirubin 
≥2.5 times the upper limit of normal) at screening and, if abnormal at screening, then 
confirmed that the levels have returned to <2.5 times upper limit of normal before 
randomization. 
• Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• Bone marrow insufficiency unrelated to active SLE (according to Investigator 
judgment) with white blood cell count <2,500/mm3; absolute neutrophil count (ANC) 
<1.3 × 103/μL; thrombocytopenia (platelet count <50,000/mm3). 
• Active bleeding disorders. 
• Current infection requiring IV antibiotics. 
9. Any overlapping autoimmune condition for which the condition or the treatment of the 
condition may affect the study assessments or outcomes (e.g., scleroderma with significant 
pulmonary hypertension; any condition for which additional immunosuppression is 
indicated). Overlapping conditions for which the condition or treatment is not expected to 
affect assessments or outcomes (e.g., Sjögren’s syndrome) are not excluded. 


 
 
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10. No vaccines using live organisms, virus or bacterial, are allowed during screening and 
while taking the study treatment. 
11. Other major physical or psychiatric illness or major traumatic injury within 6 months prior 
to screening that may affect study conduct or interfere with study assessments or outcome. 
12. Any other medical condition which, in the Investigator’s judgment, may be associated with 
increased risk to the subject or may interfere with study assessments or outcomes. 
13. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using 
adequate contraceptive precautions. 
14. Participation in another clinical study within 4 weeks prior to screening and/or receipt of 
investigational drugs within 4 weeks or 5 half-lives of the drug (whichever is longer) prior 
to screening. 
15. Subjects randomized and treated in a previous voclosporin clinical study. 
5.4 
Adequate/Effective Contraception 
Women of childbearing potential must have a negative serum pregnancy test at screening and 
a negative urine pregnancy test at baseline. Two effective forms of contraception must be used 
simultaneously unless abstinence is the chosen method. Effective contraception must be used 
before beginning study treatment, during study dosing, and for 6 weeks following 
discontinuation of study treatment or MMF dosing, even when there has been a history of 
infertility, unless due to surgical sterilization. Women not of childbearing potential are defined 
as women without menses for at least 12 consecutive months or surgically sterilized. 
Sexually active men, both reproductively competent and vasectomized, are required to use 
condoms during treatment and for at least 90 days after cessation of study treatment or MMF. 
In addition, female partners of male subjects are recommended to use an effective 
contraception during their partner’s treatment and for at least 90 days after the last dose of 
study treatment or MMF. Male subjects are to refrain from making sperm donations during 
treatment and for at least 90 days after cessation of study treatment or MMF. 
An effective and medically acceptable method of birth control means the chance of pregnancy, 
when using that type of birth control, is less than 1% per year if used correctly. These birth 
control methods (i.e., reliable forms of contraception) include birth control pills (combined 
oral contraceptives), hormone implants, hormone shots, and some intrauterine contraceptive 
devices. The use of MMF in this study can also reduce the effectiveness of the oral 
contraceptive pill.  


 
 
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Barrier methods (e.g., condoms, diaphragm, or cervical cap/sponge) when used alone are not 
highly considered effective. 
Although abstinence, when adhered to, is an effective method of birth control, other additional 
effective contraception methods should be used where there is any doubt. The method of 
contraception needs to be discussed with the Investigator throughout the study period in order 
to confirm the method used is considered effective. 
5.5 
Withdrawal of Subjects 
Subjects may voluntarily withdraw from study participation at any time for any reason. 
Alternatively, subjects may be withdrawn at the Investigator’s discretion if it is in the subject’s 
best interest. 
Every effort should be made for subjects who withdraw from the study, either voluntarily or at 
the Investigator’s discretion, to undergo end of study assessments (Visit 15), if possible. If 
possible, the subject should also be advised to come for the Safety Follow-up Visit 4 weeks 
after last dose. If a subject refuses end of study procedures, the reason for refusal should be 
fully documented in the subject’s source document and recorded in the study specific electronic 
case report form (eCRF). It is the subject’s right to withdraw from the study without providing 
a reason. In this case, the source documents and the eCRF should document the reason for 
discontinuation as “withdrawal of consent.” Withdrawn subjects will not be replaced. 
5.6 
Discontinuation of Study Treatment 
If any subject is discontinued from study treatment, the reason for discontinuation will be 
documented in the eCRF. If the reason for discontinuing study treatment is an AE or an 
abnormal laboratory test result, the specific event or test will be recorded in the eCRF. Except 
for cases involving pregnancy, subjects who are discontinued from study treatment should 
undergo all study assessments up to and including (Week 52 or Early Termination Visit – 
Visit 15), if possible. The subject should also be advised to come for the Safety Follow-up 
Visit 4 weeks after last dose. Guidance on when study treatment must be discontinued is in 
Section 7.6, Orelvo/Placebo Dose Modification.  
5.6.1 Discontinuation from Study Treatment Due to Early Non-response to 
Therapy 
Subjects will be discontinued from study treatment if their early disease response is 
suboptimal. The Investigator must contact the Medical Monitor to discuss further continuation 
in the study if the subject meets 1 of the 2 following criteria: 
• After 12 weeks of treatment, the subject shows a >30% decrease from baseline value 
in CKD-EPI eGFR in 2 successive measurements separated by at least 4 weeks 


 
 
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or 
• After 8 weeks of treatment, the subject shows a confirmed reduction in UPCR of ≤25% 
assessed by 2 consecutive measurements at least 2 weeks apart. 
If the subjects require treatment with IV methylprednisolone or any rescue medication other 
than that permitted in the protocol (see Section 7.2.2.2, Corticosteroids), they should be 
permanently discontinued from the study treatment and will be considered a treatment failure. 
Subjects who are permanently discontinued from study treatment will be treated as deemed 
appropriate by the Investigator. 
5.6.2 Discontinuation of Study Treatment Due to an Adverse Event 
Subjects may be permanently discontinued from study treatment because of the appearance of 
an unacceptable AE. It is vital to obtain follow-up data on any subject withdrawn because of 
an AE. In any case, every effort must be made to evaluate protocol-specified safety follow-up 
procedures (see Section 10.3, Reporting Procedure for AEs, SAEs, and Pregnancy). If a subject 
is withdrawn due to an AE, the event should be followed by the Investigator through contact 
with the subject until resolution or stabilization has occurred. All AEs should be followed until 
resolution, stabilization or the subject is lost to follow-up and cannot be contacted. 


 
 
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6. RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES 
6.1 
Randomization 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and subject names to enable records to be found at a later date. 
Subjects will be allocated a subject number at the screening visit and registered with an 
interactive central randomization system. Subjects meeting the required eligibility criteria will 
be randomized to treatment at Visit 2 (baseline). The randomization will be stratified by biopsy 
class (Class V only versus Others) and by prior MMF use at time of screening. The subjects 
will be randomized in a ratio of 1:1 to receive either Orelvo 23.7 mg BID or matching placebo. 
To help ensure balance, a centralized randomization will be utilized where region will be 
employed as a blocked factor. 
Details on randomization procedures will be provided in a separate manual. 
6.2 
Blinding 
In order to preserve the double-blind design, subjects randomized to the placebo group will be 
matched to the active dosage groups. Dosing schedule in the placebo group will be the same 
as that of the active treatment group. To this end, the double-blind nature of this study preserves 
the blind with respect to active study treatment and placebo. 
All study personnel and subjects will be blinded to the study treatment administered during the 
study. Orelvo and placebo will be identical in taste, smell, and appearance. The randomization 
code key will not be available to the Study Monitors, project statisticians or the project team 
at Aurinia Pharmaceuticals Inc. (Aurinia) or its representatives. The site staff, monitors, and 
study subjects will remain blinded until the end of the study. In case of emergency, the 
unblinding process below should be followed. 
6.3 
Unblinding 
In the rare event that an AE or pregnancy occurs for which knowledge of the identity of the 
study treatment administered is necessary to manage the subject’s condition, the IWRS code 
for that subject may be broken and the test substance identified. Procedures for unblinding will 
be provided in a separate manual. 
Should emergency unblinding be required, the Investigator should call the 
 
 Medical Monitor before unblinding wherever possible; however, the 
Investigator is responsible for the medical care of the individual study subject, and does not 
require the agreement of the Medical Monitor before unblinding. The reason for unblinding 
must be documented. The information on study treatment should only be used for decision 


 
 
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making in the subject’s further treatment. Details on unblinded treatment assignments should 
not be shared with the Study Monitor and project team. 


 
 
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7. STUDY TREATMENTS 
7.1 
Dosage Forms/Formulation 
All study treatment to be used in this study will be manufactured in accordance with current 
Good Manufacturing Practice (GMP). Study treatment will be supplied by Aurinia. 
7.1.1 Orelvo– Study Treatment 
Company Code: 
 
Chemical Name: 
 
Empirical Formula: 
 
Generic Name: 
Voclosporin 
Dosage Form: 
Softgel capsules 
Strength: 
7.9 mg of voclosporin per softgel capsule 
Manufacturer: 
 
7.1.2 Placebo Control 
Placebo softgel capsules, identical to 7.9 mg Orelvo softgel capsules, will be provided. 
7.1.3 Background Therapy 
7.1.3.1 Mycophenolate Mofetil 
Oral MMF in the form of 500 mg tablets will be centrally supplied by Aurinia. Aurinia will 
reimburse the cost of the MMF tablets if not centrally provided by Aurinia to the sites.  
7.1.3.2 Corticosteroids 
Intravenous and oral corticosteroids will be prescribed at the investigational sites and costs will 
be reimbursed by Aurinia. 
7.2 
Drug Dosage and Administration 
7.2.1 Treatment Arms 
All subjects will receive either 3 capsules of Orelvo (23.7 mg BID) or matching placebo BID. 


 
 
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Orelvo – 23.7 mg (3 capsules) BID 
Orelvo 23.7 mg BID; 3 capsules administered BID in combination with MMF and oral 
corticosteroids from randomization onwards. 
Placebo – 3 capsules BID 
Placebo; 3 capsules administered BID in combination with MMF and oral corticosteroids from 
randomization onwards. 
7.2.2 Dosing Guidelines 
7.2.2.1 Orelvo/Placebo – Study Treatment 
Study treatment will be taken BID with water on an empty stomach as close to a 12 hour 
schedule as possible, and with a minimum of 8 hours between doses. If the subject misses a 
dose of study treatment by less than 4 hours from the anticipated dosing time, the missed dose 
will be taken immediately. The next dose will be taken at the originally scheduled time. If a 
missed dose of study treatment is greater than 4 hours from the expected dosing time, the 
subject will skip the dose and take the next dose at the originally scheduled time. The variation 
in dosing will be recorded in the eCRFs. The dose/doses of study treatment may be held at the 
discretion of the Investigator. Subjects must avoid consumption of grapefruit or grapefruit-
containing juice (e.g., pomelo) for the duration of their participation in the study. 
Possible dose adjustments: If GI or other disturbances occur with study treatment, then study 
treatment dosing may be reduced or interrupted, and/or appropriate treatment may be initiated 
(e.g., addition of a proton pump inhibitor (see Appendix 5) and Section 7.6, Orelvo/Placebo 
Dose Modification). 
All unused study treatments (and any empty containers) dispensed to the subject will be 
returned at each study visit for capsule counts to check compliance. The Investigator will count 
the returned study treatment and this information will be used to assess subject compliance. 
This study treatment count must be documented in the eCRF and source documentation. 
7.2.2.2 Corticosteroids 
All subjects who weigh ≥45 kg should receive 0.5 g IV methylprednisolone on both Day 1 and 
Day 2 (a total of 1 g), before oral corticosteroid therapy is started on Day 3. All subjects who 
weigh <45 kg should receive 0.25 g IV methylprednisolone on both Day 1 and Day 2 (a total 
of 0.5 g). When subjects are receiving IV methylprednisolone, they should not receive oral 
corticosteroids on the same day. 
If it is considered to be in the subject’s best interest, IV methylprednisolone treatment may be 
started during the screening period, but no more than 1 g in total may be administered for the 


 
 
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screening period and Day 1 and/or Day 2 combined (0.5 g in subjects who weigh <45 kg). 
Subjects receiving IV methylprednisolone in the 3 months prior to screening must be discussed 
with the Medical Monitor prior to initiating further IV methylprednisolone. Also, IV 
corticosteroid therapy to be administered during screening must be discussed with the Medical 
Monitor in advance. If IV corticosteroid therapy is administered by the site during screening, 
the dose administered on Day 1 and/or Day 2 will be 1 g minus the dose administered during 
screening. The maximum daily dose of methylprednisolone administered on Day 1 and/or 
Day 2 is 0.5 g. See below for examples: 
• Example 1: If a 0.6 g dose of IV methylprednisolone is administered during screening, 
then (1 – 0.6) = 0.4 g IV methylprednisolone will be administered on Day 1, followed 
by the oral steroid dosing schedule in Table 1, beginning on Day 2 or 3. 
• Example 2: If the dose administered during screening is 0.3 g, then the total residual 
dose required is (1 – 0.3) = 0.7 g. Because 0.7 g is greater than the maximum daily dose 
allowed, 0.35 g will be administered on Day 1 and 0.35 g on Day 2, followed by the 
oral steroid dosing schedule in Table 1, beginning on Day 3. If IV methylprednisolone 
therapy is administered in the 2 weeks prior to the start of screening then the subject is 
excluded from the study (see Section 7.8.1, Prohibited Medications), unless approved 
by the Medical Monitor. 
• Example 3: In a 40 kg subject, if a 0.3 g dose of IV methylprednisolone is administered 
during screening then (0.5 – 0.3) = 0.2 g IV methylprednisolone will be administered 
on Day 1, followed by the oral steroid dosing schedule in Table 1, beginning on Day 2 
or 3. 
If at screening the Investigator determines a subject requires IV corticosteroid therapy, every 
effort should be made to collect both morning urine specimens (for UPCR determination) 
before initiation of the IV steroids. If this cannot be done, the Medical Monitor should be 
contacted in advance of the therapy (see Section 9.2.1, Screening Visit Procedures). 
In the case of the full 1 g IV methylprednisolone being administered prior to randomization 
(or 0.5 g in a subject <45 kg), it is acceptable for oral prednisone as per dosing schedule to be 
administered on Day 1. 
The starting dose of oral prednisone will be 20 mg/day for subjects <45 kg and 25 mg/day for 
subjects ≥45 kg. The dose will be reduced according to the tapering schedule below, see 
Table 1. Refer to Appendix 4 for a conversion table of various formulations of steroids. 


 
 
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Table 1 
Dosing Schedule for IV Methylprednisolone and Daily Oral 
Prednisone (mg) 
 
Subjects 
<45 kg 
Subjects 
≥45 kg 
In Case of Prior IV Steroids 
During Screening (Pre-randomization) 
Weeks 1-2(1) 
 
 
 
Days 1-2(2) 
0.25 g (IV) 
0.5 g (IV) 
1 g minus prior IV steroids mg or (0.5 g minus 
prior IV steroids mg for subjects who weigh 
<45 kg)(3) 
Days 3-13 
20 mg (oral) 
25 mg (oral) 
 
Week 2 (Day 14) 
15 mg (oral) 
20 mg (oral) 
 
Week 4 (Day 28) 
10 mg (oral) 
15 mg (oral) 
 
Week 6 (Day 42)(4) 
10 mg (oral) 
10 mg (oral) 
 
Week 8 (Day 56) 
5 mg (oral) 
5 mg (oral) 
 
Week 12 (Day 84) 
5 mg (oral) 
5 mg (oral) 
 
Week 16 (Day 112) 
2.5 mg (oral) 
2.5 mg (oral) 
 
1 Day 0-13: Oral steroids dosed according to subject weight and then tapered beginning at Day 14. 
2 Oral corticosteroids may be commenced on Days 1 or 2 if corticosteroids are administered during screening. 
3 It is recognized that dosing with IV methylprednisolone as described in Section 7 2 2 2, Corticosteroids may not be in the subject’s best 
interest if they have already received therapy within the 3 months prior to screening. In this case, the Investigator may be permitted to 
omit the administration of further IV methylprednisolone but only after discussion with the Medical Monitor. 
4 Week 6 is not a scheduled study visit, a phone call can be performed to decide further tapering for subjects. 
 
Notes: Oral prednisone taper should be done within ±3 days of specified timeframe. When clinically indicated, subjects are allowed to be 
completely titrated off of oral corticosteroids. 
Abbreviation: IV = Intravenous. 
 
Note that at each visit or during interim phone calls, the corticosteroid dose to be achieved is 
shown. The timing of the titration to that dose is at the discretion of the Investigator. For 
example, the Week 6 administration of steroids in a 43 kg subject should be 10 mg daily. The 
Investigator may reduce it at Week 7 to 7.5 mg until 5 mg is prescribed at Week 8. 
When clinically indicated, subjects are allowed to be completely titrated off of oral 
corticosteroids. 
Subjects with a lack of response are allowed one 4-week interval without dose reduction or 
1 dose escalation to the previous dose for 2 weeks at any time during the study. Lack of 
response is defined as no or minimal change in UPCR per Investigator judgment over 3 visits 
or deterioration in UPCR not meeting the criteria for withdrawal. All deviations from the 
prescribed dosing schedule in Table 1 above must be discussed with the Medical Monitor and 
documented in the source notes and eCRF. 
7.2.2.3 Mycophenolate Mofetil (Background Therapy) 
Subjects receiving MMF prior to randomization will continue without interruption.  


 
 
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• Subjects must be counselled on the risk of pregnancy while taking MMF and the need 
for adequate contraceptive precautions (see Section 5.4, Adequate/Effective 
Contraception). 
• Subjects on AZA or mycophenolate sodium at screening must switch to MMF at 
baseline (Day 1). 
• For subjects who are not already taking prescribed MMF prior to randomization, the 
dosing of MMF will start at 500 mg BID for a total daily dose of 1 g/day for the first 
week, increasing to 1 g BID for a total daily dose of 2 g/day for the second and 
subsequent weeks (i.e., beginning on Day 8).  
• Complete blood count must be performed locally at Weeks 1 and 3 in subjects not 
already taking MMF at screening (unscheduled visit or not). 
All subjects will take MMF BID (morning and evening), before meals (i.e., on an empty 
stomach), with a glass of water. If a dose is missed, the subject should take the next correct 
dose rather than “doubling up” at the next dosing time point. A stable dose of MMF will be 
maintained throughout the study. Dose changes or interruptions are permitted for clearly 
documented safety reasons only. 
• Approval by the Medical Monitor is required for subjects taking a dose other than 
2 g/day MMF from randomization onwards (e.g., total daily dose of 1 or 3 g/day). 
• If GI disturbance or other side-effects occur with MMF, the 1 g BID dosing may be 
changed to 500 mg four times daily. 
• If a subject has an ANC <1,500/mm3 at any study visit, the dose of MMF should be 
decreased or interrupted. If a subject has an ANC <1,000/mm3 at any visit, the dose 
should be discontinued and only recommenced when the ANC reaches 1,500/mm3. If 
the subject has a dose interruption of MMF of >14 days, then permanent 
discontinuation of MMF, therefore the study, should be considered after discussion 
with the Medical Monitor. 
• If deemed necessary by the Investigator on account of leukopenia or other adverse 
effect, or if the subject weighs 50 kg or less, the dose of MMF may be decreased to a 
minimum of 500 mg BID. 
7.3 
Package and Labeling 
All study treatments provided by Aurinia will be packaged and labeled for Aurinia by 
appropriately qualified vendors according to all applicable local and country regulatory 


 
 
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requirements. All packaging and labeling operations will be performed according to GMP and 
Good Clinical Practice (GCP). 
Study-treatment wallets provided to sites and to subjects will be labeled in the appropriate local 
language, according to local regulatory requirements. 
Wallet label information will be appropriately documented in the Drug Accountability Form 
after the container has been dispensed to the subject. 
7.4 
Study Treatment Allocation 
For purposes of randomization, each eligible subject will be assigned to 1 of the 2 treatment 
groups in a 1:1 ratio using IWRS. The randomization will be central-based and stratified by 
biopsy class (Class V only versus Others) and by prior MMF use at time of the Screening Visit. 
Randomization will additionally be blocked by region. 
7.5 
Site Supply, Storage, Accountability 
7.5.1 Site Supply 
Once a site has been approved for study initiation, the site will be supplied with an initial stock 
of study treatment. The need for study treatment resupply will be assessed on a regular basis 
taking into account the number of subjects enrolled at the site. 
7.5.2 Storage 
Orelvo softgel capsules and matching placebo capsules will be supplied in cartons containing 
168 capsules in 4 wallets of 42 capsules each. 
The Investigator must ensure the availability of proper storage conditions. All study treatment 
supplies provided for this study will be stored in a secure area with restricted access at the 
study site. The capsules must be stored at a controlled room temperature between 15 and 30°C 
(59-86°F). The Investigator must document and inform the Site Monitor about temperature 
deviations outside the acceptable range. Subjects will be instructed to store the study treatment 
at room temperature between 15 and 30°C (59-86°F). 
Each site should have a thermometer that records minimum and maximum temperatures daily. 
Maintenance of a temperature log is mandatory. The log should be updated by site personnel 
during normal working hours. This log must be available for review by the Site Monitor during 
on-site monitoring visits. 
7.5.3 Accountability 
The Investigator at each site is responsible for study treatment supplies. The Investigator will 
ensure that adequate records of the receipt, dispensing, and return of the study treatment are 


 
 
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kept and that the study treatment is used only for subjects enrolled in the study. All data 
regarding the study treatment must be recorded on the relevant forms provided. 
Each study site will maintain a drug inventory/dispensing record for all drugs dispensed and 
returned. At the end of the study, 1 copy of the drug inventory/dispensing record should be 
sent to Aurinia for the central study file. The original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all unused materials will be 
returned to Aurinia. The decision to destroy study treatment at a site must be made by Aurinia. 
If the study treatment is destroyed at a site, the Investigator must receive Aurinia approval of 
the process and forward the certificate of destruction to Aurinia. 
Records of IV methylprednisolone, oral corticosteroids, and MMF must be maintained 
(prescribed dose, dose adjustments and reasons) in the source notes and must be transcribed 
into the eCRF. 
7.6 
Orelvo/Placebo Dose Modification 
Dose modifications for background therapy (MMF and corticosteroids) are detailed in 
Section 7.2, Drug Dosage and Administration. 
7.6.1 Deterioration in Renal Function 
Serum creatinine and eGFR utilizing the CKD-EPI formula will be used for the assessment of 
renal function at every visit (Visits 1-15 and unscheduled visit(s)). Subjects will have a 
minimum of 2 eGFR measurements conducted prior to dosing at Visit 2. The lowest of the 
pre-dose eGFR assessments will be used as the marker of baseline renal function. 
It is recognized that eGFR may be unreliable at higher values (>100 mL/min/1.73 m2). Lupus 
nephritis subjects with nephrotic range proteinuria frequently have wide fluctuations in serum 
creatinine (and therefore eGFR) which are not representative of true renal dysfunction. Chronic 
kidney disease is defined as eGFR <60 mL/min/1.73 m2 for ≥3 months [20], with or without 
kidney damage.  
7.6.1.1 Decrease in eGFR >30% and eGFR <60 mL/min/1.73 m2 
During the treatment period, any subject experiencing a >30% decrease in eGFR from baseline 
to <60 mL/min/1.73 m2, will have study treatment interrupted until a repeat test can be 
performed (unscheduled visit to be completed). If the decrease is confirmed and not due to 
potential contributing factors (e.g., high baseline eGFR, the addition or modification of 
non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) 
inhibitors, angiotensin II receptor blockers (ARBs), a concurrent state of dehydration, 
overdosing with study treatment, lupus renal flare, etc.), the case should be discussed with the 


 
 
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Medical Monitor, the study treatment should be withheld, and eGFR retested within 48 hours. 
If the eGFR decrease is not confirmed, the study treatment can be restarted at 2 capsules BID 
and increased as tolerated with discussion with the Medical Monitor. 
7.6.1.2 Decrease in eGFR ≤30% and eGFR <60 mL/min/1.73 m2 
During the treatment period, any subject having a ≤30% reduction in eGFR to 
<60 mL/min/1.73 m2, should have the influence of potential contributing factors (as described 
in Section 7.6.1.1, Decrease in eGFR >30% and eGFR <60 mL/min/1.73 m2) ruled out and 
appropriate corrective action taken. Any subject having a >20-≤30% reduction compared to 
baseline in eGFR to <60 mL/min/1.73 m2 will have a confirmation measurement done within 
approximately 2 weeks (at a planned study visit, if any, or an unscheduled visit is to be 
completed). The subjects will be managed in the most medically appropriate manner in 
consultation with the Medical Monitor. The management of the decrease in eGFR may include 
reduction of dose or temporary interruption. 
7.6.1.3 Recovery of eGFR 
Subjects experiencing a decrease in eGFR with resultant decrease in dose should be reassessed 
for recovery of renal function. If the repeated eGFR is >80% of baseline, the dose should be 
increased by 1 capsule BID and eGFR assessed within 2 weeks. 
7.7 
Procedures for Overdose 
Based on clinical experience with Orelvo, symptomatic treatment of AEs or overdoses is 
indicated. Treatment for renal dysfunction, hypertension, and infection may include dose 
reduction or dose discontinuation. Magnesium supplementation may be required for 
hypomagnesemia. Treatment for GI complaints and biochemical/hematological abnormalities, 
and all other expected AEs, should be based on symptoms, with care taken to rule out other 
causes. 
7.8 
Prohibited Therapy and Concomitant Treatment 
Any concomitant treatment given for any reason during the course of the study must be 
recorded in the eCRF and in the subject’s source documents, including dosage, start and stop 
dates, and reason for use. 
Any class of medications not mentioned below and with the potential to interfere with 
evaluation of the study treatment must be discussed and documented with the Medical Monitor. 


 
 
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7.8.1 Prohibited Medications 
The following medications cannot be taking during the study: 
• IV corticosteroids within 2 weeks prior to screening (Visit 1) unless approved by the 
Medical Monitor 
• Enteric-coated oral corticosteroids during the study are not allowed. No other use of 
non-enteric coated oral corticosteroids, other than administration required as per 
protocol, is allowed 
• IV immunoglobulin treatment within 2 weeks prior to screening (Visit 1) 
• Cyclophosphamide within 4 weeks prior to screening (Visit 1) 
• Cholestyramine or other drugs that may interfere with enterohepatic recirculation of 
MMF within 4 weeks prior to screening (Visit 1) 
• Initiation of new treatment or change in dosage of ARBs and/or ACE inhibitors within 
4 weeks prior to randomization (Visit 2) 
• CNIs (e.g., cyclosporine and tacrolimus) within 1 month of screening (Visit 1) 
• Immunosuppression biologic agents (e.g., abatacept, belimumab, infliximab, 
adalimumab, etanercept, or rituximab) within 3 months prior to screening (Visit 1) 
• Vaccines using live organisms, viral or bacterial 
• MMF dose other than 2 g/day without prior discussion with the Medical Monitor 
• Concomitant therapy with other immunosuppressants after randomization, other than 
MMF administered per protocol 
• Subjects are allowed to be on AZA or mycophenolate sodium during screening but 
must switch to MMF at randomization 
• Current or planned use of ketoconazole or rifampin 
• Concomitant use of other CYP3A4/5 inhibitors and inducers should be discussed with 
the Medical Monitor 
Appendix 8 contains a summary of additional treatment and food restrictions. 


 
 
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7.8.2 Allowed Concomitant Medications 
These medications are permitted during the study: 
• Topical steroids (e.g., nose, scalp, skin, inhaled) 
• Antimalarials should be prescribed when clinically indicated 
• Herbal supplements can be used with caution and depending on active ingredients 
Treatments which may be used as medically indicated, according to the judgment of the 
Investigator can be found in Appendix 7. Treatments not included in this list may be acceptable 
in the study; such treatments should be verified with the Medical Monitor prior to use. A 
summary of treatment and food restrictions can be found in Appendix 8. 
7.9 
Increased Blood Pressure 
For all subjects, the target systolic pressure is ≤130 mmHg and the target diastolic pressure is 
≤80 mmHg. Investigators should use all means possible permitted in the protocol to maintain 
the BP within these limits. If no further adjustment of antihypertensive therapy is possible, the 
subject should be discussed with the Medical Monitor. 
If on any study day, systolic BP is >165 mmHg or diastolic BP is >105 mmHg and is associated 
with symptoms of hypertension (i.e., persistent headache, altered mental status, shortness of 
breath, chest pain consistent with angina pectoris, symptoms of heart failure, evidence of renal 
insufficiency of new onset, evidence of hypertensive retinal injury [hemorrhages, 
papilledema]), study treatment should be held, the Medical Monitor contacted, and the subject 
treated as per Investigator local practices and best judgment. The subject will continue with all 
study visits per the Schedule of Events. Study treatment must not be reintroduced without prior 
discussion with the Medical Monitor. 


 
 
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8. RISKS/PRECAUTIONS 
No evidence available at the time of the completion of this study protocol indicated that special 
warnings or precautions are required, other than those noted in the IB. 
If additional special warnings or precautions become apparent before study completion, 
Aurinia will notify the Investigator at each site. 


 
 
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9. STUDY PROCEDURES 
9.1 
Description of Study Assessments 
9.1.1 Laboratory Assessments 
Analysis of all samples for hematology, chemistry, hepatic function, lipid profiles, and 
urinalysis will be performed at a central laboratory using standard validated methods (see the 
laboratory manual). All study data analyses involving laboratory values will be based on results 
from the central laboratory. 
The UPCR will be calculated both from the first morning void and from standard urinalysis 
results. If the first morning void is for some reason not available, then standard urinalysis from 
a 24-hour urine collection may be substituted as an exception but only after agreement is 
reached with the Medical Monitor. 
Blood and urine samples for the following efficacy and safety assessments (See Table 2) will 
be drawn in accordance with the Schedule of Events. 
Table 2 
Review of Laboratory Assessments 
Test Type 
Test Parameters 
Collection at Visits 
Hematology 
Complete blood count (CBC) 
 Hematocrit 
 Hemoglobin 
 Mean corpuscular hemoglobin (MCH) 
 Mean corpuscular hemoglobin concentration 
(MCHC) 
 Mean corpuscular volume (MCV) 
 Platelet count 
 Red blood cells (RBC) 
 Red blood cell morphology 
 White blood cells (WBC) 
Differential (absolute and %) 
 Bands 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
Erythrocyte sedimentation rate 
All except Day 2 
 
 
 
 
 
 
 
 
 
 
All except Day 2 
 
 
 
 
 
 
Day 1, Week 24, and Week 52 
 


 
 
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Table 2 
Review of Laboratory Assessments (Cont’d) 
Test Type 
Test Parameters 
Collection at Visits 
Coagulation 
Coagulation 
 Activated partial thromboplastin time (aPTT) 
 Prothrombin time (PT) 
 Partial thromboplastin time (PTT) 
Screening 
Blood Chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bilirubin (direct and total) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol (total, HDL, and LDL) 
Creatine kinase 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Glycosolated hemoglobin (HbA1c) 
Lactic dehydrogenase (LDH) 
Magnesium 
Phosphorous, inorganic 
Potassium 
Protein, total 
Sodium 
Triglycerides 
c-Reactive Protein 
All except Day 2 
 
 
 
 
 
 
 
 
Day 1, Week 24, and Week 52 
Day 1, Week 24,and Week 52 
 
 
 
Day 1, Week 24, and Week 52 
 
 
Day 1, Week 24, and Week 52 
 
 
 
 
Screening, Week 24, and 
Week 52 
Urinalysis 
Complete urinalysis (to include urine protein, 
creatinine, blood, urine microscopy). First 
morning void will be performed to analyze 
urine protein/creatinine ratio. A 24-hour UPCR 
may be substituted for FMV at entry (or 
endpoint) if required. 
All except Day 2 
Pregnancy Test 
A serum pregnancy test will be performed for 
females of childbearing potential. Urine 
pregnancy tests will be done using a dipstick. 
Screening and Weeks 24 and 52 
(Serum) 
All other applicable visits (Urine) 
 


 
 
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Table 2 
Review of Laboratory Assessments (Cont’d) 
Test Type 
Test Parameters 
Collection at Visits 
Lupus Markers 
Anti-double-stranded DNA (anti-dsDNA) 
antibodies 
Anti-nuclear antibodies (ANA) 
Serum 
 Complement 3 
 Complement 4 
Antiphospholipid antibodies 
Anticardiolipin antibodies 
Lupus anticoagulant test 
Screening, Week 24, and 
Week 52 
 
 
 
 
 
 
 
Serology 
Cytomegalovirus 
Hepatitis A, B, and C 
Hepatitis B surface antigen (HBsAg) 
Screening 
 
Special Tests 
Estimated glomerular filtration rate (eGFR) 
All except Day 2 
Notes: FMV = first morning void; HDL = High-density lipoprotein; LDL = Low-density lipoprotein; UPCR = urine protein creatinine 
ratio. 
Baseline renal function will be the minimum value of any and all eGFR values taken during the screening period and at baseline 
prior to administration of drug (a minimum of the screen and baseline (pre-dose) values. The central lab will need to report a 
baseline value for the analysis. 
 
The total amount of blood that will be collected during the study from an individual subject is 
approximately 300 mL over 56 weeks. 
For details on whether laboratory abnormalities should be reported as AEs and on the 
follow-up required in such cases, see Section 10.2.5, Clinical Laboratory Evaluations. 
9.1.1.1 
Evaluation of Biomarkers 
Samples for biomarker assessments will be obtained in blood / urine and stored (frozen) for 
future analysis for subjects who consent to have their leftover samples retained. 
9.1.2 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Events. 
The physical examination will include a review of SLE-related manifestations which will also 
be recorded. A complete physical examination will be conducted at screening and an 
abbreviated physical will be performed at all other visits as per the Schedule of Events. The 
abbreviated examination will consist of checking the normality or abnormality of the following 
body systems: general appearance, cardiovascular system, and pulmonary system. Any 
abnormalities will be recorded in the eCRF and reported as an AE. Because the investigational 


 
 
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medication is an immunosuppressant, physical examination will include clinical examination 
for tumors. 
Subject weight will also be recorded at each physical examination; however, height will only 
be recorded at the screening (Visit 1). 
9.1.3 Vital Signs 
The following vital signs will be measured in accordance with the Schedule of Events: 
• Resting BP (systolic and diastolic) 
• Resting HR 
• Body temperature (°C or °F) 
To avoid variability, the same method of obtaining body temperature should be used 
throughout the study. 
9.1.3.1 Blood Pressure Management 
Blood pressure and HR will be measured with the subject in a sitting position after 5 minutes 
of rest. The procedure for standardized measurement of BP is detailed in Appendix 2. 
If the BP measure is confirmed to be >130/80 mmHg (i.e., by the mean of the second and third 
repeats of 3 readings), the subject’s BP will be managed per local practice. If the BP remains 
uncontrolled with the maximal doses of first and second-line antihypertensive therapies 
referenced in Appendix 1, then the Investigator should contact the Medical Monitor to consider 
dose adjustment of the study treatment. See Section 7.9, Increased Blood Pressure for 
management of increased BP. 
9.1.4 Standard 12-lead Electrocardiogram 
The electrocardiogram (ECG) will be a standard 12-lead tracing performed at the 
investigational site, assessed by a qualified physician at the investigational site, and retained 
as a source document. Any abnormalities will be recorded in the eCRF. Electrocardiograms 
will be recorded after the subject has been in a resting, supine position for at least 5 minutes. 
Abnormal ECG tracings can be reviewed by the Medical Monitor. Significant abnormalities, 
including findings that may prompt discontinuation of study treatment, must be discussed with 
the Medical Monitor. 
Electrocardiograms will be measured at screening, Week 12, Week 24, and Week 52. 


 
 
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9.1.4.1 Procedures to Manage a Treatment-Emergent Increase in QTc 
In the event that a subject has a QTcF value exceeding 500 msec, or an increase >60 msec from 
baseline, the Medical Monitor must be informed. The subject will be asked to return for an 
unscheduled visit within 24 hours and the ECG will be repeated (confirmed), in triplicate (i.e., 
three 10-second ECGs in rapid succession within 1 minute). If the repeat measurements 
confirm that the QTcF is >500 msec or >60 msec from baseline, the subject will be withdrawn 
from treatment with the study treatment and followed until the QTcF value either returns to 
baseline (or as appropriate) or until, in the judgment of the Investigator, further evaluation is 
not clinically indicated. 
If study treatment is discontinued, the subject should continue in the study for all remaining 
scheduled study visits. 
9.1.5 Lupus Disease Activity Assessments 
The SELENA-SLEDAI assesses disease activity within the last 10 days. Twenty-four items 
are scored for 9 organ systems, and summed to a maximum of 105 points. A score of 6 is 
considered clinically significant. See Appendix 6. 
Assessments for SELENA-SLEDAI will be conducted at baseline, Week 24, and Week 52. 
9.1.6 Orelvo Pharmacokinetics 
Blood samples will be taken at Weeks 24 and 52. PK samples will be drawn prior to study 
treatment dosing (trough sample), and at 2 hours post-dose. These samples will be analyzed 
for Orelvo. Should a subject experience an SAE, require a dose modification or be withdrawn 
from treatment, a blood PK sample will be taken (with a trough sample preferred) for later 
determination of drug level. If a subject has discontinued from study drug treatment, further 
PK samples are not required. 
9.2 
Schedule of Assessments 
A detailed schedule of assessments (including all protocol-required assessments, visits, and 
visit windows) is located on the Schedule of Events. No study related assessments will be 
performed (including changes to current medications to meet study eligibility) until the subject 
has provided signed and dated informed consent. Every effort will be made to keep the subject 
within the requested visit schedule. If a subject is seen outside of the visit window listed on the 
Schedule of Events, the reason must be clearly documented in the source notes. The 
Investigator (or designee) should contact Aurinia for assistance with getting the subject’s 
schedule back on track in order to avoid large variances in treatment exposure or to avoid 
delaying overall study timelines. 


 
 
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9.2.1 Screening Visit Procedures 
The screening visit (Visit 1) will take place within 30 days prior to Visit 2/baseline (Day 1). 
Screening will include provision of informed consent, physical examination including weight, 
and height, medical history (including SLE and LN history), vital signs measurements, 12-lead 
ECG, and review of prior and concomitant medications and entry criteria. Any AEs which 
occur after informed consent will be recorded. Urine samples will be collected for urinalysis 
and urine microscopy; first morning void urine samples (for determination of UPCR) will be 
collected on 2 days during the screening period and must be returned and the results evaluated 
prior to Visit 2. An average of the 2 screening UPCRs will be used as a marker of baseline 
urine protein excretion. Baseline proteinuria level is determined by a mean of 2 first morning 
void urine samples taken during the screening period. The lowest of pre-dose eGFR 
assessments will be used as the marker of baseline renal function. It is recommended that in 
the event that IV corticosteroids are administered during screening, the 2 first morning urine 
voids are to be collected prior to administration of the corticosteroids (see Section 7.2.2.2, 
Corticosteroids). In the case where this is not possible, then the marker of baseline urine protein 
excretion will be based upon the Visit 1 UPCR collection only. This must be discussed with 
the Medical Monitor prior to enrollment. Please note that the results of the 24-hour urine 
collection will have to be available prior to the Baseline Visit.  
Blood samples will be drawn according to Table 2. 
If the subject is from an area where TB is endemic or whose history suggests an increased 
personal risk, e.g., from contact with people with TB or travel to areas with endemic TB, the 
subject will be carefully evaluated for latent or active TB. 
Women of childbearing potential should have a negative serum pregnancy test result before 
randomization. Study treatment cannot be initiated by the physician until a report of a serum 
negative pregnancy test has been obtained. 
If a subject has not met the requirements in Inclusion Criteria #4 due to not having kidney 
biopsy result within the required time frame, a kidney biopsy can be performed as per local 
procedures, after signing the study consent, provided the results can be obtained and reviewed 
prior to randomization. 
9.2.2 Treatment Procedures 
Only subjects who satisfy all of the inclusion and exclusion criteria will be eligible for 
randomization and study treatment. 
Subjects will be fasting for at least 8 hours on the day of randomization and all visit procedures 
must occur prior to the first dose of study treatment on Day 1. The MMF dose required per 


 
 
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protocol and IV methylprednisone (or oral corticosteroids) will also be administered at baseline 
before the first dose of Orelvo. 
Subjects will complete all assessments per the Schedule of Events at Day 1, Day 2, and at 
Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, and 48. IWRS will be accessed to assign study 
treatment to subjects at appropriate visits. 
Adverse events and concomitant medication will be recorded prior to the conduct of other 
study assessments at each visit. 
Assessments at visits during the treatment period include: 
• SF-36 and LupusPRO HRQoL will be answered by the subject, as first study procedure, 
at Baseline, Week 12 and Week 24 
• Physical examination including weight 
• Vital signs 
• ECG at Week 12 and Week 24 
• Blood and urine sample collection for analysis at central laboratory 
• First morning void urine sample collection, except before Day 1 and Day 2 Visits 
• 24-hour urine collection at Week 24 (IMPORTANT: 24-hour urine collection will 
have to begin 2 days prior Week 24 visit in order not to coincide with the first morning 
void sampling due on the day of this visit) 
• Pregnancy testing (serum: Week 24; urine: Day 1 and Weeks 2, 4, 8, 12, 16, 20, 30, 36, 
42, and 48) and immunology 
• AEs 
• Concomitant medication 
• SELENA-SLEDAI will be evaluated at Baseline and Week 24 
• Dispense study treatment – including study treatment and background therapy 
• Returned capsule count and drug accountability 


 
 
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• Information for the healthcare resource utilization assessment will be collected and 
recorded at Day 1 and Week 52 
9.2.3 End of Study (or Early Discontinuation) Procedures 
On completion of treatment at Week 52 or earlier if subject is discontinued/withdrawn early, 
all assessments for Visit 15 (end of study/early termination) will be completed per the 
Schedule of Events. See also Section 5.5, Withdrawal of Subjects, for further information on 
withdrawal procedures and criteria. 
The following assessments for the end of study visit will be performed: 
• SF-36 and LupusPro HRQoL 
• Abbreviated physical examination (including body weight) 
• Vital signs 
• Standard 12-lead ECG 
• Blood sample collection for analysis at central laboratory 
• Serum pregnancy testing  
• First morning void 
• 24-hour urine sample collection (IMPORTANT: 24-hour urine collection will have to 
begin 2 days prior to Week 52 visit in order not to coincide with the first morning void 
sampling due on the day of this visit) 
• Concomitant medication 
• AEs 
• SELENA-SLEDAI 
• Returned capsule count and drug accountability 
• Confirmation of completion/discontinuation using IWRS 
• Information for the healthcare resource utilization assessment will be collected and 
recorded 


 
 
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9.2.4 Follow-up Procedures 
All subjects who complete the study but do not participate in the continuation study or 
discontinue study treatment before Week 52 will be followed up 4 weeks (±10 days) after their 
last study treatment dose to collect any new AEs and concomitant medications. This visit 
(Visit 16) will be conducted as an in-clinic visit. 
Assessments for the follow-up visit are as follows: 
• Vital signs 
• Blood sample collection for analysis at central laboratory (eGFR) 
• First morning void urine sample collection 
• Concomitant medication 
• AEs 
• Confirmation of completed follow-up visit using IWRS 
9.2.5 Unscheduled Visit 
Unscheduled visits may be performed during the course of the study for safety reasons. An 
unscheduled visit is required 2 weeks after dose reduction at any time during the study. Only 
the data relevant to the purpose of the visit will be collected in the source documents and eCRF. 
An unscheduled visit is requested in the following cases: 
• QTcF value exceeding 500 msec, or an increase >60 msec from baseline, where the 
ECG will be repeated (confirmed) at an unscheduled visit 
• Systolic BP is ≥165 mmHg or diastolic BP is ≥105 mmHg, or confirmed systolic 
BP >130 mmHg or a diastolic BP >80 mmHg 
• Decrease in eGFR >30% compared to baseline, or a confirmed decrease in 
eGFR >20-30% compared to baseline 
• Complete blood count must be performed locally at Weeks 1 and 3 in subjects not 
already taking MMF at the Screening Visit 


 
 
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9.3 
Study Specific Assessment Procedures 
9.3.1 Health-related Quality of Life Assessments (HRQoL) 
9.3.1.1 Short Form Health Survey (SF-36) 
The SF-36 HRQoL assessment is a 36-question subject HRQoL questionnaire and is presented 
in Appendix 9. 
9.3.1.2 LupusPRO 
The LupusPRO (v1.7) is a 43-question subject HRQoL questionnaire specific for lupus and is 
presented in Appendix 10. 
9.3.2 Healthcare Resource Utilization Assessment 
The collection of information on healthcare resource utilization will be collected at the time 
points specified in the Schedule of Events (Day 1 and Weeks 24 and 52) and documented in 
the EDC system. This information will be collected via interview of the subject by the study 
staff and entered into the EDC system. General information collected may include: 
• Type of insurance coverage 
• Number of visits to ANY health care professionals (HCP), other than study doctor  
• Types of HCP visited (specialists versus primary care)  
• Time spent on visits 
• Diagnostic tests performed  
• Time spent by caregivers assisting patient with HCP visits (can ask general question if 
subject required a family member or other person to assist them to attend the visit) 
• Prescriptions issued, filled 
• Community services used 


 
 
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10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
10.1 Definitions 
10.1.1 Adverse Event 
Any untoward medical occurrence in a subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment is an AE. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
10.1.2 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medical product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all unintended responses to a 
medicinal product related to any dose should be considered adverse drug reactions (ADRs). 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out. 
10.1.3 Serious Adverse Event 
An SAE (experience) or reaction is an untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Results in death (Note: death is an outcome, not an event) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused a death had it been more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is a medically important event or reaction 
The definitions and reporting requirements of International Council for Harmonisation (ICH) 
Guidelines for Clinical Safety Data Management, Definitions, and Standards for Expedited 
Reporting, Topic E2 will be adhered to. 


 
 
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Medical and scientific judgment must be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
will also usually be considered serious. 
Hospitalizations for elective or previously scheduled surgery for pre-existing conditions, 
which have not worsened after initiation of treatment, will not be classed as SAEs. Previously 
scheduled hospitalizations must be documented in the subject’s source documents before the 
subject signed the informed consent form (ICF). A kidney biopsy performed as part of the 
study to verify eligibility will not be considered an SAE. Any complication experienced during 
a kidney biopsy procedure resulting in hospitalization or a prolongation of the hospitalization 
requires SAE reporting. 
10.1.4 Suspected Unexpected Serious Adverse Reaction  
Any ADR that is both serious and unexpected (per the IB) that, based on the opinion of the 
Investigator or Aurinia, is felt to have a reasonable suspected causal relationship to a medicinal 
product is a suspected unexpected serious adverse reaction. 
10.2 Adverse Event Descriptors 
10.2.1 Intensity/Severity Categorization 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); however the event itself may be of relatively 
minor medical significance (such as severe headache). This is not the same as “serious,” which 
is based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
In general, the intensity of a particular AE to be recorded is the worst intensity experienced by 
the subject during the course of the event. The medical assessment of intensity will be 
determined by using the following definitions: 
Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to function. 
Severe: 
The AE is incapacitating and the subject is unable to work or complete usual 
activity. 


 
 
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10.2.2 Causal Relationship Categorization 
An Investigator who is qualified in medicine must make the determination of relationship to 
the study treatment for each AE and SAE. The Investigator must decide whether, in his or her 
medical judgment, there is a reasonable possibility that the event may have been caused by the 
study treatment. If there is no valid reason for suggesting a relationship, then the AE/SAE must 
be classified as not related. Otherwise, if there is any valid reason, even if undetermined or 
untested, for suspecting a cause-and-effect relationship between the study treatment and the 
occurrence of the AE/SAE, then the AE/SAE will be considered related. For SAEs, the 
Investigator must provide a brief comment explaining the rationale of his/her assessment of 
causal relationship on the SAE reporting form. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship of the clinical event to study drug administration 
indicates a causal relationship, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
Not related 
No 
The temporal relationship of the clinical event to study drug administration 
does not indicate a causal relationship, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the 
observed event. 
 
If the causal relationship between an AE/SAE and the study treatment is determined to be 
“related”, the event will be considered to be related to study treatment for the purposes of 
expedited regulatory reporting. In circumstances where the Investigator has not yet provided 
his/her assessment about the relationship, the event will be considered as “related” and qualify 
for expedited regulatory reporting. 
10.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; ongoing at end of study; fatal; or unknown. If the outcome is reported as 
recovered with sequelae for an SAE, the Investigator should specify the kind of sequelae on 
the SAE reporting form. SAEs that are ongoing at the time of death will have an outcome of 
“unknown” recorded. SAEs resulting in a fatal outcome will have an outcome of “fatal” 
recorded. 


 
 
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10.2.4 Symptoms of the Disease Under Study 
Symptoms of the disease under study will not be classed as AEs as long as they are within the 
normal day-to-day fluctuation of the disease. An explanation of these circumstances must be 
written in the source documents. 
Worsening of the symptoms however, will be recorded as an AE, and clearly marked as 
worsening or by the subject’s worst observed intensity. 
10.2.5 Clinical Laboratory Evaluations 
A change in the value of a safety laboratory investigation can represent an AE if the change is 
clinically relevant in the opinion of the Investigator or if, during treatment with the study 
treatment, a shift of a parameter is observed from a normal value to a pathological value, or a 
further worsening of an already pathological value. 
If, at the end of the treatment phase, there are pathological laboratory values which were not 
present at baseline, further clinical or laboratory investigations will be performed until the 
values return to within reference range or until a plausible explanation (e.g., concomitant 
disease) is found for the pathological laboratory values. 
If the Investigator considers such an AE as serious it must be reported as an SAE. 
10.2.6 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study treatment abuse, misuse, overdose, and medication 
error have to be documented in the subject’s eCRF and source documentation. If any 
occurrence of abuse, misuse, overdose, or medication errors leads to any event that fulfils any 
seriousness criteria, the event has to be reported as an SAE. 
10.3 Reporting Procedure for AEs, SAEs, and Pregnancy 
10.3.1 Adverse Events 
All AEs either observed by the Investigator or one of his/her medical collaborators, or reported 
by the subject spontaneously, or in response to a direct question, will be noted in the AE section 
of the subject's eCRF and source documentation. This applies to all AEs regardless of 
presumed relationship to the study treatment. Adverse events leading to discontinuation of 
study treatment must be collected. 
If any AE is reported, the date of onset, relationship to study treatment, any action taken, date 
of resolution (or the fact that it is still continuing or has become chronic), outcome, and whether 
the AE is serious or not, will be recorded. Use of colloquialisms and abbreviations should be 
avoided. Only 1 AE term should be recorded in the event field on the AE eCRF. Where 
possible, the Investigator should report a diagnosis rather than signs and symptoms or 


 
 
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abnormal laboratory values. However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the AE eCRF. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be nullified and 
replaced by one AE report based on the single diagnosis, with a starting date that corresponds 
to the starting date of the first symptom of the eventual diagnosis. 
The AE reporting period begins at the time the ICF is signed by the subject. The AE reporting 
period ends at Visit 15 (if the subject participates in the continuation study) or the study 
follow-up visit (Visit 16), if the subject does not participate in the continuation study. Adverse 
events persisting at the time of study completion will be followed by the Investigator through 
contact with the subject until resolution or stabilization has occurred (or the subject is lost to 
follow-up and cannot be contacted) and recorded in the source documents. If the subject reports 
an AE, it is the Investigator’s responsibility to acquire sufficient information in order to assess 
causality. This may require additional laboratory testing, physical examinations, telephone 
contacts, etc. In circumstances where the Investigator is unable to make contact with the 
subject, the Investigator must provide a written statement to Aurinia confirming that the subject 
is lost to follow-up. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, such 
as “How are you feeling?” It is also important to question the subject in a non-leading way 
about changes in their health or concomitant medication usage since their last visit. This 
information should be collected prior to completion of assessments at all study visits. In 
addition, any symptoms/conditions reported during assessments and deemed to be clinically 
significant by the Investigator will be considered AEs. 
10.3.2 Serious Adverse Events 
All SAEs occurring after the signing of the ICF will be reported to 
 
within 24 hours of the Investigator, designee, or site staff’s knowledge of the event regardless 
of relationship to study treatment. All SAEs are to be reported on the eCRFs. 
In the event that the site experiences a temporary disruption of the EDC system a back-up 
paper SAE Reporting Form will be available for site staff to complete. 
• Site staff will complete the paper SAE report form and e-mail it within 24 hours to the 
following address: 
 
• Only in cases where the email system is unavailable, site staff will send the SAE by fax 
to: 
 (US) and 
 (Outside US). 


 
 
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If notification is made via email or fax, site staff must enter the SAE information into the 
electronic data capture (EDC) system as soon as the system becomes available. 
All SAEs, regardless of causality, will be reported from the time the ICF is signed until 30 days 
following the last study visit or 30 days after last study treatment administration in subjects 
who withdraw or discontinue prior to study completion. No formal study visit is required but 
Investigators must report any SAEs that occur during this 30 day period on the eCRF. If the 
Investigator has not seen the subject at a clinic visit at the end of the reporting period, the 
Investigator must make reasonable efforts to contact the subject to inquire about SAEs. 
All recorded SAEs, regardless of relationship to study treatment, will be followed up until 
resolution, stabilization, or the subject is lost to follow-up and cannot be contacted. In 
circumstances where the Investigator is unable to make contact with the subject, the 
Investigator must provide a written statement to Aurinia confirming that the subject is lost to 
follow-up. 
Any SAE considered to have a causal relationship (i.e., “related”) to the study treatment and 
discovered by the Investigator at any time after the study will be reported. A rationale for the 
assessment of a causal relationship must be provided by the Investigator. Any safety 
information that is obtained after the Follow-up Visit (Visit 16) will be documented in the 
safety database only. 
A death occurring during the study or which comes to the attention of the Investigator within 
30 days after the last study visit (including the Follow-up Visit) or until 30 days after the last 
study treatment administration, whichever is longer, whether considered treatment-related or 
not, must be reported to Aurinia. If the subject died, the SAE report should include the cause 
of death as the event term and whether or not the death was related to study treatment, as well 
as the autopsy findings, if available. Preliminary reports will be followed by detailed 
descriptions which will include copies of hospital case reports, autopsy reports/certificates and 
other documents when requested and applicable. 
Additional follow-up information must be reported in the eCRF within 24 hours of awareness 
following Investigator (or site) awareness of the information. The Investigator should not delay 
reporting an SAE in order to obtain additional information. Additional information, when 
available, should be reported to 
 by the reporting procedures 
described above. 
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 


 
 
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An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the sponsor will file it along with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
The sponsor or its representative will be responsible for determining and, in turn, reporting 
SAEs to regulatory authorities according to the applicable regulatory requirements. 
10.3.3 Pregnancy 
Pregnancy occurring in a female subject or in the partner of a male subject should be reported 
to 
 within 24 hours of becoming aware of the event using the 
pregnancy eCRF. The Investigator should counsel the subject, and in the case of a male subject, 
the subject’s partner, discuss the risks of continuing with the pregnancy and the possible effects 
on the fetus. A female subject must immediately inform the Investigator if she becomes 
pregnant during the study. Monitoring of the pregnancy in a female subject should continue 
until conclusion of the pregnancy. In case of a pregnancy in the partner of a male subject, the 
Investigator should obtain informed consent of the pregnant partner prior to monitoring of the 
pregnancy. 
Women who have a positive pregnancy test during the study will be withdrawn from the study 
treatment and the procedures for withdrawal will be completed. The Medical Monitor must be 
contacted immediately to break the blind (if applicable). 
All pregnancies, subject or partner of a subject, that occur during the study or come to the 
attention of the Investigator within 30 days after the last study visit (including the Follow-up 
Visit) or until 30 days after last study treatment administration, whichever is longer, must be 
reported to 
 by the reporting procedures described above. 
The outcome of all such pregnancies (including normal births) should be followed up and 
documented, even if the subject was withdrawn from the study. Every effort should be made 
to gather information regarding the pregnancy outcome until 90 days (or otherwise as 
appropriate) post-partum. It will be the responsibility of Aurinia, together with the appropriate 
support of the Investigator, to obtain this information. 
Complications of pregnancy such as abortion (spontaneous or induced), premature birth, or 
congenital abnormality are considered SAEs and should be reported following the reporting 
procedures as outlined in Section 10.3.2, Serious Adverse Events. In the event that the site 
experiences a temporary disruption of the EDC system, a back-up paper Pregnancy Reporting 
Form will be available for site staff to complete. 


 
 
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11. CLINICAL ENDPOINTS COMMITTEE 
A CEC will be constituted to adjudicate the following renal response (primary efficacy 
endpoint) parameters for subjects in this study: 
• UPCR of ≤0.5 mg/mg, and 
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, 
and 
• Received no rescue medication for LN (see Section 7.8, Prohibited Therapy and 
Concomitant Treatment), and 
• Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in 
total during Weeks 44 through 52, just prior to the renal response assessment 
The CEC will adjudicate renal response by reviewing blinded data. Aurinia will establish a 
charter document explaining the working procedures and responsibilities of the CEC. All 
adjudication decisions of the CEC will be appropriately documented. 


 
 
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12. DATA AND SAFETY MONITORING BOARD PROCEDURES 
A DSMB will be constituted to protect the safety of study participants. The DSMB will receive 
blinded eCRF data in the form of tables and listings (prepared by an independent statistician), 
and review subject status changes and dosing decisions (where appropriate). Where 
appropriate, the DSMB may receive unblinded data (on a subject level or treatment group 
level) that should be reviewed in a closed session. The data should include, but is not limited 
to, demographics, subject enrollment, baseline characteristics, AE data, SAE data (by severity 
and causality), laboratory data, dose adjustments, protocol adherence, and subject withdrawals. 
The DSMB will evaluate the progress of the study, assess data quality and timeliness, 
participant recruitment, accrual and retention, and participant benefit versus risk. In addition 
the DSMB will monitor external factors relevant to the study, for example scientific and 
therapeutic developments that may affect participant safety or ethical status. Based on the 
observed benefits or adverse effects, the DSMB will make recommendations to Aurinia 
concerning continuation, termination, or modifications of the study. 
Aurinia will establish a charter document explaining the working procedures and 
responsibilities of the DSMB. All deliberations and decisions of the DSMB will be 
appropriately documented. 


 
 
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13. STATISTICAL ANALYSIS 
13.1 Statistical Methods 
Complete details of the statistical and analytical methods will be provided in a formal 
Statistical Analysis Plan (SAP), which will be finalized prior to the database lock. A general 
description of the planned methods is provided below. Any deviation from the SAP will be 
noted and explained in the clinical study report. 
13.2 Sample Size and Power Calculations 
The total sample size will be 324 subjects (162 subjects per treatment arm). This is based on 
the following assumptions: 
• A two group continuity corrected Chi square test with a 0.05 two-sided significance 
level will have 80% power to detect the difference between a placebo response rate of 
20.0% and a Orelvo response rate of 34.4% (odds ratio=2.1) when the sample size in 
each group is 162 (total N=324). 
• The effect of withdrawals will be investigated. Subjects withdrawing for any reason 
will be counted as non-responders in the primary analysis and therefore no adjustment 
of sample size for withdrawals is necessary. 
• The impact of withdrawals on primary endpoint will be investigated with a tipping 
point analysis. 
Table 3 shows the Orelvo response rates required to maintain a minimum 80% power at the 
planned sample size for given placebo response rates. These response rates all lead to odds 
ratios of around 2, which is a clinically relevant effect. 
Table 3 
Orelvo Response Rates Required to Maintain a Minimum 80% Power 
Placebo Response Rate 
Orelvo Response Rate 
Odds Ratio 
15% 
28.4% 
2.25 
19% 
33.2% 
2.12 
25% 
40% 
2.0 
Note: 
Based on the planned sample size of 324 subjects (162 subjects per treatment arm). 
 
13.3 Populations 
13.3.1 Intent-to-Treat Set 
The intent-to-treat set will be based on intent-to-treat (ITT) principles and will consist of all 
subjects who are randomized to treatment. This group will be analyzed based on the treatment 
to which the subject was randomized. 


 
 
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13.3.2 Safety Set 
The safety set will consist of all randomized subjects who have taken at least 1 dose of study 
treatment. The subjects in this group will be analyzed based on the treatment they received. 
Subjects who receive treatment from more than 1 arm will be assigned to the Orelvo arm. 
13.3.3 Per-protocol Set 
The per-protocol set will consist of all subjects eligible from the ITT population who do not 
have any major protocol violations. Major protocol violations will be defined in the statistical 
analysis plan and fully assessed at the subject level prior to unblinding of the study. 
13.4 Background and Demographic Characteristics 
Demographic and clinical disease characteristics will be summarized by treatment arm in a 
descriptive manner but no statistical tests will be performed.  
13.5 Study Treatment 
Compliance to the study treatment will be determined by dividing the number of softgel 
capsules taken by the expected number of softgel capsules to be taken (based on prescribed 
dose) over the subject’s participation in the study. 
Results will be summarized by means of descriptive statistics (n, mean, standard deviation, 
median, minimum, and maximum) and frequency tables, by treatment arm.  
13.6 Concomitant Therapy 
All concomitant medications will be coded by the WHO Anatomical Therapeutic Chemical 
Drug Reference List classification. The version used will be provided in the clinical study 
report. 
13.7 Efficacy Evaluations 
13.7.1 Primary Endpoint 
The primary endpoint is the number of subjects showing renal response at 52 weeks. Renal 
response at Week 52 will be adjudicated by the CEC based on the following parameters: 
• UPCR of ≤0.5 mg/mg, and 
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, 
and 
• Received no rescue medication for LN (see Section 7.8, Prohibited Therapy and 
Concomitant Treatment), and 


 
 
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• Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in 
total during Weeks 44 through 52, just prior to the renal response assessment 
Subjects who withdraw from the study prior to the Week 52 assessment will be defined as non-
responders. 
13.7.2 Secondary Endpoints 
13.7.2.1 
Key Secondary Endpoints 
• Time to UPCR of ≤0.5 mg/mg  
• Partial renal response as defined by 50% reduction from baseline UPCR at Weeks 24 
and 52 
• Time to 50% reduction in UPCR from baseline 
• Renal response at Week 52 (based on definition of primary endpoint) 
• Duration of UPCR ≤0.5 mg/mg 
• Proportion of subjects experiencing a confirmed >30% decrease from baseline in 
eGFR at each timepoint 
13.7.2.2 
Other Secondary Endpoints 
• Change from baseline in UPCR at each time point 
• Change from baseline in serum creatinine, urine protein, and eGFR 
• Change from screening in immunology parameters (C3, C4, and dsDNA) at Weeks 24 
and 52 
• Renal response with low-dose steroids (defined as renal response in the presence of 
corticosteroids of ≤2.5 mg/day between Weeks 16 to 24 and Weeks 44 to 52) 
• Change from baseline in HRQoL at Weeks 12, 24, and 52 
• Health Resource Utilization at Weeks 24 and 52 
• Change from baseline in the SELENA-SLEDAI Index score at Weeks 24 and 52 


 
 
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13.8 Statistical and Analytical Methods 
13.8.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the renal response at Week 52 (Section 13.7.1, Primary 
Endpoint).  
The study null hypothesis H0 and alternative hypothesis H1 are as follows: 
H0: There is no difference in renal response between Orelvo and placebo. 
H1: There is a difference in renal response between Orelvo and placebo. 
The null hypothesis H0 will be rejected in favor of H1 if there is evidence at the 5% significance 
level using a 2-sided test.  
The primary efficacy analysis will be conducted on the ITT set using logistic regression with 
terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline. The results being 
expressed as an odds ratio (and associated two-sided 95% CI) for Orelvo compared to placebo. 
Odds ratios greater than unity show the odds of response are greater for Orelvo than for placebo 
and therefore indicate a benefit of the Orelvo treatment arm. 
13.8.2 Sensitivity Analyses 
The following sensitivity analyses will be performed: 
• Renal response at Week 52 will be analyzed using a logistic regression including only 
a term for treatment. This analysis will be performed on the ITT set.  
• The analysis described in Section 13.8.1, Primary Efficacy Analysis will be repeated 
for the per protocol analysis set. 
• The impact of withdrawals on primary endpoint will be investigated with a tipping 
point analysis. 
13.8.3 Secondary Efficacy Analysis 
All the secondary efficacy analyses will be performed on the ITT set.  
13.8.3.1 
Response Endpoints 
The following secondary endpoints will be analyzed using logistic regression as outlined in 
Section 13.8.1, Primary Efficacy Analysis. These analyses will be conducted on the ITT 
population and will incorporate baseline variables within the model as appropriate. 
• Renal response at Week 52 (based on definition of primary endpoint) 


 
 
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• Partial renal response as defined by 50% reduction from baseline in UPCR at Weeks 24 
and 52 
• Renal response with low-dose steroids (defined as renal response in the presence of 
corticosteroids of ≤2.5 mg between Weeks 16 to 24 and Weeks 44 to 52) 
13.8.3.2 
Time to Endpoints 
The following secondary endpoints: time to renal response, time to partial renal response, and 
duration of UPCR ≤0.5 mg/mg will be analyzed by comparing the survivor function between 
treatment arms. It will be estimated using Kaplan-Meier methodology and will be presented as 
a plot showing a line for each treatment group. Median time-to-event along with two-sided 
confidence intervals will be displayed.  
Cox’s proportional hazards model will be performed to assess the significance of the 
differences between treatment arms. The model will include terms for treatment, baseline 
UPCR, biopsy class, and MMF use at baseline. Estimates of the treatment effects will be 
expressed as hazard ratios (and associated 95% CI) for Orelvo relative to placebo. Hazard 
ratios greater than unity show the hazard to be greater for Orelvo than for placebo and therefore 
indicate that the events in question generally occur earlier on active Orelvo. 
The log-rank test and Cox’s proportional hazards model assume that the hazard ratio is constant 
over time. This assumption will be checked graphically by plotting log-log survivor functions 
for the treatment groups. It should be noted that modest deviations from the proportionality 
assumption generally will not invalidate inference. 
13.8.3.3 
Change from Baseline Endpoints 
The following secondary endpoints will be analyzed using a Mixed Effect Model Repeated 
Measures analysis with treatment arm, visit, treatment by visit interaction, biopsy class, and 
MMF use at baseline included as a covariate in the model. Results will be expressed as 
differences between treatment arms (along with the associated 95% CI).  
• Change from baseline in UPCR at each visit 
• Change from baseline in serum creatinine, urine protein, and eGFR at each visit 
• Change from screening in immunology parameters (C3, C4, and anti-dsDNA) at 
Weeks 24 and 52 
• Change from baseline in HRQoL at Weeks 12, 24, and 52 
• Change from baseline in the SELENA-SLEDAI score at Weeks 24 and 52 


 
 
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13.8.3.4 
Health Resource Utilization 
• Health Resource Utilization at Weeks 24 and 52. Key aspects will be summarized by visit 
and changes over time will be explored. 
13.8.4 Multiplicity 
An overall type 1 (false-positive) error rate of 5% for the efficacy endpoints will be maintained 
so that no statistical significance for the secondary efficacy endpoints will be claimed unless 
the principal analysis of the primary efficacy endpoint using the ITT set is statistically 
significant at the 5% level. The Hochberg step-up method will be used to adjust for multiple 
comparisons amongst key secondary endpoints and maintain the overall type 1 error rate [21]. 
Data from all analyses, regardless of the level of significance, will be presented for review.  
13.9 Safety Evaluations 
Specific safety endpoints are as follows: 
• Biochemical (including liver function tests) and hematological laboratory tests 
• AE profile and routine biochemical and hematological safety parameters 
• Vital signs (BP, HR, temperature) at specific time points and change from baseline 
• Standard 12-lead ECGs change from baseline 
• Discontinuations from treatment 
• Concomitant medications 
Laboratory values, vital signs, and other safety parameters providing numeric data will be 
summarized by treatment arm, visit, and as change from baseline. 
Adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities, the version of which will be provided in the clinical study report. 
Treatment-emergent adverse events will be summarized by treatment arm, system organ class, 
and preferred term. SAEs, SAEs that led to death, and SAEs/AEs that led to withdrawal will 
also be summarized and listed. 
Only AEs which started on or after the date of first dose of study treatment will be considered 
TEAEs, though all AEs after informed consent will be recorded. SAEs occurring at any time 
after informed consent will be summarized. All concomitant medications will be summarized. 


 
 
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Details of these and other analyses will be provided in the SAP. 
All study data analyses involving laboratory values will be based on results from the central 
laboratory. 
13.10 Interim Analyses 
There are no planned interim analyses. 
13.11 Other Evaluations 
13.11.1 Pharmacokinetics 
Estimates of Orelvo exposure derived from this analysis will be examined for possible 
relationship to measures of efficacy and safety. Full details will be described in a separate 
analysis plan. 


 
 
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14. ETHICAL CONDUCT OF THE STUDY 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki [21] and the ICH guidelines for GCP [23]. Aurinia will ensure that the 
study complies with all local, federal, and country regulatory requirements. 
The Investigator must ensure the confidentiality of all subjects participating in the study. 
All anonymous data remains the property of Aurinia. 
14.1 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, federal regulations, 
and ICH guidelines; and must have been approved by the Institutional Review Board 
(IRB)/Ethics Committee (EC)/Independent Ethics Committee (IEC) prior to use. The 
Investigator or an authorized associate must explain the nature of the study and the treatment 
in such a manner that the subject is aware of potential benefits and risks. Subjects must also be 
informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. Subjects must be provided sufficient time to consider participation, 
including discussion with family members prior to signing the ICF. Documentation of the 
discussion and the date of informed consent must be recorded in the source documentation. 
After signing the ICF, subjects will be enrolled into the study and assigned a subject 
identification number that will be used on all subject documentation. 
The informed consent can be signed up to 30 days before the screening Visit 1. If more than 
30 days elapses between date of consent and the screening Visit 1, the subject should be asked 
to re-sign and date the consent form to confirm continued interest in study participation. 
14.2 Institutional Review Board or EC/IEC 
The protocol, any protocol amendments and consent form for the proposed clinical study and 
any other documents required by the local IRB/EC/IEC must be submitted by the Investigator 
for review and approval to the IRB/EC/IEC. The Investigator must also ensure that the 
IRB/EC/IEC reviews the progress of the study on a regular basis and, if necessary, renews its 
approval of the study per local requirements. 


 
 
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15. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all study-related site source data, study-related documents, 
and reports will be available, and that the provision of direct access for monitoring and auditing 
by Aurinia or its designees will be permitted. In addition, the Investigator must ensure that all 
study-related site source data, study-related documents, and reports will be made available for 
inspection by the appropriate Regulatory Authority and review by the IRB/EC/IEC. 
The Investigator is responsible for notifying Aurinia in advance of an impending regulatory 
inspection. He/she may request that Aurinia provide support for preparation, if necessary. The 
Investigator is required to provide updates to Aurinia on the ongoing activities during the 
inspection, respond to any citations/objectionable findings (i.e., U.S. Food and Drug 
Administration Form 483) and to share any follow up responses from the Regulatory 
Authority. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the Study Monitor (source document verification). 
The Monitor will also review the Investigator’s drug accountability records to ensure that the 
drug supplies are stored and dispensed appropriately. A comprehensive validation program 
will verify the data and queries will be generated for resolution by the Investigator. Throughout 
the study, Aurinia or its designates may review data as deemed necessary. 


 
 
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16. ADMINISTRATIVE PROCEDURES 
16.1 Sponsor’s Responsibilities 
16.1.1 Study Supplies 
Sites will be provided with all supplies required to manage this study. This will include but not 
be limited to the following: 
• Investigator file(s) (for filing of all study related documentation). 
• Kits for collection, storage, and transportation of applicable samples required for 
central laboratories. This will also include all applicable guidelines and contact details. 
• Contact list of all relevant study personnel. 
• eCRF and completion guidelines (or equivalent electronic data capture system). 
• Study reference manual. 
• All study forms (e.g., SAE, pregnancy, drug accountability, etc.). 
16.1.2 Insurance 
Aurinia confirms that it carries liability insurance which protects non-employee physicians or 
Investigators/study staff against claims for which they may become liable as a result of 
damages caused by Aurinia products used in clinical studies. Insurance coverage is not 
extended to damages that the Investigators or third parties may suffer by reason of acts of 
commission or omission on the part of such Investigators or third parties and that are not in 
accordance with accepted common medical practices (lege artis procedures). Aurinia will 
reimburse the subject for all study-related injuries provided that the injury does not arise from 
the subject’s misuse of the study treatment or failure to follow the Investigator’s instructions. 
16.1.3 Study Monitoring 
The study will be monitored by representatives of Aurinia (or designee, which may include a 
contract research organization). If not monitored by Aurinia, documentation of delegation will 
be described in the Clinical Trial Agreement. It is understood that the responsible Monitor will 
contact and visit the Investigator regularly and will be allowed, on request, to inspect the 
various records of the study (eCRFs and other pertinent data) provided that subject 
confidentiality is maintained in accordance with local requirements. 
It will be the Monitor's responsibility to inspect the eCRFs at regular intervals throughout the 
study (frequency outlined in a separate procedural document), to verify the adherence to the 


 
 
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protocol and the completeness, consistency, and accuracy of the data being entered on them. 
The Monitor must have access to laboratory test reports and other subject records needed to 
verify the entries on the eCRF. The Investigator (or his/her deputy) agrees to co-operate with 
the Monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
16.2 Investigator’s Responsibilities 
16.2.1 Reporting and Recording of Data 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures, and electronic signatures. Only individuals who are identified 
on the authorized signature page may enter/correct data in the eCRF. For those subjects who 
withdraw before completion of the study, all available efficacy and safety data must be entered 
in the eCRF. Incomplete or inconsistent data on the eCRF will result in data queries addressed 
to the Investigator for resolution. 
16.2.2 Investigator Training 
All Investigators and their study personnel will receive training regarding the study procedures, 
study treatments, and GCP/regulations specific to the conduct of clinical studies. This training 
will take place prior to enrollment of the first subject at the study site, and must be documented 
and filed in the Investigator’s Study Site File. 
16.2.3 Source Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
Subject clinical source documents would include subject hospital/clinic records, physician’s 
and nurse’s notes, appointment book, original laboratory reports, ECG, X-ray, pathology and 
special assessment reports, signed ICFs, consultant letters, and subject screening and 
enrollment logs. These are to be separate and distinct from eCRFs. All data for the study must 
be available in source documentation, including oral and written communication with the 
subject regarding the study treatment (including the risks and benefits of the study). The date 
of informed consent must be recorded in the source documentation. 
The Investigator must arrange for the retention of all study documentation (such as eCRFs, 
research files, and master files) for the duration specified in their respective site contract. The 
Investigator must keep these documents on file after completion or discontinuation of the study 
according to local governing guidelines. Archived data may be held electronically, provided 
that a back-up copy exists and that a hard copy can be generated if required. 


 
 
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The Investigator must inform Aurinia immediately if any documents are lost, to be transferred 
to a different facility, or to be transferred to a different owner. 


 
 
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17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
17.1 Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted. 
The Investigator should not implement any deviation from, or changes of the protocol without 
written agreement from Aurinia and prior documented approval/favorable opinion from the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to 
study subjects, or when change(s) involves only logistical or administrative aspects of the 
study. If the Investigator must implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior written approval, the 
implemented deviation or change and the reasons for it should be submitted in a timely manner 
to Aurinia and to the IRB/IEC as required by applicable local requirements. 
The Investigator, or person designated by the Investigator, will document and record the 
preventative and/or corrective measures for any deviation from the approved protocol. 
Accidental deviations from the protocol including violations of inclusion/exclusion criteria 
will be assessed as minor or major on a case-by-case basis. The criteria describing the 
deviation(s) and how they will be handled will be documented in the SAP. 
Any amendment to the protocol requires written approval/favorable opinion by the IRB/IEC 
prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must 
receive an IRB/IEC approval/favorable opinion concerning the reviewed document prior to 
administering to study subjects. 
17.2 Study Termination 
Aurinia reserves the right to terminate the study in its entirety or at a site at any time. Reasons 
for termination may include, but are not limited to the following: unsatisfactory subject 
enrollment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
In terminating the study, Aurinia and the Investigator will assure that adequate consideration 
is given to the protection of the subjects. Both parties will arrange the procedures on an 
individual basis after review and consultation and in accordance with the study contract. 


 
 
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18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
Aurinia is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles [24]. Where 
possible, authorship will be agreed at the beginning of the study. The authors will form a 
publication committee and this committee will propose and develop appropriate scientific 
manuscripts or abstracts from the study data. Investigators may not present or publish partial 
or complete study results individually. Any manuscript or abstract proposed by the 
Investigators must be reviewed and approved in writing by Aurinia before submission for 
publication. Names of all Investigators participating in the study will be included in the 
publication. 
The publication committee for a study will comprise of authors selected in adherence with the 
International Committee of Medical Journal Editors criteria [25] for authorship. If studies are 
multicenter, it may be appropriate to assign group authorship. 
In addition, certain Aurinia employees involved in the design and conception of the protocol, 
study management and data analysis and interpretation are qualified authors and will be 
included in the publication committee. 


 
 
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19. REFERENCES 
1. 
Ward MM. Changes in the incidence of end stage renal disease due to lupus nephritis 
in the United States, 1996-2004. J Rheumatol. 2009 Jan;36(1):63-7. 
2. 
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli 
MG, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing 
low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. 2010 
Jan;69(1):61-4. Epub 2009 Jan 20. 
3. 
Lee YH, Woo J-H, Choi SJ, Ji JD, Song GG. Induction and maintenance therapy for 
lupus nephritis: a systematic review and meta-analysis. Lupus. 2010 May; 19(6):703-
10. Epub 2010 Jan 11. 
4. 
Study WX17801. A prospective, randomized, active controlled, parallel group, multi-
center trial to assess the efficacy and safety of mycophenolate mofetil (MMF) in 
inducing response and maintaining remission in subjects with lupus nephritis (LN). 
Final report. Victoria (BC): Aspreva Pharmaceuticals Corporation; 2008 May 6. Report 
No.: 1024493. 
5. 
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al; Aspreva 
Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide 
for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-
12. Epub 2009 Apr 15. 
6. 
Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease 
progression. Kidney Int. 1997;51:2-15. 
7. 
Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, et al; 
Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and 
adverse outcomes. JAMA. 2010 Feb 3;303(5):423-9. 
8. 
Trivedi S, Zeier M, Reiser J. Role of podocytes in lupus nephritis. Nephrol Dial 
Transplant. 2009;24:3607-12. 
9. 
Mathieson PW. Proteinuria and immunity - an overstated relationship? N Engl J Med. 
2008 Dec 4;359(23):2492-4. 
10. 
Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV 
lupus nephritis with multitarget therapy. J Am Soc Nephrol. 2008 Oct; 19(10):2001-
10. Epub 2008 Jul 2. 
11. 
Miyasaka N, Kawai S, Hashimoto H. Efficacy and safety of tacrolimus for lupus 
nephritis: a placebo-controlled double-blind multicenter study. Mod Rheumatol. 
2009;19:606-15. 


 
 
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12. 
Cortés-Hernández J, Torres-Salido MT, Medrano AS, Tarrés MV, Ordi-Ros J. Long-
term outcomes-mycophenolate mofetil treatment for lupus nephritis with addition of 
tacrolimus for resistant cases. Nephrol Dial Transplant. 2010; 25:3939-48. Epub 2010 
Jun 10. 
13. 
Szeto C-C, Kwan BC-H, Lai FM-M, Tam L-S, Li EK-M, Chow K-M, et al. Tacrolimus 
for the treatment of systemic lupus erythematosus with pure class V nephritis. 
Rheumatology. 2008;47:1678-81. 
14. 
Uchino A, Tsukamoto H, Nakashima H, Yoshizawa S, Furugo I, Mitoma H, et al. 
Tacrolimus is effective for lupus nephritis patients with persistent proteinuria. Clin Exp 
Rheumatol. 2010 Jan-Feb;28(1):6-12. 
15. 
Tanaka H, Oki E, Tsugawa K, Nonaka K, Suzuki K, Ito E. Effective treatment of young 
subjects with pediatric-onset, long-standing lupus nephritis with tacrolimus given as a 
single daily dose: an open-label pilot study. Lupus. 2007;16(11):896-900. 
16. 
Asamiya Y, Uchida K, Otsubo S, Takei T, Nitta K. Clinical assessment of tacrolimus 
therapy in lupus nephritis: one-year follow-up study in a single center. Nephron Clin 
Pract. 2009;113(4):c330-6. Epub 2009 Sep 3. 
17. 
Tse KC, Lam MF, Tang SCW, Tang CSO, Chan TM. A pilot study on tacrolimus 
treatment in membranous or quiescent lupus nephritis with proteinuria resistant to 
angiotensin inhibition or blockade. Lupus. 2007;16(1):46-51. 
18. 
Lanata CM, Mahmood T, Fine DM, Petri M. Combination therapy of mycophenolate 
mofetil and tacrolimus in lupus nephritis. Lupus. 2010 Jul;19(8):935-40. Epub 2010 
Apr 13. 
19. 
Lee T, Oh KH, Joo KW, Kim YS, Ahn C, Han JS, et al. Tacrolimus is an alternative 
therapeutic option for the treatment of refractory lupus nephritis. Lupus. 
2010 Jul;19(8):974-80. 
20. 
KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, 
Classification, and Stratification, 2002.  
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm. 
Accessed 2 September 2014. 
21. 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;74(4):800-2. 
22. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. 64th WMA General Asssembly, Fortaleza, Brazil. 
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23. 
ICH Harmonised Tripartite Guideline.: Guideline for good clinical practice. E6 (R1) 
1996 Jun 10. 
24. 
PhRMA principles and guidelines: public disclosure of clinical trial results. 
Pharmaceutical Research and Manufacturers of America [Internet]. 2009 [cited 2009]. 
Available from: http://www.phrma.org/principles_and_guidelines. 
25. 
International Committee of Medical Journal Editors [Internet]. Uniform requirements 
for manuscripts submitted to biomedical journals: writing and editing for biomedical 
publication [updated 2010 Apr]. Available from: http://www.icmje.org. 
 
 


 
 
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Appendix 1 
Drug Therapy for the Treatment of Hypertension 
Antihypertensive drug therapy for subjects who either have hypertension at screening or who 
develop hypertension while on study treatment may include the following: 
• Dihydropyridine calcium channel blockers (e.g., amlodipine, nifedipine) 
• Alpha-1-adrenergic blocking agents (e.g., doxazosin) 
• Alpha-beta-blockers (e.g., carvedilol, labetalol) 
• Thiazide diuretics (e.g., chlorthalidone or hydrochlorothiazide) 
Excluded Drugs: While the ARBs and ACE inhibitors may also be effective in calcineurin 
inhibitor-associated hypertension, their dose adjustment or commencement is not permitted in 
this trial (see Section 7.8.1, Prohibited Medications). 
Recommended First and Second Line Therapies for Treatment of Hypertension 
Titrate the following according to the timeframe given in the respective drug label: 
First Line - select from one of the following: 
• Amlodipine, 5 mg daily to achieve BP <140/90 mmHg; titrate to 10 mg daily if 
satisfactory results not obtained within 2 weeks 
• Nifedipine XL, 30 mg daily; titrate to 60 mg and possibly 90 mg daily within 2 weeks 
• 12.5 to 25 mg/day of chlorthalidone or hydrochlorothiazide 
Second Line - may add from among the following to the first line therapy if a partial response 
is obtained: 
• Labetalol, 100 mg BID; titrate to 200 mg BID, then 300 mg BID 
Note: If the BP remains uncontrolled with the above-referenced maximum doses of first and 
second-line antihypertensive therapies, reduction of study treatment dose may be considered 
or it may be decided to discontinue study treatment and utilize antihypertensive therapies to 
achieve control of BP. 
If at any time, in the judgment of the treating physician in consultation with the Medical 
Monitor, the response to treatment is inadequate, the study treatment may be 
discontinued. 


 
 
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Appendix 2 
Measurement of Blood Pressure  
1. Whenever possible, BP measurements should be undertaken by the same study site 
personnel at each clinic visit. 
2. Whenever possible, the BP determinations should be undertaken at approximately the same 
time of day for each study visit and at the same time in relations to prior study treatment 
ingestion. 
3. The measurements should be undertaken prior to blood collection. 
4. Prior to measuring BP, the study subject should be seated in a quiet room for at least 
5 minutes, in a chair with his/her back supported and feet comfortably resting on the floor. 
5. Due to the likelihood each arm can have a slightly different BP, it is strongly encouraged 
to use the same arm that was selected at screening for all measurements, supported at heart 
level. 
6. No restrictive clothing should encircle the arm in which BP measurements are determined. 
7. An appropriately sized cuff will be required wherein the cuff bladder encircles at least 80% 
of the upper portion of the arm. 
8. Three serial BP readings will be undertaken with a minimum of 2 minutes between 
readings and with the cuff fully deflated between each determination. 
9. The mean of the second and third of these 3 readings will be used as the study day BP 
value. 
10. All measurements, along with the calculated mean value, will be recorded in the source 
documents. The mean of the second and third readings will be calculated within the EDC 
as the study day result. 
 
 


 
 
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Appendix 3 
International Society of Nephrology and the Renal Pathology Society 
(ISN/RPS) 2003 Classification of Lupus Nephritis 
Class I 
Minimal mesangial lupus nephritis 
Normal glomeruli by light microscopy, but mesangial immune deposits by 
immunofluorescence  
Class II 
Mesangial proliferative lupus nephritis 
Purely mesangial hypercellularity of any degree or mesangial matrix 
expansion by light microscopy, with mesangial immune deposits 
May be a few isolated subephithelial or subendothelial deposits visible by 
immunofluorescence or electron microscopy, but not by light microscopy 
Class III 
Focal lupus nephritisª 
Active or inactive focal, segmental or global endo- or extracapillary 
glomerulonephritis involving <50% of all glomeruli, typically with focal 
subendothelial immune deposits, with or without mesangial alterations 
Class III (A) 
Active lesions: focal proliferative lupus nephritis 
Class III (A/C) 
Active and chronic lesions: focal proliferative and sclerosing lupus nephritis 
Class III (C) 
Chronic inactive lesions with glomerular scars: focal sclerosing lupus 
nephritis 
Class IV 
Diffuse lupus nephritisb 
Active or inactive diffuse, segmental or global endo- or extracapillary 
glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse 
subendothelial immune deposits, with or without mesangial alterations. This 
class is divided into diffuse segmental (IV-S) lupus nephritis when ≥50% of 
the involved glomeruli have segmental lesions, and diffuse global (IV-G) 
lupus nephritis when ≥50% of the involved glomeruli have global lesions. 
Segmental is defined as a glomerular lesion that involves less than half of the 
glomerular tuft. This class includes cases with diffuse wire loop deposits but 
with little or no glomerular proliferation.  
Class IV-S (A) 
Active lesions: diffuse segmental proliferative lupus nephritis 
Class IV-G (A) 
Active lesions: diffuse global proliferative lupus nephritis 
Class IV-S (A/C) 
Active and chronic lesions: diffuse segmental proliferative and sclerosing 
lupus nephritis 


 
 
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Class IV-G (A/C) 
Active and chronic lesions: diffuse global proliferative and sclerosing lupus 
nephritis 
Class IV-S (C) 
Chronic inactive lesions with scars: diffuse segmental sclerosing lupus 
nephritis 
Class IV-G (C) 
Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis 
Class V 
Membranous lupus nephritis 
Global or segmental subephithelial immune deposits or their morphologic 
sequelae by light microscopy and by immunofluorescence or electron 
microscopy, with or without mesangial alterations 
Class V lupus nephritis may occur in combination with class II or IV in 
which case both will be diagnosed 
Class V lupus nephritis show advanced sclerosis 
Class VI 
Advanced sclerosis lupus nephritis 
≥90% of glomeruli globally sclerosed without residual activity 
 
a Indicate the proportion of glomeruli with active and with sclerotic lesions. 
b Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. 
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, 
severity of arteriosclerosis or other vascular lesions. 
 
1. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The 
classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 
2004;65:521-30. 
2. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The 
classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 
2004;15:241-50. 


 
 
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Appendix 4 
Conversion Table for Oral Corticosteroids 
Compound 
Equivalent Potency (mg) 
Prednisone 
5 
Prednisolone 
5 
Cortisone 
25 
Hydrocortisone (cortisol) 
20 
Methylprednisolone 
4 
Triamcinolone 
4 
Dexamethasone 
0.75 
 
i.e., 
1 mg prednisone = 1 mg prednisolone 
1 mg prednisone = 5 mg cortisone 
1 mg prednisone = 4 mg hydrocortisone (cortisol) 
1 mg prednisone = 0.8 mg methylprednisolone 
1 mg prednisone = 0.8 mg triamcinolone 
1 mg prednisone = 0.15 mg dexamethasone 
 
 


 
 
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Appendix 5 
1997 Update of the 1982 American College of Rheumatology Revised 
Criteria for the Classification of Systemic Lupus Erythematosus 
 
Four or More of: 
Criterion 
Definition 
1. Malar rash 
Fixed erythema, flat or raised, over the malar eminences, tending 
to spare the nasolabial folds 
2. Discoid rash 
Erythematous raised patches with adherent keratotic scaling and 
follicular plugging; atrophic scarring may occur in older lesions 
3. Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient 
history or physician observation 
4. Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by 
physician  
5. Arthritis 
Nonerosive arthritis involving 2 or more peripheral joints, 
characterized by tenderness, swelling, or effusion 
6. Serositis 
a) Pleuritis--convincing history of pleuritic pain or rubbing heard 
by a physician or evidence of pleural effusion  
OR 
b) Pericarditis--documented by ECG or rub or evidence of 
pericardial effusion 
7. Renal disorder 
a) Persistent proteinuria greater than 0.5 grams per day (or 
0.5 mg/mg by UPCR) or greater than 3+ if quantitation not 
performed  
OR 
b) Cellular casts--may be red cell, hemoglobin, granular, tubular, 
or mixed 
8. Neurologic 
disorder 
a) Seizures--in the absence of offending drugs or known metabolic 
derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance  
OR 
b) Psychosis--in the absence of offending drugs or known 
metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte 
imbalance 


 
 
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Four or More of: 
Criterion 
Definition 
9. Hematologic 
disorder 
a) Hemolytic anemia--with reticulocytosis  
OR 
b) Leukopenia--less than 4,000/mm3 total on 2 or more occasions 
OR 
c) Lyphopenia--less than 1,500/mm3 on 2 or more occasions 
OR 
d) Thrombocytopenia--less than 100,000/mm3 in the absence of 
offending drugs  
10. Immunologic 
disorder 
a) Anti-dsDNA: antibody to native dsDNA in abnormal titer 
OR 
b) Anti-Sm: presence of antibody to Sm nuclear antigen 
OR 
c) Positive finding of antiphospholipid antibodies based on 1) an 
abnormal serum level of IgG or IgM anticardiolipin antibodies, 2) 
a positive test result for lupus anticoagulant using a standard 
method, or 3) a false-positive serologic test for syphilis known to 
be positive for at least 6 months and confirmed by Treponema 
pallidum immobilization or fluorescent treponemal antibody 
absorption test 
11. Antinuclear 
antibody 
An abnormal titer of antinuclear antibody by immunofluorescence 
or an equivalent assay at any point in time and in the absence of 
drugs known to be associated with "drug-induced lupus" 
syndrome  
Abbreviation: ECG = Electrocardiogram. 
Sources: Hochberg MC, MD, MPH for the Diagnostic and Therapeutic Criteria Committee of the American College of Rheumatology. Tan 
EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria 
for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271-7. 
 
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus 
erythematosus [letter]. Arthritis Rheum 1997;40:1725. 
 
 


 
 
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Appendix 6 
Systemic Lupus Erythematosus Disease Activity Measure 
(SELENA-SLEDAI) 
Descriptor 
Definition 
Points 
Seizure 
Recent onset. Exclude metabolic, infectious or drug 
causes. 
8 
Psychosis 
Altered ability to function in normal activity due to 
severe disturbance in the perception of reality. Include 
hallucinations, incoherence, marked loose associations, 
impoverished thought content, marked illogical thinking, 
bizarre, disorganized or catatonic behavior. Exclude 
uremia and drug causes. 
8 
Organic brain 
syndrome 
Altered mental function with impaired orientation, 
memory or other intellectual function with rapid onset 
and fluctuating clinical features. Include clouding of 
consciousness with reduced capacity to focus and 
inability to sustain attention to environment plus at least 
2 of the following: perceptual disturbance, incoherent 
speech, insomnia or daytime drowsiness, or increased or 
decreased psychomotor activity. Exclude metabolic, 
infectious or drug causes. 
8 
Visual disturbance 
Retinal changes of SLE. Include cytoid bodies, retinal 
hemorrhages, serous exudate or hemorrhages in the 
choroid, or optic neuritis. Exclude hypertension, 
infectious or drug causes. 
8 
Cranial nerve 
disorder 
New onset of sensory or motor neuropathy involving 
cranial nerves. 
8 
Lupus headache 
Severe persistent headache; may be migrainous but must 
be nonresponsive to narcotic analgesia. 
8 
Cerebrovascular 
accident  
New onset of cerebrovascular accident(s). Exclude 
arteriosclerosis. 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual 
infarction, splinter hemorrhages, or biopsy or angiogram 
proof of vasculitis. 
8 


 
 
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Descriptor 
Definition 
Points 
Arthritis 
More than 2 joints with pain and signs of inflammation 
(i.e., tenderness, swelling, or effusion). 
4 
Myositis 
Proximal muscle aching or weakness associated with 
elevated creatine phosphokinase or aldolase, or 
electromyogram changes, or a biopsy showing myositis. 
4 
Urinary casts 
Heme-granular or RBC casts. 
4 
Hematuria 
>5 red blood cells per high powered field. Exclude 
stone, infection or other causes. 
4 
Proteinuria 
>0.5 g per 24 hours or 0.5 mg/mg UPCR by FMV. New 
onset or recent increase of more than 0.5 g per 24 hours. 
4 
Pyuria 
>5 white blood cells per high power field. Exclude 
infection. 
4 
New rash 
New onset or recurrence of inflammatory type rash. 
2 
Alopecia 
New onset or recurrence of abnormal patchy or diffuse 
loss of hair. 
2 
Mucosal ulcers 
New onset or recurrence of oral or nasal ulcerations. 
2 
Pleurisy 
Pleuritic chest pain with pleural rub or effusion or 
pleural thickening. 
2 
Pericarditis 
Pericardial pain with at least 1 one of the following: rub, 
effusion or ECG confirmation. 
2 
Low complement 
Decrease in CH50, C3 or C4 below the lower limit of 
normal for testing laboratory. 
2 
Increased DNA 
binding 
>25% binding by Farr assay or above normal range for 
testing laboratory. 
2 
Fever 
>38°C. Exclude infectious cause. 
1 
Thrombocytopenia 
<100,000 platelets per mm3. 
1 
Leukopenia 
<3,000 white blood cells per mm3. Exclude drug causes. 
1 
Abbreviations: ECG = Electrocardiogram; RBC = Red blood cells; SLE = Systemic lupus erythematosus.  
Source: Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang DH, and the Committee on Prognosis Studies in SLE. Derivation of 
the SLEDAI: a disease activity index for lupus subjects. Arthritis Rheum. 1992;35:S630-40. 
 


 
 
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Appendix 7 
Expanded List of Allowed Concomitant Medications 
• Prophylactic therapy for steroid-induced bone loss (calcium with Vitamin D and/or a 
bisphosphonate). 
• Low dose aspirin is allowed for cardiovascular prophylaxis. 
• Minor GI AEs (such as nausea, vomiting and diarrhea) may be treated symptomatically 
(e.g., with loperamide for diarrhea or standard anti-emetics such as metoclopramide or 
domperidone for nausea and vomiting). Proton pump inhibitors or ranitidine are 
permitted for dyspepsia or gastric protection. Magnesium or aluminum containing 
antacids may be used, but should not be taken at the same time as study treatment; such 
antacids, if required, should be taken either 1 hour before or 2 hours after study 
treatment. 
• Amphotericin or oral nystatin are permitted as infective prophylaxis against fungal 
infections, and low-dose sulfamethoxazole/trimethoprim is permitted as prophylaxis 
against Pneumocystis carinii pneumonia. 
• Granulocyte colony stimulating factor is allowed to manage neutropenia in the presence 
of major infection (i.e., infections requiring IV antibiotics). 
• Oral or IV iron preparations for iron deficiency and/or anemia. 
• Erythropoietin is permitted for treatment of severe anemia (hemoglobin <10 mg/dL). 
• Cytomegalovirus prophylaxis is permitted for example with oral valganciclovir. 
• Acute intermittent administration of NSAIDs for not greater than 7 consecutive days is 
permitted. 
• Lipid-lowering therapies (e.g., statins) will be used as clinically indicated. 
• Antimalarials should be prescribed when clinically indicated. 
• Angiotensin-converting enzyme inhibitors, ARBs, and aliskerin and other therapies are 
recommended, as per standard guidelines but if used their dose must be stable 
throughout the study. In addition subjects must be on a stable dose of ACE inhibitors 
or ARBs for 4 weeks prior to enrollment.  
• In the case of uncontrolled hypertension (systolic BP >165 mmHg or 
diastolic >105 mmHg on 2 successive measurements), the addition of a diuretic or 
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interruption of study treatment per the instructions in Section 7.9, Increased Blood 
Pressure. 
 
 


 
 
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Appendix 8 
Summary of Treatment and Food Restrictions 
Treatment 
Washout Period 
During Treatment 
Reason 
Immunosuppressants other 
than those allowed by 
protocol 
30 days 
Prohibited 
Interferes with 
study efficacy 
endpoints 
Aminoglycosides 
Amphotericin B 
Melphalan 
Ketoconazole 
Rifampin 
14 days 
Prohibited 
May potentiate 
toxicity 
NSAIDs chronic dosing 
(>7 consecutive days) 
Prohibited 
Prohibited 
May potentiate 
nephrotoxicity 
P-gp substrates 
To be monitored 
To be monitored 
Drug-drug 
interaction 
P-gp inhibitors 
To be discussed with 
Medical Monitor 
To be discussed with 
Medical Monitor 
Drug-drug 
interaction 
Androgenic steroids 
Cimetidine 
Fluconazole, itraconazole 
Macrolide antibiotics 
(azithromycin, 
clarithromycin, 
erythromycin) 
Metoclopramide 
Barbiturates and derivatives 
Carbamazepine 
Octreotide acetate 
Phenytoin 
Sulfadimidine (intravenous) 
Theophylline 
To be discussed with 
Medical Monitor 
To be discussed with 
Medical Monitor 
Drugs interfering 
with Orelvo 
metabolism 
ACE inhibitors and ARBs 
No change or introduction 
during screening 
Change or 
commencement 
prohibited 
Interfere with 
primary endpoint 
assessment 
Foods 
Grapefruit and grapefruit 
juice 
 
24 hours 
 
Prohibited 
 
May affect the 
metabolism of 
Orelvo 
Abbreviations: ACE = Angiotensin converting enzyme; ARB = Angiotensin receptor blocker; NSAID = Non-steroidal anti-inflammatory 
drug; P-gp = P-glycoprotein. 
 
 


 
 
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Appendix 9 
Short Form Health Survey (SF-36) HRQoL Assessment 


 
 
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Appendix 10 LupusPRO (v1.7) HRQoL Assessment  
 
 


 
 
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Prot_001.pdf: 
 
This trial will be conducted in compliance with this protocol, ICH GCP and applicable regulatory requirements. 
The information contained in this document is proprietary to Aurinia Pharmaceuticals, Inc. and is not to be copied, disclosed or 
otherwise distributed by an outside authority to any person or persons without the prior written permission of Aurinia. 
 
 
A Randomized, Controlled Double-blind Study Comparing the 
Efficacy and Safety of Orelvo (voclosporin) (23.7 mg Twice 
Daily) with Placebo in Achieving Renal Response in Subjects 
with Active Lupus Nephritis 
 
Clinical Protocol Number: 
AUR-VCS-2016-01 
 
 
Study Name: 
AURORA (AURinia Orelvo Renal 
Assessments) 1: Aurinia Renal Response in 
Active Lupus with Orelvo (voclosporin) 
 
 
Date: 
01 December 2016 
 
 
Version Number: 
1.0 
 
 
IND Number: 
114577 
 
 
EudraCT Number: 
2016-004045-81 
 
 
 


 
 
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NAMES AND ADDRESSES 
Lead Investigator 
Name: 
 
 
 
 
 
Address: 
 
 
 
 
 
 
Tel: 
 
 
Fax: 
 
 
Email: 
 
 
Sponsor 
Name: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
Fax: 
 
 
24 Hour: 
 
 
Medical Monitor 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 


 
 
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Regulatory Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Trial Statistician 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals, Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 


 
 
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DECLARATION OF SPONSOR 
Title: A Randomized, Controlled Double-blind Study Comparing the Efficacy and Safety of 
Orelvo (voclosporin) (23.7 mg Twice Daily) with Placebo in Achieving Renal Response in 
Subjects with Active Lupus Nephritis 
Version Number/Date: 1.0/01 December 2016 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the study treatment, as well as with the 
moral, ethical and scientific principles governing clinical research as set out in the Declaration 
of Helsinki, and the International Council for Harmonisation Guidelines on Good Clinical 
Practice. 
Sponsor Representatives 
 
 
 
 
Vice President, Clinical Affairs 
 
Date (e.g., DD Month Year) 
 
 
 
 
Vice President, Quality and Regulatory 
Affairs 
 
Date (e.g., DD Month Year) 
 
02 December 2016
02DEC2016


 
 
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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: A Randomized, Controlled Double-blind Study 
Comparing the Efficacy and Safety of Orelvo (voclosporin) (23.7 mg Twice Daily) with 
Placebo in Achieving Renal Response in Subjects with Active Lupus Nephritis. 
Version Number/Date: 1.0/01 December 2016 
I agree to comply with the current International Council for Harmonisation Guidelines on Good 
Clinical Practice and applicable regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• me (including, if applicable, my spouse (or legal partner) and dependent children); 
• my sub-investigators 
before the start of the study and to report any changes that affect my financial disclosure status 
for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Aurinia Pharmaceuticals Inc. 
Signature by the Investigator on this form documents review, agreement and approval of the 
requirements contained within this protocol. 
 
 
 
Signature 
 
Date (e.g., DD Month Year) 
 


 
 
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SYNOPSIS 
Title: 
A Randomized, Controlled Double-blind Study Comparing the Efficacy and Safety 
of Orelvo (voclosporin) (23.7 mg Twice Daily) with Placebo in Achieving Renal 
Response in Subjects with Active Lupus Nephritis. 
Short Title: 
AURORA (AURinia Orelvo Renal Assessments) 1: Aurinia Renal Response in 
Active Lupus with Voclosporin 
Study Product: 
Orelvo (voclosporin) 
Indication: 
Active lupus nephritis 
Phase: 
3 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VCS-2016-01 
Objectives: 
Primary Objective: 
• To assess the efficacy of Orelvo (voclosporin) compared with placebo in 
achieving renal response after 24 weeks of therapy in subjects with active lupus 
nephritis (LN) 
Secondary Objective: 
• To assess the safety, tolerability, and efficacy of Orelvo over 52 weeks compared 
with placebo in subjects with active LN 
Design: 
Prospective, randomized, placebo-controlled, double-blind, parallel-group, 52-week, 
international, multicenter, 2-arm comparison study of Orelvo versus matching 
placebo. 
Treatment: 
Investigational Treatment: 
Orelvo softgel capsules containing 7.9 mg drug. Approximately 324 subjects will be 
randomized to Orelvo (23.7 mg twice daily (BID)) or matching placebo (162 subjects 
per arm). 
All subjects will receive an initial treatment of intravenous (IV) methylprednisolone, 
followed by a reducing taper of oral corticosteroid. Additionally, all subjects will 
receive background therapy with mycophenolate mofetil (MMF).   
All subjects who complete participation and study treatment through 52 weeks and 
provide consent will have the opportunity to enroll into a continuation study (design 
pending finalization). 
Inclusion Criteria: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 (or legal age of consent 
if >18 years) to 75 years of age, inclusive, at the time of screening (Visit 1). 
3. Previous diagnosis of systemic lupus erythematosus (SLE) according to the 
American College of Rheumatology criteria (1997; see Appendix 3).  
 


 
 
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4. Subjects with evidence of active nephritis, defined as follows: 
Kidney biopsy result within 2 years prior to screening indicating Class III, 
IV-S or IV-G (alone or in combination with Class V) LN with a doubling or 
greater increase of urine protein creatinine ratio (UPCR) within the last 
6 months to a minimum of ≥1.5 mg/mg at screening. 
OR 
Kidney biopsy result within 6 months prior to screening indicating Class III, 
IV-S or IV-G (alone or in combination with Class V) LN with a UPCR of 
≥1.5 mg/mg at screening. 
OR 
Kidney biopsy result within 6 months prior to screening indicating Class V LN 
and a UPCR of ≥2 mg/mg at screening. 
A biopsy can be performed during screening, if not available. The above 
criteria must be fulfilled at baseline. 
5. In the opinion of the Investigator, subject requires high-dose corticosteroids and 
immunosuppressive therapy. 
6. Subject is willing to take oral MMF for the duration of the study, either by 
continuing current MMF therapy or by initiating it on or before the Baseline 
Visit. 
7. Women of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline. Two effective forms 
of contraception must be used simultaneously unless abstinence is the chosen 
method. Subjects must use effective contraception during the study (see 
Section 5.4, Adequate/Effective Contraception). 
Exclusion Criteria: 
1. Subjects unable or unwilling to give written informed consent and/or to comply 
with study procedures. 
2. Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney 
Disease Epidemiology Collaboration equation of ≤45 mL/minute/1.73 m2 at 
screening confirmed before randomization. 
3. Currently taking or known need for any of the medications listed in Section 7.8, 
Prohibited Therapy and Concomitant Treatment at screening or during the study. 
This includes prohibited medications prior to screening as specified in 
Section 7.8.1, Prohibited Medications. 
4. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or 
expected to require dialysis during the study period. 
5. A previous kidney transplant or planned transplant within study treatment 
period. 
6. Any known hypersensitivity or contraindication to MMF, mycophenolic acid, 
cyclosporine, corticosteroids or any components of these drug products. 


 
 
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7. Current or medical history of: 
• 
Congenital or acquired immunodeficiency. 
• 
In the opinion of the Investigator, clinically significant drug or alcohol abuse 
within 2 years prior to screening. 
• 
Malignancy within 5 years of screening, with the exception of basal and 
squamous cell carcinomas treated by complete excision. Subjects with 
cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been 
treated with conization or loop electrosurgical excision procedure and have 
had a normal repeat Papanicolaou test are allowed. 
• 
Lymphoproliferative disease or previous total lymphoid irradiation. 
• 
Severe viral infection (e.g., cytomegalovirus, hepatitis B virus, hepatitis C 
virus) within 3 months of screening; or known HIV infection. Severe viral 
infection is defined as active disease requiring antiviral therapy. 
• 
Active tuberculosis (TB), or known history of TB/evidence of old TB if not 
taking prophylaxis with isoniazid (see Section 9.2.1, Screening Visit 
Procedures). 
8. Other known clinically significant active medical conditions, such as: 
• 
Severe cardiovascular disease including congestive heart failure, history of 
cardiac dysrhythmia or congenital long QT syndrome. QT interval duration 
corrected for heart rate using method of Fridericia exceeding 480 msec in the 
presence of a normal QRS interval (<110 msec) at time of screening will result 
in exclusion. 
• 
Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or 
bilirubin ≥2.5 times the upper limit of normal) at screening and, if abnormal at 
screening, then confirmed that the levels have returned to <2.5 times upper 
limit of normal before randomization. 
• 
Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• 
Bone marrow insufficiency unrelated to active SLE (according to Investigator 
judgment) with white blood cell count <2,500/mm3; absolute neutrophil count 
<1.3 × 103/μL; thrombocytopenia (platelet count <50,000/mm3). 
• 
Active bleeding disorders. 
• 
Current infection requiring IV antibiotics. 
9. Any overlapping autoimmune condition for which the condition or the treatment 
of the condition may affect the study assessments or outcomes (e.g., scleroderma 
with significant pulmonary hypertension; any condition for which additional 
immunosuppression is indicated). Overlapping conditions for which the 
condition or treatment is not expected to affect assessments or outcomes (e.g., 
Sjögren’s syndrome) are not excluded. 
10. No vaccines using live organisms, virus or bacterial, are allowed during 
screening and while taking the study treatment. 


 
 
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11. Other major physical or psychiatric illness or major traumatic injury within 
6 months prior to screening that may affect study conduct or interfere with study 
assessments or outcome. 
12. Any other medical condition which, in the Investigator’s judgment, may be 
associated with increased risk to the subject or may interfere with study 
assessments or outcomes. 
13. Subjects who are pregnant, breast feeding or, if of childbearing potential, not 
using adequate contraceptive precautions. 
14. Participation in another interventional clinical study within 4 weeks prior to 
screening and/or receipt of investigational drugs within 4 weeks or 5 half-lives 
of the drug (whichever is longer) prior to screening. 
15. Subjects randomized and treated in a previous voclosporin clinical study. 
Primary Endpoint: 
Renal response at Week 24 will be adjudicated by the Clinical Endpoints Committee 
based on the following parameters: 
• 
UPCR of ≤0.7 mg/mg, and 
• 
eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR 
of >20%, and 
• 
Received no rescue medication for LN (see Section 7.8, Prohibited Therapy 
and Concomitant Treatment), and 
• 
Received ≤10 mg/day prednisone from Weeks 16 through 24. 
Subjects who withdraw from the study prior to the Week 24 assessment will be 
defined as non responders. 
Secondary 
Endpoints: 
• 
Time to UPCR of ≤0.7 mg/mg. 
• 
Partial renal response as defined by 50% reduction from baseline in UPCR 
at Weeks 24 and 52. 
• 
Time to 50% reduction in UPCR from baseline.  
• 
Renal response at Week 52 (based on definition of primary endpoint). 
• 
Duration of UPCR ≤0.7 mg/mg. 
• 
Change from baseline in UPCR at each time point. 
• 
Change from baseline in serum creatinine, urine protein, and eGFR. 
• 
Change from screening in immunology parameters (complement 3 (C3), C4, 
and anti-double-stranded DNA). 
• 
Renal response with low-dose steroids (defined as renal response in the 
presence of corticosteroids of ≤2.5 mg between Weeks 16 to 24 and 
Weeks 36 to 52). 
• 
Change from baseline in health-related quality of life at Weeks 12, 24, and 
52. 


 
 
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• 
Health Resource Utilization at Weeks 24 and 52. 
• 
Change from baseline in the Safety of Estrogens in Lupus Erythematosus 
National Assessment - Systemic Lupus Erythematosus Disease Activity 
(SELENA-SLEDAI) Index score at Weeks 24 and 52. 
Procedures: 
See Schedule of Events for full details of protocol required procedures and applicable 
visits (and timings). Subjects who have provided signed and dated informed consent 
will be screened for entry into this study. Baseline proteinuria level is determined by 
a mean of 2 first morning void urine samples taken during the screening period. If a 
subject has not had a kidney biopsy within the required timeframe for study 
eligibility, one may be performed to assess eligibility into the study, provided consent 
is in place and provided the results are received before randomization. Subjects 
meeting the required eligibility criteria will be randomized in a ratio of 1:1 to receive 
either Orelvo (23.7 mg BID) or matching placebo starting on Day 1. All subjects will 
receive initial treatment with 0.5 to 1.0 g IV methylprednisolone. In consultation with 
the Medical Monitor, and if it is in the subject’s best interest, IV methylprednisolone 
may 
be 
started 
during 
the 
screening 
period. 
Subjects 
receiving 
IV 
methylprednisolone in the 3 months prior to screening must be discussed with the 
Medical Monitor prior to initiating further IV methylprednisolone. For subjects who 
are not already taking prescribed MMF prior to randomization, the dosing of MMF 
will start at 500 mg BID for a total daily dose of 1 g/day for the first week, increasing 
to 1 g BID for a total daily dose of 2 g/day for the second and subsequent weeks (i.e., 
beginning on Day 8).  
All subjects will complete dosing through 52 weeks of study treatment. Subjects who 
permanently discontinue study treatment before the Week 52 visit will return for all 
remaining study visits and assessments unless they have withdrawn consent. All 
subjects who complete participation and study treatment through 52 weeks and 
provide consent will have the opportunity to enroll into a continuation study for 
which the details are not yet finalized. 
Sample Size: 
A 2 group continuity corrected Chi square test with a 0.05 two-sided significance 
level will have 80% power to detect the difference between a placebo response rate 
of 20.0% and an Orelvo response rate of 34.4% (odds ratio=2.1) when the sample 
size in each group is 162 (total N=324). While the effect of withdrawals will be 
investigated, subjects withdrawing for any reason will be counted as non-responders 
in the primary analysis and therefore no adjustment of sample size for withdrawals is 
necessary. 
Statistical Methods: 
Analysis: 
All statistical analyses will be undertaken at study closure and will incorporate all 
Week 24 and Week 52 endpoints. 
Populations: 
The efficacy analysis will be based on the intent-to-treat (ITT) principles and will 
consist of all randomized subjects. 
The per-protocol set will be a subset of subjects in the ITT population who do not 
have any major protocol violations (to be defined prior to unblinding). 


 
 
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The safety analysis set will consist of all subjects who receive at least 1 dose of study 
treatment. 
Methods: 
The primary analysis of the primary endpoint, renal response at Week 24, will be 
conducted on the ITT population. The relative renal response for Orelvo compared 
to placebo will be determined using logistic regression. The logistic regression model 
will include terms for treatment, baseline UPCR, biopsy class, and MMF use at 
baseline. Results of this logistic regression will be displayed as odds ratios and a 
2-sided confidence interval (CI) (Orelvo compared to placebo). The proportion of 
subjects exhibiting renal response at Weeks 24 and 52 will be summarized by 
treatment group. 
The analyses of the secondary endpoints are described below: 
Other binary endpoints will be analyzed in a similar manner to the primary endpoint. 
Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Orelvo will be compared to placebo using a Cox proportional hazard 
model. The model will include terms for treatment and appropriate baseline 
assessments. Median time-to-event along with 2-sided CIs will be displayed. 
Other endpoints will be summarized by visit and differences between baseline and 
on-treatment values at weeks up to and including Week 52 will be analyzed using 
Mixed Effect Model Repeated Measures (MMRM). The MMRM model will include 
terms for treatment, visit, treatment by visit interaction and baseline. Results will be 
expressed as differences between treatment arms (along with associated 95% CI).  
Safety Endpoints: 
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables. 
Laboratory values (based on results from the central laboratory), vital signs and other 
safety parameters will be summarized by visit as absolute values and change from 
baseline. Laboratory values outside of defined normal ranges will be summarized. 
The impact of withdrawals on primary endpoint will be investigated with a tipping 
point analysis. 
 
 




 
 
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AUR-VCS-2016-01 SCHEDULE OF EVENTS 
Visit(1) 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visits 
4-8 
Visit 
9 
Visit 10 
Visits 
11-13 
Visit 14 
Visit 15 
End of 
Treatment/ 
Early 
Termination(2) 
Visit 16 
Safety 
Follow-up(3) 
Day/Week 
Day -30 to 
Day -1 
Day 1 
 
Day 2 
Wks 2, 
4, 8, 12, 
16 
±3 days 
Wk 20 
±3 days 
Wk 24 
±10 days 
Wks 30, 
36, 42 
±10 days 
Wk 48 
±10 days 
Wk 52  
±10 days 
Wk 56 
±10 days 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
 
Kidney biopsy(4) 
 
 
See footnote(4) 
Randomization 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical/SLE/LN 
history 
 
 
 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
 
 
 
Physical examination(5) 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, pulse, 
temperature)  
 
 
 
 
 
 
 
 
 
 
ECG(6) 
 
 
 
(7) 
 
 
 
 
 
 
Laboratory assessments(8) 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics(9) 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
FMV urine collection 
(10) 
 
 
 
 
 
 
 
 
 
24-hour urine  (11) 
 
 
 
 
 
 
 
 
 
 


 
 
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Visit(1) 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visits 
4-8 
Visit 
9 
Visit 10 
Visits 
11-13 
Visit 14 
Visit 15 
End of 
Treatment/ 
Early 
Termination(2) 
Visit 16 
Safety 
Follow-up(3) 
Day/Week 
Day -30 to 
Day -1 
Day 1 
 
Day 2 
Wks 2, 
4, 8, 12, 
16 
±3 days 
Wk 20 
±3 days 
Wk 24 
±10 days 
Wks 30, 
36, 42 
±10 days 
Wk 48 
±10 days 
Wk 52  
±10 days 
Wk 56 
±10 days 
Pregnancy test(12) 
 
 
 
 
 
 
 
 
 
 
AEs 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications(13) 
 
 
 
 
 
 
 
 
 
 
SELENA-SLEDAI 
 
 
 
 
 
 
 
 
 
 
SF-36 and LupusPro(14) 
 
 
 
(7) 
 
 
 
 
 
 
Healthcare Resource 
Utilization(15) 
 
 
 
 
 
 
 
 
 
 
Dispense study 
treatment/compliance 
 
 
 
 
 
 
 
 
(16) 
 
First dose of study 
treatment (at the study 
site)(17) 
 
 
 
 
 
 
 
 
 
 
MMF dispensing(18) 
 
 
 
 
 
 
 
 
 
 
IV methylprednisolone 
administration(19) 
 
 
 
 
 
 
 
 
 
 
Oral corticosteroid 
tapering(20) 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1 
Unscheduled visits/assessments can be done as needed. Adverse events, concomitant medications and verbal compliance check is needed. 
2 
Subjects who discontinue study treatment or terminate the study early, are to attend an Early Termination Visit and have the assessments listed performed. Subjects who complete study 
treatment will attend the End of Treatment at Week 52 and have the assessments listed performed.  
3 
Subjects who do not enroll into the continuation study will have a follow up safety visit 4 weeks after the last dose of study treatment. 
4 
If a subject has not had a recent kidney biopsy, one may be performed to assess eligibility for the study provided informed consent has been given and results are 
received prior to randomization. If one is performed as part of standard of care after randomization, the results will be recorded in the electronic case report form. 
5 
Complete physical examination at screening, abbreviated examination at all other applicable visits. Height is measured at screening only. 
6 
During the study, and after screening, in the event that a subject is noted to have a QTcF value exceeding 500 msec, or >60 msec more than baseline, the ECG 
will be repeated; see Section 9.1.4.1, Procedures to Manage a Treatment-Emergent Increase in QTc. Electrocardiograms will be recorded digitally after the 
subject has been in a resting, supine position for at least 5 minutes. 
7 
Week 12 only. 
8 
Laboratory assessments will be performed according to the schedule in Section 9.1.1, Laboratory Assessments; subjects must be fasting for at least 8 to 12 hours 
at baseline and end of study/early termination. 
9 
Blood samples will be collected at 0 and 2 hours post dose on subjects who provide consent for pharmacokinetics. 
10 
Two FMV specimens, to be performed and resulted before baseline. 
11 
24-hour urine collection should begin 2 days prior to the scheduled study visit in order not to coincide with the FMV sampling due on the day of the study visit. 
12 
Serum pregnancy test to be evaluated at central laboratory at screening, Week 24, and Week 52; urine pregnancy test will be performed locally at all other 
applicable visits. 
13 
Concomitant medications include all herbal medicines and supplements taken by the subject. 
14 
For details on HRQoL assessments, see Section 9.3.1, Health-related Quality of Life Assessments (HRQoL). 
15 
For details on Healthcare Resource Utilization, see Section 9.3.2, Healthcare Resource Utilization Assessment. 
16 
Compliance only. 
17 
 All scheduled procedures must be done prior to first dose, including IV methylprednisolone and MMF. 
18 
For subjects not on MMF during screening, will start receiving MMF therapy at the Baseline Visit and return for local complete blood count assessments at 
Weeks 1 and 3 after randomization (see Section 7 2 2 3, Mycophenolate Mofetil (Background Therapy)). 
19 
IV methylprednisolone administered 0.5 g on baseline and Day 2. If IV corticosteroids must be administered during screening then the FMV urine specimens 
will be collected prior to the infusion (see Section 7.2.2.2, Corticosteroids). 
20 
See Section 7.2.2.2, Corticosteroids. 
Notes: Subjects who discontinue therapy will attend their regularly scheduled study visits to the end of the study. Subjects who withdraw consent and terminate the 
study early or discontinue treatment early should be advised to attend both Visit 17 and the Safety Follow up Visit (Visit 18). 
Abbreviations: AE=adverse event; BP=blood pressure; CBC=complete blood count; ECG=electrocardiogram; FMV=first morning void; HRQoL=health-related quality of life; IV=intravenous; 
LN=lupus nephritis; MMF=mycophenolate mofetil; QTcF=QT interval duration corrected for heart rate using method of Fridericia; SAE=serious adverse event; SELENA-SLEDAI=Safety of 
Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index; SLE=systemic lupus erythematosus. 
 


 
 
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TABLE OF CONTENTS 
Page 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................4 
INVESTIGATOR AGREEMENT FORM ............................................................................5 
SYNOPSIS ................................................................................................................................6 
SCHEMA ................................................................................................................................12 
AUR-VCS-2016-01 SCHEDULE OF EVENTS ..................................................................13 
TABLE OF CONTENTS ......................................................................................................16 
LIST OF TABLES .................................................................................................................21 
LIST OF APPENDICES .......................................................................................................22 
LIST OF ABBREVIATIONS ...............................................................................................23 
1. 
INTRODUCTION AND BACKGROUND ..................................................................26 
1.1 
Background of the Disease and Treatment Options – Lupus Nephritis .......................26 
1.1.1 
Limitations of Current Treatment .............................................................................26 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Lupus Nephritis ............................28 
1.2.1 
Mechanism of Action................................................................................................28 
1.2.2 
Use of Immunosuppression in Lupus Nephritis .......................................................28 
1.2.3 
Clinical Studies of Calcineurin Inhibitors in Lupus Nephritis .................................29 
1.2.4 
Voclosporin ...............................................................................................................30 
1.2.4.1 
Pharmacokinetic Considerations ............................................................................30 
1.2.4.2 
Lupus Nephritis Clinical Development .................................................................31 
1.2.5 
Potential Toxicities ...................................................................................................32 
2. 
RATIONALE .................................................................................................................34 
2.1 
Dose Rationale .............................................................................................................34 
3. 
STUDY OBJECTIVES ..................................................................................................36 
3.1 
Primary Objective ........................................................................................................36 
3.2 
Secondary Objective ....................................................................................................36 
3.3 
Endpoints .....................................................................................................................36 
3.3.1 
Primary Endpoint ......................................................................................................36 
3.3.2 
Secondary Endpoints ................................................................................................36 
3.3.2.1 
Key Secondary Endpoints ......................................................................................36 
3.3.2.2 
Other Secondary Endpoints ...................................................................................37 
4. 
INVESTIGATIONAL PLAN .......................................................................................38 


 
 
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4.1 
Overall Study Design ...................................................................................................38 
4.2 
Duration of Subject Participation and Study ...............................................................38 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ................................................................................39 
5.1 
Number of Subjects......................................................................................................39 
5.2 
Inclusion Criteria .........................................................................................................39 
5.3 
Exclusion Criteria ........................................................................................................40 
5.4 
Adequate/Effective Contraception ...............................................................................42 
5.5 
Withdrawal of Subjects ................................................................................................43 
5.6 
Discontinuation of Study Treatment ............................................................................43 
5.6.1 
Discontinuation from Study Treatment Due to Early Non-response to Therapy .....43 
5.6.2 
Discontinuation of Study Treatment Due to an Adverse Event................................44 
6. 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ..............45 
6.1 
Randomization .............................................................................................................45 
6.2 
Blinding........................................................................................................................45 
6.3 
Unblinding ...................................................................................................................45 
7. 
STUDY TREATMENTS ...............................................................................................46 
7.1 
Dosage Forms/Formulation .........................................................................................46 
7.1.1 
Orelvo– Study Treatment..........................................................................................46 
7.1.2 
Placebo Control.........................................................................................................46 
7.1.3 
Background Therapy.................................................................................................46 
7.1.3.1 
Mycophenolate Mofetil ..........................................................................................46 
7.1.3.2 
Corticosteroids .......................................................................................................46 
7.2 
Drug Dosage and Administration ................................................................................46 
7.2.1 
Treatment Arms ........................................................................................................46 
7.2.2 
Dosing Guidelines.....................................................................................................47 
7.2.2.1 
Orelvo/Placebo – Study Treatment ........................................................................47 
7.2.2.2 
Corticosteroids .......................................................................................................47 
7.2.2.3 
Mycophenolate Mofetil (Background Therapy) ....................................................49 
7.3 
Package and Labeling ..................................................................................................50 
7.4 
Study Treatment Allocation .........................................................................................51 
7.5 
Site Supply, Storage, Accountability ...........................................................................51 
7.5.1 
Site Supply ................................................................................................................51 
7.5.2 
Storage ......................................................................................................................51 
7.5.3 
Accountability ...........................................................................................................51 
7.6 
Orelvo/Placebo Dose Modification..............................................................................52 
7.6.1 
Deterioration in Renal Function ...............................................................................52 
7.6.1.1 
Decrease in eGFR >30% and eGFR <60 mL/min/1.73 m2 ....................................52 
7.6.1.2 
Decrease in eGFR ≤30% and eGFR <60 mL/min/1.73 m2 ....................................53 


 
 
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7.6.1.3 
Recovery of eGFR .................................................................................................53 
7.7 
Procedures for Overdose ..............................................................................................53 
7.8 
Prohibited Therapy and Concomitant Treatment .........................................................53 
7.8.1 
Prohibited Medications .............................................................................................54 
7.8.2 
Allowed Concomitant Medications ..........................................................................55 
7.9 
Increased Blood Pressure .............................................................................................55 
7.9.1 
Symptomatic Increased Blood Pressure ...................................................................55 
8. 
RISKS/PRECAUTIONS ...............................................................................................56 
9. 
STUDY PROCEDURES ...............................................................................................57 
9.1 
Description of Study Assessments ...............................................................................57 
9.1.1 
Laboratory Assessments ...........................................................................................57 
9.1.2 
Physical Examinations ..............................................................................................59 
9.1.3 
Vital Signs.................................................................................................................60 
9.1.3.1 
Blood Pressure Management .................................................................................60 
9.1.4 
Standard 12-lead Electrocardiogram ........................................................................60 
9.1.4.1 
Procedures to Manage a Treatment-Emergent Increase in QTc ............................60 
9.1.5 
Lupus Disease Activity Assessments .......................................................................61 
9.1.6 
Orelvo Pharmacokinetics ..........................................................................................61 
9.2 
Schedule of Assessments .............................................................................................61 
9.2.1 
Screening Visit Procedures .......................................................................................61 
9.2.2 
Treatment Procedures ...............................................................................................62 
9.2.3 
End of Study (or Early Discontinuation) Procedures ...............................................63 
9.2.4 
Follow-up Procedures ...............................................................................................64 
9.2.5 
Unscheduled Visit .....................................................................................................65 
9.3 
Study Specific Assessment Procedures .......................................................................65 
9.3.1 
Health-related Quality of Life Assessments (HRQoL) .............................................65 
9.3.1.1 
Short Form Health Survey (SF-36) ........................................................................65 
9.3.1.2 
LupusPRO ..............................................................................................................66 
9.3.2 
Healthcare Resource Utilization Assessment ...........................................................66 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............67 
10.1 
Definitions....................................................................................................................67 
10.1.1 
Adverse Event ...........................................................................................................67 
10.1.2 
Adverse Drug Reaction .............................................................................................67 
10.1.3 
Serious Adverse Event ..............................................................................................67 
10.1.4 
Suspected Unexpected Serious Adverse Reaction....................................................68 
10.2 
Adverse Event Descriptors ..........................................................................................68 
10.2.1 
Intensity/Severity Categorization .............................................................................68 
10.2.2 
Causal Relationship Categorization ..........................................................................69 
10.2.3 
Outcome Categorization ...........................................................................................69 


 
 
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10.2.4 
Symptoms of the Disease Under Study ....................................................................69 
10.2.5 
Clinical Laboratory Evaluations ...............................................................................70 
10.2.6 
Abuse, Misuse, Overdose and Medication Error ......................................................70 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................70 
10.3.1 
Adverse Events .........................................................................................................70 
10.3.2 
Serious Adverse Events ............................................................................................71 
10.3.3 
Pregnancy..................................................................................................................73 
11. CLINICAL ENDPOINTS COMMITTEE ..................................................................74 
12. DATA AND SAFETY MONITORING BOARD PROCEDURES ...........................75 
13. STATISTICAL ANALYSIS .........................................................................................76 
13.1 
Statistical Methods .......................................................................................................76 
13.2 
Sample Size and Power Calculations ...........................................................................76 
13.3 
Populations ...................................................................................................................76 
13.3.1 
Intent-to-Treat Set .....................................................................................................76 
13.3.2 
Safety Set ..................................................................................................................77 
13.3.3 
Per-protocol Set ........................................................................................................77 
13.4 
Background and Demographic Characteristics ............................................................77 
13.5 
Study Treatment ...........................................................................................................77 
13.6 
Concomitant Therapy...................................................................................................77 
13.7 
Efficacy Evaluations ....................................................................................................77 
13.7.1 
Primary Endpoint ......................................................................................................77 
13.7.2 
Secondary Endpoints ................................................................................................78 
13.7.2.1 
Key Secondary Endpoints ......................................................................................78 
13.7.2.2 
Other Secondary Endpoints ...................................................................................78 
13.8 
Statistical and Analytical Methods ..............................................................................78 
13.8.1 
Primary Efficacy Analysis ........................................................................................78 
13.8.2 
Sensitivity Analyses ..................................................................................................79 
13.8.3 
Secondary Efficacy Analysis ....................................................................................79 
13.8.3.1 
Response Endpoints ...............................................................................................79 
13.8.3.2 
Time to Endpoints ..................................................................................................80 
13.8.3.3 
Change from Baseline Endpoints...........................................................................80 
13.8.3.4 
Health Resource Utilization ...................................................................................80 
13.8.4 
Multiplicity ...............................................................................................................81 
13.9 
Safety Evaluations .......................................................................................................81 
13.10 Interim Analyses ..........................................................................................................82 
13.11 Other Evaluations.........................................................................................................82 
13.11.1 Pharmacokinetics ......................................................................................................82 
14. ETHICAL CONDUCT OF THE STUDY ...................................................................83 
14.1 
Informed Consent.........................................................................................................83 


 
 
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14.2 
Institutional Review Board or EC/IEC ........................................................................83 
15. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................84 
16. ADMINISTRATIVE PROCEDURES .........................................................................85 
16.1 
Sponsor’s Responsibilities ...........................................................................................85 
16.1.1 
Study Supplies ..........................................................................................................85 
16.1.2 
Insurance ...................................................................................................................85 
16.1.3 
Study Monitoring ......................................................................................................85 
16.2 
Investigator’s Responsibilities .....................................................................................86 
16.2.1 
Reporting and Recording of Data .............................................................................86 
16.2.2 
Investigator Training.................................................................................................86 
16.2.3 
Source Documentation ..............................................................................................86 
17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .............................................................................88 
17.1 
Protocol Waivers, Deviations and Violations ..............................................................88 
17.2 
Study Termination .......................................................................................................88 
18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................89 
19. REFERENCES ...............................................................................................................90 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Dosing Schedule for IV Methylprednisolone and Daily Oral 
Prednisone (mg) ...............................................................................................49 
Table 2 
Review of Laboratory Assessments .................................................................57 
Table 3 
Orelvo Response Rates Required to Maintain a Minimum 80% Power ..........76 
 


 
 
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LIST OF APPENDICES 
Page 
Appendix 1 
Drug Therapy for the Treatment of Hypertension ...........................................93 
Appendix 2 
Measurement of Blood Pressure and Pulse ......................................................94 
Appendix 3 
International Society of Nephrology and the Renal Pathology Society 
(ISN/RPS) 2003 Classification of Lupus Nephritis .........................................95 
Appendix 4 
Conversion Table for Oral Corticosteroids ......................................................97 
Appendix 5 
1997 Update of the 1982 American College of Rheumatology Revised Criteria 
for the Classification of Systemic Lupus Erythematosus ................................98 
Appendix 6 
Systemic Lupus Erythematosus Disease Activity Measure 
(SELENA-SLEDAI) ......................................................................................100 
Appendix 7 
Expanded List of Allowed Concomitant Medications ...................................102 
Appendix 8 
Summary of Treatment and Food Restrictions ..............................................104 
Appendix 9 
Short Form Health Survey (SF-36) HRQoL Assessment ..............................105 
Appendix 10 LupusPRO (v1.7) HRQoL Assessment .........................................................111 


 
 
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LIST OF ABBREVIATIONS 
ACE 
Angiotensin converting enzyme 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALMS 
Aspreva Lupus Management Study 
ANC 
Absolute neutrophil count 
ARB 
Angiotensin receptor blocker 
AUC0-12 
Area under the curve between 0 and 12 hours 
AUC0-24 
Area under the curve between 0 and 24 hours 
AURA-LV 
Aurinia Urinary protein Reduction Active – Lupus with 
Voclosporin 
AURION 
Aurinia early Urinary protein ReductION Predicts Response 
AURORA 
AURinia Orelvo Renal Assessments 
Aurinia 
Aurinia Pharmaceuticals Inc. 
AZA 
Azathioprine 
BID 
Twice daily 
BP 
Blood pressure 
C3 / C4 
Complement 3 / complement 4 
CEC 
Clinical Endpoints Committee 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum concentration 
CNI 
Calcineurin inhibitor 
CsA 
Cyclosporine A 
CYP3A4/5 
Cytochrome P450 3A4/5 
DMC 
Data Monitoring Committee 
dsDNA 
Double-stranded deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 


 
 
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EDC 
Electronic data capture 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HCP 
Health care professional 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVC 
Intravenous cyclophosphamide 
IWRS 
Interactive web response system 
LN 
Lupus nephritis 
MMF 
Mycophenolate mofetil 
MMRM 
Mixed Effect Model Repeated Measures 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Odds ratio 
Orelvo 
Voclosporin (for Phase 3 lupus nephritis indication) 
P-gp 
P-glycoprotein 


 
 
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PK 
Pharmacokinetic 
QTc 
Corrected QT interval 
QTcF 
QT interval duration corrected for heart rate using method of 
Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SELENA 
Safety of Estrogens in Lupus Erythematosus National Assessment 
SLE 
Systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
t1/2 
Terminal elimination half-life 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
UPCR 
Urine protein creatinine ratio 
 
 
WHO 
World Health Organization 


 
 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options – Lupus 
Nephritis 
Lupus nephritis (LN) is the most common serious manifestation of systemic lupus 
erythematosus (SLE). Lupus nephritis is divided into different classes according to the level of 
treatment required, using a classification system for renal biopsy pathology originally 
developed by the World Health Organization (WHO). The classification of LN has evolved 
and the “International Society of Nephrology/Renal Pathology Society 2003 Classification of 
Lupus Nephritis” is now widely used and has a higher level of inter-observer reproducibility 
than the original classification. For subjects with Class III, IV (proliferative), or V 
(membranous), or combinations of these forms of LN, the standard of care is treatment with 
corticosteroids and immunosuppressive therapy. 
Lupus nephritis manifests as diverse patterns of immune complex-mediated renal disease 
affecting glomerular, tubulointerstitial, and vascular compartments. It can lead to permanent 
and irreversible tissue damage within the kidney, resulting in end-stage renal disease (ESRD), 
and thus making LN a serious and potentially life-threatening condition. In subjects with LN, 
renal damage results in proteinuria and/or hematuria and a decrease in renal function as 
evidenced by reduced creatinine clearance and estimated glomerular filtration rate (eGFR), and 
increased serum creatinine levels. 
In LN as in other serious renal diseases, the main clinical outcomes are progression to ESRD 
(i.e., the need for long-term dialysis or transplantation) and death. The current standard of care 
for LN, corticosteroids and immunosuppressants, has improved the prognosis of the disease 
considerably. Incidence rates of ESRD in LN, however, appear to have been stable over recent 
years, possibly reflecting the limits of effectiveness of current treatments or lack of adherence 
to treatments by subjects. The most recent studies have reported 10-year survival rates of over 
90% and, although the overall risk of developing ESRD in subjects with LN is approximately 
15%, the 5-year risk of developing ESRD has been found to be as low as 5% [1]. Recently, 
10-year follow-up data of LN subjects treated with intravenous cyclophosphamide (IVC) for 
active disease followed by maintenance treatment with azathioprine (AZA) found rates of 
ESRD to be approximately 7% [2]. 
1.1.1 Limitations of Current Treatment 
The current treatment paradigm for LN includes 2 goals, based on the severity of disease. The 
first goal of treatment in subjects with active LN is intended to bring the disease under control 
as quickly as possible to limit the potential for extensive renal scarring or loss of life. This 
phase of treatment is particularly critical for those subjects at highest risk for ESRD (i.e., 
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proliferative nephritis, active urinary sediment, elevated serum creatinine, and/or proteinuria). 
In subjects with severe LN, the achievement of complete or partial remission, as demonstrated 
by stabilization or improvement in renal function, improvement in proteinuria, and 
normalization of active urinary sediment, has been shown to be associated with better patient 
and renal survival. Treatment of active LN (i.e., induction treatment) typically consists of high 
doses of both corticosteroids and immunosuppressants. 
The second goal of treatment, after the patient successfully responds to treatment, is to 
maintain remission by preventing renal flares and any resulting deterioration in renal function. 
In this second phase of treatment, lower doses of both corticosteroids and immunosuppressants 
are used. 
Corticosteroids are the cornerstone of treatment in SLE, and have been the standard since the 
1950s to treat both renal and non-renal manifestations. Intravenous (IV) steroid pulse therapy 
is widely used to rapidly treat relapsing LN, but does not provide long-term management. Oral 
corticosteroids taken for prolonged periods and at high doses are often needed, but have 
potentially severe, and at times irreversible adverse effects including risk of infection, 
hyperlipidemia, hypertension, osteoporosis, diabetes, and accelerated atherosclerosis. 
Induction treatment recommendations advocate the use of immunosuppressants in conjunction 
with high-dose oral corticosteroids, to enable a rapid taper to a lower maintenance dose of 
steroids. Steroid-sparing therapies are needed in order to treat disease activity and also 
minimize cumulative and high-dose steroid exposure. 
Intravenous cyclophosphamide, while classically considered the standard of care for induction 
therapy, is still associated with significant potentially life-threatening toxicities, such as the 
increased risk of severe infections including sepsis, malignancy, and major morbidity, such as 
permanent gonadal failure. 
Recent studies have shown that induction treatment with mycophenolate mofetil (MMF) has 
similar efficacy to that of IVC. The authors of a recent meta-analysis concluded that MMF is 
as efficacious as IVC and is not associated with the risk of infertility, which is a significant 
toxicity of IVC in this patient population [3]. In the Aspreva Lupus Management Study 
(ALMS), a comparison of MMF and IVC in the treatment of active LN, 50.4% subjects with 
active LN entering the study had nephrotic-range proteinuria (>3 g/day) [4]. Intravenous 
cyclophosphamide and MMF reduced proteinuria to a similar extent. However, even after 
24 weeks of therapy with either MMF or IVC in the setting of a clinical study, subjects had 
substantial residual proteinuria. At the end of 24 weeks of therapy, normal (<500 mg/24 hours) 
protein excretion levels were observed in only 27% of subjects who received IVC and 23.8% 
of subjects who received MMF [5]. The findings from ALMS indicate that there exists a 
substantial unmet medical need for more effective treatments for active LN with heavy 
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The importance of proteinuria and reduction of proteinuria as prognostic factors for renal 
flares, ESRD and death in subjects with LN is well documented. Proteinuria in itself is related 
to progression of renal disease through effects on the glomerulus and tubulointerstitium [6]. In 
observational studies, proteinuria has been shown to be a predictor of adverse renal outcomes, 
cardiovascular disease, and mortality in subjects with non-diabetic proteinuric 
nephropathies [7]. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Lupus Nephritis 
1.2.1 Mechanism of Action 
Calcineurin inhibitors (CNIs) are a class of immunosuppressants which reversibly inhibit 
immunocompetent lymphocytes, particularly T-lymphocytes in the G0 and G1 phase of the 
cell-cycle, and also reversibly inhibit the production and release of lymphokines. Voclosporin, 
a CNI, mediates its suppressive effects by binding to an ubiquitous intracellular protein 
cyclophilin. This complex, in turn, inhibits the calcium- and calmodulin-dependent 
serine/threonine phosphatase activity of the enzyme calcineurin. Calcineurin inhibition then 
prevents the activation of various transcription factors necessary for the induction of cytokine 
genes during T-cell activation, such as interleukin-2, interleukin-4, tumor necrosis factor-α, 
granulocyte-macrophage colony stimulating factor, and interferon-γ. 
1.2.2 Use of Immunosuppression in Lupus Nephritis 
Calcineurin inhibitors are standard treatment to prevent acute rejection in subjects who have 
received transplants. Since the development of cyclosporine in the early 1980s, standard 
immunosuppression regimens to prevent rejection post-transplantation have included steroids 
and a CNI; more recently other immunosuppressants, such as MMF, have been added to 
standard therapy. The rationale for use of CNIs in autoimmune diseases include potent effects 
on T-cell activation and immunomodulatory effects. AT-cell mediated immune response is an 
important feature of the pathogenesis of many of these diseases, including LN. Calcineurin 
inhibitors also have specific anti-proteinuric effects. The podocyte is a key cell in the 
glomerular capillary wall that maintains the integrity of the filtration barrier and prevents the 
development of proteinuria in healthy individuals, while being the primary target of injury in 
proteinuric kidney disease. Podocyte injury is an important factor in the progression of LN. It 
typically occurs due to immune complex deposition but may also occur in the absence of this 
histologic feature [8]. Podocyte function depends on a complex and unique structure that, in 
turn, depends on a tightly regulated actin cytoskeleton. Synaptopodin acts as a key stabilizer 
of the actin cytoskeleton in podocytes. When synaptopodin is phosphorylated, it binds to 
another protein, 14-3-3, and is thus protected from degradation. Calcineurin dephosphorylates 
synaptopodin allowing its degradation, thus promoting proteinuria by destabilization of the 
podocyte actin cytoskeleton. Expression of activated calcineurin in podocytes leads to 
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anti-proteinuric effect by preventing the degradation of the podocyte-stabilizing protein 
synaptodin. Taken together, these data suggest that the anti-proteinuric effects of CNIs may be 
explained by their direct effect on the podocyte actin cytoskeleton as well as 
immunomodulatory effects on T-lymphocytes [9]. 
1.2.3 Clinical Studies of Calcineurin Inhibitors in Lupus Nephritis 
Bao et al, 2008 [10] performed an open-label study in 40 subjects with Class V+IV LN. 
Subjects were randomized to either IVC and prednisolone or “multi-target therapy” with MMF 
plus tacrolimus (4 mg/day) and prednisolone. In the multi-target group, 50% achieved 
complete remission compared with 5% in the standard IVC group at 6 months. Estimated 
glomerular filtration rate normalized in both groups, but there was a significantly larger 
reduction in proteinuria in the multi-target therapy group.  
Miyasaka et al, 2009 [11] evaluated the efficacy and safety of tacrolimus in 63 subjects 
receiving glucocorticoid therapy for LN in a double-blind, placebo-controlled, randomized 
trial. Subjects with persistent nephritis requiring 10 mg/day prednisone were randomized to 
receive 28 weeks of treatment with tacrolimus (3 mg/day) or placebo. There was a statistically 
significant improvement in the primary endpoint, the Lupus Nephritis Disease Activity Index, 
in the tacrolimus group compared to the placebo group. Daily urinary protein excretion (the 
percentage of subjects with urine protein <0.3 g/day at the final evaluation) also showed a 
significant decrease in the tacrolimus group. However, measures of glucose intolerance were 
more frequent in tacrolimus-treated subjects. The authors concluded that tacrolimus should be 
considered one of the options to treat LN. On the basis of the results of this study, tacrolimus 
was approved for the treatment of LN in Japan. 
In an observational study conducted by Cortes-Hernandez et al, 2010 [12], 70 subjects who 
had received MMF as continuous therapy were followed over a 5-year period. Tacrolimus was 
added as rescue therapy in 17 subjects who were treatment failures or had renal flares on 
treatment with MMF. The authors reported a significant reduction in proteinuria at 3 months, 
and after 2 years of follow-up, it was concluded that tacrolimus was a safe and effective 
treatment for MMF non-responsive cases. 
Several smaller pilot studies and case series in subjects with LN, including subjects with 
membranous nephropathy, have suggested a treatment benefit of tacrolimus with or without 
MMF [13-19]. 
The available data suggest a plausible mechanism of action by which CNIs may provide 
treatment benefits in LN. The clinical evidence is suggestive of improvement in measures of 
response in active LN and improvement in extrarenal manifestations of SLE and immunologic 
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1.2.4 Voclosporin 
Voclosporin is a next-generation CNI developed for the treatment of autoimmune diseases and 
for use in the prevention of organ graft rejection. Voclosporin is structurally similar to 
cyclosporine A (CsA) except for a novel modification of a functional group on the amino acid 1 
residue of the molecule. This alteration has changed the binding of voclosporin to calcineurin 
leading to a 3- to 5-fold increase in potency when compared to CsA. This modification has 
also shifted metabolism away from amino acid 1, the major site of metabolism for CsA, thus 
altering the metabolic profile. This in turn has led to faster elimination of metabolites resulting 
in lower measured metabolite exposure as compared to CsA. The combination of increased 
potency and decreased measured metabolite exposure, for voclosporin as compared to CsA, 
has led to better pharmacokinetic (PK)/ pharmacodynamic predictability. 
During the development of this investigational product the legacy names of voclosporin, VCS, 
 are referenced in discussions related to historical usage. However, for the LN Phase 3 
clinical development program, the name of the investigational product will be referred to as 
Orelvo, the proposed trade name. These legacy names should all be considered interchangeable 
unless specifically identified as different. 
Prior to the LN clinical development program, approximately 2,200 subjects received 
investigational products containing voclosporin in 14 Phase 1 and 10 Phase 2/3 clinical studys 
in the indications of transplant rejection, psoriasis and non-infectious uveitis. Detailed data for 
these clinical studys are presented in the Investigator’s Brochure (IB).  
1.2.4.1 Pharmacokinetic Considerations 
Voclosporin approximates linear multiexponential PKs. Exposure to voclosporin was 
dose-related with maximum concentrations occurring ≤2 hours with a terminal elimination 
half-life (t1/2) of ≥30 hours. Drug accumulation was minor with accumulation factors of 
approximately 2 hours after twice daily (BID) dosing. Administration of voclosporin oral 
solution with either low- or high-fat meals decreased both the rate and extent of absorption 
which appeared to be related to the fat content of the meal. It is therefore recommended that 
Orelvo (voclosporin) be administered on an empty stomach to ensure adequate absorption. 
Voclosporin has been shown to be a substrate of cytochrome P450 3A4/5 (CYP3A4/5). 
Concomitant administration of ketoconazole, a strong CYP3A4/5 inhibitor, led to a 6-fold 
increase in maximum concentration (Cmax) and an 18-fold increase in area under the curve 
between 0 and 12 hours (AUC0-12) for voclosporin. Concomitant administration of rifampin, 
an inducer of CYP3A4/5, resulted in a decrease in exposure to voclosporin. Maximum 
concentration decreased approximately 70%, the area under the concentration curve decreased 
approximately 90%, and t1/2 decreased 85%. Consequently, both ketoconazole and rifampin 
are contraindicated with Orelvo (voclosporin). Concomitant administration of voclosporin and 


 
 
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midazolam, a model substrate of CYP3A4/5 and potential inhibitor of CYP3A4/5, did not 
result in statistically significant changes in the rate or extent of exposure to midazolam or 
α-hydroxy-midazolam. 
Voclosporin is both a substrate for and an inhibitor of P-glycoprotein (P-gp). Concomitant 
administration of verapamil, a known inhibitor of P-gp, demonstrated an approximate 3-fold 
increase in Cmax and AUC0-12 of voclosporin. Concomitant administration of digoxin, a P-gp 
substrate, resulted in statistically significant increases in digoxin Cmax and area under the curve 
between 0 and 24 hours (AUC0-24) and a decrease in clearance. Therefore concomitant 
administration of P-gp substrates with voclosporin would be expected to result in increased 
exposure to the substrate. Clinicians are advised to consider the benefit/risk of concomitant 
P-gp substrate drugs carefully. 
1.2.4.2 Lupus Nephritis Clinical Development 
The AURA-LV study (Protocol AUR-VCS-2012-01) is a randomized, controlled, 
double-blind Phase 2 study comparing the efficacy and safety of voclosporin (23.7 mg BID or 
39.5 mg BID) with placebo in achieving remission in patients with active LN. The duration of 
the study is 48 weeks and is ongoing. All patients received background therapy with MMF and 
corticosteroid taper. The primary endpoint of complete remission was defined as: urine protein 
creatinine ratio (UPCR) of ≤0.5 mg/mg at 24 weeks (using first morning void) and eGFR 
≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of ≥20%. In addition, 
patients could not receive rescue medications for LN (defined as >10 mg prednisone/day 
for >3 consecutive days or >7 days total from Weeks 16-24) to be considered for complete 
remission.  
A total of 265 subjects were randomized into the AURA-LV study. The 24-week primary 
endpoint assessment for the AURA-LV clinical study demonstrated that the groups were 
generally well balanced for age, gender and race, with a trend to higher proteinuria and lower 
eGFR data in the low-dose voclosporin arm. The low dose achieved a statistically significant 
benefit over placebo for the primary efficacy assessment of complete remission at 24 weeks 
(odds ratio (OR) [95% CI] = 2.03, [1.01, 4.05], p=0.045), without a statistically significant 
improvement seen in the high dose. The results were confirmed by 24 hour urine collections 
(p=0.047). Both the low- and high-dose voclosporin were statistically superior to placebo in 
partial remission, time to complete remission, and time to partial remission. A mean reduction 
in serum creatinine was seen in both arms (0.2 mg/dL low, 0.1 high; p<0.001). In the 
voclosporin groups, eGFR fell by a median of 8-9 mL/min by Week 4 and then stabilized over 
the course of the study. Blood pressure did not vary by group. The correlation of 24-hour urine 
protein and using the first morning void was assessed from the results of the AURA-LV study 
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Over 90% of subjects experienced at least 1 adverse event (AE); the most common being 
infectious disease (56.2% low-dose, 63.6% high-dose and 50.0% placebo), GI disorders 
(41.6% low-dose, 52.3% high-dose and 36.4% placebo). More serious adverse events (SAEs) 
occurred in the voclosporin groups (25.8% low-dose, 25.0% high-dose, 15.8% placebo), and 
were consistent with those observed in LN patients. There were 13 deaths (4.9%) during the 
study. There were more deaths in the voclosporin low-dose arm (10) than in either the 
voclosporin high-dose (2) or placebo (1) arms, with the majority (11/13) occurring in Asia. All 
deaths were assessed by the Investigators as unrelated to study treatment.  
In summary, no unexpected safety signals were observed with the use of voclosporin in LN 
subjects; voclosporin was generally well tolerated. The overall safety profile is consistent with 
the expectations for the class of drug, the patient population, and concomitant therapies.  
The AURION study (protocol AUR-VCS-2014-01) is an exploratory open-label Phase 2 study 
assessing the short-term predictors of remission of voclosporin 23.7 mg BID in combination 
with standard of care in patients with active LN. The duration of the study is 48 weeks with 
10 subjects randomized. All subjects received background therapy with MMF and 
corticosteroids. At 24 weeks, 4/7 (57.1%) subjects continued to be in complete remission as 
measured by a UPCR of ≤0.5 mg/mg, eGFR within 20% of baseline, and concomitant steroid 
dose of less than 5 mg/day. Within these 7 AURION patients, there was a 54% mean reduction 
in proteinuria at 24 weeks compared to pre-treatment levels along with consistent 
improvements in complement 3 (C3), C4 and anti-double-stranded DNA. Renal function as 
measured by eGFR remained stable. voclosporin was well tolerated with no unexpected safety 
signals observed.  
1.2.5 Potential Toxicities 
Voclosporin has been studied in numerous disease states. When examining LN, there were a 
small proportion of voclosporin treated subjects that experienced an early drop of ≥30% in 
eGFR, however that proportion then remains stable over time. None of these treatment-
emergent adverse events (TEAEs) were classed as serious. The majority of TEAEs of 
decreased GFR were classed as mild or moderate, and resulted in permanent discontinuation 
of study drug in 1 (1.1%) placebo subject, 6 (6.7%) voclosporin low-dose subjects and 5 (5.6%) 
voclosporin high-dose subjects. There were more TEAEs of hypertension seen in the 
voclosporin-treated patients compared to placebo however, overall mean systolic and diastolic 
blood pressure (BP) decreased in all groups, without statistically significant differences seen 
between groups. Overall, only 1 (1.1%) subject, in the voclosporin high-dose group, had a 
TEAE of hypertension that resulted in permanent discontinuation of study drug.  
There was evidence of an increased incidence of TEAEs over placebo and with increased dose 
of voclosporin in the System Organ Classes of Infections and Infestations, Gastrointestinal 
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There were more deaths in the voclosporin low-dose arm (10) than in either the voclosporin 
high-dose (2) or placebo (1) arms, with the majority (11/13) occurring in South-East Asia. All 
deaths were assessed by the Investigator and Data and Safety Monitoring Board (DSMB) as 
unrelated to study treatment. A full description of adverse events can be found in the IB. 


 
 
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2. RATIONALE 
The rationale for the development of Orelvo and the choice of doses is to introduce a novel 
CNI to the LN patient population, with meaningful efficacy while minimizing toxicities 
common to other CNIs. In clinical studies, a favorable efficacy/safety profile for Orelvo has 
been demonstrated in the prevention of renal transplant rejection. 
As evaluated in nonclinical and clinical studies (healthy volunteers, moderate to severe 
psoriasis, renal transplantation, and uveitis) Orelvo is well tolerated and exhibits AEs that are 
typical of other CNIs yet seen to a lesser extent than that seen historically with other CNIs. 
The aim of the current study is to investigate whether Orelvo, added to the standard of care 
treatment in active LN, is able to reduce disease activity over a treatment period of 52 weeks. 
The background therapy will be MMF at a dose of at least 1 g/day and initial treatment with 
IV methylprednisolone, followed by a reducing course of oral corticosteroids. Subjects with 
active, flaring LN will be eligible to enter the study. They are required to have a diagnosis of 
LN according to established diagnostic criteria (American College of Rheumatology) and 
clinical and biopsy features suggestive of active nephritis. Efficacy will be assessed by the 
ability of the drug combination to reduce the level of proteinuria (as measured by urine 
protein/creatinine ratio (UPCR)) while demonstrating an acceptable safety profile. Normally, 
most subjects will respond to treatment by 6 months. Therefore, the primary endpoint of the 
Phase 3 study will be complete renal response at 24 weeks. 
2.1 
Dose Rationale 
This Phase 3 study is designed to evaluate the treatment benefit of Orelvo 23.7 mg BID versus 
placebo. Orelvo and/or placebo are herein referred to as study treatment. The selection of 
Orelvo dose in this study (see Section 7, Study Treatments) was based on the previous 
experience with this drug in the Phase 2 study (AURA-LV). In AURA-LV, subjects were 
administered voclosporin 23.7 mg BID, 39.5 mg BID, or matching placebo. Low-dose 
voclosporin was significantly superior to placebo in the proportion of subjects achieving 
complete renal response at Week 24 (p=0.045). There was no increase in efficacy with the 
higher dose and no significant differences between the 2 voclosporin groups in achievement 
of renal response.  
Orelvo 23.7 mg BID will be administered as a fixed dose without the use of therapeutic drug 
monitoring. Population PK analyses of voclosporin concentrations from the clinical 
development program (including healthy subjects, subjects with renal impairment, subjects 
with hepatic impairment, renal transplant, and plaque psoriasis) demonstrated that weight did 
not have a significant effect on the PKs of voclosporin. The protocol contains provisions for 
management of dose based on safety concerns, in particular, BP and renal function. The safety 


 
 
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data from the use of voclosporin demonstrates that these risks are dose-related, reversible, and 
can be managed by dose reduction and temporary interruption.   


 
 
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the efficacy of Orelvo compared with placebo in achieving renal response after 
24 weeks of therapy in subjects with active LN 
3.2 
Secondary Objective 
• To assess the safety, tolerability, and efficacy of Orelvo over 52 weeks compared with 
placebo in subjects with active LN 
3.3 
Endpoints 
3.3.1 Primary Endpoint 
Renal response at Week 24 will be adjudicated by the Clinical Endpoints Committee (CEC) 
based on the following parameters: 
• UPCR of ≤0.7 mg/mg, and 
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, 
and 
• Received no rescue medication for LN (see Section 7.8, Prohibited Therapy and 
Concomitant Treatment), and 
• Received ≤10 mg/day prednisone from Weeks 16 through 24 
Subjects who withdraw from the study prior to the Week 24 assessment will be defined as 
non-responders. 
3.3.2 Secondary Endpoints 
3.3.2.1 Key Secondary Endpoints 
• Time to UPCR of ≤0.7 mg/mg 
• Partial renal response as defined by 50% reduction from baseline in UPCR at Weeks 24 
and 52 
• Time to 50% reduction in UPCR from baseline 
• Renal response at Week 52 (based on definition of primary endpoint) 
• Duration of UPCR ≤0.7 mg/mg 


 
 
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3.3.2.2 Other Secondary Endpoints 
• Change from baseline in UPCR at each time point 
• Change from baseline in serum creatinine, urine protein, and eGFR 
• Change from screening in immunology parameters (complement 3 (C3), C4, and anti- 
double-stranded deoxyribonucleic acid (dsDNA)) at Weeks 24 and 52 
• Renal response with low-dose steroids (defined as renal response in the presence of 
corticosteroids of ≤2.5 mg/day between Weeks 16 to 24 and Weeks 36 to 52) 
• Change from baseline in health-related quality of life (HRQoL) at Weeks 12, 24, and 
52 
• Health Resource Utilization at Weeks 24 and 52 
• Change from baseline in the Safety of Estrogens in Lupus Erythematosus National 
Assessment - Systemic Lupus Erythematosus Disease Activity (SELENA-SLEDAI) 
Index score at Weeks 24 and 52 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 3, multicenter, randomized, prospective, double-blind, parallel-group, 
placebo-controlled, 2-arm comparison study of Orelvo versus matching placebo. Subjects who 
have provided a signed and dated informed consent will be screened into the study up to 
30 days before randomization. During the screening period, eligibility criteria will be assessed. 
A kidney biopsy may be performed, provided the subject has given consent and provided the 
results can be obtained and reviewed before baseline. Subjects who meet all of the inclusion 
criteria and none of the exclusion criteria will be eligible for randomization into the study. 
Baseline assessments will be performed before the first dose of study treatment is administered 
on Day 1. The baseline assessments of the serum creatinine and urine protein laboratory 
parameters will be established by using the mean of the 2 pre-randomization values. Using an 
interactive web response system (IWRS), eligible subjects will be randomized to receive either 
oral Orelvo 23.7 mg BID or matching placebo for 52 weeks. All subjects should receive 
0.5 g/day IV methylprednisolone on Days 1 and 2 before changing to a reducing course of oral 
corticosteroid therapy on Day 3. (For additional details and exceptions, see Section 7.2.2.2, 
Corticosteroids). Starting at the Baseline Visit, all subjects will also receive background 
therapy with MMF (see Section 7.2.2.3, Mycophenolate Mofetil (Background Therapy). 
All subjects will return for assessment of efficacy and safety at Day 2 and Weeks 2, 4, 8, 12, 
16, 20, 24, 30, 36, 42, 48, and 52. See Schedule of Events, for detailed information regarding 
visits. In addition, subjects not on MMF during screening, will start receiving MMF at the 
Baseline Visit and will return for local complete blood count assessments at Weeks 1 and 3 
after randomization. 
All subjects, completed or withdrawn, will complete the End of Treatment/Early Termination 
assessments (Visit 15) at Week 52 or at the time of early termination. Subjects who do not 
enroll in the continuation study will attend the Safety Follow-up Visit (Visit 16) at Week 56 to 
collect any new AEs and concomitant medications. At the follow-up visit, UPCR and eGFR 
will be assessed as well. For subject withdrawal procedures and criteria, see Section 5.5, 
Withdrawal of Subjects. 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is approximately 60 weeks. The screening 
period is up to 30 days and the treatment duration is 52 weeks, with a further follow-up visit 
4 weeks after last dose (completion or early termination) if not participating in the continuation 
study. 


 
 
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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
It is anticipated that approximately 324 subjects (162 in the Orelvo 23.7 mg BID treatment 
group and 162 subjects in the placebo group) will be randomized in this study.  
5.2 
Inclusion Criteria 
The following inclusion criteria must be met for each subject: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 (or legal age of consent if >18 years) 
to 75 years of age, inclusive, at the time of screening (Visit 1). 
3. Previous diagnosis of SLE according to the American College of Rheumatology criteria 
(1997; see Appendix 3). 
4. Subjects with evidence of active nephritis, defined as follows: 
Kidney biopsy result within 2 years prior to screening indicating Class III, IV-S or IV-G 
(alone or in combination with Class V) LN with a doubling or greater increase of UPCR 
within the last 6 months to a minimum of ≥1.5 mg/mg at screening.  
OR 
Kidney biopsy result within 6 months prior to screening indicating Class III, IV-S or 
IV-G (alone or in combination with Class V) LN with a UPCR of ≥1.5 mg/mg at 
screening. 
OR 
Kidney biopsy result within 6 months prior to screening indicating Class V LN and a 
UPCR of ≥2 mg/mg at screening.  
A biopsy can be performed during screening, if not available. The above criteria must be 
fulfilled at baseline. 
5. In the opinion of the Investigator, subject requires high-dose corticosteroids and 
immunosuppressive therapy. 


 
 
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6. Subject is willing to take oral MMF for the duration of the study, either by continuing 
current MMF therapy or by initiating it on or before the Baseline Visit. 
7. Women of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline. Two effective forms of contraception must 
be used simultaneously unless abstinence is the chosen method. Subjects must use effective 
contraception during the study (see Section 5.4, Adequate/Effective Contraception). 
5.3 
Exclusion Criteria 
1. Subjects unable or unwilling to give written informed consent and/or to comply with study 
procedures. 
2. eGFR as calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation of ≤45 mL/min/1.73 m2 at screening confirmed before randomization. 
3. Currently taking or known need for any of the medications listed in Section 7.8, Prohibited 
Therapy and Concomitant Treatment at screening or during the study. This includes 
prohibited medications prior to screening as specified in Section 7.8.1, Prohibited 
Medications. 
4. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to 
require dialysis during the study period. 
5. A previous kidney transplant or planned transplant within study treatment period. 
6. Any known hypersensitivity or contraindication to MMF, mycophenolic acid, 
cyclosporine, corticosteroids or any components of these drug products. 
7. Current or medical history of: 
• Congenital or acquired immunodeficiency. 
• In the opinion of the Investigator, clinically significant drug or alcohol abuse within 
2 years prior to screening. 
• Malignancy within 5 years of screening, with the exception of basal and squamous cell 
carcinomas treated by complete excision. Subjects with cervical dysplasia that is 
cervical intraepithelial neoplasia 1, but have been treated with conization or loop 
electrosurgical excision procedure, and have had a normal repeat Papanicolaou test are 
allowed. 
• Lymphoproliferative disease or previous total lymphoid irradiation. 


 
 
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• Severe viral infection (e.g., cytomegalovirus, hepatitis B virus, hepatitis C virus) within 
3 months of screening; or known HIV infection. Severe viral infection is defined as 
active disease requiring antiviral therapy. 
• Active TB, or known history of TB/evidence of old TB if not taking prophylaxis with 
isoniazid (see Section 9.2.1, Screening Visit Procedures). 
8. Other known clinically significant active medical conditions, such as: 
• Severe cardiovascular disease including congestive heart failure, history of cardiac 
dysrhythmia or congenital long QT syndrome. QT interval duration corrected for heart 
rate using method of Fridericia (QTcF) exceeding 480 msec in the presence of a normal 
QRS interval (<110 msec) at time of screening will result in exclusion. 
• Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or bilirubin 
≥2.5 times the upper limit of normal) at screening and, if abnormal at screening, then 
confirmed that the levels have returned to <2.5 times upper limit of normal before 
randomization. 
• Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• Bone marrow insufficiency unrelated to active SLE (according to Investigator 
judgment) with white blood cell count <2,500/mm3; absolute neutrophil count (ANC) 
<1.3 × 103/μL; thrombocytopenia (platelet count <50,000/mm3). 
• Active bleeding disorders. 
• Current infection requiring IV antibiotics. 
9. Any overlapping autoimmune condition for which the condition or the treatment of the 
condition may affect the study assessments or outcomes (e.g., scleroderma with significant 
pulmonary hypertension; any condition for which additional immunosuppression is 
indicated). Overlapping conditions for which the condition or treatment is not expected to 
affect assessments or outcomes (e.g., Sjögren’s syndrome) are not excluded. 
10. No vaccines using live organisms, virus or bacterial, are allowed during screening and 
while taking the study treatment. 
11. Other major physical or psychiatric illness or major traumatic injury within 6 months prior 
to screening that may affect study conduct or interfere with study assessments or outcome. 


 
 
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12. Any other medical condition which, in the Investigator’s judgment, may be associated with 
increased risk to the subject or may interfere with study assessments or outcomes. 
13. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using 
adequate contraceptive precautions. 
14. Participation in another clinical study within 4 weeks prior to screening and/or receipt of 
investigational drugs within 4 weeks or 5 half-lives of the drug (whichever is longer) prior 
to screening. 
15. Subjects randomized and treated in a previous voclosporin clinical study. 
5.4 
Adequate/Effective Contraception 
Women of childbearing potential must have a negative serum pregnancy test at screening and 
a negative urine pregnancy test at baseline. Two effective forms of contraception must be used 
simultaneously unless abstinence is the chosen method. Effective contraception must be used 
before beginning study treatment, during study dosing, and for 6 weeks following 
discontinuation of study treatment or MMF dosing, even when there has been a history of 
infertility, unless due to surgical sterilization. Women not of childbearing potential are defined 
as women without menses for at least 12 consecutive months or surgically sterilized. 
Sexually active men, both reproductively competent and vasectomized, are required to use 
condoms during treatment and for at least 90 days after cessation of study treatment or MMF. 
In addition, female partners of male subjects are recommended to use an effective 
contraception during their partner’s treatment and for at least 90 days after the last dose of 
study treatment or MMF. Male subjects are to refrain from making sperm donations during 
treatment and for at least 90 days after cessation of study treatment or MMF. 
An effective and medically acceptable method of birth control means the chance of pregnancy, 
when using that type of birth control, is less than 1% per year if used correctly. These birth 
control methods (i.e., reliable forms of contraception) include birth control pills (combined 
oral contraceptives), hormone implants, hormone shots, and some intrauterine contraceptive 
devices. The use of MMF in this study can also reduce the effectiveness of the oral 
contraceptive pill.  
Barrier methods (e.g., condoms, diaphragm, or cervical cap/sponge) when used alone are not 
highly considered effective. 
Although abstinence, when adhered to, is an effective method of birth control, other additional 
effective contraception methods should be used where there is any doubt. The method of 


 
 
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contraception needs to be discussed with the Investigator throughout the study period in order 
to confirm the method used is considered effective. 
5.5 
Withdrawal of Subjects 
Subjects may voluntarily withdraw from study participation at any time for any reason. 
Alternatively, subjects may be withdrawn at the Investigator’s discretion if it is in the subject’s 
best interest. 
Every effort should be made for subjects who withdraw from the study, either voluntarily or at 
the Investigator’s discretion, to undergo end of study assessments (Visit 15), if possible. If 
possible, the subject should also be advised to come for the Safety Follow-up Visit 4 weeks 
after last dose. If a subject refuses end of study procedures, the reason for refusal should be 
fully documented in the subject’s source document and recorded in the study specific electronic 
case report form (eCRF). It is the subject’s right to withdraw from the study without providing 
a reason. In this case, the source documents and the eCRF should document the reason for 
discontinuation as “withdrawal of consent.” Withdrawn subjects will not be replaced. 
5.6 
Discontinuation of Study Treatment 
If any subject is discontinued from study treatment, the reason for discontinuation will be 
documented in the eCRF. If the reason for discontinuing study treatment is an AE or an 
abnormal laboratory test result, the specific event or test will be recorded in the eCRF. Except 
for cases involving pregnancy, subjects who are discontinued from study treatment should 
undergo all study assessments up to and including (Week 52 or Early Termination Visit – 
Visit 15), if possible. The subject should also be advised to come for the Safety Follow-up 
Visit 4 weeks after last dose. Guidance on when study treatment must be discontinued is in 
Section 7.6, Orelvo/Placebo Dose Modification.  
5.6.1 Discontinuation from Study Treatment Due to Early Non-response to 
Therapy 
Subjects will be discontinued from study treatment if their early disease response is 
suboptimal. The Investigator must contact the Medical Monitor to discuss further continuation 
in the study if the subject meets 1 of the 2 following criteria: 
• After 12 weeks of treatment, the subject shows a >30% decrease from baseline value 
in CKD-EPI eGFR in 2 successive measurements separated by at least 4 weeks 
or 
• After 8 weeks of treatment, the subject shows a confirmed reduction in UPCR of ≤25% 
assessed by 2 consecutive measurements at least 2 weeks apart. 


 
 
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If the subjects require treatment with IV methylprednisolone or any rescue medication other 
than that permitted in the protocol (see Section 7.2.2.2, Corticosteroids), they should be 
permanently discontinued from the study treatment and will be considered a treatment failure. 
Subjects who are permanently discontinued from study treatment will be treated as deemed 
appropriate by the Investigator. 
5.6.2 Discontinuation of Study Treatment Due to an Adverse Event 
Subjects may be permanently discontinued from study treatment because of the appearance of 
an unacceptable AE. It is vital to obtain follow-up data on any subject withdrawn because of 
an AE. In any case, every effort must be made to evaluate protocol-specified safety follow-up 
procedures (see Section 10.3, Reporting Procedure for AEs, SAEs, and Pregnancy). If a subject 
is withdrawn due to an AE, the event should be followed by the Investigator through contact 
with the subject until resolution or stabilization has occurred. All AEs should be followed until 
resolution, stabilization or the subject is lost to follow-up and cannot be contacted. 


 
 
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6. RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES 
6.1 
Randomization 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and subject names to enable records to be found at a later date. 
Subjects will be allocated a subject number at the screening visit and registered with an 
interactive central randomization system. Subjects meeting the required eligibility criteria will 
be randomized to treatment at Visit 2 (baseline). The randomization will be stratified by region, 
biopsy class (Class V only versus Others), and by prior MMF use at time of screening. The 
subjects will be randomized in a ratio of 1:1 to receive either Orelvo 23.7 mg BID or matching 
placebo. A centralized randomization will be utilized to ensure balance. 
Details on randomization procedures will be provided in a separate manual. 
6.2 
Blinding 
In order to preserve the double-blind design, subjects randomized to the placebo group will be 
matched to the active dosage groups. Dosing schedule in the placebo group will be the same 
as that of the active treatment group. To this end, the double-blind nature of this study preserves 
the blind with respect to active study treatment and placebo. 
All study personnel and subjects will be blinded to the study treatment administered during the 
study. Orelvo and placebo will be identical in taste, smell, and appearance. The randomization 
code key will not be available to the Study Monitors, project statisticians or the project team 
at Aurinia Pharmaceuticals Inc. (Aurinia) or its representatives. The site staff, monitors, and 
study subjects will remain blinded until the end of the study. In case of emergency, the 
unblinding process below should be followed. 
6.3 
Unblinding 
In the rare event that an AE or pregnancy occurs for which knowledge of the identity of the 
study treatment administered is necessary to manage the subject’s condition, the IWRS code 
for that subject may be broken and the test substance identified. Procedures for unblinding will 
be provided in a separate manual. 
Should emergency unblinding be required, the Investigator should call the 
 
 Medical Monitor before unblinding wherever possible; however, the 
Investigator is responsible for the medical care of the individual study subject, and does not 
require the agreement of the Medical Monitor before unblinding. The reason for unblinding 
must be documented. The information on study treatment should only be used for decision 
making in the subject’s further treatment. Details on unblinded treatment assignments should 
not be shared with the Study Monitor and project team. 


 
 
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7. STUDY TREATMENTS 
7.1 
Dosage Forms/Formulation 
All study treatment to be used in this study will be manufactured in accordance with current 
Good Manufacturing Practice (GMP). Study treatment will be supplied by Aurinia. 
7.1.1 Orelvo– Study Treatment 
Company Code: 
 
Chemical Name: 
 
Empirical Formula: 
 
Generic Name: 
Voclosporin 
Dosage Form: 
Softgel capsules 
Strength: 
7.9 mg of voclosporin per softgel capsule 
Manufacturer: 
 
7.1.2 Placebo Control 
Placebo softgel capsules, identical to 7.9 mg Orelvo softgel capsules, will be provided. 
7.1.3 Background Therapy 
7.1.3.1 Mycophenolate Mofetil 
Oral MMF in the form of 500 mg tablets will be centrally supplied by Aurinia. Aurinia will 
reimburse the cost of the MMF tablets if not centrally provided by Aurinia to the sites.  
7.1.3.2 Corticosteroids 
Intravenous and oral corticosteroids will be prescribed at the investigational sites and costs will 
be reimbursed by Aurinia. 
7.2 
Drug Dosage and Administration 
7.2.1 Treatment Arms 
All subjects will receive either 3 capsules of Orelvo (23.7 mg BID) or matching placebo BID. 


 
 
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Orelvo – 23.7 mg (3 capsules) BID 
Orelvo 23.7 mg BID; 3 capsules administered BID in combination with MMF and oral 
corticosteroids from randomization onwards. 
Placebo – 3 capsules BID 
Placebo; 3 capsules administered BID in combination with MMF and oral corticosteroids from 
randomization onwards. 
7.2.2 Dosing Guidelines 
7.2.2.1 Orelvo/Placebo – Study Treatment 
Study treatment will be taken BID with water on an empty stomach as close to a 12 hour 
schedule as possible, and with a minimum of 8 hours between doses. If the subject misses a 
dose of study treatment by less than 4 hours from the anticipated dosing time, the missed dose 
will be taken immediately. The next dose will be taken at the originally scheduled time. If a 
missed dose of study treatment is greater than 4 hours from the expected dosing time, the 
subject will skip the dose and take the next dose at the originally scheduled time. The variation 
in dosing will be recorded in the eCRFs. The dose/doses of study treatment may be held at the 
discretion of the Investigator. Subjects must avoid consumption of grapefruit or grapefruit-
containing juice (e.g., pomelo) for the duration of their participation in the study. 
Possible dose adjustments: If GI or other disturbances occur with study treatment, then study 
treatment dosing may be reduced or interrupted, and/or appropriate treatment may be initiated 
(e.g., addition of a proton pump inhibitor (see Appendix 5) and Section 7.6, Orelvo/Placebo 
Dose Modification). 
All unused study treatments (and any empty containers) dispensed to the subject will be 
returned at each study visit for capsule counts to check compliance. The Investigator will count 
the returned study treatment and this information will be used to assess subject compliance. 
This study treatment count must be documented in the eCRF and source documentation. 
7.2.2.2 Corticosteroids 
All subjects who weigh ≥45 kg should receive 0.5 g IV methylprednisolone on both Day 1 and 
Day 2 (a total of 1 g), before oral corticosteroid therapy is started on Day 3. All subjects who 
weigh <45 kg should receive 0.25 g IV methylprednisolone on both Day 1 and Day 2 (a total 
of 0.5 g). When subjects are receiving IV methylprednisolone, they should not receive oral 
corticosteroids on the same day. 
If it is considered to be in the subject’s best interest, IV methylprednisolone treatment may be 
started during the screening period, but no more than 1 g in total may be administered for the 


 
 
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screening period and Day 1 and/or Day 2 combined (0.5 g in subjects who weigh <45 kg). 
Subjects receiving IV methylprednisolone in the 3 months prior to screening must be discussed 
with the Medical Monitor prior to initiating further IV methylprednisolone. Also, IV 
corticosteroid therapy to be administered during screening must be discussed with the Medical 
Monitor in advance. If IV corticosteroid therapy is administered by the site during screening, 
the dose administered on Day 1 and/or Day 2 will be 1 g minus the dose administered during 
screening. The maximum daily dose of methylprednisolone administered on Day 1 and/or 
Day 2 is 0.5 g. See below for examples: 
• Example 1: If a 0.6 g dose of IV methylprednisolone is administered during screening, 
then (1 – 0.6) = 0.4 g IV methylprednisolone will be administered on Day 1, followed 
by the oral steroid dosing schedule in Table 1, beginning on Day 2 or 3. 
• Example 2: If the dose administered during screening is 0.3 g, then the total residual 
dose required is (1 – 0.3) = 0.7 g. Because 0.7 g is greater than the maximum daily dose 
allowed, 0.35 g will be administered on Day 1 and 0.35 g on Day 2, followed by the 
oral steroid dosing schedule in Table 1, beginning on Day 3. If IV methylprednisolone 
therapy is administered in the 2 weeks prior to the start of screening then the subject is 
excluded from the study (see Section 7.8.1, Prohibited Medications), unless approved 
by the Medical Monitor. 
• Example 3: In a 40 kg subject, if a 0.3 g dose of IV methylprednisolone is administered 
during screening then (0.5 – 0.3) = 0.2 g IV methylprednisolone will be administered 
on Day 1, followed by the oral steroid dosing schedule in Table 1, beginning on Day 2 
or 3. 
If at screening the Investigator determines a subject requires IV corticosteroid therapy, every 
effort should be made to collect both morning urine specimens (for UPCR determination) 
before initiation of the IV steroids. If this cannot be done, the Medical Monitor should be 
contacted in advance of the therapy (see Section 9.2.1, Screening Visit Procedures). 
In the case of the full 1 g IV methylprednisolone being administered prior to randomization 
(or 0.5 g in a subject <45 kg), it is acceptable for oral prednisone as per dosing schedule to be 
administered on Day 1. 
The starting dose of oral prednisone will be 20 mg/day for subjects <45 kg and 25 mg/day for 
subjects ≥45 kg. The dose will be reduced according to the tapering schedule below, see 
Table 1. Refer to Appendix 4 for a conversion table of various formulations of steroids. 


 
 
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Table 1 
Dosing Schedule for IV Methylprednisolone and Daily Oral 
Prednisone (mg) 
 
Subjects 
<45 kg 
Subjects 
≥45 kg 
In Case of Prior IV Steroids 
During Screening (Pre-randomization) 
Weeks 1-2(1) 
 
 
 
Days 1-2(2) 
0.25 g (IV) 
0.5 g (IV) 
1 g minus prior IV steroids mg or (0.5 g minus 
prior IV steroids mg for subjects who weigh 
<45 kg)(3) 
Days 3-13 
20 mg (oral) 
25 mg (oral) 
 
Week 2 (Day 14) 
15 mg (oral) 
20 mg (oral) 
 
Week 4 (Day 28) 
10 mg (oral) 
15 mg (oral) 
 
Week 6 (Day 42)(4) 
10 mg (oral) 
10 mg (oral) 
 
Week 8 (Day 56) 
5 mg (oral) 
5 mg (oral) 
 
Week 12 (Day 84) 
5 mg (oral) 
5 mg (oral) 
 
Week 16 (Day 112) 
2.5 mg (oral) 
2.5 mg (oral) 
 
1 Day 0-13: Oral steroids dosed according to subject weight and then tapered beginning at Day 14. 
2 Oral corticosteroids may be commenced on Days 1 or 2 if corticosteroids are administered during screening. 
3 It is recognized that dosing with IV methylprednisolone as described in Section 7 2 2 2, Corticosteroids may not be in the subject’s best 
interest if they have already received therapy within the 3 months prior to screening. In this case, the Investigator may be permitted to 
omit the administration of further IV methylprednisolone but only after discussion with the Medical Monitor. 
4 Week 6 is not a scheduled study visit, a phone call can be performed to decide further tapering for subjects. 
 
Notes: Oral prednisone taper should be done within ±3 days of specified timeframe. When clinically indicated, subjects are allowed to be 
completely titrated off of oral corticosteroids. 
Abbreviation: IV = Intravenous. 
 
Note that at each visit or during interim phone calls, the corticosteroid dose to be achieved is 
shown. The timing of the titration to that dose is at the discretion of the Investigator. For 
example, the Week 6 administration of steroids in a 43 kg subject should be 10 mg daily. The 
Investigator may reduce it at Week 7 to 7.5 mg until 5 mg is prescribed at Week 8. 
When clinically indicated, subjects are allowed to be completely titrated off of oral 
corticosteroids. 
Subjects with a lack of response are allowed one 4-week interval without dose reduction or 
1 dose escalation to the previous dose for 2 weeks at any time during the study. Lack of 
response is defined as no or minimal change in UPCR per Investigator judgment over 3 visits 
or deterioration in UPCR not meeting the criteria for withdrawal. All deviations from the 
prescribed dosing schedule in Table 1 above must be discussed with the Medical Monitor and 
documented in the source notes and eCRF. 
7.2.2.3 Mycophenolate Mofetil (Background Therapy) 
Subjects receiving MMF prior to randomization will continue without interruption.  


 
 
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• Subjects must be counselled on the risk of pregnancy while taking MMF and the need 
for adequate contraceptive precautions (see Section 5.4, Adequate/Effective 
Contraception). 
• Subjects on AZA or mycophenolate sodium at screening must switch to MMF at 
baseline (Day 1). 
• For subjects who are not already taking prescribed MMF prior to randomization, the 
dosing of MMF will start at 500 mg BID for a total daily dose of 1 g/day for the first 
week, increasing to 1 g BID for a total daily dose of 2 g/day for the second and 
subsequent weeks (i.e., beginning on Day 8).  
• Complete blood count must be performed locally at Weeks 1 and 3 in subjects not 
already taking MMF at screening (unscheduled visit or not). 
All subjects will take MMF BID (morning and evening), before meals (i.e., on an empty 
stomach), with a glass of water. If a dose is missed, the subject should take the next correct 
dose rather than “doubling up” at the next dosing time point. A stable dose of MMF will be 
maintained throughout the study. Dose changes or interruptions are permitted for clearly 
documented safety reasons only. 
• Approval by the Medical Monitor is required for subjects taking a dose other than 
2 g/day MMF from randomization onwards (e.g., total daily dose of 1 or 3 g/day). 
• If GI disturbance or other side-effects occur with MMF, the 1 g BID dosing may be 
changed to 500 mg four times daily. 
• If a subject has an ANC <1,500/mm3 at any study visit, the dose of MMF should be 
decreased or interrupted. If a subject has an ANC <1,000/mm3 at any visit, the dose 
should be discontinued and only recommenced when the ANC reaches 1,500/mm3. If 
the subject has a dose interruption of MMF of >14 days, then permanent 
discontinuation of MMF, therefore the study, should be considered after discussion 
with the Medical Monitor. 
• If deemed necessary by the Investigator on account of leukopenia or other adverse 
effect, or if the subject weighs 50 kg or less, the dose of MMF may be decreased to a 
minimum of 500 mg BID. 
7.3 
Package and Labeling 
All study treatments provided by Aurinia will be packaged and labeled for Aurinia by 
appropriately qualified vendors according to all applicable local and country regulatory 


 
 
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requirements. All packaging and labeling operations will be performed according to GMP and 
Good Clinical Practice (GCP). 
Study-treatment wallets provided to sites and to subjects will be labeled in the appropriate local 
language, according to local regulatory requirements. 
Wallet label information will be appropriately documented in the Drug Accountability Form 
after the container has been dispensed to the subject. 
7.4 
Study Treatment Allocation 
For purposes of randomization, each eligible subject will be assigned to 1 of the 2 treatment 
groups in a 1:1 ratio using IWRS. The randomization will be central-based and stratified by 
biopsy class (Class V only versus Others) and by prior MMF use at time of the Screening Visit. 
7.5 
Site Supply, Storage, Accountability 
7.5.1 Site Supply 
Once a site has been approved for study initiation, the site will be supplied with an initial stock 
of study treatment. The need for study treatment resupply will be assessed on a regular basis 
taking into account the number of subjects enrolled at the site. 
7.5.2 Storage 
Orelvo softgel capsules and matching placebo capsules will be supplied in cartons containing 
168 capsules in 4 wallets of 42 capsules each. 
The Investigator must ensure the availability of proper storage conditions. All study treatment 
supplies provided for this study will be stored in a secure area with restricted access at the 
study site. The capsules must be stored at a controlled room temperature between 15 and 30°C 
(59-86°F). The Investigator must document and inform the Site Monitor about temperature 
deviations outside the acceptable range. Subjects will be instructed to store the study treatment 
at room temperature between 15 and 30°C (59-86°F). 
Each site should have a thermometer that records minimum and maximum temperatures daily. 
Maintenance of a temperature log is mandatory. The log should be updated by site personnel 
during normal working hours. This log must be available for review by the Site Monitor during 
on-site monitoring visits. 
7.5.3 Accountability 
The Investigator at each site is responsible for study treatment supplies. The Investigator will 
ensure that adequate records of the receipt, dispensing, and return of the study treatment are 


 
 
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kept and that the study treatment is used only for subjects enrolled in the study. All data 
regarding the study treatment must be recorded on the relevant forms provided. 
Each study site will maintain a drug inventory/dispensing record for all drugs dispensed and 
returned. At the end of the study, 1 copy of the drug inventory/dispensing record should be 
sent to Aurinia for the central study file. The original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all unused materials will be 
returned to Aurinia. The decision to destroy study treatment at a site must be made by Aurinia. 
If the study treatment is destroyed at a site, the Investigator must receive Aurinia approval of 
the process and forward the certificate of destruction to Aurinia. 
Records of IV methylprednisolone, oral corticosteroids, and MMF must be maintained 
(prescribed dose, dose adjustments and reasons) in the source notes and must be transcribed 
into the eCRF. 
7.6 
Orelvo/Placebo Dose Modification 
Dose modifications for background therapy (MMF and corticosteroids) are detailed in 
Section 7.2, Drug Dosage and Administration. 
7.6.1 Deterioration in Renal Function 
Serum creatinine and eGFR utilizing the CKD-EPI formula will be used for the assessment of 
renal function at every visit (Visits 1-15 and unscheduled visit(s)). Subjects will have a 
minimum of 2 eGFR measurements conducted prior to dosing at Visit 2. The lowest of the 
pre-dose eGFR assessments will be used as the marker of baseline renal function. 
It is recognized that eGFR may be unreliable at higher values (>100 mL/min/1.73 m2). Lupus 
nephritis subjects with nephrotic range proteinuria frequently have wide fluctuations in serum 
creatinine (and therefore eGFR) which are not representative of true renal dysfunction. Chronic 
kidney disease is defined as eGFR <60 mL/min/1.73 m2 for ≥3 months [20], with or without 
kidney damage.  
7.6.1.1 Decrease in eGFR >30% and eGFR <60 mL/min/1.73 m2 
During the treatment period, any subject experiencing a >30% decrease in eGFR from baseline 
to <60 mL/min/1.73 m2, will have study treatment interrupted until a repeat test can be 
performed (unscheduled visit to be completed). If the decrease is confirmed and not due to 
potential contributing factors (e.g., high baseline eGFR, the addition or modification of 
non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) 
inhibitors, angiotensin II receptor blockers (ARBs), a concurrent state of dehydration, 
overdosing with study treatment, lupus renal flare, etc.), the case should be discussed with the 


 
 
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Medical Monitor, the study treatment should be witheld, and eGFR retested within 48 hours. 
If the eGFR decrease is not confirmed, the study treatment can be restarted at 2 capsules BID 
and increased as tolerated with discussion with the Medical Monitor. 
7.6.1.2 Decrease in eGFR ≤30% and eGFR <60 mL/min/1.73 m2 
During the treatment period, any subject having a ≤30% reduction in eGFR to 
<60 mL/min/1.73 m2, should have the influence of potential contributing factors (as described 
in Section 7.6.1.1, Decrease in eGFR >30% and eGFR <60 mL/min/1.73 m2) ruled out and 
appropriate corrective action taken. Any subject having a >20-≤30% reduction compared to 
baseline in eGFR to <60 mL/min/1.73 m2 will have a confirmation measurement done within 
approximately 2 weeks (at a planned study visit, if any, or an unscheduled visit is to be 
completed). The subjects will be managed in the most medically appropriate manner in 
consultation with the Medical Monitor. The management of the decrease in eGFR may include 
reduction of dose or temporary interruption. 
7.6.1.3 Recovery of eGFR 
Subjects experiencing a decrease in eGFR with resultant decrease in dose should be reassessed 
for recovery of renal function. If the repeated eGFR is >80% of baseline, the dose should be 
increased by 1 capsule BID and eGFR assessed within 2 weeks. 
7.7 
Procedures for Overdose 
Based on clinical experience with Orelvo, symptomatic treatment of AEs or overdoses is 
indicated. Treatment for renal dysfunction, hypertension, and infection may include dose 
reduction or dose discontinuation. Magnesium supplementation may be required for 
hypomagnesemia. Treatment for GI complaints and biochemical/hematological abnormalities, 
and all other expected AEs, should be based on symptoms, with care taken to rule out other 
causes. 
7.8 
Prohibited Therapy and Concomitant Treatment 
Any concomitant treatment given for any reason during the course of the study must be 
recorded in the eCRF and in the subject’s source documents, including dosage, start and stop 
dates, and reason for use. 
Any class of medications not mentioned below and with the potential to interfere with 
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7.8.1 Prohibited Medications 
The following medications cannot be taking during the study: 
• IV corticosteroids within 2 weeks prior to screening (Visit 1) unless approved by the 
Medical Monitor 
• Enteric-coated oral corticosteroids during the study are not allowed. No other use of 
non-enteric coated oral corticosteroids, other than administration required as per 
protocol, is allowed 
• IV immunoglobulin treatment within 2 weeks prior to screening (Visit 1) 
• Cyclophosphamide within 4 weeks prior to screening (Visit 1) 
• Cholestyramine or other drugs that may interfere with enterohepatic recirculation of 
MMF within 4 weeks prior to screening (Visit 1) 
• Initiation of new treatment or change in dosage of ARBs and/or ACE inhibitors within 
4 weeks prior to randomization (Visit 2) 
• CNIs (e.g., cyclosporine and tacrolimus) within 1 month of screening (Visit 1) 
• Immunosuppression biologic agents (e.g., abatacept, belimumab, infliximab, 
adalimumab, etanercept, or rituximab) within 3 months prior to screening (Visit 1) 
• Vaccines using live organisms, viral or bacterial 
• MMF dose other than 2 g/day without prior discussion with the Medical Monitor 
• Concomitant therapy with other immunosuppressants after randomization, other than 
MMF administered per protocol 
• Subjects are allowed to be on AZA or mycophenolate sodium during screening but 
must switch to MMF at randomization 
• Current or planned use of ketoconazole or rifampin 
• Concomitant use of other CYP3A4/5 inhibitors and inducers should be discussed with 
the Medical Monitor 
Appendix 8 contains a summary of additional treatment and food restrictions. 


 
 
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7.8.2 Allowed Concomitant Medications 
These medications are permitted during the study: 
• Topical steroids (e.g., nose, scalp, skin, inhaled) 
• Antimalarials should be prescribed when clinically indicated 
• Herbal supplements can be used with caution and depending on active ingredients 
Treatments which may be used as medically indicated, according to the judgment of the 
Investigator can be found in Appendix 7. Treatments not included in this list may be acceptable 
in the study; such treatments should be verified with the Medical Monitor prior to use. A 
summary of treatment and food restrictions can be found in Appendix 8. 
7.9 
Increased Blood Pressure 
For all subjects, the target systolic pressure is ≤130 mmHg and the target diastolic pressure is 
≤80 mmHg. Investigators must use all means possible permitted in the protocol to maintain the 
BP below these limits. If no further adjustment of antihypertensive therapy is possible, the 
subject should be discussed with the Medical Monitor. Any study subject whose BP is found 
to be elevated will have repeat measurements within 2 weeks (at planned study visit if during 
this timeframe or an unscheduled visit). 
It is recognized that during a LN flare, BP may be significantly raised due to disease activity 
and high-dose corticosteroid therapy. Therefore the above applies to Week 4 (Visit 5) onwards. 
7.9.1 Symptomatic Increased Blood Pressure 
If on any study day, systolic BP is >165 mmHg or diastolic BP is >105 mmHg and is associated 
with symptoms of hypertension (i.e, persistent headache, altered mental status, shortness of 
breath, chest pain consistent with angina pectoris, symptoms of heart failure, evidence of renal 
insufficiency of new onset, evidence of hypertensive retinal injury (hemorrhages, 
papilledema)), study treatment should be discontinued and the subject will be treated as per 
Investigator local practices and best judgment. Additionally, Aurinia considers symptomatic 
increased BP as medically important and requires it to be reported as an SAE according to 
Section 10.3.2, Serious Adverse Events. The subject will continue with all study visits per the 
Schedule of Events. Study treatment must not be reintroduced without prior discussion with 
the Medical Monitor. 


 
 
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8. RISKS/PRECAUTIONS 
No evidence available at the time of the completion of this study protocol indicated that special 
warnings or precautions are required, other than those noted in the IB. 
If additional special warnings or precautions become apparent before study completion, 
Aurinia will notify the Investigator at each site. 


 
 
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9. STUDY PROCEDURES 
9.1 
Description of Study Assessments 
9.1.1 Laboratory Assessments 
Analysis of all samples for hematology, chemistry, hepatic function, lipid profiles, and 
urinalysis will be performed at a central laboratory using standard validated methods (see the 
laboratory manual). All study data analyses involving laboratory values will be based on results 
from the central laboratory. 
The UPCR will be calculated both from the first morning void and from standard urinalysis 
results. If the first morning void is for some reason not available, then standard urinalysis may 
be substituted as an exception but only after agreement is reached with the Medical Monitor. 
Blood and urine samples for the following efficacy and safety assessments (See Table 2) will 
be drawn in accordance with the Schedule of Events. 
Table 2 
Review of Laboratory Assessments 
Test Type 
Test Parameters 
Collection at Visits 
Hematology 
Complete blood count (CBC) 
 Hematocrit 
 Hemoglobin 
 Mean corpuscular hemoglobin (MCH) 
 Mean corpuscular hemoglobin concentration 
(MCHC) 
 Mean corpuscular volume (MCV) 
 Platelet count 
 Red blood cells (RBC) 
 Red blood cell morphology 
 White blood cells (WBC) 
Differential (absolute and %) 
 Bands 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
Erythrocyte sedimentation rate 
All except Day 2 
 
 
 
 
 
 
 
 
 
 
All except Day 2 
 
 
 
 
 
 
Day 1, Week 24, and Week 52 
 


 
 
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Table 2 
Review of Laboratory Assessments (Cont’d) 
Test Type 
Test Parameters 
Collection at Visits 
Coagulation 
Coagulation 
 Activated partial thromboplastin time (aPTT) 
 Prothrombin time (PT) 
 Partial thromboplastin time (PTT) 
Screening 
Blood Chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bilirubin (direct and total) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol (total, HDL, and LDL) 
Creatine kinase 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Glycosolated hemoglobin (HbA1c) 
Lactic dehydrogenase (LDH) 
Magnesium 
Phosphorous, inorganic 
Potassium 
Protein, total 
Sodium 
Triglycerides 
c-Reactive Protein 
All except Day 2 
 
 
 
 
 
 
 
 
Day 1, Week 24, and Week 52 
Day 1, Week 24,and Week 52 
 
 
 
Day 1, Week 24, and Week 52 
 
 
Day 1, Week 24, and Week 52 
 
 
 
 
Screening, Week 24, and 
Week 52 
Urinalysis 
Complete urinalysis (to include urine protein, 
creatinine, blood, urine microscopy). First 
morning void will be performed to analyze 
urine protein/creatinine ratio. 
All except Day 2 
Pregnancy Test 
A serum pregnancy test will be performed for 
females of childbearing potential. Urine 
pregnancy tests will be done using a dipstick. 
Screening and Weeks 24 and 52 
(Serum) 
All other applicable visits (Urine) 
 


 
 
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Table 2 
Review of Laboratory Assessments (Cont’d) 
Test Type 
Test Parameters 
Collection at Visits 
Lupus Markers 
Anti-double-stranded DNA (anti-dsDNA) 
antibodies 
Anti-nuclear antibodies (ANA) 
Serum 
 Complement 3 
 Complement 4 
Antiphospholipid antibodies 
Anticardiolipin antibodies 
Lupus anticoagulant test 
Screening, Week 24, and 
Week 52 
 
 
 
 
 
 
 
Serology 
Cytomegalovirus 
Hepatitis A, B, and C 
Hepatitis B surface antigen (HBsAg) 
Screening 
 
Special Tests 
Estimated glomerular filtration rate (eGFR) 
All except Day 2 
Notes: HDL = High-density lipoprotein; LDL = Low-density lipoprotein. 
Baseline renal function will be the minimum value of any and all eGFR values taken during the screening period and at baseline 
prior to administration of drug (a minimum of the screen and baseline (pre-dose) values. The central lab will need to report a 
baseline value for the analysis. 
 
The total amount of blood that will be collected during the study from an individual subject is 
approximately 300 mL over 56 weeks. 
For details on whether laboratory abnormalities should be reported as AEs and on the 
follow-up required in such cases, see Section 10.2.5, Clinical Laboratory Evaluations. 
 
9.1.2 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Events. 
The physical examination will include a review of SLE-related manifestations which will also 
be recorded. A complete physical examination will be conducted at screening and an 
abbreviated physical will be performed at all other visits as per the Schedule of Events. The 
abbreviated examination will consist of checking the normality or abnormality of the following 
body systems: general appearance, cardiovascular system, and pulmonary system. Any 
abnormalities will be recorded in the eCRF and reported as an AE. Because the investigational 
medication is an immunosuppressant, physical examination will include clinical examination 
for tumors. 
Subject weight will also be recorded at each physical examination; however, height will only 
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9.1.3 Vital Signs 
The following vital signs will be measured in accordance with the Schedule of Events: 
• Resting BP (systolic and diastolic) 
• Resting HR 
• Body temperature (°C or °F) 
To avoid variability, the same method of obtaining body temperature should be used 
throughout the study. 
9.1.3.1 Blood Pressure Management 
Blood pressure and HR will be measured with the subject in a sitting position after 5 minutes 
of rest. The procedure for standardized measurement of BP and HR is detailed in Appendix 2. 
If the BP measure is confirmed to be >130/80 mmHg (i.e., by the mean of the second and third 
repeats of 3 readings) and dose reductions are required, the subject’s BP will be managed per 
local practice. If the BP remains uncontrolled with the maximal doses of first and second-line 
antihypertensive therapies referenced in Appendix 1 and dose reductions of study treatment, 
then the Investigator and the Medical Monitor should consider permanent discontinuation of 
study treatment. If study treatment is discontinued, the subject should continue in the study for 
all remaining scheduled study visits. See Section 7.9.1, Symptomatic Increased Blood Pressure 
for managment of symptomatic increased BP. 
9.1.4 Standard 12-lead Electrocardiogram 
The electrocardiogram (ECG) will be a standard 12-lead tracing performed at the 
investigational site, assessed by a qualified physician at the investigational site, and retained 
as a source document. Any abnormalities will be recorded in the eCRF. Electrocardiograms 
will be recorded after the subject has been in a resting, supine position for at least 5 minutes. 
Abnormal ECG tracings can be reviewed by the Medical Monitor. Significant abnormalities, 
including findings that may prompt discontinuation of study treatment, must be discussed with 
the Medical Monitor. 
Electrocardiograms will be measured at screening, Week 12, Week 24, and Week 52. 
9.1.4.1 Procedures to Manage a Treatment-Emergent Increase in QTc 
In the event that a subject has a QTcF value exceeding 500 msec, or an increase >60 msec from 
baseline, the Medical Monitor must be informed. The subject will be asked to return for an 
unscheduled visit within 24 hours and the ECG will be repeated (confirmed), in triplicate (i.e., 


 
 
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three 10-second ECGs in rapid succession within 1 minute). If the repeat measurements 
confirm that the QTcF is >500 msec or >60 msec from baseline, the subject will be withdrawn 
from treatment with the study treatment and followed until the QTcF value either returns to 
baseline (or as appropriate) or until, in the judgment of the Investigator, further evaluation is 
not clinically indicated. 
If study treatment is discontinued, the subject should continue in the study for all remaining 
scheduled study visits. 
9.1.5 Lupus Disease Activity Assessments 
The SELENA-SLEDAI assesses disease activity within the last 10 days. Twenty-four items 
are scored for 9 organ systems, and summed to a maximum of 105 points. A score of 6 is 
considered clinically significant. See Appendix 6. 
Assessments for SELENA-SLEDAI will be conducted at baseline, Week 24, and Week 52. 
9.1.6 Orelvo Pharmacokinetics 
All subjects will be asked to participate in PK monitoring of Orelvo. Blood samples will be 
taken at Weeks 24 and 52. PK samples will be drawn prior to study treatment dosing (trough 
sample), and at 2 hours post-dose. These samples will be analyzed for Orelvo. Should a subject 
experience an SAE, require a dose modification or be withdrawn from treatment, an blood PK 
sample will be taken (with a trough sample preferred) for later determination of drug level. If 
a subject has discontinued from study drug treatment, further PK samples are not required. 
9.2 
Schedule of Assessments 
A detailed schedule of assessments (including all protocol-required assessments, visits, and 
visit windows) is located on the Schedule of Events. No study related assessments will be 
performed (including changes to current medications to meet study eligibility) until the subject 
has provided signed and dated informed consent. Every effort will be made to keep the subject 
within the requested visit schedule. If a subject is seen outside of the visit window listed on the 
Schedule of Events, the reason must be clearly documented in the source notes. The 
Investigator (or designee) should contact Aurinia for assistance with getting the subject’s 
schedule back on track in order to avoid large variances in treatment exposure or to avoid 
delaying overall study timelines. 
9.2.1 Screening Visit Procedures 
The screening visit (Visit 1) will take place within 30 days prior to Visit 2/baseline (Day 1). 
Screening will include provision of informed consent, physical examination including weight, 
and height, medical history (including SLE and LN history), vital signs measurements, 12-lead 
ECG, and review of prior and concomitant medications and entry criteria. Urine samples will 


 
 
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be collected for urinalysis and urine microscopy; first morning void urine samples (for 
determination of UPCR) will be collected on 2 days during the screening period and must be 
returned and the results evaluated prior to Visit 2. An average of the 2 screening UPCRs will 
be used as a marker of baseline urine protein excretion. Baseline proteinuria level is determined 
by a mean of 2 first morning void urine samples taken during the screening period. The lowest 
of pre-dose eGFR assessments will be used as the marker of baseline renal function. It is 
recommended that in the event that IV corticosteroids are administered during screening, the 
2 first morning urine voids are to be collected prior to administration of the corticosteroids (see 
Section 7.2.2.2, Corticosteroids). In the case where this is not possible, then the marker of 
baseline urine protein excretion will be based upon the Visit 1 UPCR collection only. This 
must be discussed with the Medical Monitor prior to enrollment. Please note that 24-hour urine 
collection will have to begin 2 days prior to the Baseline Visit.  
Blood samples will be drawn according to Table 2. 
If the subject is from an area where TB is endemic or whose history suggests an increased 
personal risk, e.g., from contact with people with TB or travel to areas with endemic TB, the 
subject will be carefully evaluated for latent or active TB. 
Women of childbearing potential should have a negative serum pregnancy test result before 
randomization. Study treatment cannot be initiated by the physician until a report of a serum 
negative pregnancy test has been obtained. 
If a subject has not met the requirements in Inclusion Criteria #4 due to not having kidney 
biopsy result within the required time frame, a kidney biopsy can be performed as per local 
procedures, after signing the study consent, provided the results can be obtained and reviewed 
prior to randomization. 
9.2.2 Treatment Procedures 
Only subjects who satisfy all of the inclusion and exclusion criteria will be eligible for 
randomization and study treatment. 
Subjects will be fasting for at least 8 hours on the day of randomization and all visit procedures 
must occur prior to the first dose of study treatment on Day 1. The MMF dose required per 
protocol and IV methylprednisone (or oral corticosteroids) will also be administered at baseline 
before the first dose of Orelvo. 
Subjects will complete all assessments per the Schedule of Events at Day 1, Day 2, and at 
Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, and 48. IWRS will be accessed to assign study 
treatment to subjects at appropriate visits. 


 
 
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Adverse events and concomitant medication will be recorded prior to the conduct of other 
study assessments at each visit. 
Assessments at visits during the treatment period include: 
• SF-36 and LupusPRO HRQoL will be answered by the subject, as first study procedure, 
at Baseline, Week 12 and Week 24 
• Physical examination including weight 
• Vital signs 
• ECG at Week 12 and Week 24 
• Blood and urine sample collection for analysis at central laboratory 
• First morning void urine sample collection, except before Day 1 and Day 2 Visits 
• 24-hour urine collection at Week 24 (IMPORTANT: 24-hour urine collection will 
have to begin 2 days prior Week 24 visit in order not to coincide with the first morning 
void sampling due on the day of this visit) 
• Pregnancy testing (serum: Week 24; urine: Day 1 and Weeks 2, 4, 8, 12, 16, 20, 30, 36, 
42, and 48) and immunology 
• AEs 
• Concomitant medication 
• SELENA-SLEDAI will be evaluated at Baseline and Week 24 
• Dispense study treatment – including study treatment and background therapy 
• Returned capsule count and drug accountability 
• Information for the healthcare resource utilization assessment will be collected and 
recorded at Day 1 and Week 24 
9.2.3 End of Study (or Early Discontinuation) Procedures 
On completion of treatment at Week 52 or earlier if subject is discontinued/withdrawn early, 
all assessments for Visit 15 (end of study/early termination) will be completed per the 


 
 
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Schedule of Events. See also Section 5.5, Withdrawal of Subjects, for further information on 
withdrawal procedures and criteria. 
The following assessments for the end of study visit will be performed: 
• SF-36 and LupusPro HRQoL 
• Abbreviated physical examination (including body weight) 
• Vital signs 
• Standard 12-lead ECG 
• Blood sample collection for analysis at central laboratory 
• Serum pregnancy testing  
• First morning void 
• 24-hour urine sample collection (IMPORTANT: 24-hour urine collection will have to 
begin 2 days prior to Week 52 visit in order not to coincide with the first morning void 
sampling due on the day of this visit) 
• Concomitant medication 
• AEs 
• SELENA-SLEDAI 
• Returned capsule count and drug accountability 
• Confirmation of completion/discontinuation using IWRS 
• Information for the healthcare resource utilization assessment will be collected and 
recorded 
9.2.4 Follow-up Procedures 
All subjects who complete the study but do not participate in the continuation study or 
discontinue study treatment before Week 52 will be followed up 4 weeks (±10 days) after their 
last study treatment dose to collect any new AEs and concomitant medications. This visit 
(Visit 16) will be conducted as an in-clinic visit. 


 
 
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Assessments for the follow-up visit are as follows: 
• Vital signs 
• Blood sample collection for analysis at central laboratory (eGFR) 
• First morning void urine sample collection 
• Concomitant medication 
• AEs 
• Confirmation of completed follow-up visit using IWRS 
9.2.5 Unscheduled Visit 
Unscheduled visits may be performed during the course of the study for safety reasons. An 
unscheduled visit is required 2 weeks after dose reduction at any time during the study. Only 
the data relevant to the purpose of the visit will be collected in the source documents and eCRF. 
An unscheduled visit is requested in the following cases: 
• QTcF value exceeding 500 msec, or an increase >60 msec from baseline, where the 
ECG will be repeated (confirmed) at an unscheduled visit 
• Systolic BP is ≥165 mmHg or diastolic BP is ≥105 mmHg, or confirmed systolic 
BP >130 mmHg or a diastolic BP >80 mmHg 
• Decrease in eGFR >30% compared to baseline, or a confirmed decrease in 
eGFR >20-30% compared to baseline 
• Complete blood count must be performed locally at Weeks 1 and 3 in subjects not 
already taking MMF at the Screening Visit 
9.3 
Study Specific Assessment Procedures 
9.3.1 Health-related Quality of Life Assessments (HRQoL) 
9.3.1.1 Short Form Health Survey (SF-36) 
The SF-36 HRQoL assessment is a 36-question subject HRQoL questionnaire and is presented 
in Appendix 9. 


 
 
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9.3.1.2 LupusPRO 
The LupusPRO (v1.7) is a 43-question subject HRQoL questionnaire specific for lupus and is 
presented in Appendix 10. 
9.3.2 Healthcare Resource Utilization Assessment 
The collection of information on healthcare resource utilization will be collected at the time 
points specified in the Schedule of Events (Day 1 and Weeks 24 and 52) and documented in 
the EDC system. This information will be collected via interview of the subject by the study 
staff and entered into the EDC system. General information collected may include: 
• Type of insurance coverage 
• Number of visits to ANY health care professionals (HCP), other than study doctor  
• Types of HCP visited (specialists versus primary care)  
• Time spent on visits 
• Diagnostic tests performed  
• Time spent by caregivers assisting patient with HCP visits (can ask general question if 
subject required a family member or other person to assist them to attend the visit) 
• Prescriptions issued, filled 
• Community services used 


 
 
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10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
10.1 Definitions 
10.1.1 Adverse Event 
Any untoward medical occurrence in a subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment is an AE. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
10.1.2 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medical product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all unintended responses to a 
medicinal product related to any dose should be considered adverse drug reactions (ADRs). 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out. 
10.1.3 Serious Adverse Event 
An SAE (experience) or reaction is an untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Results in death (Note: death is an outcome, not an event) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused a death had it been more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is a medically important event or reaction 
The definitions and reporting requirements of International Council for Harmonisation (ICH) 
Guidelines for Clinical Safety Data Management, Definitions, and Standards for Expedited 
Reporting, Topic E2 will be adhered to. 


 
 
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Medical and scientific judgment must be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
will also usually be considered serious. 
Hospitalizations for elective or previously scheduled surgery for pre-existing conditions, 
which have not worsened after initiation of treatment, will not be classed as SAEs. Previously 
scheduled hospitalizations must be documented in the subject’s source documents before the 
subject signed the informed consent form (ICF). A kidney biopsy performed as part of the 
study to verify eligibility will not be considered an SAE. Any complication experienced during 
a kidney biopsy procedure resulting in hospitalization or a prolongation of the hospitalization 
requires SAE reporting. 
10.1.4 Suspected Unexpected Serious Adverse Reaction  
Any ADR that is both serious and unexpected (per the IB) that, based on the opinion of the 
Investigator or Aurinia, is felt to have a reasonable suspected causal relationship to a medicinal 
product is a suspected unexpected serious adverse reaction. 
10.2 Adverse Event Descriptors 
10.2.1 Intensity/Severity Categorization 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); however the event itself may be of relatively 
minor medical significance (such as severe headache). This is not the same as “serious,” which 
is based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
In general, the intensity of a particular AE to be recorded is the worst intensity experienced by 
the subject during the course of the event. The medical assessment of intensity will be 
determined by using the following definitions: 
Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to function. 
Severe: 
The AE is incapacitating and the subject is unable to work or complete usual 
activity. 


 
 
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10.2.2 Causal Relationship Categorization 
An Investigator who is qualified in medicine must make the determination of relationship to 
the study treatment for each AE and SAE. The Investigator must decide whether, in his or her 
medical judgment, there is a reasonable possibility that the event may have been caused by the 
study treatment. If there is no valid reason for suggesting a relationship, then the AE/SAE must 
be classified as not related. Otherwise, if there is any valid reason, even if undetermined or 
untested, for suspecting a cause-and-effect relationship between the study treatment and the 
occurrence of the AE/SAE, then the AE/SAE will be considered related. For SAEs, the 
Investigator must provide a brief comment explaining the rationale of his/her assessment of 
causal relationship on the SAE reporting form. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship of the clinical event to study drug administration 
indicates a causal relationship, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
Not related 
No 
The temporal relationship of the clinical event to study drug administration 
does not indicate a causal relationship, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the 
observed event. 
 
If the causal relationship between an AE/SAE and the study treatment is determined to be 
“related”, the event will be considered to be related to study treatment for the purposes of 
expedited regulatory reporting. In circumstances where the Investigator has not yet provided 
his/her assessment about the relationship, the event will be considered as “related” and qualify 
for expedited regulatory reporting. 
10.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing at end of study; fatal; or unknown. If the outcome is reported as recovered 
with sequelae for an SAE, the Investigator should specify the kind of sequelae on the SAE 
reporting form. SAEs that are ongoing at the time of death will have an outcome of “unknown” 
recorded. SAEs resulting in a fatal outcome will have an outcome of “fatal” recorded. 
10.2.4 Symptoms of the Disease Under Study 
Symptoms of the disease under study will not be classed as AEs as long as they are within the 
normal day-to-day fluctuation of the disease. An explanation of these circumstances must be 
written in the source documents. 


 
 
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Worsening of the symptoms however, will be recorded as an AE, and clearly marked as 
worsening or by the subject’s worst observed intensity. 
10.2.5 Clinical Laboratory Evaluations 
A change in the value of a safety laboratory investigation can represent an AE if the change is 
clinically relevant in the opinion of the Investigator or if, during treatment with the study 
treatment, a shift of a parameter is observed from a normal value to a pathological value, or a 
further worsening of an already pathological value. 
If, at the end of the treatment phase, there are pathological laboratory values which were not 
present at baseline, further clinical or laboratory investigations will be performed until the 
values return to within reference range or until a plausible explanation (e.g., concomitant 
disease) is found for the pathological laboratory values. 
If the Investigator considers such an AE as serious it must be reported as an SAE. 
10.2.6 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study treatment abuse, misuse, overdose, and medication 
error have to be documented in the subject’s eCRF and source documentation. If any 
occurrence of abuse, misuse, overdose, or medication errors leads to any event that fulfils any 
seriousness criteria, the event has to be reported as an SAE. 
10.3 Reporting Procedure for AEs, SAEs, and Pregnancy 
10.3.1 Adverse Events 
All AEs either observed by the Investigator or one of his/her medical collaborators, or reported 
by the subject spontaneously, or in response to a direct question, will be noted in the AE section 
of the subject's eCRF and source documentation. This applies to all AEs regardless of 
presumed relationship to the study treatment. Adverse events leading to discontinuation of 
study treatment must be collected. 
If any AE is reported, the date of onset, relationship to study treatment, any action taken, date 
of resolution (or the fact that it is still continuing or has become chronic), outcome, and whether 
the AE is serious or not, will be recorded. Use of colloquialisms and abbreviations should be 
avoided. Only 1 AE term should be recorded in the event field on the AE eCRF. Where 
possible, the Investigator should report a diagnosis rather than signs and symptoms or 
abnormal laboratory values. However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the AE eCRF. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be nullified and 


 
 
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replaced by one AE report based on the single diagnosis, with a starting date that corresponds 
to the starting date of the first symptom of the eventual diagnosis. 
The AE reporting period begins at the time the ICF is signed by the subject. The AE reporting 
period ends at Visit 15 (if the subject participates in the continuation study) or the study 
follow-up visit (Visit 16), if the subject does not participate in the continuation study. Adverse 
events persisting at the time of study completion will be followed by the Investigator through 
contact with the subject until resolution or stabilization has occurred (or the subject is lost to 
follow-up and cannot be contacted) and recorded in the source documents. If the subject reports 
an AE, it is the Investigator’s responsibility to acquire sufficient information in order to assess 
causality. This may require additional laboratory testing, physical examinations, telephone 
contacts, etc. In circumstances where the Investigator is unable to make contact with the 
subject, the Investigator must provide a written statement to Aurinia confirming that the subject 
is lost to follow-up. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, such 
as “How are you feeling?” It is also important to question the subject in a non-leading way 
about changes in their health or concomitant medication usage since their last visit. This 
information should be collected prior to completion of assessments at all study visits. In 
addition, any symptoms/conditions reported during assessments and deemed to be clinically 
significant by the Investigator will be considered AEs. 
10.3.2 Serious Adverse Events 
All SAEs occurring after the signing of the ICF will be reported to 
 
within 24 hours of the Investigator, designee, or site staff’s knowledge of the event regardless 
of relationship to study treatment. All SAEs are to be reported on the eCRFs. 
In the event that the site experiences a temporary disruption of the EDC system a back-up 
paper SAE Reporting Form will be available for site staff to complete. 
• Site staff will complete the paper SAE report form and e-mail it within 24 hours to the 
following address: 
 
• Only in cases where the email system is unavailable, site staff will send the SAE by fax 
to: 
 (US) and 
 (Outside US). 
If notification is made via email or fax, site staff must enter the SAE information into the 
electronic data capture (EDC) system as soon as the system becomes available. 
All SAEs, regardless of causality, will be reported from the time the ICF is signed until 30 days 
following the last study visit or 30 days after last study treatment administration in subjects 


 
 
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who withdraw or discontinue prior to study completion. No formal study visit is required but 
Investigators must report any SAEs that occur during this 30 day period on the eCRF. If the 
Investigator has not seen the subject at a clinic visit at the end of the reporting period, the 
Investigator must make reasonable efforts to contact the subject to inquire about SAEs. 
All recorded SAEs, regardless of relationship to study treatment, will be followed up until 
resolution, stabilization, or the subject is lost to follow-up and cannot be contacted. In 
circumstances where the Investigator is unable to make contact with the subject, the 
Investigator must provide a written statement to Aurinia confirming that the subject is lost to 
follow-up. 
Any SAE considered to have a causal relationship (i.e., “related”) to the study treatment and 
discovered by the Investigator at any time after the study will be reported. A rationale for the 
assessment of a causal relationship must be provided by the Investigator. Any safety 
information that is obtained after the Follow-up Visit (Visit 16) will be documented in the 
safety database only. 
A death occurring during the study or which comes to the attention of the Investigator within 
30 days after the last study visit (including the Follow-up Visit) or until 30 days after the last 
study treatment administration, whichever is longer, whether considered treatment-related or 
not, must be reported to Aurinia. If the subject died, the SAE report should include the cause 
of death as the event term and whether or not the death was related to study treatment, as well 
as the autopsy findings, if available. Preliminary reports will be followed by detailed 
descriptions which will include copies of hospital case reports, autopsy reports/certificates and 
other documents when requested and applicable. 
Additional follow-up information must be reported in the eCRF within 24 hours of awareness 
following Investigator (or site) awareness of the information. The Investigator should not delay 
reporting an SAE in order to obtain additional information. Additional information, when 
available, should be reported to 
 by the reporting procedures 
described above. 
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the sponsor will file it along with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
The sponsor or its representative will be responsible for determining and, in turn, reporting 
SAEs to regulatory authorities according to the applicable regulatory requirements. 


 
 
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10.3.3 Pregnancy 
Pregnancy occurring in a female subject or in the partner of a male subject should be reported 
to 
 within 24 hours of becoming aware of the event using the 
pregnancy eCRF. The Investigator should counsel the subject, and in the case of a male subject, 
the subject’s partner, discuss the risks of continuing with the pregnancy and the possible effects 
on the fetus. A female subject must immediately inform the Investigator if she becomes 
pregnant during the study. Monitoring of the pregnancy in a female subject should continue 
until conclusion of the pregnancy. In case of a pregnancy in the partner of a male subject, the 
Investigator should obtain informed consent of the pregnant partner prior to monitoring of the 
pregnancy. 
Women who have a positive pregnancy test during the study will be withdrawn from the study 
treatment and the procedures for withdrawal will be completed. The Medical Monitor must be 
contacted immediately to break the blind (if applicable). 
All pregnancies, subject or partner of a subject, that occur during the study or come to the 
attention of the Investigator within 30 days after the last study visit (including the Follow-up 
Visit) or until 30 days after last study treatment administration, whichever is longer, must be 
reported to 
 by the reporting procedures described above. 
The outcome of all such pregnancies (including normal births) should be followed up and 
documented, even if the subject was withdrawn from the study. Every effort should be made 
to gather information regarding the pregnancy outcome until 90 days (or otherwise as 
appropriate) post-partum. It will be the responsibility of Aurinia, together with the appropriate 
support of the Investigator, to obtain this information. 
Complications of pregnancy such as abortion (spontaneous or induced), premature birth, or 
congenital abnormality are considered SAEs and should be reported following the reporting 
procedures as outlined in Section 10.3.2, Serious Adverse Events. In the event that the site 
experiences a temporary disruption of the EDC system, a back-up paper Pregnancy Reporting 
Form will be available for site staff to complete. 


 
 
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11. CLINICAL ENDPOINTS COMMITTEE 
A CEC will be constituted to adjudicate the following renal response (primary efficacy 
endpoint) parameters for subjects in this study: 
• UPCR of ≤0.7 mg/mg, and 
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, 
and 
• Received no rescue medication for LN (see Section 7.8, Prohibited Therapy and 
Concomitant Treatment), and 
• Received ≤10 mg/day prednisone from Weeks 16 through 24 
The CEC will adjudicate renal response by reviewing blinded data. Aurinia will establish a 
charter document explaining the working procedures and responsibilities of the CEC. All 
adjudication decisions of the CEC will be appropriately documented. 


 
 
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12. DATA AND SAFETY MONITORING BOARD PROCEDURES 
A DSMB will be constituted to protect the safety of study participants. The DSMB will receive 
blinded eCRF data in the form of tables and listings (prepared by an independent statistician), 
and review subject status changes and dosing decisions (where appropriate). Where 
appropriate, the DSMB may receive unblinded data (on a subject level or treatment group 
level) that should be reviewed in a closed session. The data should include, but is not limited 
to, demographics, subject enrollment, baseline characteristics, AE data, SAE data (by severity 
and causality), laboratory data, dose adjustments, protocol adherence, and subject withdrawals. 
The DSMB will evaluate the progress of the study, assess data quality and timeliness, 
participant recruitment, accrual and retention, and participant benefit versus risk. In addition 
the DSMB will monitor external factors relevant to the study, for example scientific and 
therapeutic developments that may affect participant safety or ethical status. Based on the 
observed benefits or adverse effects, the DSMB will make recommendations to Aurinia 
concerning continuation, termination, or modifications of the study. 
Aurinia will establish a charter document explaining the working procedures and 
responsibilities of the DSMB. All deliberations and decisions of the DSMB will be 
appropriately documented. 


 
 
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13. STATISTICAL ANALYSIS 
13.1 Statistical Methods 
Complete details of the statistical and analytical methods will be provided in a formal 
Statistical Analysis Plan (SAP), which will be finalized prior to the database lock. A general 
description of the planned methods is provided below. Any deviation from the SAP will be 
noted and explained in the clinical study report. 
13.2 Sample Size and Power Calculations 
The total sample size will be 324 subjects (162 subjects per treatment arm). This is based on 
the following assumptions: 
• A two group continuity corrected Chi square test with a 0.05 two-sided significance 
level will have 80% power to detect the difference between a placebo response rate of 
20.0% and a Orelvo response rate of 34.4% (odds ratio=2.1) when the sample size in 
each group is 162 (total N=324). 
• The effect of withdrawals will be investigated. Subjects withdrawing for any reason 
will be counted as non-responders in the primary analysis and therefore no adjustment 
of sample size for withdrawals is necessary. 
• The impact of withdrawals on primary endpoint will be investigated with a tipping 
point analysis. 
Table 3 shows the Orelvo response rates required to maintain a minimum 80% power at the 
planned sample size for given placebo response rates. These response rates all lead to odds 
ratios of around 2, which is a clinically relevant effect. 
Table 3 
Orelvo Response Rates Required to Maintain a Minimum 80% Power 
Placebo Response Rate 
Orelvo Response Rate 
Odds Ratio 
15% 
28.4% 
2.25 
19% 
33.2% 
2.12 
25% 
40% 
2.0 
Note: 
Based on the planned sample size of 324 subjects (162 subjects per treatment arm). 
 
13.3 Populations 
13.3.1 Intent-to-Treat Set 
The intent-to-treat set will be based on intent-to-treat (ITT) principles and will consist of all 
subjects who are randomized to treatment. This group will be analyzed based on the treatment 
to which the subject was randomized. 


 
 
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13.3.2 Safety Set 
The safety set will consist of all randomized subjects who have taken at least 1 dose of study 
treatment. The subjects in this group will be analyzed based on the treatment they received. 
Subjects who receive treatment from more than 1 arm will be assigned to the Orelvo arm. 
13.3.3 Per-protocol Set 
The per-protocol set will consist of all subjects eligible from the ITT population who do not 
have any major protocol violations. Major protocol violations will be defined in the statistical 
analysis plan and fully assessed at the subject level prior to unblinding of the study. 
13.4 Background and Demographic Characteristics 
Demographic and clinical disease characteristics will be summarized by treatment arm in a 
descriptive manner but no statistical tests will be performed.  
13.5 Study Treatment 
Compliance to the study treatment will be determined by dividing the number of softgel 
capsules taken by the expected number of softgel capsules to be taken (based on prescribed 
dose) over the subject’s participation in the study. 
Results will be summarized by means of descriptive statistics (n, mean, standard deviation, 
median, minimum, and maximum) and frequency tables, by treatment arm.  
13.6 Concomitant Therapy 
All concomitant medications will be coded by the WHO Anatomical Therapeutic Chemical 
Drug Reference List classification. The version used will be provided in the clinical study 
report. 
13.7 Efficacy Evaluations 
13.7.1 Primary Endpoint 
The primary endpoint is the number of subjects showing renal response at 24 weeks. Renal 
response at Week 24 will be adjudicated by the CEC based on the following parameters: 
• UPCR of ≤0.7 mg/mg, and 
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, 
and 
• Received no rescue medication for LN (see Section 7.8, Prohibited Therapy and 
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• Received ≤10 mg prednisone from Weeks 16 through 24 
Subjects who withdraw from the study prior to the Week 24 assessment will be defined as non-
responders. 
13.7.2 Secondary Endpoints 
13.7.2.1 
Key Secondary Endpoints 
• Time to UPCR of ≤0.7 mg/mg  
• Partial renal response as defined by 50% reduction from baseline UPCR at Weeks 24 
and 52 
• Time to 50% reduction in UPCR from baseline 
• Renal response at Week 52 (based on definition of primary endpoint) 
• Duration of UPCR ≤0.7 mg/mg 
13.7.2.2 
Other Secondary Endpoints 
• Change from baseline in UPCR at each time point 
• Change from baseline in serum creatinine, urine protein, and eGFR 
• Change from screening in immunology parameters (C3, C4, and dsDNA) at Weeks 24 
and 52 
• Renal response with low-dose steroids (defined as renal response in the presence of 
corticosteroids of ≤2.5 mg/day between Weeks 16 to 24 and Weeks 36 to 52) 
• Change from baseline in HRQoL at Weeks 12, 24, and 52 
• Health Resource Utilization at Weeks 24 and 52 
• Change from baseline in the SELENA-SLEDAI Index score at Weeks 24 and 52 
13.8 Statistical and Analytical Methods 
13.8.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the renal response at Week 24 (Section 13.7.1, Primary 
Endpoint).  
The study null hypothesis H0 and alternative hypothesis H1 are as follows: 


 
 
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H0: There is no difference in renal response between Orelvo and placebo. 
H1: There is a difference in renal response between Orelvo and placebo. 
The null hypothesis H0 will be rejected in favor of H1 if there is evidence at the 5% significance 
level using a 2-sided test.  
The primary efficacy analysis will be conducted on the ITT set using logistic regression with 
terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline. The results being 
expressed as an odds ratio (and associated two-sided 95% CI) for Orelvo compared to placebo. 
Odds ratios greater than unity show the odds of response are greater for Orelvo than for placebo 
and therefore indicate a benefit of the Orelvo treatment arm. 
13.8.2 Sensitivity Analyses 
The following sensitivity analyses will be performed: 
• Renal response at Week 24 will be analyzed using a logistic regression including only 
a term for treatment. This analysis will be performed on the ITT set.  
• The analysis described in Section 13.8.1, Primary Efficacy Analysis will be repeated 
for the per protocol analysis set. 
• The impact of withdrawals on primary endpoint will be investigated with a tipping 
point analysis. 
13.8.3 Secondary Efficacy Analysis 
All the secondary efficacy analyses will be performed on the ITT set.  
13.8.3.1 
Response Endpoints 
The following secondary endpoints will be analyzed using logistic regression as outlined in 
Section 13.8.1, Primary Efficacy Analysis. These analyses will be conducted on the ITT 
population and will incorporate baseline variables within the model as appropriate. 
• Renal response at Week 52 (based on definition of primary endpoint) 
• Partial renal response as defined by 50% reduction from baseline in UPCR at Weeks 24 
and 52 
• Renal response with low-dose steroids (defined as renal response in the presence of 
corticosteroids of ≤2.5 mg between Weeks 16 to 24 and Weeks 36 to 52) 


 
 
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13.8.3.2 
Time to Endpoints 
The following secondary endpoints: time to renal response, time to partial renal response, and 
duration of UPCR ≤0.7 mg/mg will be analyzed by comparing the survivor function between 
treatment arms. It will be estimated using Kaplan-Meier methodology and will be presented as 
a plot showing a line for each treatment group. Median time-to-event along with two-sided 
confidence intervals will be displayed.  
Cox’s proportional hazards model will be performed to assess the significance of the 
differences between treatment arms. The model will include terms for treatment, baseline 
UPCR, biopsy class, and MMF use at baseline. Estimates of the treatment effects will be 
expressed as hazard ratios (and associated 95% CI) for Orelvo relative to placebo. Hazard 
ratios greater than unity show the hazard to be greater for Orelvo than for placebo and therefore 
indicate that the events in question generally occur earlier on active Orelvo. 
The log-rank test and Cox’s proportional hazards model assume that the hazard ratio is constant 
over time. This assumption will be checked graphically by plotting log-log survivor functions 
for the treatment groups. It should be noted that modest deviations from the proportionality 
assumption generally will not invalidate inference. 
13.8.3.3 
Change from Baseline Endpoints 
The following secondary endpoints will be analyzed using a Mixed Effect Model Repeated 
Measures analysis with treatment arm, visit, treatment by visit interaction, biopsy class, and 
MMF use at baseline included as a covariate in the model. Results will be expressed as 
differences between treatment arms (along with the associated 95% CI).  
• Change from baseline in UPCR at each visit 
• Change from baseline in serum creatinine, urine protein, and eGFR at each visit 
• Change from screening in immunology parameters (C3, C4, and anti-dsDNA) at 
Weeks 24 and 52 
• Change from baseline in HRQoL at Weeks 12, 24, and 52 
• Change from baseline in the SELENA-SLEDAI score at Weeks 24 and 52 
13.8.3.4 
Health Resource Utilization 
• Health Resource Utilization at Weeks 24 and 52. Key aspects will be summarized by visit 
and changes over time will be explored. 


 
 
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13.8.4 Multiplicity 
An overall type 1 (false-positive) error rate of 5% for the efficacy endpoints will be maintained 
so that no statistical significance for the secondary efficacy endpoints will be claimed unless 
the principal analysis of the primary efficacy endpoint using the ITT set is statistically 
significant at the 5% level. The Hochberg step-up method will be used to adjust for multiple 
comparisons amongst key secondary endpoints and maintain the overall type 1 error rate [21]. 
Data from all analyses, regardless of the level of significance, will be presented for review.  
13.9 Safety Evaluations 
Specific safety endpoints are as follows: 
• Biochemical (including liver function tests) and hematological laboratory tests 
• AE profile and routine biochemical and hematological safety parameters 
• Vital signs (BP, HR, temperature) at specific time points and change from baseline 
• Standard 12-lead ECGs change from baseline 
• Discontinuations from treatment 
• Concomitant medications 
Laboratory values, vital signs, and other safety parameters providing numeric data will be 
summarized by treatment arm, visit, and as change from baseline. 
Adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities, the version of which will be provided in the clinical study report. 
Treatment-emergent adverse events will be summarized by treatment arm, system organ class, 
and preferred term. SAEs, SAEs that led to death, and SAEs/AEs that led to withdrawal will 
also be summarized and listed. 
Only AEs which started on or after the date of first dose of study treatment will be considered 
TEAEs. SAEs occurring at any time after informed consent will be summarized. All 
concomitant medications will be summarized. 
Details of these and other analyses will be provided in the SAP. 
All study data analyses involving laboratory values will be based on results from the central 
laboratory. 


 
 
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13.10 Interim Analyses 
There are no planned interim analyses. The analysis of the primary endpoint (renal response at 
Week 24) will be conducted at the end of the study. 
13.11 Other Evaluations 
13.11.1 Pharmacokinetics 
Estimates of Orelvo exposure derived from this analysis will be examined for possible 
relationship to measures of efficacy and safety. Full details will be described in a separate 
analysis plan. 


 
 
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14. ETHICAL CONDUCT OF THE STUDY 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki [21] and the ICH guidelines for GCP [23]. Aurinia will ensure that the 
study complies with all local, federal, and country regulatory requirements. 
The Investigator must ensure the confidentiality of all subjects participating in the study. 
All anonymous data remains the property of Aurinia. 
14.1 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, federal regulations, 
and ICH guidelines; and must have been approved by the Institutional Review Board 
(IRB)/Ethics Committee (EC)/Independent Ethics Committee (IEC) prior to use. The 
Investigator or an authorized associate must explain the nature of the study and the treatment 
in such a manner that the subject is aware of potential benefits and risks. Subjects must also be 
informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. Subjects must be provided sufficient time to consider participation, 
including discussion with family members prior to signing the ICF. Documentation of the 
discussion and the date of informed consent must be recorded in the source documentation. 
After signing the ICF, subjects will be enrolled into the study and assigned a subject 
identification number that will be used on all subject documentation. 
The informed consent can be signed up to 30 days before the screening Visit 1. If more than 
30 days elapses between date of consent and the screening Visit 1, the subject should be asked 
to re-sign and date the consent form to confirm continued interest in study participation. 
14.2 Institutional Review Board or EC/IEC 
The protocol, any protocol amendments and consent form for the proposed clinical study and 
any other documents required by the local IRB/EC/IEC must be submitted by the Investigator 
for review and approval to the IRB/EC/IEC. The Investigator must also ensure that the 
IRB/EC/IEC reviews the progress of the study on a regular basis and, if necessary, renews its 
approval of the study per local requirements. 


 
 
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15. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all study-related site source data, study-related documents, 
and reports will be available, and that the provision of direct access for monitoring and auditing 
by Aurinia or its designees will be permitted. In addition, the Investigator must ensure that all 
study-related site source data, study-related documents, and reports will be made available for 
inspection by the appropriate Regulatory Authority and review by the IRB/EC/IEC. 
The Investigator is responsible for notifying Aurinia in advance of an impending regulatory 
inspection. He/she may request that Aurinia provide support for preparation, if necessary. The 
Investigator is required to provide updates to Aurinia on the ongoing activities during the 
inspection, respond to any citations/objectionable findings (i.e., U.S. Food and Drug 
Administration Form 483) and to share any follow up responses from the Regulatory 
Authority. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the Study Monitor (source document verification). 
The Monitor will also review the Investigator’s drug accountability records to ensure that the 
drug supplies are stored and dispensed appropriately. A comprehensive validation program 
will verify the data and queries will be generated for resolution by the Investigator. Throughout 
the study, Aurinia or its designates may review data as deemed necessary. 


 
 
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16. ADMINISTRATIVE PROCEDURES 
16.1 Sponsor’s Responsibilities 
16.1.1 Study Supplies 
Sites will be provided with all supplies required to manage this study. This will include but not 
be limited to the following: 
• Investigator file(s) (for filing of all study related documentation). 
• Kits for collection, storage, and transportation of applicable samples required for 
central laboratories. This will also include all applicable guidelines and contact details. 
• Contact list of all relevant study personnel. 
• eCRF and completion guidelines (or equivalent electronic data capture system). 
• Study reference manual. 
• All study forms (e.g., SAE, pregnancy, drug accountability, etc.). 
16.1.2 Insurance 
Aurinia confirms that it carries liability insurance which protects non-employee physicians or 
Investigators/study staff against claims for which they may become liable as a result of 
damages caused by Aurinia products used in clinical studies. Insurance coverage is not 
extended to damages that the Investigators or third parties may suffer by reason of acts of 
commission or omission on the part of such Investigators or third parties and that are not in 
accordance with accepted common medical practices (lege artis procedures). Aurinia will 
reimburse the subject for all study-related injuries provided that the injury does not arise from 
the subject’s misuse of the study treatment or failure to follow the Investigator’s instructions. 
16.1.3 Study Monitoring 
The study will be monitored by representatives of Aurinia (or designee, which may include a 
contract research organization). If not monitored by Aurinia, documentation of delegation will 
be described in the Clinical Trial Agreement. It is understood that the responsible Monitor will 
contact and visit the Investigator regularly and will be allowed, on request, to inspect the 
various records of the study (eCRFs and other pertinent data) provided that subject 
confidentiality is maintained in accordance with local requirements. 
It will be the Monitor's responsibility to inspect the eCRFs at regular intervals throughout the 
study (frequency outlined in a separate procedural document), to verify the adherence to the 


 
 
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protocol and the completeness, consistency, and accuracy of the data being entered on them. 
The Monitor must have access to laboratory test reports and other subject records needed to 
verify the entries on the eCRF. The Investigator (or his/her deputy) agrees to co-operate with 
the Monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
16.2 Investigator’s Responsibilities 
16.2.1 Reporting and Recording of Data 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures, and electronic signatures. Only individuals who are identified 
on the authorized signature page may enter/correct data in the eCRF. For those subjects who 
withdraw before completion of the study, all available efficacy and safety data must be entered 
in the eCRF. Incomplete or inconsistent data on the eCRF will result in data queries addressed 
to the Investigator for resolution. 
16.2.2 Investigator Training 
All Investigators and their study personnel will receive training regarding the study procedures, 
study treatments, and GCP/regulations specific to the conduct of clinical studys. This training 
will take place prior to enrollment of the first subject at the study site, and must be documented 
and filed in the Investigator’s Study Site File. 
16.2.3 Source Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
Subject clinical source documents would include subject hospital/clinic records, physician’s 
and nurse’s notes, appointment book, original laboratory reports, ECG, X-ray, pathology and 
special assessment reports, signed ICFs, consultant letters, and subject screening and 
enrollment logs. These are to be separate and distinct from eCRFs. All data for the study must 
be available in source documentation, including oral and written communication with the 
subject regarding the study treatment (including the risks and benefits of the study). The date 
of informed consent must be recorded in the source documentation. 
The Investigator must arrange for the retention of all study documentation (such as eCRFs, 
research files, and master files) for the duration specified in their respective site contract. The 
Investigator must keep these documents on file after completion or discontinuation of the study 
according to local governing guidelines. Archived data may be held electronically, provided 
that a back-up copy exists and that a hard copy can be generated if required. 


 
 
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The Investigator must inform Aurinia immediately if any documents are lost, to be transferred 
to a different facility, or to be transferred to a different owner. 


 
 
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17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
17.1 Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted. 
The Investigator should not implement any deviation from, or changes of the protocol without 
written agreement from Aurinia and prior documented approval/favorable opinion from the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to 
study subjects, or when change(s) involves only logistical or administrative aspects of the 
study. If the Investigator must implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior written approval, the 
implemented deviation or change and the reasons for it should be submitted in a timely manner 
to Aurinia and to the IRB/IEC as required by applicable local requirements. 
The Investigator, or person designated by the Investigator, will document and record the 
preventative and/or corrective measures for any deviation from the approved protocol. 
Accidental deviations from the protocol including violations of inclusion/exclusion criteria 
will be assessed as minor or major on a case-by-case basis. The criteria describing the 
deviation(s) and how they will be handled will be documented in the SAP. 
Any amendment to the protocol requires written approval/favorable opinion by the IRB/IEC 
prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must 
receive an IRB/IEC approval/favorable opinion concerning the reviewed document prior to 
administering to study subjects. 
17.2 Study Termination 
Aurinia reserves the right to terminate the study in its entirety or at a site at any time. Reasons 
for termination may include, but are not limited to the following: unsatisfactory subject 
enrollment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
In terminating the study, Aurinia and the Investigator will assure that adequate consideration 
is given to the protection of the subjects. Both parties will arrange the procedures on an 
individual basis after review and consultation and in accordance with the study contract. 


 
 
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18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
Aurinia is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles [24]. Where 
possible, authorship will be agreed at the beginning of the study. The authors will form a 
publication committee and this committee will propose and develop appropriate scientific 
manuscripts or abstracts from the study data. Investigators may not present or publish partial 
or complete study results individually. Any manuscript or abstract proposed by the 
Investigators must be reviewed and approved in writing by Aurinia before submission for 
publication. Names of all Investigators participating in the study will be included in the 
publication. 
The publication committee for a study will comprise of authors selected in adherence with the 
International Committee of Medical Journal Editors criteria [25] for authorship. If studies are 
multicenter, it may be appropriate to assign group authorship. 
In addition, certain Aurinia employees involved in the design and conception of the protocol, 
study management and data analysis and interpretation are qualified authors and will be 
included in the publication committee. 


 
 
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19. REFERENCES 
1. 
Ward MM. Changes in the incidence of end stage renal disease due to lupus nephritis 
in the United States, 1996-2004. J Rheumatol. 2009 Jan;36(1):63-7. 
2. 
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli 
MG, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing 
low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. 2010 
Jan;69(1):61-4. Epub 2009 Jan 20. 
3. 
Lee YH, Woo J-H, Choi SJ, Ji JD, Song GG. Induction and maintenance therapy for 
lupus nephritis: a systematic review and meta-analysis. Lupus. 2010 May; 19(6):703-
10. Epub 2010 Jan 11. 
4. 
Study WX17801. A prospective, randomized, active controlled, parallel group, multi-
center trial to assess the efficacy and safety of mycophenolate mofetil (MMF) in 
inducing response and maintaining remission in subjects with lupus nephritis (LN). 
Final report. Victoria (BC): Aspreva Pharmaceuticals Corporation; 2008 May 6. Report 
No.: 1024493. 
5. 
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al; Aspreva 
Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide 
for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-
12. Epub 2009 Apr 15. 
6. 
Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease 
progression. Kidney Int. 1997;51:2-15. 
7. 
Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, et al; 
Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and 
adverse outcomes. JAMA. 2010 Feb 3;303(5):423-9. 
8. 
Trivedi S, Zeier M, Reiser J. Role of podocytes in lupus nephritis. Nephrol Dial 
Transplant. 2009;24:3607-12. 
9. 
Mathieson PW. Proteinuria and immunity - an overstated relationship? N Engl J Med. 
2008 Dec 4;359(23):2492-4. 
10. 
Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV 
lupus nephritis with multitarget therapy. J Am Soc Nephrol. 2008 Oct; 19(10):2001-
10. Epub 2008 Jul 2. 
11. 
Miyasaka N, Kawai S, Hashimoto H. Efficacy and safety of tacrolimus for lupus 
nephritis: a placebo-controlled double-blind multicenter study. Mod Rheumatol. 
2009;19:606-15. 


 
 
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12. 
Cortés-Hernández J, Torres-Salido MT, Medrano AS, Tarrés MV, Ordi-Ros J. Long-
term outcomes-mycophenolate mofetil treatment for lupus nephritis with addition of 
tacrolimus for resistant cases. Nephrol Dial Transplant. 2010; 25:3939-48. Epub 2010 
Jun 10. 
13. 
Szeto C-C, Kwan BC-H, Lai FM-M, Tam L-S, Li EK-M, Chow K-M, et al. Tacrolimus 
for the treatment of systemic lupus erythematosus with pure class V nephritis. 
Rheumatology. 2008;47:1678-81. 
14. 
Uchino A, Tsukamoto H, Nakashima H, Yoshizawa S, Furugo I, Mitoma H, et al. 
Tacrolimus is effective for lupus nephritis patients with persistent proteinuria. Clin Exp 
Rheumatol. 2010 Jan-Feb;28(1):6-12. 
15. 
Tanaka H, Oki E, Tsugawa K, Nonaka K, Suzuki K, Ito E. Effective treatment of young 
subjects with pediatric-onset, long-standing lupus nephritis with tacrolimus given as a 
single daily dose: an open-label pilot study. Lupus. 2007;16(11):896-900. 
16. 
Asamiya Y, Uchida K, Otsubo S, Takei T, Nitta K. Clinical assessment of tacrolimus 
therapy in lupus nephritis: one-year follow-up study in a single center. Nephron Clin 
Pract. 2009;113(4):c330-6. Epub 2009 Sep 3. 
17. 
Tse KC, Lam MF, Tang SCW, Tang CSO, Chan TM. A pilot study on tacrolimus 
treatment in membranous or quiescent lupus nephritis with proteinuria resistant to 
angiotensin inhibition or blockade. Lupus. 2007;16(1):46-51. 
18. 
Lanata CM, Mahmood T, Fine DM, Petri M. Combination therapy of mycophenolate 
mofetil and tacrolimus in lupus nephritis. Lupus. 2010 Jul;19(8):935-40. Epub 2010 
Apr 13. 
19. 
Lee T, Oh KH, Joo KW, Kim YS, Ahn C, Han JS, et al. Tacrolimus is an alternative 
therapeutic option for the treatment of refractory lupus nephritis. Lupus. 
2010 Jul;19(8):974-80. 
20. 
KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, 
Classification, and Stratification, 2002.  
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm. 
Accessed 2 September 2014. 
21. 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;74(4):800-2. 
22. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. 64th WMA General Asssembly, Fortaleza, Brazil. 
October 2013. 


 
 
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23. 
ICH Harmonised Tripartite Guideline.: Guideline for good clinical practice. E6 (R1) 
1996 Jun 10. 
24. 
PhRMA principles and guidelines: public disclosure of clinical trial results. 
Pharmaceutical Research and Manufacturers of America [Internet]. 2009 [cited 2009]. 
Available from: http://www.phrma.org/principles_and_guidelines. 
25. 
International Committee of Medical Journal Editors [Internet]. Uniform requirements 
for manuscripts submitted to biomedical journals: writing and editing for biomedical 
publication [updated 2010 Apr]. Available from: http://www.icmje.org. 
 
 


 
 
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Appendix 1 
Drug Therapy for the Treatment of Hypertension 
Antihypertensive drug therapy for subjects who either have hypertension at screening or who 
develop hypertension while on study treatment may include the following: 
• Dihydropyridine calcium channel blockers (e.g., amlodipine, nifedipine) 
• Alpha-1-adrenergic blocking agents (e.g., doxazosin) 
• Alpha-beta-blockers (e.g., carvedilol, labetalol) 
• Thiazide diuretics (e.g., chlorthalidone or hydrochlorothiazide) 
Excluded Drugs: While the ARBs and ACE inhibitors may also be effective in calcineurin 
inhibitor-associated hypertension, their dose adjustment or commencement is not permitted in 
this trial (see Section 7.8.1, Prohibited Medications). 
Recommended First and Second Line Therapies for Treatment of Hypertension 
Titrate the following according to the timeframe given in the respective drug label: 
First Line - select from one of the following: 
• Amlodipine, 5 mg daily to achieve BP <140/90 mmHg; titrate to 10 mg daily if 
satisfactory results not obtained within 2 weeks 
• Nifedipine XL, 30 mg daily; titrate to 60 mg and possibly 90 mg daily within 2 weeks 
• 12.5 to 25 mg/day of chlorthalidone or hydrochlorothiazide 
Second Line - may add from among the following to the first line therapy if a partial response 
is obtained: 
• Labetalol, 100 mg BID; titrate to 200 mg BID, then 300 mg BID 
Note: If the BP remains uncontrolled with the above-referenced maximum doses of first and 
second-line antihypertensive therapies, reduction of study treatment dose may be considered 
or it may be decided to discontinue study treatment and utilize antihypertensive therapies to 
achieve control of BP. 
If at any time, in the judgment of the treating physician in consultation with the Medical 
Monitor, the response to treatment is inadequate, the study treatment may be 
discontinued. 


 
 
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Appendix 2 
Measurement of Blood Pressure and Pulse 
1. Whenever possible, BP measurements should be undertaken by the same study site 
personnel at each clinic visit. 
2. Whenever possible, the BP determinations should be undertaken at approximately the same 
time of day for each study visit and at the same time in relations to prior study treatment 
ingestion. 
3. The measurements should be undertaken prior to blood collection. 
4. Prior to measuring BP, the study subject should be seated in a quiet room for at least 
5 minutes, in a chair with his/her back supported and feet comfortably resting on the floor. 
5. Due to the likelihood each arm can have a slightly different BP, it is strongly encouraged 
to use the same arm that was selected at screening for all measurements, supported at heart 
level. 
6. No restrictive clothing should encircle the arm in which BP measurements are determined. 
7. An appropriately sized cuff will be required wherein the cuff bladder encircles at least 80% 
of the upper portion of the arm. 
8. Three serial BP readings will be undertaken with a minimum of 2 minutes between 
readings and with the cuff fully deflated between each determination. 
9. The mean of the second and third of these 3 readings will be used as the study day BP 
value. 
10. All triplicate measurements, along with the calculated mean value, will be recorded in the 
source documents. The mean of the second and third readings will be calculated within the 
EDC as the study day result. 
11. Similarly, pulse will be obtained following the second and third BP readings. These will 
be recorded, along with the mean value of these determinations, in the source documents. 
The mean value will be entered into the eCRF and utilized as the study day pulse rate. 
 
 


 
 
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Appendix 3 
International Society of Nephrology and the Renal Pathology Society 
(ISN/RPS) 2003 Classification of Lupus Nephritis 
Class I 
Minimal mesangial lupus nephritis 
Normal glomeruli by light microscopy, but mesangial immune deposits by 
immunofluorescence  
Class II 
Mesangial proliferative lupus nephritis 
Purely mesangial hypercellularity of any degree or mesangial matrix 
expansion by light microscopy, with mesangial immune deposits 
May be a few isolated subephithelial or subendothelial deposits visible by 
immunofluorescence or electron microscopy, but not by light microscopy 
Class III 
Focal lupus nephritisª 
Active or inactive focal, segmental or global endo- or extracapillary 
glomerulonephritis involving <50% of all glomeruli, typically with focal 
subendothelial immune deposits, with or without mesangial alterations 
Class III (A) 
Active lesions: focal proliferative lupus nephritis 
Class III (A/C) 
Active and chronic lesions: focal proliferative and sclerosing lupus nephritis 
Class III (C) 
Chronic inactive lesions with glomerular scars: focal sclerosing lupus 
nephritis 
Class IV 
Diffuse lupus nephritisb 
Active or inactive diffuse, segmental or global endo- or extracapillary 
glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse 
subendothelial immune deposits, with or without mesangial alterations. This 
class is divided into diffuse segmental (IV-S) lupus nephritis when ≥50% of 
the involved glomeruli have segmental lesions, and diffuse global (IV-G) 
lupus nephritis when ≥50% of the involved glomeruli have global lesions. 
Segmental is defined as a glomerular lesion that involves less than half of the 
glomerular tuft. This class includes cases with diffuse wire loop deposits but 
with little or no glomerular proliferation.  
Class IV-S (A) 
Active lesions: diffuse segmental proliferative lupus nephritis 
Class IV-G (A) 
Active lesions: diffuse global proliferative lupus nephritis 
Class IV-S (A/C) 
Active and chronic lesions: diffuse segmental proliferative and sclerosing 
lupus nephritis 


 
 
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Class IV-G (A/C) 
Active and chronic lesions: diffuse global proliferative and sclerosing lupus 
nephritis 
Class IV-S (C) 
Chronic inactive lesions with scars: diffuse segmental sclerosing lupus 
nephritis 
Class IV-G (C) 
Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis 
Class V 
Membranous lupus nephritis 
Global or segmental subephithelial immune deposits or their morphologic 
sequelae by light microscopy and by immunofluorescence or electron 
microscopy, with or without mesangial alterations 
Class V lupus nephritis may occur in combination with class II or IV in 
which case both will be diagnosed 
Class V lupus nephritis show advanced sclerosis 
Class VI 
Advanced sclerosis lupus nephritis 
≥90% of glomeruli globally sclerosed without residual activity 
 
a Indicate the proportion of glomeruli with active and with sclerotic lesions. 
b Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. 
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, 
severity of arteriosclerosis or other vascular lesions. 
 
1. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The 
classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 
2004;65:521-30. 
2. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The 
classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 
2004;15:241-50. 


 
 
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Appendix 4 
Conversion Table for Oral Corticosteroids 
Compound 
Equivalent Potency (mg) 
Prednisone 
5 
Prednisolone 
5 
Cortisone 
25 
Hydrocortisone (cortisol) 
20 
Methylprednisolone 
4 
Triamcinolone 
4 
Dexamethasone 
0.75 
 
i.e., 
1 mg prednisone = 1 mg prednisolone 
1 mg prednisone = 5 mg cortisone 
1 mg prednisone = 4 mg hydrocortisone (cortisol) 
1 mg prednisone = 0.8 mg methylprednisolone 
1 mg prednisone = 0.8 mg triamcinolone 
1 mg prednisone = 0.15 mg dexamethasone 
 
 


 
 
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Appendix 5 
1997 Update of the 1982 American College of Rheumatology Revised 
Criteria for the Classification of Systemic Lupus Erythematosus 
 
Four or More of: 
Criterion 
Definition 
1. Malar rash 
Fixed erythema, flat or raised, over the malar eminences, tending 
to spare the nasolabial folds 
2. Discoid rash 
Erythematous raised patches with adherent keratotic scaling and 
follicular plugging; atrophic scarring may occur in older lesions 
3. Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient 
history or physician observation 
4. Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by 
physician  
5. Arthritis 
Nonerosive arthritis involving 2 or more peripheral joints, 
characterized by tenderness, swelling, or effusion 
6. Serositis 
a) Pleuritis--convincing history of pleuritic pain or rubbing heard 
by a physician or evidence of pleural effusion  
OR 
b) Pericarditis--documented by ECG or rub or evidence of 
pericardial effusion 
7. Renal disorder 
a) Persistent proteinuria greater than 0.5 grams per day (or 
0.5 mg/mg by UPCR) or greater than 3+ if quantitation not 
performed  
OR 
b) Cellular casts--may be red cell, hemoglobin, granular, tubular, 
or mixed 
8. Neurologic 
disorder 
a) Seizures--in the absence of offending drugs or known metabolic 
derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance  
OR 
b) Psychosis--in the absence of offending drugs or known 
metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte 
imbalance 


 
 
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Four or More of: 
Criterion 
Definition 
9. Hematologic 
disorder 
a) Hemolytic anemia--with reticulocytosis  
OR 
b) Leukopenia--less than 4,000/mm3 total on 2 or more occasions 
OR 
c) Lyphopenia--less than 1,500/mm3 on 2 or more occasions 
OR 
d) Thrombocytopenia--less than 100,000/mm3 in the absence of 
offending drugs  
10. Immunologic 
disorder 
a) Anti-dsDNA: antibody to native dsDNA in abnormal titer 
OR 
b) Anti-Sm: presence of antibody to Sm nuclear antigen 
OR 
c) Positive finding of antiphospholipid antibodies based on 1) an 
abnormal serum level of IgG or IgM anticardiolipin antibodies, 2) 
a positive test result for lupus anticoagulant using a standard 
method, or 3) a false-positive serologic test for syphilis known to 
be positive for at least 6 months and confirmed by Treponema 
pallidum immobilization or fluorescent treponemal antibody 
absorption test 
11. Antinuclear 
antibody 
An abnormal titer of antinuclear antibody by immunofluorescence 
or an equivalent assay at any point in time and in the absence of 
drugs known to be associated with "drug-induced lupus" 
syndrome  
Abbreviation: ECG = Electrocardiogram. 
Sources: Hochberg MC, MD, MPH for the Diagnostic and Therapeutic Criteria Committee of the American College of Rheumatology. Tan 
EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria 
for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271-7. 
 
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus 
erythematosus [letter]. Arthritis Rheum 1997;40:1725. 
 
 


 
 
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Appendix 6 
Systemic Lupus Erythematosus Disease Activity Measure 
(SELENA-SLEDAI) 
Descriptor 
Definition 
Points 
Seizure 
Recent onset. Exclude metabolic, infectious or drug 
causes. 
8 
Psychosis 
Altered ability to function in normal activity due to 
severe disturbance in the perception of reality. Include 
hallucinations, incoherence, marked loose associations, 
impoverished thought content, marked illogical thinking, 
bizarre, disorganized or catatonic behavior. Exclude 
uremia and drug causes. 
8 
Organic brain 
syndrome 
Altered mental function with impaired orientation, 
memory or other intellectual function with rapid onset 
and fluctuating clinical features. Include clouding of 
consciousness with reduced capacity to focus and 
inability to sustain attention to environment plus at least 
2 of the following: perceptual disturbance, incoherent 
speech, insomnia or daytime drowsiness, or increased or 
decreased psychomotor activity. Exclude metabolic, 
infectious or drug causes. 
8 
Visual disturbance 
Retinal changes of SLE. Include cytoid bodies, retinal 
hemorrhages, serous exudate or hemorrhages in the 
choroid, or optic neuritis. Exclude hypertension, 
infectious or drug causes. 
8 
Cranial nerve 
disorder 
New onset of sensory or motor neuropathy involving 
cranial nerves. 
8 
Lupus headache 
Severe persistent headache; may be migrainous but must 
be nonresponsive to narcotic analgesia. 
8 
Cerebrovascular 
accident  
New onset of cerebrovascular accident(s). Exclude 
arteriosclerosis. 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual 
infarction, splinter hemorrhages, or biopsy or angiogram 
proof of vasculitis. 
8 


 
 
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Descriptor 
Definition 
Points 
Arthritis 
More than 2 joints with pain and signs of inflammation 
(i.e., tenderness, swelling, or effusion). 
4 
Myositis 
Proximal muscle aching or weakness associated with 
elevated creatine phosphokinase or aldolase, or 
electromyogram changes, or a biopsy showing myositis. 
4 
Urinary casts 
Heme-granular or RBC casts. 
4 
Hematuria 
>5 red blood cells per high powered field. Exclude 
stone, infection or other causes. 
4 
Proteinuria 
>0.5 g per 24 hours or 0.5 mg/mg UPCR by FMV. New 
onset or recent increase of more than 0.5 g per 24 hours. 
4 
Pyuria 
>5 white blood cells per high power field. Exclude 
infection. 
4 
New rash 
New onset or recurrence of inflammatory type rash. 
2 
Alopecia 
New onset or recurrence of abnormal patchy or diffuse 
loss of hair. 
2 
Mucosal ulcers 
New onset or recurrence of oral or nasal ulcerations. 
2 
Pleurisy 
Pleuritic chest pain with pleural rub or effusion or 
pleural thickening. 
2 
Pericarditis 
Pericardial pain with at least 1 one of the following: rub, 
effusion or ECG confirmation. 
2 
Low complement 
Decrease in CH50, C3 or C4 below the lower limit of 
normal for testing laboratory. 
2 
Increased DNA 
binding 
>25% binding by Farr assay or above normal range for 
testing laboratory. 
2 
Fever 
>38°C. Exclude infectious cause. 
1 
Thrombocytopenia 
<100,000 platelets per mm3. 
1 
Leukopenia 
<3,000 white blood cells per mm3. Exclude drug causes. 
1 
Abbreviations: ECG = Electrocardiogram; RBC = Red blood cells; SLE = Systemic lupus erythematosus.  
Source: Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang DH, and the Committee on Prognosis Studies in SLE. Derivation of 
the SLEDAI: a disease activity index for lupus subjects. Arthritis Rheum. 1992;35:S630-40. 
 


 
 
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Appendix 7 
Expanded List of Allowed Concomitant Medications 
• Prophylactic therapy for steroid-induced bone loss (calcium with Vitamin D and/or a 
bisphosphonate). 
• Low dose aspirin is allowed for cardiovascular prophylaxis. 
• Minor GI AEs (such as nausea, vomiting and diarrhea) may be treated symptomatically 
(e.g., with loperamide for diarrhea or standard anti-emetics such as metoclopramide or 
domperidone for nausea and vomiting). Proton pump inhibitors or ranitidine are 
permitted for dyspepsia or gastric protection. Magnesium or aluminum containing 
antacids may be used, but should not be taken at the same time as study treatment; such 
antacids, if required, should be taken either 1 hour before or 2 hours after study 
treatment. 
• Amphotericin or oral nystatin are permitted as infective prophylaxis against fungal 
infections, and low-dose sulfamethoxazole/trimethoprim is permitted as prophylaxis 
against Pneumocystis carinii pneumonia. 
• Granulocyte colony stimulating factor is allowed to manage neutropenia in the presence 
of major infection (i.e., infections requiring IV antibiotics). 
• Oral or IV iron preparations for iron deficiency and/or anemia. 
• Erythropoietin is permitted for treatment of severe anemia (hemoglobin <10 mg/dL). 
• Cytomegalovirus prophylaxis is permitted for example with oral valganciclovir. 
• Acute intermittent administration of NSAIDs for not greater than 7 consecutive days is 
permitted. 
• Lipid-lowering therapies (e.g., statins) will be used as clinically indicated. 
• Antimalarials should be administered to all subjects unless contraindicated. 
• Angiotensin-converting enzyme inhibitors, ARBs, and aliskerin and other therapies are 
recommended, as per standard guidelines but if used their dose must be stable 
throughout the study. In addition subjects must be on a stable dose of ACE inhibitors 
or ARBs for 4 weeks prior to enrollment.  
• In the case of uncontrolled hypertension (systolic BP >165 mmHg or 
diastolic >105 mmHg on 2 successive measurements), the addition of a diuretic or 
calcium channel blocker only are permitted, together with dose decreases or 


 
 
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interruption of study treatment per the instructions in Section 7.9, Increased Blood 
Pressure. 
 
 


 
 
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Appendix 8 
Summary of Treatment and Food Restrictions 
Treatment 
Washout Period 
During Treatment 
Reason 
Immunosuppressants other 
than those allowed by 
protocol 
30 days 
Prohibited 
Interferes with 
study efficacy 
endpoints 
Aminoglycosides 
Amphotericin B 
Melphalan 
Ketoconazole 
Rifampin 
14 days 
Prohibited 
May potentiate 
toxicity 
NSAIDs chronic dosing 
(>7 consecutive days) 
Prohibited 
Prohibited 
May potentiate 
nephrotoxicity 
P-gp substrates 
To be monitored 
To be monitored 
Drug-drug 
interaction 
P-gp inhibitors 
To be discussed with 
Medical Monitor 
To be discussed with 
Medical Monitor 
Drug-drug 
interaction 
Androgenic steroids 
Cimetidine 
Fluconazole, itraconazole 
Macrolide antibiotics 
(azithromycin, 
clarithromycin, 
erythromycin) 
Metoclopramide 
Barbiturates and derivatives 
Carbamazepine 
Octreotide acetate 
Phenytoin 
Sulfadimidine (intravenous) 
Theophylline 
To be discussed with 
Medical Monitor 
To be discussed with 
Medical Monitor 
Drugs interfering 
with Orelvo 
metabolism 
ACE inhibitors and ARBs 
No change or introduction 
during screening 
Change or 
commencement 
prohibited 
Interfere with 
primary endpoint 
assessment 
Foods 
Grapefruit and grapefruit 
juice 
 
24 hours 
 
Prohibited 
 
May affect the 
metabolism of 
Orelvo 
Abbreviations: ACE = Angiotensin converting enzyme; ARB = Angiotensin receptor blocker; NSAID = Non-steroidal anti-inflammatory 
drug; P-gp = P-glycoprotein. 
 
 




 
 
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Appendix 10 LupusPRO (v1.7) HRQoL Assessment  


 
 
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SAP_000.pdf: 
 
 
AURORA 
 
AUR-VCS-2016-01 
 
Statistical Analysis Plan 
 
Version 5.0 
 
Issue Date 21st Oct 2019 
 
  
 
Page 1 of 77 
 
 
STATISTICAL ANALYSIS PLAN 
AURORA 1 CLINICAL TRIAL 
(AUR-VCS-2016-01) 
 
 
 
Clinical Protocol Number: 
AUR-VCS-2016-01 
 
 
Study Name: 
AURORA 
(AURinia 
Orelvo 
Renal 
Assessments) 1: Aurinia Renal Response in 
Active Lupus with Orelvo (voclosporin)  
 
 
Study Title: 
A Randomized, Controlled Double-blind 
Study Comparing the Efficacy and Safety of 
Orelvo (voclosporin) (23.7 mg Twice Daily) 
with Placebo in Achieving Renal Response 
in Subjects with Active Lupus Nephritis 
 
Date: 
21st Oct 2019 
 
 
Version: 
V5.0 
 
 
Sponsor Address: 
Aurinia Pharmaceuticals Inc. 
#1203 – 4464 Markham Street 
Victoria, B.C., V8Z 7X8 
Canada 
 
Author: 
 
 
 
 




 
 
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Statistical Analysis Plan 
 
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Issue Date 21st Oct 2019 
 
  
 
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AMENDMENTS BEFORE DATABASE LOCK 
 
Version  Issue Date 
Section 
Revision/Addition 
Rationale 
2.0 
Jul 2018 
6.11.2.2 
11 
Adding additional covariate to 
the sensitivity analysis for the 
primary endpoint. Covariate will 
be MMF ≤2g versus MMF >2g. 
MMF dose to be defined as each 
patient’s maximum dose during 
the study. 
To assess possible 
differences between 
responses for patients 
taking higher levels of 
MMF. 
2.0 
Jul 2018 
6.11.2.3 
11 
Component analysis for primary 
endpoint to be undertaken for 
both Adjudicated response and 
programmed response 
To ensure full details 
of the analysis are 
available should 
differences between 
adjudicated response 
and programmed 
response become 
apparent. 
2.0 
Jul 2018 
6.11.2.2 
11 
Sensitivity analysis using 
regional covariate will be 
defined at both continental and 
country level 
To ensure sufficient 
information is 
available re: regional 
differences. 
2.0 
Jul 2018 
6.11.3.3 
Confirming Week 24 Renal 
Response will be a programmed 
endpoint only. This will not be 
adjudicated by the CEC 
Ensuring consistency 
between the SAP and 
the CRC charter 
2.0 
Sep 2018 
6.13.1 
Updating assumptions for 
missing AE relationships 
Ensure definitions are 
as per current 
requirements 
2.0 
Sep 2018 
5 
6.2.12 
9 
Confirming that region (used as 
blocking factor) will be in the 
primary model 
Regulatory Agency 
feedback requesting 
clarification 
2.0 
Sep 2018 
6.11.1 
Adding clarification around the 
make-up of the CEC: blind and 
independent 
Regulatory agency 
feedback 
2.0 
Sep 2018 
6.11.1 
Adding rescue medication 
clarifications 
Regulatory Agency 
feedback 
2.0 
Sep 2018 
6.11.2.1 
6.11.2.2 
6.11.2.3 
Adding clarification around the 
sensitivity analyses, 
supplementary analyses and the 
tipping point analysis. 
Regulatory agency 
feedback 


 
 
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2.0 
Sep 2018 
3.1 
Clarifying that subjects who 
withdraw from the study are 
defined as non-responders 
Regulatory Agency 
feedback 
2.0 
Sep 2018 
3.2.1 
3.2.2 
9 
Duration of UPCR ≤0.5 moved 
from key secondary to other 
secondary 
Regulatory Agency 
feedback 
2.0 
Sep 2018 
1 
Clarification around IV 
methylprednisolone 
Ensure consistency 
with protocol 
2.0 
Sep 2018 
6.4 
Clarification withdrawal versus 
discontinuation 
Ensure consistent use 
throughout the SAP 
2.0 
Sep 2018 
6.11.3.2 
6.11.3.3 
6.11.4.1 
6.11.4.2 
6.11.4.3 
6.11.4.4 
Referencing baseline section for 
endpoints that use non-standard 
calculations 
Ensure baseline 
calculations are clear 
for each endpoint 
2.0 
Sep 2018 
6.13.1 
Add adverse event displays 
using exposure-adjusted 
incidence rates as a summary 
Regulatory agency 
feedback 
2.0 
Sep 2018 
6.13.1 
Changing relative risk to risk 
difference in overall summary 
of AEs table 
Retain consistency 
between treatment 
comparisons given the 
additional exposure 
adjusted summary 
tables 
2.0 
Sep 2018 
Various 
Consistently referring to 
‘population’ rather than ‘set’ 
Language consistency 
3.0 
March 
2019 
3.1 
Paragraph added to detail the 
primary estimand 
Regulatory agency 
feedback 
3.0 
March 
2019 
6.11.2.4 
Step 3 updated to make it clear 
that stratification variables are 
to be included in the model and 
that different data is generated 
for each of the 50 analyses 
Regulatory agency 
feedback 
4.0 
May 2019 
6.11.2.4 
Tipping point analysis: 
imputation model brought into 
line with the analysis model 
Regulatory feedback 
4.0 
May 2019 
Table 
14.3.8.1 
 
Section 
6.13.1 
Treatment Emergent Adverse 
Events by Descending 
Frequency of Preferred Term  
Safety Analysis Population 
Added following 
review 


 
 
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4.0 
May 2019 
Table 
14.3.8.2 
 
Section 
6.13.1 
Non-Serious Treatment 
Emergent Adverse Events by 
System Organ Class and 
Preferred Term  
Safety Analysis Population 
Added following 
review 
4.0 
May 2019 
6.7 Medical 
History 
(Glossary 
16.2.9.1) 
 
6.8 Prior 
and 
Concomitant 
Medications 
(Glossary 
16.2.9.2) 
 
6.13.1 
Adverse 
Events 
(Glossary 
16.2.9.3) 
Glossaries for medications, 
medical conditions and adverse 
events added 
 
Added following 
review 
5.0 
Oct 2019 
Section 
6.2.2 
Updated baseline definition for 
urine creatinine. 
Updated following 
review 
5.0 
Oct 2019 
Section 6.6 
Added table for regions and 
countries in baseline 
comparability section. 
Updated following 
review 
5.0 
Oct 2019 
Section 6.7 
Updated calculation of ‘Years 
sinc …’ variables. 
Updated following 
review 
5.0 
Oct 2019 
Section 
6.11.2.3 
Added clarifications for eGFR 
success. 
Updated following 
review 
5.0 
Oct 2019 
Section 
6.13.1 
Updated definition of TEAEs to 
be up to last dose + 30 days. 
Removed detailed list of AE 
tables and referring to list of 
tables instead. 
Updated following 
review 
5.0 
Oct 2019 
Section 11 
Updated list of tables, listings 
and figures based on TFL 
review. 
Updated following 
review 
5.0 
Oct 2019 
Whole 
document 
Finalization of the text 
throughout the document. 
 


 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ..................................................................................................................... 2 
AMENDMENTS BEFORE DATABASE LOCK ...................................................................... 3 
TABLE OF CONTENTS ............................................................................................................. 6 
LIST OF TABLES ........................................................................................................................ 8 
LIST OF FIGURES ...................................................................................................................... 9 
LIST OF ABBREVIATIONS .................................................................................................... 10 
1 
INTRODUCTION ............................................................................................................... 11 
1.1 
Schedule of Events ........................................................................................................ 12 
2 
STUDY OBJECTIVES ....................................................................................................... 16 
2.1 
Primary Objective ......................................................................................................... 16 
2.2 
Secondary Objective ..................................................................................................... 16 
3 
ENDPOINTS ........................................................................................................................ 17 
3.1 
Primary Endpoint .......................................................................................................... 17 
3.2 
Secondary Endpoints .................................................................................................... 18 
 
Key Secondary Endpoints ..................................................................................... 18 
 
Other Secondary Endpoints .................................................................................. 18 
4 
SAMPLE SIZE .................................................................................................................... 20 
5 
RANDOMIZATION ........................................................................................................... 21 
6 
PLANNED ANALYSES ..................................................................................................... 22 
6.1 
Analysis Populations ..................................................................................................... 22 
 
Screened Population .............................................................................................. 22 
 
Intent-to-Treat Population ..................................................................................... 22 
 
Per-Protocol Population ........................................................................................ 22 
 
Safety Population .................................................................................................. 23 
6.2 
Derived Data ................................................................................................................. 23 
 
Race....................................................................................................................... 23 
 
Baseline ................................................................................................................. 23 
 
Early Terminations Assessments .......................................................................... 24 
 
Duration/Study Day/Time ..................................................................................... 24 
 
Conventions for Missing and Partial Dates .......................................................... 24 
 
Missing/Partial Start/Stop Date of AEs and Concomitant Medications ............... 24 
 
Missing Last Dates of Study Drug Dosing ........................................................... 25 
 
Missing Diagnosis Dates....................................................................................... 26 
 
Exposure to Study Drug ........................................................................................ 26 


 
 
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Electrocardiogram Data ........................................................................................ 26 
 
Unscheduled Visits ............................................................................................... 26 
 
Randomization Strata ............................................................................................ 26 
 
eGFR ..................................................................................................................... 27 
 
FMV and 24-Hour Urine ...................................................................................... 27 
 
Adverse events ...................................................................................................... 27 
6.3 
Conventions .................................................................................................................. 27 
 
Decimal Places ...................................................................................................... 28 
6.4 
Subject Disposition ....................................................................................................... 28 
6.5 
Protocol Deviations ....................................................................................................... 29 
6.6 
Baseline Comparability ................................................................................................. 29 
6.7 
Medical History ............................................................................................................ 30 
6.8 
Prior and Concomitant Medications ............................................................................. 32 
6.9 
Exposure to Study Drugs .............................................................................................. 32 
6.10 
Treatment Compliance .................................................................................................. 33 
6.11 
Efficacy Analyses ......................................................................................................... 34 
 
Primary Endpoint .................................................................................................. 34 
 
Primary Efficacy Analysis .................................................................................... 35 
 
Key Secondary Endpoints ..................................................................................... 41 
 
Other Secondary Endpoints .................................................................................. 43 
 
Multiplicity ........................................................................................................... 50 
6.12 
Pharmacokinetic Analyses ............................................................................................ 52 
6.13 
Safety Analyses ............................................................................................................. 52 
 
Adverse Events ..................................................................................................... 52 
 
Laboratory Data .................................................................................................... 54 
 
Vital Signs ............................................................................................................. 58 
 
Electrocardiogram Data ........................................................................................ 58 
 
Physical Examination............................................................................................ 58 
7 
INTERIM ANALYSIS ........................................................................................................ 59 
8 
DATA AND SAFETY MONITORING BOARD ANALYSES ....................................... 60 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ................................................... 61 
10 REFERENCES .................................................................................................................... 62 
11 LIST OF TABLES, FIGURES AND LISTINGS ............................................................. 63 
 


 
 
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LIST OF TABLES 
Page 
Table 1.1 
AUR-VCS-2016-01 Schedule of Events .................................................................. 13 
Table 4.1  Voclosporin Response Rates Required to Maintain a Minimum 80% Power .......... 20 
Table 6.1 
Exposure calculation example .................................................................................. 32 
Table 6.2 
SF-36 responses and weighting ................................................................................ 46 
Table 6.3 
SF-36 Scales.............................................................................................................. 47 
Table 6.4  LupusPRO questionnaire .......................................................................................... 48 
Table 6.5 
Laboratory Parameters .............................................................................................. 56 
 
 
 


 
 
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LIST OF FIGURES 
Page 
Figure 1.1 Schema ........................................................................................................................ 12 
Figure 6.1 Hochberg procedure .................................................................................................... 50 
 


 
 
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Statistical Analysis Plan 
 
Version 5.0 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AURORA 
AURinia Orelvo Renal Assessments 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BID 
Twice daily 
BP 
Blood pressure 
C3 / C4 
Complement 3 / complement 4 
CEC 
Clinical Endpoints Committee 
CI 
Confidence interval 
dsDNA 
anti-double-stranded deoxyribonucleic acid 
EDC 
Electronic data capture 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
HR 
Heart rate 
HRQoL 
Health-related quality of life 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVC 
Intravenous cyclophosphamide 
IWRS 
Interactive web response system 
LN 
Lupus nephritis 
MMF 
Mycophenolate mofetil 
MMRM 
Mixed Effect Model Repeated Measures 
OR 
Odds ratio 
Orelvo 
Voclosporin (for Phase 3 lupus nephritis indication) 
PK 
Pharmacokinetic 
QTc 
Corrected QT interval 
QTcF 
QT interval duration corrected for heart rate using method of 
Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SELENA 
Safety of Estrogens in Lupus Erythematosus National Assessment 
SLE 
Systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
TEAE 
Treatment-emergent adverse event 
UPCR 
Urine protein creatinine ratio 
 
 


 
 
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1 INTRODUCTION 
This document details the planned statistical analyses for the AURORA, protocol 
“AUR-VCS-2016-01” study titled “A Randomized, Controlled Double-blind Study Comparing 
the Efficacy and Safety of Orelvo (voclosporin) (23.7 mg Twice Daily) with Placebo in Achieving 
Renal Response in Subjects with Active Lupus Nephritis”. 
The proposed analyses are based on the contents of the final version of the protocol 
(Amendment 1 dated 04 May 2017). 
Lupus nephritis (LN) manifests as diverse patterns of immune complex-mediated renal disease 
affecting glomerular, tubulointerstitial, and vascular compartments. It can lead to permanent and 
irreversible tissue damage within the kidney, resulting in end-stage renal disease (ESRD), and thus 
making LN a serious and potentially life-threatening condition. In subjects with LN, renal damage 
results in proteinuria and/or hematuria and a decrease in renal function as evidenced by reduced 
creatinine clearance and estimated glomerular filtration rate (eGFR), and increased serum 
creatinine levels.  
This is a Phase 3, multicenter, randomized, prospective, double-blind, parallel-group, placebo-
controlled, 2-arm comparison study of voclosporin (herein referred to as voclosporin (VCS)) 
versus matching placebo. Subjects who provide a signed and dated informed consent will be 
screened into the study up to 30 days before randomization. During the screening period, eligibility 
criteria will be assessed. A kidney biopsy may be performed, provided the subject has given 
consent and provided the results can be obtained and reviewed before baseline. Subjects who meet 
all of the inclusion criteria and none of the exclusion criteria will be eligible for randomization 
into the study.  
Baseline assessments will be performed before the first dose of study treatment is administered on 
Day 1. Using an interactive web response system (IWRS), eligible subjects will be randomized to 
receive either oral voclosporin 23.7 mg twice daily (BID) or matching placebo for 52 weeks. All 
subjects who weigh ≥45 kg should receive 0.5 g IV methylprednisolone on both Day 1 and Day 2 
(a total of 1 g), before oral corticosteroid therapy is started on Day 3. All subjects who weigh 
<45 kg should receive 0.25 g IV methylprednisolone on both Day 1 and Day 2 (a total of 0.5 g). 
When subjects are receiving IV methylprednisolone, they should not receive oral corticosteroids 
on the same day. Starting at the Baseline Visit, all subjects will also receive background therapy 
with mycophenolate mofetil (MMF). 
 






 
 
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Visit(1) 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visits 
4-8 
Visit 
9 
Visit 10 
Visits 11-
13 
Visit 14 
Visit 15 
End of 
Treatment/ 
Early 
Termination(2) 
Visit 16 
Safety 
Follow-up(3) 
Day/Week 
Day -30 to 
Day -1 
Day 1 
 
Day 2 
Wks 2, 4, 
8, 12, 16 
±3 days 
Wk 20 
±3 days 
Wk 24 
±10 days 
Wks 30, 
36, 42 
±10 days 
Wk 48 
±10 days 
Wk 52  
±10 days 
Wk 56 
±10 days 
SELENA-SLEDAI 
 
 
 
 
 
 
 
 
 
 
SF-36 and LupusPro(14) 
 
 
 
(7) 
 
 
 
 
 
 
Healthcare Resource 
Utilization(15) 
 
 
 
 
 
 
 
 
 
 
Dispense study 
treatment/compliance 
 
 
 
 
 
 
 
 
(16) 
 
First dose of study treatment 
(at the study site)(17) 
 
 
 
 
 
 
 
 
 
 
MMF dispensing(18) 
 
 
 
 
 
 
 
 
 
 
IV methylprednisolone 
administration(19) 
 
 
 
 
 
 
 
 
 
 
Oral corticosteroid tapering 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1 
Unscheduled visits/assessments can be done as needed. Adverse events, concomitant medications and verbal compliance check is needed. 
2 
Subjects who discontinue study treatment or terminate the study early, are to attend an Early Termination Visit and have the assessments listed performed. Subjects who complete study 
treatment will attend the End of Treatment at Week 52 and have the assessments listed performed.  
3 
Subjects who do not enroll into the continuation study will have a follow up safety visit 4 weeks after the last dose of study treatment. 
4 
If a subject has not had a recent kidney biopsy, one may be performed to assess eligibility for the study provided informed consent has been given and results are 
received prior to randomization. If one is performed as part of standard of care after randomization, the results will be recorded in the electronic case report form. 
5 
Complete physical examination at screening, abbreviated examination at all other applicable visits. Height is measured at screening only. 
6 
During the study, and after screening, in the event that a subject is noted to have a QTcF value exceeding 500 msec, or >60 msec more than baseline, the ECG will 
be repeated. Electrocardiograms will be recorded digitally after the subject has been in a resting, supine position for at least 5 minutes. 
7 
Week 12 only. 
8 
Laboratory assessments will be performed according to the schedule in Section 6.13.2; subjects must be fasting for at least 8 to 12 hours at baseline and end of 
study/early termination. 
9 
Blood samples will be collected at 0 and 2 hours post dose on subjects who provide consent for pharmacokinetics. 
10 
Two FMV specimens, to be performed and resulted before baseline. 
11 
24-hour urine collection should begin 2 days prior to the scheduled study visit in order not to coincide with the FMV sampling due on the day of the study visit. 
12 
Serum pregnancy test to be evaluated at central laboratory at screening, Week 24, and Week 52; urine pregnancy test will be performed locally at all other 
applicable visits. 
13 
Concomitant medications include all herbal medicines and supplements taken by the subject. 
14 
For details on HRQoL assessments, see Section 6.11.4.8. 
15 
For details on Healthcare Resource Utilization, see Section 6.11.4.11. 
16 
Compliance only. 
17 
 All scheduled procedures must be done prior to first dose, including IV methylprednisolone and MMF. 
18 
For subjects not on MMF during screening, will start receiving MMF therapy at the Baseline Visit and return for local complete blood count assessments at Weeks 
1 and 3 after randomization. 
19 
IV methylprednisolone administered 0.5 g on baseline and Day 2. If IV corticosteroids must be administered during screening then the FMV urine specimens will 
be collected prior to the infusion. 
Notes: Subjects who discontinue therapy will attend their regularly scheduled study visits to the end of the study. Subjects who withdraw consent and terminate the 
study early or discontinue treatment early should be advised to attend both Visit 17 and the Safety Follow up Visit (Visit 18). 
Abbreviations: AE=adverse event; BP=blood pressure; CBC=complete blood count; ECG=electrocardiogram; FMV=first morning void; HRQoL=health-related quality of life; IV=intravenous; 
LN=lupus nephritis; MMF=mycophenolate mofetil; QTcF=QT interval duration corrected for heart rate using method of Fridericia; SAE=serious adverse event; SELENA-SLEDAI=Safety of 
Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index; SLE=systemic lupus erythematosus. 


 
 
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2 STUDY OBJECTIVES 
2.1 Primary Objective 
To assess the efficacy of voclosporin compared with placebo in achieving renal response after 
52 weeks of therapy in subjects with active LN.  
2.2 Secondary Objective 
To assess the safety and tolerability of voclosporin over 52 weeks compared with placebo in 
subjects with active LN. 


 
 
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3 ENDPOINTS 
3.1 Primary Endpoint 
Renal response at Week 52 will be adjudicated by the Clinical Endpoints Committee (CEC) based 
on the following parameters:  
• UPCR of ≤0.5 mg/mg, and  
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, and  
• Received no rescue medication for LN (see Protocol Section 7.8, Prohibited Therapy and 
Concomitant Treatment), and  
• Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total 
during Weeks 44 through 52, just prior to the renal response assessment  
The CEC will also take into account the following: 
• Subjects who withdraw from the study prior to the Week 52 assessment and provide 
insufficient week 52 data to determine response will be defined as non-responders. Subjects 
who discontinue study drug but continue to attend study visits (as is the expectation) will 
have their data assessed for response. 
• eGFR values eliminating a subject from complete remission should be accompanied by a 
treatment or disease-related treatment-emergent adverse event (TEAE) that impacts eGFR. 
Full details are given in Section 6.11.1. 
• The CEC is independent and blinded from the treatment groups. 
The primary endpoint estimand is the proportion of subjects showing renal response as adjudicated 
by the CEC in the ITT population when comparing voclosporin and placebo at Week 52. It is 
assessed in all randomized subjects who were recruited according to the inclusion/exclusion 
criteria of the protocol.  
The variable is binary and indicates a response if a subject shows, at 1 year, adequate UPCR with 
no signs of detrimental impact on eGFR. Subjects who cannot be shown to be responders 
through their 1 year data (or absence thereof) are defined as non-responders. 


 
 
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Intercurrent events include: 
• 
Treatment discontinuation for any reason 
o the subject remains on study, allowing the primary endpoint to be assessed at 1 
year. 
• 
Study discontinuation 
o resulting in insufficient information at 1 year to ascertain response status leading to 
assumed non-response. 
• 
Rescue medication taken at any time prior to the primary assessment at 1 year 
o results in non-response. Rescue medication is adjudicated by the Clinical Endpoints 
Committee. 
• 
Death at any time prior to the 1 year primary assessment 
o results in assumed non-response. 
 
3.2 Secondary Endpoints 
3.2.1 
Key Secondary Endpoints  
• Time to UPCR of ≤0.5 mg/mg  
• Partial renal response as defined by 50% reduction from baseline in UPCR at Weeks 24 
and 52  
• Time to 50% reduction in UPCR from baseline  
• Renal response at Week 24 (based on definition of primary endpoint) 
3.2.2 
Other Secondary Endpoints  
• Duration of UPCR ≤0.5 mg/mg  
• Change from baseline in UPCR at each time point  
• Change from baseline in serum creatinine, urine protein, and eGFR at each time point 


 
 
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• Proportion of subjects experiencing a confirmed >30% decrease from baseline in eGFR at 
each time point 
• Change from baseline in immunology parameters (complement 3 (C3), C4, and anti-
double-stranded deoxyribonucleic acid (dsDNA)) at Weeks 24 and 52  
• Renal response with low-dose steroids at Weeks 24 and 52 (defined as renal response in 
the presence of corticosteroids of ≤2.5 mg/day between Weeks 16 to 24 and Weeks 44 to 
52)  
• Change from baseline in health-related quality of life (HRQoL) at Weeks 12, 24, and 52  
• Health Resource Utilization at Weeks 24 and 52 
• Change from baseline in the Safety of Estrogens in Lupus Erythematosus National 
Assessment - Systemic Lupus Erythematosus Disease Activity (SELENA-SLEDAI) Index 
score at Weeks 24 and 52 


 
 
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4 SAMPLE SIZE 
The total sample size will be approximately 324 subjects (162 subjects per treatment arm). This is 
based on the following assumptions:  
• A two group continuity corrected Chi square test with a 0.05 two-sided significance level 
will have 80% power to detect the difference between a placebo response rate of 20.0% 
and a voclosporin response rate of 34.4% (odds ratio=2.1) when the sample size in each 
group is 162 (total N=324).  
• The effect of withdrawals will be investigated. Subjects withdrawing for any reason will 
be counted as non-responders in the primary analysis and therefore no adjustment of 
sample size for withdrawals is necessary.  
• The impact of withdrawals on primary endpoint will be investigated in the tipping point 
analysis.  
Table 4.1 shows the voclosporin response rates required to maintain a minimum 80% power at the 
planned sample size for given placebo response rates. These response rates all lead to odds ratios 
of around 2, which is a clinically relevant effect.  
Table 4.1  
Voclosporin Response Rates Required to Maintain a Minimum 80% Power 
 
Placebo Response Rate  
Voclosporin Response Rate  
Odds Ratio  
15%  
28.4%  
2.25  
19%  
33.2%  
2.12  
25%  
40%  
2.0  
 
 


 
 
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5 RANDOMIZATION 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain a 
list of subject numbers and subject names to enable records to be found at a later date. Subjects 
will be allocated a subject number at the screening visit and registered with an interactive central 
randomization system. Subjects meeting the required eligibility criteria will be randomized to 
treatment at Visit 2 (baseline).  
The randomization will be stratified by biopsy class (Class V only versus Others) and by prior 
MMF use at time of screening. The subjects will be randomized in a ratio of 1:1 to receive either 
voclosporin 23.7 mg BID or matching placebo. To help ensure balance, a centralized 
randomization will be utilized where region will be employed as a blocking factor. This will ensure 
balance between treatment groups within each of the 4 regions: North America, Latin America, 
Europe / South Africa and Asia Pacific.  


 
 
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6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final clinical study report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained. The justification for any such additional analyses will be fully documented 
in the final CSR. 
6.1 Analysis Populations 
Subjects excluded from the analysis populations and the reason for their exclusion will be listed in 
Appendix 16.2. 
6.1.1 
Screened Population 
The Screened population includes all subjects who were screened and were allocated a subject 
number.  
6.1.2 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will be based on ITT principles and will consist of all subjects 
who are randomized to treatment. This group will be analyzed based on the treatment to which the 
subject was randomized. 
6.1.3 
Per-Protocol Population 
The Per-Protocol (PP) population will be a subset of the ITT consisting of those subjects who: 
• Satisfy all of the inclusion / exclusion criteria 
• Do not have any treatment administration errors 
• Do not take prohibited concomitant medications 
All protocol deviations will be assessed and documented on a case-by-case basis before the 
database lock and in a blinded fashion. Deviations considered to have a serious impact (major 
protocol violation) on the efficacy results will lead to the relevant subject being excluded from the 
PP population. Before database lock, potential subject exclusions from PP population will be 
reviewed by the Sponsor and documented in a subject evaluability document (
).  


 
 
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6.1.4 
Safety Population 
The Safety population will consist of all randomized subjects who have taken at least 1 dose of 
study treatment. The subjects in this group will be analyzed based on the treatment they received. 
Subjects who receive treatment from more than 1 arm will be assigned to the voclosporin arm. 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 
Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories.  
6.2.2 
Baseline 
Except for parameters detailed later in this section, baseline is defined as the last non-missing value 
(either scheduled, unscheduled or repeat) before the subject receives the first dose of study drug 
on Day 1. As assessments on day 1 are scheduled to be undertaken prior to taking study drug, day 
1 assessments can be defined as baseline. 
eGFR baseline will be calculated as the lowest measurement available prior to dosing. 
Urine creatinine baseline will be calculated as the mean of the latest 2 pre-randomization values. 
Should only 1 value be available it will be used as the baseline value. 
Urine protein baseline will be calculated as the mean of the latest 2 pre-randomization values. 
Should only 1 value be available it will be used as the baseline value. 
UPCR values are calculated by the laboratory as the ratio of urine protein to creatinine. The ratio 
is only calculated where laboratory tests produce a result for both the creatinine and the protein. 
UPCR baseline will be calculated as the mean of the latest 2 pre-randomization values. Should 
only 1 value be available it will be used as the baseline value. 
For the endpoints of change from baseline in UPCR and also for partial response endpoints (that 
incorporate a 50% reduction from baseline in UPCR), a second definition of baseline (alternative 
baseline) UPCR will be defined as the lowest measurement available prior to dosing. 


 
 
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6.2.3 
Early Terminations Assessments 
Data collected at Early Termination (ET) assessments will be mapped to the visits closest to the 
date of termination. 
6.2.4 
Duration/Study Day/Time  
Study day will be calculated as the number of days from first dose of study drug (Day 1).  
• Date of event – date of first dose of study drug + 1, for events on or after first dose  
• Date of event – date of first dose of study drug, for events before first dose  
• To this end, Day 0 remains undefined. 
For all time to event analyses, subjects not reporting the specified endpoint will be censored at the 
time that the subjects were last known not to have experienced the endpoint. For all endpoints not 
encompassing death, all deaths will be treated as censoring events. In complex cases where the 
censoring time of the subject is uncertain, the case will be reviewed by the 
 statistician and a 
censoring time will be assigned and programmed prior to database lock. 
6.2.5 
Conventions for Missing and Partial Dates 
All rules explained below for partial/missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
6.2.6 
Missing/Partial Start/Stop Date of AEs and Concomitant Medications  
Missing and partial start and stop date will be imputed for analysis purposes as follows 
Partial or missing stop date will be imputed as follows: 
• If the stop date is completely missing and the event has resolved or the subject has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the subject’s 
last clinic visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year. 


 
 
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• If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the subject’s last clinic visit in which 
case the date of subject’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
• If the stop date occurs before the start of study drug, the start date of the event/concomitant 
medication will be imputed as the subject’s screening date or the stop date of the 
event/concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• If the stop date occurs before the start of study drug, the start date of the event/concomitant 
medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month and 
year unless this partial start date is in same month as the first dose of study drug in which 
case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
6.2.7 
Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then the date of last dose of study drug 
will be taken for analysis purposes as the date when the subject would have run out of study drug 
assuming full compliance from the date the study drug was last dispensed or the date of subject’s 
last clinic visit in the study or early withdrawal or death whichever is earlier. 


 
 
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If only the month and year of the last dose was recorded, then the date of last dosing will be taken 
for analysis purposes as the date the subject would have run out of study drug assuming full 
compliance from the date the study drug was last dispensed, the last day of the month of the 
recorded last dose or the date of subject’s last clinic visit in the study or early withdrawal or death 
whichever the earlier. 
6.2.8 
Missing Diagnosis Dates  
If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year.  
6.2.9 
Exposure to Study Drug  
Exposure to study drug will be calculated from the date of last dosing minus the first day of dosing 
+ 1 for each prescribing record. Exposure will be summarized as the number of days on medication 
and mean daily dose. Mean daily dose will take into account periods where zero dose was 
prescribed.  
6.2.10 Electrocardiogram Data 
For ECG data recorded on continuous scales, if more than one value is recorded at a time point, 
the mean value rounded to the integer will be presented. For overall interpretation if more than one 
value is recorded, the most severe (worst case) of the respective readings will be taken. 
6.2.11 Unscheduled Visits 
All visits whether scheduled or unscheduled will be mapped to the closest scheduled protocol visit 
according to the protocol schedule of assessments. However, visits, when sorted by visit number 
and visit date, must remain in chronological order. In summary tables by visit, a subject’s latest 
observation per visit will be tabulated. For assessments of continuous periods of remission, all 
available observations will be used. 
All assessments will be listed in the relevant appendices to the CSR.  
6.2.12 Randomization Strata 
The randomization will be stratified by biopsy class (Class V only versus Others) and by prior 
MMF use at time of screening. A regional blocking factor will also be used for supply purposes 
ensuring balance within region. The stratification factors and the regional blocking factor will be 
used as covariates in the primary analyses. 


 
 
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6.2.13 eGFR 
For the purposes of all eGFR summary tables and endpoints incorporating eGFR measures, an 
eGFR ceiling will be set at 90 mL/min/1.73m2. In doing so, all values greater than 90 will be 
constrained to 90, thereby removing the reductions from renal hyperfiltration to normal renal 
function. These eGFR values will be labelled as ‘Corrected eGFR’. Original, raw- eGFR measures 
will be displayed in listings. In addition, eGFR change from baseline tables will be produced using 
raw-eGFR values. 
6.2.14 FMV and 24-Hour Urine 
UPCR values will be determined using FMV urinalysis samples. In the event that the Investigator 
determines that the Screening, Week 24 or Week 52 FMV urinalysis sample was invalid, the UPCR 
values from the 24-hour urinalysis at the corresponding visit will be used instead of the FMV 
urinalysis in the calculation of efficacy endpoints. FMV analysis results will still be used for all 
other timepoints.  
6.2.15 Adverse events 
An AE with missing intensity of AE will be coded “Severe” which is the worst case. An AE with 
a missing relationship to Study Drug will be coded as “related”. An AE with missing relationship 
to disease under Study will be coded as “related” to the disease unless the AE is recorded as 
being related to treatment. 
6.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.3 or higher [1]. 
Summaries will be presented by treatment group or overall. Treatment group labels will be 
displayed as follows: 
Placebo 
Voclosporin 
Overall 
 
Overall columns are to be included within the table shells as follows: 
Demography 
Treatment and overall 
Baseline 
Treatment and overall 
Disposition 
Treatment and overall 
Efficacy 
Treatment 
TEAEs 
Treatment 
Other safety 
Treatment 
 


 
 
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Tables of events or medications will be ordered in descending frequency of subjects followed by 
(where applicable) events for the higher level term (system organ class or ATC levels 4 and 2) 
followed by the preferred term. Ordering will be for the VCS treatment group first followed by the 
placebo group and alphabetical thereafter. 
Listings will be sorted in the following order treatment group, subject, parameter, and visit unless 
otherwise stated. All data will be listed, subjects who were not randomized will be displayed after 
the randomized treatment groups.  
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum. For all tabulations of changes from 
baseline data, the lower and upper 95% confidence limits for the mean for the individual treatments 
will be given.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations out of the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
6.3.1 
Decimal Places 
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g., standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place.  
P-Values will be quoted to 3 decimal places. P-values < 0.001 will be presented as p<0.001.  
6.4 Subject Disposition 
Subject disposition will be summarized as follows:  
• The number of subjects who entered the study, were randomized and who are in each 
analysis population will be summarized by treatment group and overall for the ITT 
population. This summary will be repeated for individual levels of the stratification and 
blocking variables. The reasons for exclusion from the Per-Protocol population will be 
summarized by treatment group and overall.  


 
 
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• The number of subjects who failed screening and the reasons for failure will be tabulated 
for all subjects. The number of subjects that were screened once, twice, 3 times, and total 
number of screened subjects will also be summarized. 
• The number of early withdrawals and the reasons for withdrawals will be tabulated by 
treatment group and overall for the ITT population. 
• The number of subjects that discontinue study drug will be presented by treatment group 
and visit for the ITT population. 
• The number of subjects who complete Week 24, and those who complete Week 52 will be 
summarized for the ITT population. 
• A summary of study drug discontinuation will be provided by visit for the ITT population. 
6.5 Protocol Deviations 
Major protocol deviations will be grouped into categories and summarized by treatment group and 
overall for the Safety and ITT populations. A listing of protocol deviations will be provided.  
6.6 Baseline Comparability 
The comparability of treatment groups with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed. 
Standard continuous or categorical variable summaries will be presented for the following 
variables based on the SS. Demography and disease history will also be summarized for the ITT 
and safety populations. 
• Demographic data (summarized additionally by country and region for the Safety 
population) 
• Disease history (including eGFR and UPCR measures) 
• Medical/Surgical/ Systemic Lupus Erythematosus /Renal history 
• Physical examination by body system at screening. 




 
 
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• Neurological 
• Musculoskeletal 
• Cardiorespiratory 
• Vasculitis 
• Hematology 
• Antiphospholipid Syndrome 
• Any other current SLE involvement to record (If ‘Yes’ it will be recorded) 
 
For each of these categories, the following items will be summarized: Ever Involved (Yes/No), 
Currently Involved (Yes/No), years since onset. 
 
The summary of the history of SLE related conditions will include the following categories: 
• Diabetes Mellitus 
• Hypertension 
• Myocardial Infarction 
• Stroke 
• Deep Vein Thrombosis 
• Hyperlipidemia 
For each of these categories, both ever diagnosed and SLE related will be summarized. 
Details of specific conditions falling into these categories will also appear in the General Medical 
History summary and treatments in the prior and/or concomitant medication summaries. 
The number of years prior to baseline since diagnosis of the first occurrence of SLE will be 
summarized. For Renal History, the number of years prior to baseline since the 1st instance of a 
significant proteinuria (>500 mg/day), and the number of years prior to baseline since the first 
diagnosis of LN will be summarized as a continuous variable. Any previous dialysis (Yes/No), 


 
 
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and the number of years prior to baseline since the last dialysis will also be summarized. ‘Years 
since…’ variables will be calculated as year of informed consent – year of event + 1. 
All data will be listed and a glossary of unique verbatim terms with coding information will be 
provided. 
6.8 Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by 
treatment group and overall for the Safety population. Prior medications are defined as all 
medications starting and stopping before the date of first dose of study drug. Concomitant 
medications are defined as medications taken on or after the date of first dose of study drug. 
Medications will be summarized using ATC Level 2, 4, and preferred term. 
The following previous LN therapies will also be summarized: MMF, IVC, Corticosteroids, 
Methotrexate, CNI, Biologic, Azathioprine, Antimalarial, other. The responses for these LN 
therapies are Yes or No. 
All medications will be listed and a glossary of unique verbatim terms with coding information 
will be provided. 
6.9 Exposure to Study Drugs 
Overall exposure to study drugs (number of days of exposure to study drugs and mean dose) will 
be presented for both the Safety and ITT populations. Exposure will be based on prescribed dose. 
Exposure will not be summarized by visit but for the overall study duration. Overall study drug 
exposure will be calculated from the first dose date to the last dose date plus 1 for each prescribing 
record. Care should be taken to not double-count days. It is expected that prescription records will 
cover each study day between randomization and the end of study (or early termination). Periods 
of zero dose will be assigned as such.  
 
The following gives an example of a subject with 4 prescription records over the 52-week (365 
day) period. 
 
Table 6.1 
Exposure calculation example 
Start Day 
End Day 
Dose (bid) 
Duration 
1 
180 
3 
180 days 
181 
200 
0 
20 days 
201 
230 
2 
30 days 
231 
365 
3 
135 days 


 
 
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For the purposes of analysis this subject will have ‘days on treatment’ calculated as 180+30+135 
= 345 days. Their mean daily dose will be: 
 
(180*3 + 20*0 + 30*2 + 135*3) / 365 = 2.75 caps BID (converted to 43.45 mg per day). 
 
Gaps between dosing records will be counted as a zero dose. For IV methylprednisolone, gaps 
between doses will not be taken into consideration. 
 
For subjects who are lost to follow-up, and for whom the last dose date from the termination record 
is unknown, the date of the last available visit will be used as the last dose date. 
 
Exposure to study drug will be summarized for the following: 
 
• VCS/placebo 
• MMF 
• IV methylprednisolone 
• Corticosteroids 
 
Prescribed dose changes (Yes/No) at visit intervals and overall will be summarized for 
VCS/Placebo and for MMF.  
6.10 Treatment Compliance 
All unused study treatments (and any empty containers) dispensed to the subject will be returned 
at each study visit for capsule counts to check compliance. The Investigator will count the returned 
study treatment and this information will be used to assess subject compliance. Each subject is 
expected to take 6 capsules a day (47.4 mg/day, 23.7 mg BID, 3 capsules BID) with each softgel 
capsule = 7.9 mg. It should be noted that compliance will not be summarized by visit but for the 
overall study period. 
Subject compliance with study drug (VCS / placebo) will be summarized by treatment group. 
Counts of the returned study treatment will be used to assess subject compliance. The study 
treatment count will be documented in the eCRF and source documentation.  


 
 
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Subject compliance will be calculated as:  
Compliance (%) = 
number of dispensed capsules – number of returned or lost capsules 
number of prescribed capsules
 x 100 
 The number of prescribed doses will be calculated as per the exposure calculation.  
Compliance with the protocolled steroid taper will also be assessed and summarized. Subjects will 
be assessed as being either compliant or non-compliant. 
6.11  Efficacy Analyses 
All statistical tests will be performed using a two-tailed 5% overall significance level, unless 
otherwise stated. All comparisons between treatments will be reported with 95% confidence 
intervals for the odds ratio, hazard ratio or difference as applicable.  
6.11.1 Primary Endpoint 
The primary endpoint is the number of subjects showing renal response at 52 weeks. Renal 
response at Week 52 will be adjudicated by the CEC based on the following parameters: 
• UPCR of ≤0.5 mg/mg, and 
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, and 
• Received no rescue medication for LN, and 
• Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total 
during Weeks 44 through 52, just prior to the renal response assessment  
The CEC will be blind to treatment group and completely independent of Aurinia. They will also 
take into consideration the following: 
• Subjects who withdraw from the study prior to the Week 52 assessment and thus provide 
insufficient Week 52 data will be defined as non-responders 
• Medication listings will be reviewed by the CEC as part of the adjudication process. The 
CEC will have complete autonomy to adjudicate any treatment as rescue medication. 
However, as any dose of MMF is permitted within this protocol there is no MMF dose 
level that necessarily classifies it as being rescue medication. As part of this review the 
CEC will also adjudicate on steroid drug use beyond the protocolled taper. 


 
 
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• 
eGFR values eliminating a subject from complete remission should be accompanied by a 
treatment or disease-related TEAE that impacts eGFR. To this end, eGFR measures which 
would ordinarily result in a subject not being in remission will only be used if the first eGFR 
assessment occurs on a date where there is also a treatment or disease-related, eGFR associated 
TEAE. The following is a list of MedDRA preferred terms that are associated with eGFR 
decreases: 
o BLOOD CREATININE INCREASED 
o CREATININE RENAL CLEARANCE DECREASED  
o GLOMERULAR FILTRATION RATE DECREASED 
o SERUM CREATININE INCREASED  
o RENAL IMPAIRMENT  
o RENAL FAILURE  
o RENAL FAILURE ACUTE 
• 
Confirmation of eGFR decreases from baseline require that two consecutive measures at least 
3 days apart exhibit the decrease. 
The null hypothesis H0 will be rejected in favor of H1 if there is evidence at the 5% significance 
level using a 2-sided test.  
H0:  
There is no statistically significant difference in renal response between voclosporin 
and placebo at Week 52 
H1:  
There is a statistically significant difference in renal response between voclosporin 
and placebo at Week 52.  
6.11.2 Primary Efficacy Analysis 
6.11.2.1 Renal response at Week 52 
Renal response at Week 52 will be adjudicated by the Clinical Endpoints Committee (CEC) and 
as such the analysis will incorporate the CEC’s assessments of each subject. In order to perform 
their adjudication, the CEC will be provided UPCR data, eGFR data, steroid taper data, rescue and 
prohibited medication data and adverse event data. Full details of the adjudication process are 
detailed in a separate CEC Charter. 
The primary efficacy analysis will be conducted on the ITT population using a logistic regression 
model with terms for treatment, baseline UPCR, biopsy class, MMF use at baseline and region, 
and renal response (Yes/No) at week 52 as the response variable (Table 14.2.1.1.2).  


 
 
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The results will be expressed as an odds ratio (and associated two sided- 95% CI) for voclosporin 
compared to placebo. Odds ratios greater than unity will mean the odds of response are greater for 
voclosporin than for placebo and therefore indicate a benefit of the voclosporin treatment arm. The 
p-value of the treatment effect will also be reported. 
The following SAS program will be used for the primary efficacy analysis: 
Proc Logistic data = data; 
Class Treatment_arm MMF_Use Biopsy_Class Region; 
Model Response = Treatment_arm MMF_Use Biopsy_Class Baseline_UPCR Region; 
Run; 
 
The number of responders and non-responders at Week 52 will be summarized by treatment arm 
and a listing of renal responders and non-responders will also be provided.  
6.11.2.2 Sensitivity Analyses of the Primary Endpoint 
The primary endpoint of adjudicated renal response at Week 52 in the ITT population will be 
analyzed using two different logistic regression models. The first sensitivity analysis will include 
only a term for treatment while the second sensitivity analysis will include terms for treatment, 
baseline UPCR, biopsy class and MMF use at baseline (i.e., omitting the regional covariate). 
Results will be reported in Table 14.2.1.2. The Odds ratios, 95% confidence intervals and p-values 
for voclosporin compared to placebo will be reported. 
• The primary endpoint will also be analyzed, using the same ITT population, controlling in 
turn for each the following factors:  
o age (≤30 versus >30),  
o gender,  
o race (White, Asian, Other),  
o biopsy class,  
o region (defined at the continental level and, where numbers allow, country level),  
o MMF use at screening,  
o Maximum MMF Dose (≤2g versus >2g).  


 
 
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• An interaction between the factor and treatment group will be added to the model. A p-
value for the main effect of the covariate in question along with the p-value for the 
interaction between treatment and covariate will be reported (Tables 14.2.1.7.1-7). 
These sensitivity analyses will be performed on the same endpoint in the same population as set 
out in the primary analysis section; the only difference being the logistic models.  
6.11.2.3 Supplementary Analyses based on the Primary Endpoint 
A number of supplementary analyses based around the primary endpoint will be undertaken. 
Different aspects of the endpoint, be they the calculation method, different data assumptions or 
different populations will be varied to assess the impact of each. 
• Renal response at Week 52 will be derived programmatically and analyzed in an identical 
fashion to the primary analysis (Table 14.2.1.1.2). Using the same definition as given to 
the CEC and as set out in the primary endpoint section, renal response at week 52 will be 
derived programmatically. All components of the primary response endpoint will be 
independently programmed apart from the use of rescue medication. The CEC adjudication 
on the use of rescue medication will be incorporated into the programmed endpoint. 
• The analysis described in Section 6.11.2 will be repeated for the PPS (Table 14.2.1.3). 
• The analysis described in Section 6.11.2 will be repeated for each biopsy class category 
(Class III, Class III/V, Class IV, Class IV/V, Class V and Class VI). The combining of 
classes may be necessary should subject numbers in any individual class be deemed 
insufficient. A separate category defined as “All but Pure Class V” will be defined 
(Table 14.2.1.4). 
• For both the adjudicated week 52 renal response (primary endpoint) and the programmed 
week 52 renal response (supplementary endpoint), each individual component (and some 
component groups) of the endpoint will be summarized by treatment group and analyzed 
in the same manner using a logistic regression. Analysis will be undertaken where possible, 
however, it is recognized that individual components may include very low numbers of 
subjects (either responders or non-responders). “eGFR success” is defined as an eGFR 
measure of ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20% 
or no disease-related or treatment-related AE impacting eGFR. Where data allows, the 
numbers of subjects achieving each of the following will be summarized (Table 14.2.1.5.1 
(adjudicated) and Table 14.2.1.5.2 (programmed)): 
• 
UPCR ≤0.5 mg/mg  


 
 
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• 
eGFR success 
• 
UPCR ≤0.5 mg/mg and eGFR success 
• 
Received no rescue medication for LN 
• 
No withdrawal prior to remission assessment  
• 
Did not receive more than 10 mg prednisone equivalent for ≥3 consecutive days or 
for ≥7 days in total during Weeks 44 through 52, just prior to the renal response 
assessment  
• “eGFR success” will also be summarized by individual components: 
• 
eGFR ≥60 
• 
eGFR <60 with no confirmed decrease >20% 
• 
eGFR <60 with confirmed decrease >20% but with no disease-related or treatment-
related eGFR associated AE present at time of assessment. 
Confirmed decrease >20% in eGFR is two consecutive measurements, three or more days 
apart by the visit where response is defined. 
 
 


 
 
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6.11.2.4 Tipping point analysis for primary endpoint (CEC adjudicated Renal Response) 
The impact of withdrawals on the primary endpoint will be investigated in a tipping point analysis 
where subjects whose response assessment was assumed due to missing data (missing data always 
results in a non-response assessment) will have their assessment re-assigned in a series of analyses 
that are progressively more in favor of placebo. Assuming that the primary analysis is significantly 
in favor of voclosporin, at some point, the series of analyses in the tipping point analysis is likely 
to show a lack of significance. It is of interest to assess how extreme the assumptions have to be 
around the subjects with missing data before primary significance is lost.  
The tipping point analysis will consider the full range of possible response rates in the subjects 
with missing data in the primary analysis. This will be done by systematically changing assumed 
response rates from 0% to 100% in a stepwise manner. The imputation will be performed 
independently within the two treatment groups so that, in the most extreme case, the imputed 
response rate in the voclosporin arm will be 0% and 100% in the Placebo arm.  
Multiple imputation will be used for each pair of response rates under consideration. Both the 
imputation model and the analysis model will incorporate the covariates as used in the primary 
analysis: Treatment arm, MMF use at screening, Biopsy Class, Baseline UPCR and Region. The 
combined results for each pair of response rates will be displayed graphically with the vertical axis 
being 
imputed 
placebo 
response 
(0 
to 
100%) 
and 
the horizontal axis 
being 
imputed voclosporin response (0 to 100%). Such a graph will be a comprehensive map of p-values 
using all plausible assumptions about missing outcomes and will provide a contour between 
significance and non-significance. 
 
 
 


 
 
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The following algorithm will be used for the imputation; 
Step 1: Use efficacy data to identify subjects classed as non-responders due to missing data. 
Step 2: 441 pairs of response rates for voclosporin and placebo in the table below will be used for 
the imputation.  
 
 
 
Placebo Response Rate (Y) 
1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
.95 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
.9 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
60 
61 
62 
63 
.85 
64 
65 
66 
67 
68 
69 
70 
71 
72 
73 
74 
75 
76 
77 
78 
79 
80 
81 
82 
83 
84 
.8 
85 
86 
87 
88 
89 
90 
91 
92 
93 
94 
95 
96 
97 
98 
99 
100 
101 
102 
103 
104 
105 
.75 
106 
107 
108 
109 
110 
111 
112 
113 
114 
115 
116 
117 
118 
119 
120 
121 
122 
123 
124 
125 
126 
.7 
127 
128 
129 
130 
131 
132 
133 
134 
135 
136 
137 
138 
139 
140 
141 
142 
143 
144 
145 
146 
147 
.65 
148 
149 
150 
151 
152 
153 
154 
155 
156 
157 
158 
159 
160 
161 
162 
163 
164 
165 
166 
167 
168 
.6 
169 
170 
171 
172 
173 
174 
175 
176 
177 
178 
179 
180 
181 
182 
183 
184 
185 
186 
187 
188 
189 
.55 
190 
191 
192 
193 
194 
195 
196 
197 
198 
199 
200 
201 
202 
203 
204 
205 
206 
207 
208 
209 
210 
.5 
211 
212 
213 
214 
215 
216 
217 
218 
219 
220 
221 
222 
223 
224 
225 
226 
227 
228 
229 
230 
231 
.45 
232 
233 
234 
235 
236 
237 
238 
239 
240 
241 
242 
243 
244 
245 
246 
247 
248 
249 
250 
251 
252 
.4 
253 
254 
255 
256 
257 
258 
259 
260 
261 
262 
263 
264 
265 
266 
267 
268 
269 
270 
271 
272 
273 
.35 
274 
275 
276 
277 
278 
279 
280 
281 
282 
283 
284 
285 
286 
287 
288 
289 
290 
291 
292 
293 
294 
.3 
295 
296 
297 
298 
299 
300 
301 
302 
303 
304 
305 
306 
307 
308 
309 
310 
311 
312 
313 
314 
315 
.25 
316 
317 
318 
319 
320 
321 
322 
323 
324 
325 
326 
327 
328 
329 
330 
331 
332 
333 
334 
335 
336 
.2 
337 
338 
339 
340 
341 
342 
343 
344 
345 
346 
347 
348 
349 
350 
351 
352 
353 
354 
355 
356 
357 
.15 
358 
359 
360 
361 
362 
363 
364 
365 
366 
367 
368 
369 
370 
371 
372 
373 
374 
375 
376 
377 
378 
.1 
379 
380 
381 
382 
383 
384 
385 
386 
387 
388 
389 
390 
391 
392 
393 
394 
395 
396 
397 
398 
399 
.05 
400 
401 
402 
403 
404 
405 
406 
407 
408 
409 
410 
411 
412 
413 
414 
415 
416 
417 
418 
419 
420 
0 
421 
422 
423 
424 
425 
426 
427 
428 
429 
430 
431 
432 
433 
434 
435 
436 
437 
438 
439 
440 
441 
 
 
0 
.05 
.1 
.15 
.2 
.25 
.3 
.35 
.4 
.45 
.5 
.55 
.6 
.65 
.7 
.75 
.8 
.85 
.9 
.95 
1 
 
 
Voclosporin Response Rate (X) 
 
For each of the 441 pairs of response rates in the table above, (e.g., for pair number 255, response 
rate for voclosporin = 0.1, while response rate for placebo = 0.4.): 
• For each subject identified in Step 1, generate a continuous response score between 0 (non-
response) and 1 (response) using SAS proc mi adjusting for the covariates of treatment 
group, biopsy, MMF use at screening, baseline UPCR and region. Example SAS code is 
given below. 
• Assign the imputed response (1 = response, 0 = non-response) based on the response score 
and the current tipping point. Using the example values above:  
o Given a voclosporin tipping point response rate of 0.1, subjects in the voclosporin 
group with a response score ≥0.9 would be imputed as responders and non-
responders otherwise.  
o Given a placebo tipping point response rate of 0.4, subjects in the voclosporin group 
with a response score ≥0.6 would be imputed as responders and non-responders 
otherwise.  


 
 
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Example SAS code for the generation of a response score on the continuous scale (between 0 and 
1): 
proc mi data=impute01 out=impute20 nimpute=50 seed=3435 minimum=0 maximum=1;  
class TREATMENT BIOPSY MMF REGION;  
fcs nbiter=10 reg(RESPONSE = TREATMENT BIOPSY MMF UPCR REGION);  
var RESPONSE TREATMENT BIOPSY MMF UPCR REGION;  
run;  
 
For example, consider the case where 7 subjects (4 voclosporin, 3 placebo) in the data are 
considered non-responders due to missing data. Using the response rate number 299 (voclosporin 
= .2, placebo = .3) 
Subject 
Treatment 
 Continuous Response 
Score 
Response 
Rate 
Imputed 
Response 
1 
VCS 
0.728119 
.2 
0 
2 
VCS 
0.876749 
.2 
1 
3 
VCS 
0.345234 
.2 
0 
4 
VCS 
0.784817 
.2 
0 
5 
Placebo 
0.923842 
.3 
1 
6 
Placebo 
0.546724 
.3 
0 
7 
Placebo 
0.734184 
.3 
1 
 
Replace the response observed for the subjects in Step 1 (which, by definition, will be non-
response) with their imputed data. 
Step 3: Run the analysis of the primary endpoint (including stratification covariates) using the data 
in step 2. Repeat the imputation (step 2) and analyze 50 times to generate 50 individual odds ratios. 
Step 4: Use Proc Mianalyze in SAS to pool the 50 odds ratios and output a common p-value. 
Repeat Step 1 to 4 for all 441 pairs of response rates. 
 
6.11.3 Key Secondary Endpoints 
All the secondary efficacy analyses will be performed on the ITT population. The following key 
secondary endpoints will be analyzed. For all time to event analysis, estimates and 95% confidence 


 
 
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intervals of the 25th, 50th and 75th quantiles will be reported. The hazard ratio, 95% confidence 
interval, and p-value of voclosporin versus placebo will be reported. A Kaplan-Meier plot with 
both treatment arms will also be provided. 
6.11.3.1 Time (weeks) to UPCR of ≤0.5 mg/mg  
Time to UPCR of ≤0.5 mg/mg will be analyzed by comparing the survivor function between 
treatment arms. It will be estimated using Kaplan-Meier methodology and will be presented as a 
plot showing a line for each treatment group as well as the numbers remaining at risk for each 
treatment group at different time points. Median time to UPCR of ≤0.5 mg/mg along with 
two-sided confidence intervals will be displayed. Time to event will be measured as the number 
of weeks from day of randomization to the day of the event. Subjects who do not experience an 
event will be censored on the day of their last assessment of UPCR. 
A Cox’s proportional hazards model will be fitted to assess the significance of the differences 
between treatment arms. The model will include terms for treatment arm, baseline UPCR, biopsy 
class, MMF use at baseline and region. Estimates of the treatment effects will be expressed as 
hazard ratios (and associated 95% CI) for voclosporin relative to placebo. Hazard ratios greater 
than unity will indicate the hazard to be greater for voclosporin than for placebo and therefore 
indicate that the events in question generally occur earlier on active voclosporin and, for this 
endpoint, a benefit of voclosporin (Table 14.2.2). The log-log survivor function to proportional 
hazards will be assessed. A listing of time (weeks) to UPCR of ≤0.5 mg/mg responders and censors 
will be provided. 
6.11.3.2 Partial renal response as defined by 50% reduction from baseline UPCR at Weeks 
24 and 52 
Change from baseline in UPCR will be calculated as the post baseline measurement minus the 
baseline measurement. Percent change from baseline will be calculated as: 
• Percent change from baseline (UPCR_pc) = ቀ
𝐶𝐶ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵
ቁx 100 
A 50% reduction in UPCR will be indicated by UPCR_pc ≤ -50. Subjects with missing UPCR_pc 
values will be considered non-responders. This endpoint will be analyzed and presented similarly 
to the primary efficacy endpoint as described in Section 6.11.2 (Table 14.2.3). A listing of subjects 
considered responders will be provided. 
A supplementary analysis of partial response at both Week 24 and Week 52 will be undertaken 
using the alternative baseline definition (Section 6.2.2) of the lowest UPCR value pre-dosing. 


 
 
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6.11.3.3 Time to 50% reduction in UPCR from baseline 
Time to 50% reduction in UPCR will be analyzed similarly to the end point described in Section 
6.11.3.1. The definition and calculation of 50% reduction in UPCR is consistent with that 
described in Section 6.11.3.2 (Table 14.2.4). A listing of time (weeks) to a 50% reduction in UPCR, 
and censors will be provided.  
A supplementary analysis of time to 50% reduction in UPCR will be undertaken using the 
alternative baseline definition (Section 6.2.2) of the lowest UPCR value pre-dosing. 
6.11.3.4 Renal response at Week 24  
• Renal response at Week 24 will be adjudicated by the CEC and also programmatically 
derived using similar definitions to those used to derive response at week 52. Steroid dosing 
will be assessed between weeks 16 and 24 and only rescue medication taken prior to the 
week 24 assessment will disqualify a subject from response. 
• Renal response at week 24 (adjudicated and programmed) will be analyzed in a similar 
manner to that described in Section 6.11.2 (Table 14.2.5.1 and 14.2.5.2).  
A listing of subjects with renal response at Week 24 will be provided. 
6.11.4 Other Secondary Endpoints 
The other Secondary endpoint analyses will be performed on the ITT population. 
Change from baseline endpoints 
Change from baseline in UPCR endpoints will be analyzed using a Mixed Effect Model Repeated 
Measures analysis with treatment arm, visit, treatment by visit interaction, biopsy class, MMF use 
at baseline, region and baseline UPCR included as a covariates in the model. Results will be 
expressed as differences between treatment arms (along with the associated 95% CI). The observed 
and change from baseline values will be summarized by treatment visit and treatment arms. The 
LS means and their corresponding 95% CI of the change from baseline values will also be 
presented for each visit and for the overall change. The model will be fitted using an unstructured 
(UN) covariance matrix. Should the UN covariance matrix not converge, then an autoregressive 
(AR(1)) covariance matrix will be used. The covariance matrix used will be indicated in the 
footnotes. The Kenward-Roger degree of freedom adjustment will be applied. LS mean plots of 
mean change from baseline versus visit will be presented for UPCR and eGFR. 


 
 
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The SAS code anticipated to be used for analysis of the change from baseline endpoints is as 
follows: 
Proc Mixed data=dataset; 
Class Treatment biopsy_class MMF_use Region visit subject; 
Model response = Treatment biopsy_class MMF_use Region visit visit*treatment baseline/ DDFM=KR 
Repeated Visit/subject =subject Type= UN R Corr; 
LSmeans visit*treatment/PDIFF CL E; 
Run; 
6.11.4.1 Duration of UPCR ≤0.5 mg/mg 
Duration of UPCR ≤0.5 mg/mg refers to the time (weeks) from the onset of the first UPCR 
≤0.5 mg/mg to the subsequent, second occurrence of UPCR >0.5 mg/mg (i.e., allowing a single 
spike in UPCR). An event occurs at the time of the subsequent, second UPCR >0.5 mg/mg. 
Subjects who do not experience a subsequent, second UPCR >0.5 mg/mg will be censored at the 
date of the last UPCR assessment. Only subjects who achieved an initial response (UPCR 
≤0.5 mg/mg) will be included in the analysis of this endpoint. Duration of UPCR ≤0.5 mg/mg will 
be analyzed in a similar manner to that described in Section 6.11.3.1 (Table 14.2.6). 
An additional summary of this endpoint will be undertaken by summing the weeks between each 
UPCR measure ≤0.5 mg/mg and a subsequent measure >0.5 mg/mg. This will give an 
approximation of time spent with UPCR ≤0.5 mg/mg for each subject. This will be summarized 
and analyzed as a continuous endpoint and comparison between both treatment arms will be 
carried out using a 2 sample Wilcoxon test. 
6.11.4.2 Proportion of subjects experiencing a confirmed >30% decrease from baseline in 
eGFR at each timepoint.  
Percent eGFR change for a subject at a given visit will be calculated as: 
• 
 change from baseline
Baseline
𝑥𝑥 100 
At any two consecutive time points, a subject that achieves a clinically significant >30% decrease 
in eGFR from baseline will be considered a confirmed eGFR drop subject at the earlier timepoint, 
otherwise they will be considered a non-eGFR drop subject. The proportion of subjects with a 
confirmed eGFR drop at each visit will be compared using the Chi Square or Fisher exact test if 
applicable. The proportion of eGFR drop subjects will be summarized at weeks 2, 4, 8, 12, 16, 20, 
24, 30, 36, 42, 48 and 52 by treatment group. P-values of the differences at each visit will be 
reported (Table 14.2.7). 


 
 
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6.11.4.3 Change from baseline in UPCR at each time point 
The response variable for the MMRM model will be the change from baseline in serum creatinine. 
Change from baseline in UPCR will be summarized at weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48 
and 52 (Table 14.2.8.1). Listings of this endpoint will be provided with lab data. Baseline is 
calculated as defined in Section 6.2.2. 
A supplementary analysis of change from baseline in UPCR will be undertaken using the 
alternative baseline definition (section 6.2.2) of the lowest UPCR value pre-dosing. 
6.11.4.4 Change from baseline in serum creatinine 
Serum creatinine data will be available in lab data. The response variable, change from baseline in 
serum creatinine, will be summarized at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48 and 52 
(Table 14.2.9). Listings of this endpoint will be provided with lab data. Baseline is calculated as 
defined in Section 6.2.2 
6.11.4.5 Change from baseline in urine protein 
Urine protein will also be collected from lab data. The response variable, change from baseline in 
urine protein will be summarized at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48 and 52 (Table 
14.2.10). Listings of this endpoint will be provided with lab data. Baseline is calculated as defined 
in Section 6.2.2. 
6.11.4.6 Change from baseline in eGFR 
Estimated glomerular filtration rate (eGFR) will be measured at all visits except Visit 2. The 
response variable change from baseline in eGFR will be summarized at Weeks 2, 4, 8, 12, 16, 20, 
24, 30, 36, 42, 48 and 52 (Table 14.2.11.1). Baseline is calculated as defined in Section 6.2.2. 
These change from baseline tables will be produced using both corrected and raw eGFR values. 
Listings of this endpoint will be provided with lab data. 
6.11.4.7 Change from baseline in immunology parameters (C3, C4, and dsDNA) at Weeks 
24 and 52 
Each of the Lupus Markers: Complement 3, (C3), Complement 4 (C4), and dsDNA will be 
analyzed separately at weeks 24 and 52. C3, C4, and dsDNA is measured at screening, Week 24, 
and Week 52 (Table 14.2.12). Listings of this endpoint will be provided with lab data. 


 
 
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6.11.4.8 Renal response with low-dose steroids at weeks 24 and 52  
Renal response with low-dose steroids is defined as renal response in the presence of 
corticosteroids of ≤2.5 mg/day between Weeks 16 to 24 (for Week 24 endpoint) and Weeks 44 to 
52 (for Week 52 endpoint). This endpoint will be analyzed in a similar manner as that described 
in Section 6.11.2 (Table 14.2.13). 
6.11.4.9 Change from baseline in HRQoL at Weeks 12, 24, and 52 
SF-36 and LupusPRO HRQoL will be answered by the subject at Baseline, Week 12, 24 and 52. 
Listings of observed and change from baseline HRQoL scores will be presented. A baseline 
HRQoL value is defined as the last HRQoL value prior to the first dose on Day 1. HRQoL total 
scores will be analyzed as a change from baseline endpoints described above for the ITT 
population. 
6.11.4.9.1 Change from baseline in Short Form Health Survey (SF-36) 
The SF-36 HRQoL assessment is a 36-question subject HRQoL questionnaire.The SF-36 
responses will be weighted as indicated in Table 6.2. 
Table 6.2 
SF-36 responses and weighting 
Item number 
Original Response 
Weight 
1, 2, 20, 22, 34, 36 
1 → 
100 
 
2 → 
75 
 
3 → 
50 
 
4 → 
25 
 
5 → 
0 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
1 → 
0 
 
2 → 
50 
 
3 → 
100 
13, 14, 15, 16, 17, 18, 19 
1 → 
0 
 
2 → 
100 
21, 23, 26, 27, 30 
1 → 
100 
 
2 → 
80 
 
3 → 
60 
 
4 → 
40 


 
 
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Item number 
Original Response 
Weight 
 
5 → 
20 
 
6 → 
0 
24, 25, 28, 29, 31 
1 → 
0 
 
2 → 
20 
 
3 → 
40 
 
4 → 
60 
 
5 → 
80 
 
6 → 
100 
32, 33, 35 
1 → 
0 
 
2 → 
25 
 
3 → 
50 
 
4 → 
 75 
 
5 → 
100 
 
These items will be further grouped into the following scales as shown in Table 6.3. 
Table 6.3 
SF-36 Scales 
Scales 
Number of items 
Mean of Items 
Physical functioning 
10 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
Role limitations due to physical health 
4 
13, 14, 15, 16 
Role limitations due to emotional problems 
3 
17, 18, 19 
Energy/fatigue 
4 
23, 27, 29, 31 
Emotional well-being  
5 
24, 25, 26, 28, 30 
Social functioning 
2 
20, 32 
Pain 
2 
21, 22 
General health 
5 
1, 33, 34, 35, 36 
Total mean score 
36 
All 36 items 
 


 
 
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Each scale will be calculated for each subject by taking the mean of its corresponding item. The 
observed and change from baseline scales values will be summarized by visit and treatment arm. 
Only the scales (Physical functioning, Role limitations due to physical health, Role limitations due 
to emotional problems, Energy/fatigue, Emotional well-being, Social functioning, Pain, General 
health, Total mean score) will be summarized (Table 14.2.14.1). An MMRM model of the change 
from baseline in total mean score will also be presented. The individual items and scales will be 
listed.  
6.11.4.9.2 Change from baseline in LupusPRO(v1.7) 
The LupusPRO (v1.7) is a 43-question subject HRQoL questionnaire specific for lupus. The 
questionnaire will be grouped into the following domains: 
Table 6.4  
LupusPRO questionnaire 
Items 
Construct 
Domain 
Reverse Coding needed? 
1-3 
HRQOL 
Lupus Symptoms  
Yes 
4-5 
HRQOL 
Cognition  
Yes 
6-7 
HRQOL 
Lupus Medications  
Yes 
8-9 
HRQOL 
Procreation  
Yes 
10-14 
HRQOL 
Physical Health  
Yes 
15-19 
HRQOL 
Pain Vitality  
Yes 
20-25 
HRQOL 
Emotional Health  
Yes 
26-30 
HRQOL 
Body Image  
Yes 
31-34 
N- HRQOL 
Desires-Goals  
Yes 
35-36 
N- HRQOL 
Social support 
No 
37-39 
N- HRQOL 
Coping 
No 
40-43 
N- HRQOL 
Satisfaction with care 
No 
 
The LupusPRO© has 5 point Likert response format, where 0= None of the time/not applicable, 
1= A little of the time, 2= Some of the time, 3=Most of the time, 4= All of the time, 5= Not 
applicable (recode as 0 for scoring). Reverse scoring for some items is required (as above). There 
are 12 observed domains. Item scores are totaled for each domain item and the mean domain score 
is obtained by dividing the total score by the number of items in that domain. The mean raw domain 
score is transformed to scores ranging from 0 (worst QOL) to 100 (best QOL) by dividing by 4 
(the number of Likert responses {5 responses} minus 1) and then multiplying by 100, as below: 
(Mean raw domain score/4) x 100= Transformed score for the domain. Transformed domain scores 
will be obtainable when at least 50% of the items are answered. Total HRQOL and N-HRQOL 
scores are obtained by averaging the transformed domain scores within each construct. Observed 
and change from baseline values will be summarized by visit and treatment (Table 14.2.15). An 


 
 
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MMRM model of the change from baseline in HRQOL and N-HRQOL score will also be presented. 
A listing of the 43 items, the domains, and the total HRQOL and total N-HRQOL will be provided. 
6.11.4.10 Change from baseline in the SELENA-SLEDAI Index score at Weeks 24 and 52 
The SELENA-SLEDAI assesses disease activity within the last 10 days. Twenty-four items are 
scored for 9 organ systems, and summed to a maximum of 105 points. A score of 6 is considered 
clinically significant. Assessments for SELENA-SLEDAI will be conducted at baseline, Week 24, 
and Week 52. A patient’s SELENA-SLEDAI total score at a given visit is the sum of the weighted 
scores of all marked SLE-related descriptors. A total score can fall between 0 and 105, with a 
higher score representing a more significant degree of disease activity. Change from baseline in 
SELENA-SLEDAI total score will be the response variable in the MMRM model (Table 14.2.16). 
The scores of the individual SELENA-SLEDAI items and the total score of each subject will be 
listed. 
6.11.4.11 
Health Resource Utilization at Weeks 24 and 52 
Information on healthcare resource utilization will be collected at time points: baseline (Day 1), 
Week 24, and Week 52, and documented in the EDC system. This information will be collected 
via interview of the subject by the study staff and entered into the EDC system. General 
information collected may include: 
• Type of insurance coverage (private, NHS, other) 
• Number of visits to ANY health care professionals (HCP), other than study doctor  
• Types of HCP visited (specialists versus primary care)  
• Time spent on visits (in minutes) 
• Diagnostic tests performed (Yes/No) 
• Time (in minutes) spent by caregivers assisting patient with HCP visits  
• Prescriptions issued (Yes/No), filled (Yes/No) 
• Community services used (Yes/No) 
Each item in the Health Resource Utilization questionnaire will be summarized for baseline 
(Day 1), Week 24, and Week 52. All the items will also be listed at subject level.  


 
 
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6.11.5 Multiplicity 
An overall type 1 (false-positive) error rate of 5% for the efficacy endpoints will be maintained so 
that no statistical significance for the key secondary efficacy endpoints will be claimed unless the 
principal analysis of the primary efficacy endpoint using the ITT population is statistically 
significant at the 5% level. The Hochberg step-up procedure [2] will be used to adjust for multiple 
comparisons amongst key secondary endpoints and maintain the overall type 1 error rate. Data 
from all analyses, regardless of the level of significance, will be presented for review. 
Figure 6.1 
Hochberg procedure 
 
 
 
 
 
 
 
 
 
 
 
6.11.5.1 First Overall Comparison -Voclosporin 23.7 mg BID versus Placebo for Primary 
Efficacy Endpoint. 
The comparison of voclosporin 23.7 mg BID versus Placebo in the primary efficacy endpoint, 
renal response at Week 52, will be tested first at a 0.05 significance level. If the p-value for this 
comparison ≥0.05, then testing will stop. Otherwise, the comparisons of voclosporin 23.7 mg BID 
versus Placebo for the Key secondary efficacy endpoints will be tested using the Hochberg 
procedure. 
Voclosporin 23.7 mg BID vs Placebo (ITT) 
Primary Efficacy endpoint tested at 0.05 
level. 
Testing will stop 
Voclosporin 23.7 mg BID vs Placebo (ITT) 
Key Secondary Efficacy endpoint tested 
using Hochberg procedure at 0.05 level. 
 
P-value ≥0.05 
P-value <0.05 


 
 
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6.11.5.2 Secondary Comparisons - Voclosporin 23.7 mg BID versus Placebo for Secondary 
Efficacy Endpoint. 
The key secondary endpoints are: 
• Time to UPCR ≤0.5 mg/mg 
• Partial renal response at Week 52 
• Partial renal response at Week 24 
• Time to 50% reduction from baseline in UPCR 
• Renal response at Week 24 (Adjudicated) 
If the testing proceeds to the comparison of voclosporin 23.7 mg BID versus Placebo treatment 
groups for the key secondary endpoints, then Hochberg testing procedure will be utilized. The p-
values from the key secondary efficacy endpoints will be ordered from smallest to largest. The 
largest of these p-values will be compared to a significance level of 0.05. If the test rejects the null 
hypothesis of no treatment difference, then all p-values for the key secondary efficacy endpoints 
for voclosporin 23.7 mg BID versus Placebo treatment group will be declared statistically 
significant. If the largest p-value is not less than 0.05, then this p-value will not be declared 
statistically significant and testing will proceed to the next largest p-value. 
If the largest p-value is not found to be statistically significant, then the second-largest p-value will 
be compared to a significance level of 0.05/2 = 0.025. If this p-value is less than 0.025, then this 
p-value and the remaining p-values will be declared to be statistically significant. If the second 
largest p-value is not less than 0.025, then this p-value will not be declared to be statistically 
significant and testing will proceed to the third largest p-value. 
If the second largest p-value is not found to be statistically significant, then the third largest p-
value will be compared to a significance level of 0.05/3 = 0.0167. If this p-value is less than 0.0167, 
then this p-value and the remaining p-values will be declared to be statistically significant. If the 
third largest p-value is not less than 0.0167, then this p-value will not be declared to be statistically 
significant and testing will proceed to the fourth largest p-value. 
This process will continue until all p-values have been assessed as non-significant or significant. 


 
 
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6.12 Pharmacokinetic Analyses 
Estimates of voclosporin exposure derived from this analysis will be examined for possible 
relationship to measures of efficacy and safety. Full details will be described in a separate analysis 
plan. 
6.13 Safety Analyses 
The safety analyses will be presented by the treatment received. The following safety endpoints 
will be summarized; 
• Biochemical (including liver function tests) and hematological laboratory tests 
• AE profile and routine biochemical and hematological safety parameters 
• Vital signs (BP, HR, temperature) at specific time points and change from baseline 
• Standard 12-lead ECGs change from baseline 
• Discontinuations from treatment 
• Concomitant medications 
 
 
6.13.1 Adverse Events 
A treatment emergent adverse event (TEAE) is defined as: 
• Any AE that has an onset on or after the first dose of study drug up to last dose + 30 days. 
For subjects consenting to the AURORA 2 continuation study there will be an additional 
constraint to the TEAE definition: events must have an onset date prior to the first dose of 
AURORA 2 study drug. 
A treatment-related TEAE is defined as a TEAE that is assessed by the Investigator or Sponsor as 
being related to study drug. If a TEAE has a missing relationship to study drug it is assumed to be 
related to the study drug for analysis purposes. 
A disease-related TEAE is defined as a TEAE that is assessed by the Investigator or Sponsor as 
being related to the disease under study. If a TEAE has a missing relationship to the disease under 
study it is assumed to be related to the disease under study for analysis purposes. 
Missing severity assessments will be summarised as severe. 


 
 
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The following tables will be presented for AEs: 
• Summary table of overall incidence, the number of events, risk difference and 95% CI 
(voclosporin-placebo) including the following top line summaries: 
• 
Any AE 
• 
Any TEAE 
• 
Any Treatment-Related TEAE 
• 
Any Serious TEAE 
• 
Any Treatment-Related Serious TEAE 
• 
Any TEAE Leading to Voclosporin/Placebo Discontinuation 
• 
Any TEAE Leading to Death 
• 
Treatment-Related TEAE Leading to Death 
• 
Disease-Related TEAE 
• 
Disease-Related Serious TEAE 
 
Detailed list of AE tables is given at the end of this SAP. 
In counting the number of AEs reported, a continuous event (i.e., reported more than once and 
which did not cease), will be counted only once for a subject; a non-continuous AE reported several 
times by the same subject will be counted as multiple events. 
Additional tables for serious TEAEs will be provided for each of the four regions: North America, 
Latin America, Europe/South Africa and Asia Pacific. Similar tables will also be provided for 
serious TEAEs occurring between day 1 and day 84 (Up to week 12), day 85 to day 168 (Week 12 
to 24) and greater than day 168 (after week 24). 
All AEs will be listed and a glossary of unique verbatim terms with coding information will be 
provided. 
6.13.1.1 Exposure-adjusted incidence rates 
Additional tables of exposure-adjusted incidence rates (EAIR) for certain groups of adverse events 
will be provided. The exposure for a given preferred term will be calculated for each treatment 
group as the total time at risk of an event. Each subject will have their exposure (ti) calculated with 
the exposures being summed to generate an overall exposure (T) for the event in question for each 
treatment group. Exposures will be calculated differently depending on whether the subject did or 
did not experience the event in question. 


 
 
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For subjects experiencing the event in question exposure is calculated as the number of days from 
first dose of study drug to the time of the event. 
For subjects not experiencing the event in question exposure is calculated as the number of days 
from first dose to the end of the study. 
Incidence rates (IR) for each preferred term are calculated within treatment group as the number 
of subjects (n) experiencing the event divided by the total time at risk for all subjects in the 
treatment group. Exposure-adjusted incidence rates will be displayed as the number of events / 
100 years of exposure. The difference (voclosporin minus placebo) between the exposure adjusted 
incidence rates along with a 95% CI for the difference will be reported for each preferred term 
using the normal approximation [3]. 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸= 𝑛𝑛
𝑇𝑇= 𝑛𝑛
∑𝑡𝑡𝑖𝑖
 
 The test statistic is given by (v=voclosporin, p=placebo): 
𝐸𝐸= ቆ𝑛𝑛𝑣𝑣
𝑇𝑇𝑣𝑣
− 𝑛𝑛𝑝𝑝
𝑇𝑇𝑝𝑝
ቇ
ඨ
𝑛𝑛𝑣𝑣
𝑇𝑇𝑣𝑣2 + 𝑛𝑛𝑝𝑝
𝑇𝑇𝑝𝑝2
൙
  
The 95% CI for the difference in EAIR will be calculated as follows: 
ቆ𝑛𝑛𝑣𝑣
𝑇𝑇𝑣𝑣
− 𝑛𝑛𝑝𝑝
𝑇𝑇𝑝𝑝
ቇ−𝑍𝑍𝛼𝛼2
⁄ ඨ
𝑛𝑛𝑣𝑣
𝑇𝑇𝑣𝑣2 + 𝑛𝑛𝑝𝑝
𝑇𝑇𝑝𝑝2         ,
ቆ𝑛𝑛𝑣𝑣
𝑇𝑇𝑣𝑣
− 𝑛𝑛𝑝𝑝
𝑇𝑇𝑝𝑝
ቇ+ 𝑍𝑍𝛼𝛼2
⁄ ඨ
𝑛𝑛𝑣𝑣
𝑇𝑇𝑣𝑣2 + 𝑛𝑛𝑝𝑝
𝑇𝑇𝑝𝑝2   
Using exposure adjusted incidence rates, the following tables will be provided: 
• Treatment-Emergent Adverse Events by System Organ Class and Preferred Term using 
Exposure-Adjusted Incidence Rate [subjects (n), exposure and treatment comparisons] 
• Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
using Exposure-Adjusted Incidence Rate [subjects (n), exposure and treatment 
comparisons] 
6.13.2 Laboratory Data 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each hematology, urinalysis and serum chemistry 


 
 
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continuous parameter. Each measurement will be classed as below, within, or above normal range, 
based on ranges supplied by the laboratory used. Shift tables in relation to the normal range from 
baseline to each follow-up visit will be presented.  
Analysis of all samples for hematology, chemistry, hepatic function, lipid profiles, and urinalysis 
will be performed at a central laboratory using standard validated methods (see the laboratory 
manual). All study data analyses involving laboratory values will be based on results from the 
central laboratory. 
The table below shows the tests, parameters, and time points that will be summarized by treatment 
arm. For the screening time points, only the last non-missing measurements will be included in the 
summary. 
 
 
 




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Test Type 
Test Parameters 
Time Points 
Urinalysis 
Complete urinalysis (to include urine protein, 
creatinine, blood, urine microscopy). First morning 
void will be performed to analyze urine 
protein/creatinine ratio. A 24-hour UPCR may be 
substituted for FMV at entry (or endpoint) if 
required. 
All except Day 2 
Pregnancy Test 
A serum pregnancy test will be performed for 
females of childbearing potential. Urine pregnancy 
tests will be done using a dipstick. 
Screening and Weeks 24 and 52 
(Serum) 
All other applicable visits (Urine) 
Serology 
Cytomegalovirus 
Hepatitis A, B, and C 
Hepatitis B surface antigen (HBsAg) 
Screening 
Special Tests 
Estimated glomerular filtration rate (eGFR) 
All except Day 2 
Blood Chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bilirubin (direct and total) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol (total, HDL, and LDL) 
Creatine kinase 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Glycosolated hemoglobin (HbA1c) 
Lactic dehydrogenase (LDH) 
Magnesium 
Phosphorous, inorganic 
Potassium 
Protein, total 
Sodium 
Triglycerides 
c-Reactive Protein
All except Day 2 
Day 1, Week 24, and Week 52 
Day 1, Week 24, and Week 52 
Day 1, Week 24, and Week 52 
Day 1, Week 24, and Week 52 
Screening, Week 24, and Week 52 
A listing of all laboratory measurements recorded throughout the study will be presented. 


 
 
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6.13.3 Vital Signs 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
o Systolic blood pressure (mmHg) 
o Diastolic blood pressure (mmHg) 
o Pulse rate (bpm)  
o Body temperature (degrees Celsius) 
Mean values for systolic and diastolic blood pressure will be used in the summary tables. Where 
the mean value is unavailable, an individual measure at the visit in question will be used. Listings 
of all vital sign measurements will be provided. 
 
6.13.4 Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables at screening, Week12, Week 24, and Week 52 will be tabulated at each follow-up: 
o Heart rate (bpm) 
o PR interval (ms) 
o QRS complex (ms)  
o QT interval (ms)  
o QTc interval (ms)  
o QTcF interval (ms) 
Shift tables in relation to the overall interpretation (Normal, Abnormal NCS, and Abnormal CS) 
from baseline to each follow-up visit will be presented. Listings of all ECG measurements will be 
provided. 
6.13.5 Physical Examination 
Physical examination will be summarized for the safety population at timepoints: screening, Day 1 
(Baseline), Week 24, and Week 52. The following parameters will be summarized: Height (as part 
of demography at screening only) and Weight. 
Physical examination results with clinically significant abnormalities (Yes/No) will be listed.  


 
 
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7 INTERIM ANALYSIS 
There are no planned interim analyses. The analysis of the primary endpoint (renal response at 
Week 52) will be conducted at the end of the study. 


 
 
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8 DATA AND SAFETY MONITORING BOARD ANALYSES 
Data and Safety Monitoring Board (DSMB) analyses are detailed in a separate DSMB charter and 
associated documents. 


 
 
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9 CHANGES TO PLANNED PROTOCOL ANALYSIS 
In the randomization, regional differences were not expected and blocking by region was done 
more for drug distribution reasons. While the analysis specified in the protocol stipulated that the 
regional blocking factor was not to be used in the analysis models, following feedback from 
regulatory agencies, the models will include terms for each of the factors used in the randomization 
process: 
• Biopsy Class (Class V versus Others) 
• MMF use at screening (Yes versus No) 
• Region (North America, Latin America, Europe+South Africa and Asia Pacific) 
During the regulatory agency review and feedback process it was decided to remove the ‘Duration 
of UPCR ≥0.5’ endpoint from the list of key-secondary endpoints and place it within the list of 
‘Other Secondary Endpoints’. The proportion of subjects experiencing a confirmed >30% decrease 
from baseline in eGFR at each timepoint was also removed from the list of key secondary 
endpoints. To this end, neither endpoint will form part of the hierarchical testing procedure. 


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10 REFERENCES 
1.
SAS Institute Inc. The SAS System, Version 9.3. Cary, NC, SAS Institute Inc. 2012.
2.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988; 75 (4):800-2.
3.
Cao, D and He, X (2011). Statistical Analysis of Adverse Events in Randomized Clinical 
Trials Using SAS. PharmaSUG2011 Paper SP07. 


 
 
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11 LIST OF TABLES, FIGURES AND LISTINGS 


 
 
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